Pharmacology

To the Editor: We report two episodes of serotonin toxicity (or serotonin syndrome) caused by drug interaction in one individual chronically treated with dexamphetamine. The interacting drugs were venlafaxine, then later citalopram. We are not aware of any previous reports of serotonin toxicity caused by dexamphetamine in combination with either venlafaxine or any selective serotonin reuptake inhibitor (SSRI). A 32-year-old man presented after two days of marked agitation, anxiety, shivering and tremor. He was being treated with dexamphetamine, 5 mg three times daily, for adult attention deficit hyperactivity disorder. He had started venlafaxine (75 mg daily) two weeks previously, and this had been increased to 150 mg daily after a week. On examination, he was alert and oriented, but diaphoretic, shivering and had fine motor tremor. His heart rate was 140 bpm, blood pressure was 142/93 mmHg and temperature 37.3°C. Pupils were 3 mm diameter and reactive, with no nystagmus or ocular clonus. There was generalised hypertonia, hyperreflexia, 1–2 beats of inducible ankle clonus, frequent myoclonic jerking and tonic spasm of the right side of his orbicularis oris muscle. His abdomen was tense, but non-tender, with normal bowel sounds. An electrocardiogram showed sinus tachycardia with a baseline tremor, but no other abnormality. Therapy with dexamphetamine and venlafaxine was ceased, and cyproheptadine (8 mg doses up to a total of 32 mg over three hours) was given. The patient had a stepwise reduction in heart rate, with complete resolution of his symptoms, and was discharged the next morning. Dexamphetamine therapy was restarted three days later and citalopram therapy was commenced one week after discharge. Two weeks after discharge, he reported similar symptoms, and ceased citalopram. Three days later he was still agitated, with nausea, diarrhoea and teeth clenching. There was no rigidity, tremor or diaphoresis, and his heart rate was 76 bpm. He was given two 8 mg doses of cyproheptadine and was asymptomatic two days later. Some of this patient's symptoms could be attributed to noradrenaline excess. However, the combination of neuromuscular and autonomic features is more consistent with serotonin toxicity. The fact the symptoms resolved after administration of cyproheptadine (a 5-HT2-receptor antagonist) supports this hypothesis. There is no theoretical reason why the interaction of citalopram (a pure SSRI) and dexamphetamine should cause catecholamine excess, and again the more likely explanation is serotonin toxicity. Dexamphetamine causes psychostimulation and increased peripheral sympathomimetic activity. Centrally it causes presynaptic release of serotonin,1 and dopamine and catecholamine release.2 Venlafaxine and its metabolite, O-desmethylvenlafaxine, inhibit both neuronal 5-HT reuptake and noradrenaline reuptake,3 whereas citalopram, an SSRI, has little effect on noradrenaline reuptake.4 The combination of serotonin reuptake blockade and either presynaptic release of serotonin or monoamine oxidase inhibition by dexamphetamine will cause increased serotonin levels in the central nervous system, and is the likely mechanism of toxicity in this patient. This is consistent with the mechanism for other reports of serotonin toxicity.5 Increased awareness and cautious monitoring is advised when using a combination of dexamphetamine and either venlafaxine or an SSRI. This is particularly important in people using amphetamines recreationally and in children taking dexamphetamine for attention deficit hyperactivity disorder.

Felicity H Prior BPharm, GradDipEpi · Geoffrey K Isbister BSc, MB BS · Andrew H Dawson MB BS, FRCP, FRACP · Ian M Whyte MB BS, FRACP FRCP

To the Editor: We report a case of bilateral acute angle closure glaucoma associated with venlafaxine. A 45-year-old woman with a history of bipolar affective disorder and borderline personality traits was admitted with increasing depression and suicidal ideation. She was taking sodium valproate (1500 mg/day) and slow-release lithium (450 mg/day). She had also taken dothiepin (50 mg nightly) for seven days, but this therapy was ceased on admission. Her only previous ophthalmological history was hypermetropia, and she had been taking low-potency neuroleptic medications and selective serotonin reuptake inhibitors in the past with no significant adverse effects. She was treated with chlorpromazine (up to 150 mg daily), and venlafaxine therapy (extended release, 75 mg/day) was commenced. After three days of taking venlafaxine, she developed left retro-orbital pain associated with nausea and vomiting, with subsequent swelling and drooping of the left upper lid and a dilated and fixed pupil. The eye was congested and visual acuity was reduced to counting fingers. She was diagnosed with acute angle closure glaucoma, treated with timolol, and transferred to a tertiary referral hospital. During this period, she sustained an injury to her right eye following an assault by a third party. A computed tomography scan revealed a right blow-out fracture with inferior rectus muscle entrapment. On admission, intraocular pressures were 16 mmHg in the right and 50 mmHg in the left eye, and gonioscopy revealed closed angles (grade 1–2). Ninety minutes after being given intravenous mannitol, topical apraclonidine hydrochloride, latanoprost and pilocarpine eye drops, the intraocular pressure dropped to 35 mmHg in the left eye. Initial laser iridotomy was unsuccessful because of a hazy cornea. Laser iridotomy was repeated several times after topical steroid therapy until it was successful. The right orbital floor fracture was repaired with a Medpor implant (Porex Surgical Products Group, Atlanta, Georgia). Eight days after starting venlafaxine therapy, she developed similar symptoms in her right eye, despite prophylactic treatment with pilocarpine eye drops four times a day. Venlafaxine was discontinued, and three days later a successful right laser iridotomy was performed. Her visual acuity was 6/5 in her right and 6/18 in her left eye. After eight weeks she was receiving no ophthalmic treatment and her intraocular pressures were well controlled. In a MEDLINE search, we found no published reports of venlafaxine associated with acute angle closure glaucoma. The manufacturers report it as a rare adverse event (fewer than 1/1000; data on file; Wyeth-Ayerst Laboratories). There has been one previous report of increased intraocular pressures in two patients with known narrow-angle glaucoma who began taking venlafaxine.2 Glaucoma has also been reported with paroxetine.3-4 Our patient had no associated family history of glaucoma, but her eyes were predisposed to angle closure glaucoma owing to hypermetropia. Patients with acute angle closure glaucoma usually have a structural defect that produces a narrow drainage angle, and thus moderate dilation of the pupil may precipitate an attack. Drugs like tricyclic antidepressants cause mydriasis and may cause the narrow angles to close as a result of anticholinergic effects. Venlafaxine, however, is a serotonin and noradrenaline reuptake inhibitor without anticholinergic activity. This fact and the time course suggest that a combination drug interaction may have occurred in this patient, perhaps by the hepatic inhibition of chlorpromazine metabolism by venlafaxine, increasing anticholinergic activity, or by a direct effect of venlafaxine on the eye unrelated to mydriasis.

Bradley Ng MB ChB · G Mark C Sanbrook MB BS, FRANZCP · Anthony J Malouf · Smita A Agarwal

To the Editor: Akathisia is a clinical syndrome that manifests as the subjective sense of unease or restlessness, or observable motor manifestations such as shuffling or tramping movements of the legs and feet, or both.1 The marked distress associated with akathisia can lead to impulsive suicide attempts.2 It is commonly associated with antipsychotic medications, as well as various antidepressants, including tricyclics and selective serotonin reuptake inhibitors (SSRIs). Mirtazapine is a novel antidepressant. It acts centrally to increase both noradrenergic and serotonergic neurotransmission. Common side effects include sedation, weight gain and increased appetite. Tremor is listed as an adverse reaction, but this does not represent akathisia. A MEDLINE database search (up to September 2001), using the words "akathisia" and "mirtazapine", did not reveal any reports of an association. However, as of mid-November 2001, the Adverse Drug Reactions Advisory Committee (ADRAC) had received five reports of "hyperkinesia (probably equivalent to akathisia)" associated with mirtazapine. We would like to report two cases of acute akathisia associated with mirtazapine. A 52-year-old man was referred by his psychiatrist for inpatient management of his depressive illness. He had previously tried multiple antidepressants, including various tricyclics and SSRIs. However, because of the sexual side effect anorgasmia, adherence to antidepressant treatment was poor. He was prescribed mirtazapine (30 mg at night). Within an hour of taking the first dose, he complained of feeling restless and unable to keep his legs still. He was given 1 mg of clonazepam, which settled his symptoms after 30 minutes. He was also observed to jiggle his legs and feet while at rest. His symptoms recurred the next day, necessitating further successful treatment with clonazepam. Mirtazapine therapy was continued, and the patient's depression improved significantly over the next few days, and the akathisia gradually resolved with regular use of clonazepam. A 73-year-old woman with chronic depression was admitted after an overdose. Her medications on admission were omeprazole, amiodarone, bendrofluazide and fluvoxamine (50 mg). The fluvoxamine was changed to mirtazapine (15 mg/day initially, increased to 30 mg/day after three days). After the first 30 mg dose, she described intense restlessness in her legs lasting up to two hours. The distress necessitated reintroducing the fluvoxamine in place of the mirtazapine. Within three weeks the patient was readmitted with depressed mood and suicidal ideation. Mirtazapine (30 mg at night) was re-introduced, with consequent acute return of restless legs. The patient's akathisia settled when the mirtazapine was reduced to 15 mg at night. No additional treatment was required. The neurobiological basis for akathisia remains unclear. Involvement of central serotonergic and adrenergic neurotransmitter systems has been postulated. One of mirtazapine's main actions is blockade of α2-adrenoreceptors. Clonidine, an α2-agonist, is effective in treating akathisia.3 We suggest that mirtazapine's adrenoceptor action might be the basis for the occurrence of akathisia in these patients.

Boregowda G Girishchandra MB BS, DPM, DipNB · Liana Johnson BPharm, MPS · Rebecca M Cresp MB BS · Kenneth G D Orr MB BS, FRANZCP

To the Editor: There is much conflicting evidence that increased intake of vitamin C enhances the natural protective mechanisms of the body and decreases both the incidence and severity of the common cold.1 It is regrettable that the study by Audera and colleagues failed to show a significant therapeutic effect of megadose vitamin C in treatment of the common cold.2 The groups compared had, on average, similar composition after randomisation. However, the viral infections that cause the common cold and its progression to ill health, as evidenced by multiple symptoms, are affected by many factors, while symptom severity is well known to vary greatly. Therefore, the study's reliance on respondents' self-diagnosis of symptom severity and onset is a significant weakness in design. Randomisation of participants to the treatment groups may have been insufficient to override this design deficit, thereby significantly biasing the outcome. A better design might have combined patient self-report of symptom severity with physical examination, thus allowing independent and professional assessment of severity. Also, proper assessment of previous history of severity of cold symptoms is crucial for proper randomisation to treatment groups. If Audera and colleagues' study failed to control for this history, then randomisation may have also failed to balance its effect equally between treatment groups, significantly compromising the study's validity to detect any therapeutic benefit of vitamin C. Cold symptoms also vary diurnally, while severity varies with alcohol use and smoking status,3,4 which also affect vitamin C absorption.5,6 No information was provided on study participants' alcohol consumption and smoking status. Finally, the study did not assess stress, which may constitute a further, important uncontrolled bias. A recent cohort study of stress and the common cold concluded that all four dimensions of stress investigated — stressful life events, negative affects, positive affects and perceived stress — were significantly related to occurrence of the common cold.7 Stress may also have significantly affected symptom severity and participants' perception of their symptoms. Certainly, the trend observed in the placebo group of shorter duration of some symptoms and lower mean severity could have been due to less severe symptom history, compounded by a lower degree of overall stress.

Luis Vitetta · Avni Sali · Bill Paspaliaris · Nicola J Reavley

In reply: Precisely because of the temporal variation in symptom severity described by Vitetta and colleagues, we judged that medical professionals are not as well able, in a variably timed interview, to quantify patients' cold symptoms as the patients themselves can do on a continuing basis. Therefore, we consider that our study1 would have been no more valid if the detailed symptom severity cards had been supplemented by one or more physical examinations. In that respect, we are in good company with others who have studied the common cold over many years.2 We agree that double-blind randomisation does not necessarily distribute all relevant variables equally. That is why, in Box 2 of our study report, we presented four variables — age, sex, mean number of colds in the previous year, and mean number of days unwell with colds in the previous year.1 The likelihood that stress, smoking and alcohol status would have been sufficiently maldistributed in this large group to mask a significantly beneficial effect in even one of the three groups which received high-dose vitamin C seems vanishingly small. Nevertheless, we acknowledge that the study would have been stronger if we could have reported the distribution of these three potential confounders. We contest the view of Vitetta and colleagues that the evidence from randomised controlled trials of vitamin C in treating the common cold conflicts significantly (see Box 1 of our article1). The overview finding — that mega-doses of vitamin C for prophylaxis produce a relatively trivial reduction in cold severity but no reduction in incidence3 — was the stimulus for our own study. No community studies of this issue have been flawless, but the mounting collective evidence suggests that we should look elsewhere for a cold panacea.

Carmen Audera · Roger V Patulny · Beate H Sander · Robert M Douglas

Objectives: To determine whether the occurrence of paracetamol and non-paracetamol analgesic deliberate self-poisoning (DSP) and accidental paediatric poisoning was affected by two periods of recall of paracetamol products.Design: Retrospective, observational audit of proportions of poisonings with tablet and capsule formulations of paracetamol, ibuprofen and aspirin products during two recall periods compared with the number of poisonings during the same periods of the previous three years.Setting: A national poisons information centre and a regional toxicology service.Main outcome measures: Rates of DSP and accidental paediatric poisoning with paracetamol, ibuprofen and aspirin.Results: During the two recall periods, there was a significant increase in ibuprofen DSP calls to the poisons information centre (RR, 1.86; 95% CI, 1.41–2.44; P = 0.001). There was no significant change in paracetamol or aspirin DSP calls over the two recall periods. However, there was a non-significant reduction in DSP calls with paracetamol in the first recall period alone (P = 0.057). There was a significant increase in the proportion of aspirin DSP presentations for the toxicology service (RR, 3.33; 95% CI, 0.97–11.4; P = 0.043), but no significant changes in paracetamol and ibuprofen DSP presentations. For accidental paediatric ingestions there was a significant increase in the proportion of ibuprofen calls (RR, 2.35; 95% CI, 1.85–2.98; P = 0.001), but no significant change in paracetamol or aspirin calls.Conclusions: Reduced paracetamol availability increased poisoning with alternative analgesics, but had little effect on the incidence of paracetamol poisoning. Restriction of paracetamol-containing products may inadvertently increase poisoning with potentially more toxic agents.

Corrine R Balit BPharm · Geoffrey K Isbister BSc, MB BS · Andrew H Dawson FRCP(Ed), FRACP · Ian M Whyte MB BS, FRACP · Jennifer Peat PhD

To the Editor: In their recent article on the use of modelling in pharmacoeconomics to estimate the potential benefits, risks and costs of preventive drugs, Liew and colleagues highlighted important strengths and limitations of this technique.1 One limitation is that modelling is discretionary: different analysts elect different models and get different answers. We argue that modelling is the first step. The next step is testing the predictive validity of the model by systematically collecting cost and effectiveness data over a period of time. Then the predictions of the original analysis could be compared to what actually transpired. The goal of pharmacoeconomics is the most accurate estimation of costs and benefits. The more these variables are truly study outcomes (that is, experimental and not constrained by assumptions of the economic model), the more valid the process. This will help reduce model discretion, improve data quality and increase the likelihood that the experiment could be replicated independently, the acid test of validity. In reducing the discretion inherent in pharmacoeconomics, we can allay the concerns of those who have questioned its underlying theory2 and validity.3 If one does not know the benefit of a drug, one conducts a study. Equally, if one does not know the cost of a drug, one needs a study. This has been the impetus for randomisation in design of pharmacoeconomic studies, thereby decreasing reliance on economic modelling.4 Furthermore, there are well-tested methods for quantifying the uncertainty of estimates obtained with randomised studies. In contrast, economic modelling assesses the robustness of the model assumptions, as reflected in the estimate, using sensitivity analysis. However, this analysis cannot separate uncertainties attributable to the model assumptions, uncertainty inherent in the data put into the model, and uncertainty of outcome estimates. One is left with nostalgia for the simplicity of the null hypothesis. How can we move forward? To reduce reliance on modelling and to collect better data, we propose that Australia, with its "culture of evaluation",5 again take the lead by creating a new "conditional listing" category on the Pharmaceutical Benefits Scheme for all drugs, not just preventive therapy. This would be available for selected products with strong biological rationale but inadequate current evidence on cost-effectiveness. By necessity, these would include only high-volume/low-cost and low-volume/high-cost products, as high-volume/high-cost products are rarely developed, and low-volume/low-cost products are not problematic. The sellers would then collect prospective data to substantiate cost-effectiveness of the products or would have them delisted. This would be truly innovative and, like the Pharmaceutical Benefits Advisory Committee itself, a first for the Commonwealth. Certainly, no other jurisdiction is even considering this, let alone proposing systematic study. With better data, we would learn which models and model assumptions yield accurate predictions. Of course, many challenges and difficulties will need to be addressed regarding this proposal, but in our opinion none are insurmountable, and the benefits of a program of this type clearly exceed the risks.

Kent R Johnson · Marissa N Lassere

To the Editor: Preparations containing isoflavone phytoestrogens are widely used as an alternative therapy for treating symptoms of the menopause. Although Australian government regulations strictly control the components of alternative therapies, adherence to the stated amounts of the components in alternative therapies is not routinely assessed. Isoflavones exist in two forms — aglycone (the free form) and glycosylated or glycone (the conjugated form) — the relative proportions of which vary between preparations. As glycosylation contributes considerably to the mass of isoflavone molecules, it is relevant to consider the total amount of potentially available isoflavone in alternative therapy preparations. Isoflavone-containing preparations which had a recommended daily dose on their labels were purchased at random from pharmacies around Sydney during September 1999. Where possible, products from more than one manufacturing batch were purchased and all products were well within their stated shelf life. The tablets, capsules or powder were removed from their packaging to conceal their identity and randomly allocated to numbered plastic bags by the hospital pharmacy department. The samples were then sent to PhytoChem Technologies Inc (Chelmsford, Mass, USA), an independent reference laboratory for the assay of isoflavones. There, isoflavones were extracted within four months of purchase (and before their stated use-by date) from 500 mg of each specimen after dissolution in 70% methanol. Glycosylated and free isoflavones were assayed in duplicate by gradient high-pressure liquid chromatography, with detection of isoflavones at 254 nm using a Waters 996 series photodiode detector with a limit of detection of 0.2 µg/mL. The identity of chromatogram peaks was confirmed by UV–V spectral analysis, and by comparison with standards. The mobile phase was acetonitrile, and adequate peak separation, linearity, accuracy and reproducibility were demonstrated. The total amount of available aglycone isoflavones in each sample was estimated (see Table). Only two products (Phytolife and Promensil) had total isoflavone contents close to the stated amount, and the content of the Phytolife product was variable. Estimated aglycone contents of preparations demonstrated that glycosylated isoflavones contributed substantially to the stated content of the product. A previous study of isoflavone-containing preparations marketed in the United States produced similar results to ours.1 Consumers may wish to consider not only whether an alternative therapy is of use, but also whether the product they purchase contains what they expect. Actual and stated isoflavone content of commercially available preparations Manufacturer Product No. of batches assayed Stated isoflavone content (mg) in recommended daily maximum dose of product Actual total isoflavone content per daily dose (mg) Estimated aglycone isoflavone content per daily dose (mg) Blackmores Phytolife one a day 5 40 41.02 ± 6.12 25.75 ± 6.04 Bioglan Soy powder plus 4 68 48.75 ± 1.42 30.44 ± 0.86 Earths Own Soy + calcium 1 68 42.52 25.67 Health Direction Femme phase 1 235 mg soy protein* 0.29 0.20 Herron Phyto source 1 22.5 16.27 9.93 Natural Nutrition Menopause 1 60 0.56 0.51 Natural Nutrition Phytobalance 3 90 58.12 ± 6.26 34.96 ± 3.79 Novogen Promensil 4 40 40.12 ± 1.98 38.38 ± 1.20 Pretorius Maxi soy plus red clover wild yam and calcium 4 68 50.36 ± 1.64 31.24 ± 1.13 Wagner Probiotics Femme soy plus with red clover 2 27 30.76 ± 0.12 19.65 ± 0.05 * Soy protein has a high isoflavone content. Values are the mean ± standard deviation. Total isoflavones = glycone plus aglycone. Estimated available aglycone isoflavones = weight of aglycone isoflavones plus weight of glycone isoflavones corrected for glycone content.

Jan B Howes · Laurence G Howes

To the Editor: I am concerned that several statements in the article on cyclooxygenase-2 (COX-2) inhibition by Cleland and colleagues1 do not accurately reflect the clinical data. The authors postulate a prothrombotic tendency of celecoxib on the basis of the CLASS study (comparing celecoxib with ibuprofen or diclofenac)2 and four case reports. The authors concede that celecoxib has no effect on the rate of myocardial infarction (MI) in the CLASS study (a conclusion also reached by the United States Food and Drug Administration [FDA] review of CLASS3), which would seem to contradict their hypothesis that celecoxib is prothrombotic. Cleland and colleagues speculate that the differences between the CLASS study and the VIGOR study (which compared rofecoxib with naproxen)4 may be explained by low-dose aspirin use in CLASS and failure to use aspirin in 4% of patients in VIGOR with "CV [cardiovacular] risk factors". This speculation is unfounded. In the CLASS study patients in all treatment groups who used aspirin had higher MI rates than non-aspirin users, and presumably this higher rate would have been observed in VIGOR if aspirin users had been enrolled. This higher rate is probably because aspirin use serves as a marker for increased CV risk. In patients in CLASS similar to the 4% with "CV risk factors" in VIGOR, MI rates were similar in the celecoxib and non-steroidal anti-inflammatory drug (NSAID) groups (data on file, Pharmacia) and numerically much lower than in the VIGOR study subgroup. On the basis of these two flawed arguments, Cleland and colleagues apparently extrapolate the high rate of MI seen with the use of rofecoxib to celecoxib and suggest that high MI rates are a "class" effect. This proposal is scientifically unsound and is not supported by other clinical data, including over 12 000 patients in the celecoxib registration program (data on file, Pharmacia). No celecoxib study has shown an increased risk of MI compared with traditional NSAIDs. The authors correctly assert there is "little clinical evidence from community use to suggest that selective COX-2 inhibition has serious unwanted effects other than those seen with standard NSAIDs", but imply there are few community data. In fact, community use of celecoxib in Australia (at least 1.5 million patients exposed) and worldwide (more than 20 million) has been extensive, and with this degree of exposure one would expect significant adverse event patterns to emerge. Reference to the Adverse Drug Reactions Advisory Committee and FDA database does not indicate a prothrombotic tendency of celecoxib. Further, we at Pharmacia do not consider that the four case studies presented by Cleland et al provide strong support for a prothrombotic tendency for celecoxib, especially as all patients described had diseases with high risk for thrombosis. On the basis of a large body of controlled trial data (including CLASS) and extensive community exposure, the evidence does not show any more thrombosis with celecoxib than with NSAIDs. Results of the CLASS and VIGOR studies clearly differ. It is clinically unjustified and scientifically unsound to suggest that rates of MI seen with rofecoxib can be ascribed to celecoxib and described as a "class effect".

Christopher G Fenn

In reply: The response from the Medical Director of Pharmacia to our article highlights some problems for all clinicians and independent scientists seeking to evaluate the balance of risks and benefits of pharmaceuticals and to validate the marketing messages of pharmaceutical companies. On the one hand, we lack the time and statistical resources to trawl through all data related to all trials with a test drug. On the other, our efforts to evaluate data are confounded by the publication and reporting biases associated with company-sponsored studies. In this regard, it is notable that the definitive results of CLASS1 have not been published, although the Food and Drug Administration (FDA) review of the data is available through an FDA website,2 as indicated by Fenn. While this document places data in the public domain, its location is neither within the pathway of MEDLINE search engines, nor is it known to the general body of clinicians. As reported in the FDA presentation, CLASS was a very large, double-blind safety study of at least six months' treatment that failed to achieve its primary endpoint of reduced complicated upper gastrointestinal events with celecoxib relative to the comparator, non-steroidal anti-inflammatory drugs (NSAIDs). While an interim analysis at six months was published, with extrapolation of event rates to 12 months,3 failure to publish the final results has withheld important results from wider scrutiny. In essence, the FDA document shows no overall long-term safety advantage of celecoxib over standard NSAIDs.2 The FDA analysis4 of the VIGOR study5 also shows no overall safety advantage for rofecoxib compared with NSAID, with fewer complicated upper gastrointestinal events being offset by a highly statistically significant (P = 0.0016) increase in serious thrombotic cardiovascular events. Collectively, these FDA analyses invalidate the promotion of selective cyclooxygenase-2 (COX-2) inhibitors as a safe alternative to NSAIDs, notwithstanding encouraging results from short-term trials. Further, although an increase in serious cardiovascular events was not seen in the CLASS study, its design was not optimal for detecting increased cardiovascular risk, and it is unlikely that CLASS was sufficiently powered to detect the degree of increased risk seen with rofecoxib in VIGOR. As explained in our article,6 unbalanced prothrombotic eicosanoid production associated with selective COX-2 inhibition (ie, a class effect) appears the most likely explanation for the increased cardiovascular events seen in VIGOR. Finally, we wish to reassert that, for effective postmarketing surveillance, it is essential that prescribers be adequately informed about safety concerns associated with new drugs, particularly when they involve events that are common and not usually seen as unwanted drug effects.

Leslie G Cleland · Michael J James

Clinical pharmacology is the clinical application of the action of drugs on the body, and involves understanding how the body handles and modifies drugs, and their side effects and interactions. Significant advances have occurred in the development of new drugs, and the genetics of drug actions, metabolism and transporters. Pharmacogenomics and new drug development. Pharmacogenomics1,2 is the use of molecular biology techniques (eg, microarray chips, expressed-sequence tags and proteomics) to identify and study genes relevant to drug therapy. Thousands of potential new targets for drug therapy have been described. Combinatorial and computational chemistry and high-throughput screening allow the synthesis and evaluation of large numbers of compounds. These strategies have resulted in new antiangiogenic (SU5416) and antileukaemic (ST1571, or glivec) drugs for cancer. Increasing sophistication of in-vitro testing may lead to virtual studies and reduce the requirement for animal and human investigations. Pharmacogenetics and drug response. Pharmacogenetics, a subsection of pharmacogenomics, studies the genetic basis for differences in individual responses to drugs. Common alterations to gene structure are single-base changes in the genome (single-nucleotide polymorphisms). Examples include the lack of response of some people to certain drugs (eg, salbutamol) due to genetic variation in the β2-adrenergic receptor;2 polymorphisms in both the cholesteryl ester transfer protein and stromelysin-1 affecting the efficacy of pravastatin in coronary atherosclerosis; and the cardioprotective effect of ACE inhibitors being greater in whites than African-Americans.2 Pretreatment genetic screening of patients will eventually enable this knowledge to be applied in clinical practice. Pharmacogenetics and drug metabolism. The genetics of the absorption, distribution, metabolism and elimination of drugs may also result in interindividual differences in treatment responses.1,2 Functionally significant polymorphisms have been detected in the genes for cytochrome P450 (oxidising) enzymes (eg, CYP2D6, CYP2C9), and many genotypes have been identified for ultrarapid, extensive, and poor metabolisers,3 with individuals with these genotypes requiring extremely high, average or low doses, respectively, of many drugs to achieve useful effects. Thus, extensive metabolisers for CYP2C19 need larger doses of protein-pump inhibitors (eg, omeprazole) to treat peptic ulcer and, conversely, poor metabolisers for CYP2D6 suffer from perhexilene toxicity caused by high blood levels even at low doses. Some analgesics (eg, codeine, tramadol) require activation by CYP2D6; poor metabolisers may not obtain any pain relief, but may suffer respiratory side effects. Drug transporters. Drug transporters are proteins that mediate the efflux of drugs from cells and tissues. They are widely expressed in normal tissues and also limit the uptake of foreign molecules (including drugs) across the blood–brain barrier and the gastrointestinal mucosa. They may contribute to the poor oral bioavailability of some drugs. Interest in transporters followed the observation that overexpression of P-glycoprotein (PGP) in cancer cells imparted resistance to many anticancer agents (multidrug resistance). Inhibition of PGP by drugs (eg, verapamil) increases the retention of cytotoxic agents in cancer cells. Genetically engineered mice that no longer express PGP develop neurotoxicity when given drugs that normally do not cross the blood–brain barrier (eg, vinca alkaloids, ivermectin). Some opiates are substrates for PGP and differences in analgesic response to these drugs may relate to PGP. Drug interactions. Our understanding of drug interactions has increased by identifying the drugs metabolised by CYP450 enzymes4 and/or excreted by PGP. Inducers and inhibitors of both these systems affect target drugs. CYP3A4 inhibitors (eg, ketoconazole, erythromycin) increase blood levels of drugs such as terfenidine, astemizole or cisapride and can provoke life-threatening arrhythmias. Coadministration of inhibitors with some "statins" increases the risk of rhabdomyolysis. Many inhibitors and inducers of CYP3A4 act similarly on PGP. PGP pumps drugs (eg, digoxin) into the gut lumen, thereby reducing its bioavailability.5 Consequently, blood levels of digoxin are increased when PGP is inhibited (eg, by macrolide antibiotics) or decreased when PGP is induced (eg, by rifampicin or St John's wort). The future. Rationally synthesised drugs and knowledge of molecular factors determining drug actions, toxicity and interactions may enable "individualised therapy", but will not remove the need for good clinical judgement. Glossary Microarray chips: Miniaturised assay systems enabling evaluation of structure and simultaneous expression of thousands of genes. Expressed-sequence tags: Short sequences of cDNA from specific tissues that can be "mined" for genetic polymorphisms and novel proteins. Combinatorial chemistry: Simultaneous synthesis of chemical compounds with multiple permutations of substituents. High-throughput screening: High speed robotic, often miniaturised, testing of new compounds against purified receptors, enzymes and cellular systems.

Gillian M Shenfield DM, FRACP · David G Le Couteur PhD, FRACP · Laurent P Rivory PhD

Progress in new diagnostic tools and therapeutic strategies has been rapid in gastroenterology and hepatology, and pending advances include the use of magnification endoscopy with dye spraying to detect early cancers, and endoscopic sewing procedures for reflux oesophagitis. Prevention. Genetic tests have recently been developed for the hereditary colon cancer syndromes (< 3% of all colon cancers). This major advance helps to identify at-risk family members, so that premalignant lesions and early cancers can be removed, and those who are not carrying the gene can be reassured. Accuracy in both familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) approaches 100%, as long as the index case is positive for the mutation tested. The rate of carriage of an easily identifiable mutation is about 80% in FAP, but presently substantially less in HNPCC.1 Pilot testing of population screening for common (sporadic) colorectal cancer is about to begin in Australia. More specific immunochemical tests for occult gastrointestinal bleeding are now available. Diagnosis. First described in 1991, magnetic resonance cholangiopancreatography (MRCP) continues to evolve. It produces diagnostic-quality images of normal and diseased biliary ducts, is non-invasive, and does not require contrast media or ionising radiation. MRCP is gradually replacing invasive techniques, such as endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography, for purely diagnostic imaging, leaving these procedures for interventional or problem cases. MRCP is indicated for detecting biliary stenosis and level of obstruction, and depicting the biliary tree on both sides of the stricture. It is also useful in identifying cases of choledocholithiasis likely to benefit from ERCP calculus removal. Avoiding intubation of the biliary tree decreases the risk of bacterial colonisation in cases of biliary stricture (including primary sclerosing cholangitis [PSC]) and choledocholithiasis. MRCP is not particularly good for detecting ampullary calculi, or assessing chronic pancreatitis or the very early changes of PSC. Availability is the main limiting factor to its widespread use.2 Intervention. Localised hepatocellular carcinoma (HCC) in patients with non-cirrhotic livers is best managed by surgical resection. Liver transplantation has been associated with excellent long term survival in highly selected cases of cirrhosis, but is limited in Australia by a small donor pool. Effective local control of small HCCs has been achieved with percutaneous ethanol injection (PEI), and radiofrequency ablation (RFA). The main determinant of outcome is the size of the tumour. PEI, under ultrasound or computed tomography guidance, is simple, inexpensive and safe in patients with advanced cirrhosis. It is suitable for HCCs less than 3 cm in size, with fewer than three nodules, but multiple treatments may be required. There is minimal discomfort, so it can be performed as an outpatient procedure. RFA involves placing the needle electrode percutaneously with laparoscopic control or ultrasound guidance under local anaesthesia. However, heavy sedation or anaesthesia may be required as significant pain may occur. Both PEI and RFA have very low complication rates, and treatment can be repeated for recurrence or new lesions. Long-term survival rates have been reported at over 70% (three years) and over 40% (five years), but unfortunately no randomised controlled trials have been performed.3 The management of chronic hepatitis B infection has changed recently with approval of lamivudine, a nucleoside analogue and potent inhibitor of viral DNA replication. Sustained viral inhibition is seen within four weeks in over 95% of cases, with 15%–20% becoming e-antigen negative at 12 months. There is also evidence that liver fibrosis and inflammation decrease during therapy, even without seroconversion. A high proportion of patients with hepatitis B e-antigen seroconversion (73%) have a sustained virological remission for up to 19 months (median). As with other therapies, loss of surface antigen is relatively uncommon. The development of a drug-resistant mutant form of the virus (YMDD) emerges with prolonged therapy (about 50% at three years), and can be associated with significant flares of hepatitis.4 Infliximab, a cytokine-directed biological therapy, represents a significant advance in the understanding of Crohn's disease. This chimeric monoclonal antibody blocks tumour necrosis factor α (ΤΝF-α), a key cytokine in bowel inflammation. Therapy results in rapid reduction in the signs and symptoms of Crohn's disease in two-thirds of cases, with a decrease in bowel inflammation, and improved mucosal healing and quality of life. Three infusions are given for fistulous disease and rapid closure occurs usually within two weeks, with a median benefit exceeding three months. Serious adverse events are infrequent and have been successfully managed with medications. However, the cost of this therapy currently restricts widespread use. Allergic reactions are also a serious consideration, but may be addressed in the future with modified molecules already in trial.5

Amanda J Nicoll PhD, FRACP · Ian J Kronborg FRACP · Neville D Yeomans MD, FRACP

Several recent developments in the basic and applied sciences have been incorporated into neurological and neurosurgical practice. Diagnosis. New magnetic resonance imaging (MRI) and molecular technologies have facilitated neurological diagnoses. Diffusion-weighted MRI (DWI) is the most sensitive imaging technique for acute brain lesions (eg, infarction), and distinguishes acute from chronic lesions. Coupling DWI with perfusion-weighted MRI (PWI) promises to identify which ischaemic stroke patients benefit from thrombolysis. Magnetic resonance spectroscopy, which detects metabolites (eg, lactate, choline) and N-acetyl-aspartate (NAA), can distinguish tumours (high in choline) from infarcts (low NAA and normal or low choline levels). Functional MRI (fMRI), which combines anatomical with physiological imaging, allows preoperative planning for resecting lesions in functionally important brain regions. Anatomical imaging by MRI, combined with functional imaging by ictal single- photon-emission computed tomography (SPECT) and interictal positron-emission tomography (PET), aids video-electroencephalogram monitoring and clinical assessment in localising seizure foci. The chromosomal position of many genes which, when mutated, cause neurological disorders is now known. In some (eg, Huntington's disease, muscular dystrophy, childhood-onset generalised primary dystonia), the genes, their disease-causing mutations, and gene products have been characterised. This has facilitated the development of new diagnostic techniques, implementation of predictive testing and genetic counselling services, and promise of novel approaches to treatment and prevention.1 Treatment. For patients with chronic tension-type headaches, the combination of antidepressant medication and stress management therapy is more effective than monotherapy.2 Among the newer specific acute migraine therapies, the triptans are of comparable efficacy, but differ in their onset and duration of action and adverse effect profile. Sodium valproate is an effective prophylactic for migraine. Ischaemic stroke patients benefit from 300 mg aspirin immediately or intravenous thrombolysis within three hours of onset. Anticoagulation with heparins causes 20 more deaths per 1000 patients treated (mainly intracranial haemorrhage) than aspirin, despite preventing 10 more symptomatic deep venous thromboses per 1000 patients treated. Stroke care by a multidisciplinary team in a stroke unit maximises survival free of handicap. The treatment of focal spasticity and dystonias has been revolutionised by botulinum toxin injections into affected muscle groups. The benefit lasts about 3–5 months, after which the injections can be repeated. In early Parkinson's disease, dopamine agonist monotherapy controls symptoms in a third of patients for up to five years, with fewer motor complications than with levodopa therapy. For other patients, levodopa remains the most effective symptomatic treatment. In patients with motor fluctuations due to "wearing off" of pharmacotherapy, "on" time may be increased by 10%–25% with slow-release levodopa, dopamine agonists, and catechol-o-methlytransferase inhibitors. Amantadine is an effective form of chemical pallidotomy for dopa-induced dyskinesia. In some patients, neurosurgical interventions may alleviate drug-resistant tremor and control parkinsonian symptoms. Frameless stereotaxy enables neurosurgeons to navigate and operate safely in high-risk areas of the brain. Neuroendoscopy is used in the ventricular system (eg, to remove dislodged shunt tubes, intraventricular blood, and colloid cysts, and to treat obstructive hydrocephalus by ventriculostomy) and assist trans-sphenoidal pituitary surgery. Prevention. For patients with a history of transient ischaemic attack or stroke of any type (and no contraindication to blood-pressure-lowering therapy), gradually introducing antihypertensive medication, to slowly lower blood pressure by at least 9/4 mmHg, reduces the risk of recurrent serious vascular events by at least a quarter.3 Interventional neuroradiology offers potential strategies for stroke prevention with techniques such as coiling of intracranial aneurysms and carotid angioplasty and stenting for patients with symptomatic severe carotid stenosis.4 Several newer anti-epileptic drugs (lamotrigine, topiramate, vigabatrin, gabapentin, tiagabine) have been approved as "add-on" agents in patients who have seizures despite conventional first-line treatment. For patients with temporal lobe epilepsy refractory to anti-epileptic medication, surgical resection of a part of the temporal lobe improves the proportion of patients seizure-free at one year from 8% to 58% (P < 0.001), and improves quality of life.5 For patients with multiple sclerosis who have at least two disabling relapses every two years, interferon betas reduce the relapse rate by a third, and may delay the progression of disability. Glatiramer acetate and mitoxantrone, a new immunomodulatory drug, also reduce relapses and possibly delay the progression of disability.

Graeme J Hankey MB BS, MD, FRCP, FRCPEdin, FRACP

We report the first instance in Australia of treatment failure due to a strain of methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to vancomycin — heteroresistant vancomycin-intermediate S. aureus (hVISA). The infection occurred in a 41-year-old man with multiple risk factors. No transmission of the organism to other patients or the environment was detected. This case may herald the beginning of a new phase of staphylococcal resistance in Australia. Peter B Ward, Paul D R Johnson, Elizabeth A Grabsch, Barrie C Mayall and M Lindsay Grayson MJA 2001; 175: 480-483 Clinical record - Assessment of patient isolates - Results - Discussion - Competing interests - Acknowledgements - References - Author's details - - - More articles on Infectious diseases and parasitology The glycopeptides, vancomycin and, to a lesser extent, teicoplanin, are the mainstay of therapy for infections caused by methicillin-resistant Staphylococcus aureus (MRSA),1,2 and currently up to half of all S. aureus strains isolated in hospitals in Australia are MRSA.3,4 Despite substantial glycopeptide use over many years, the emergence of MRSA strains with reduced susceptibility to vancomycin and teicoplanin has been reported only recently.5-7 Subsequently, MRSA strains have been reported that contain limited subpopulations with intermediate resistance to glycopeptides, while most of the population remains glycopeptide-susceptible.8-14 These are termed heteroresistant vancomycin-intermediate S. aureus (hVISA) (see glossary in Box 1). We report here the first Australian case of infection due to hVISA. Clinical record A 41-year-old male smoker with long-standing type 1 diabetes, haemodialysis-dependent end-stage renal failure, hepatitis C and peripheral vascular disease was admitted to hospital in late August 2000 with bilateral lower-limb ischaemia refractory to prostacyclin therapy. Despite hyperbaric oxygen and multiple courses of antibiotics (including cephalexin, flucloxacillin, gentamicin and clindamycin), the patient developed increasing lower-limb gangrene, necessitating a right below-knee amputation on Day 41 of hospital admission. On Day 47, ulcers on his left foot were found to be infected with MRSA and Enterobacter spp. Therapy with vancomycin (1 g) and meropenem (500 mg) postdialysis (ie, three times a week) was commenced. Intravenous teicoplanin (400 mg every third day) was later substituted for vancomycin, as the patient developed a rash after the initial dose of vancomycin. However, his condition worsened, necessitating a left below-knee amputation on Day 50. Therapy was continued with teicoplanin, intravenous gentamicin (160 mg daily) and metronidazole (500 mg twice daily), but both amputation wounds broke down and repeated cultures grew MRSA and E. coli, finally necessitating a left above-knee amputation on Day 105. Despite therapeutic serum levels of teicoplanin (troughs of 6.5-15.9 mg/L, measured on 10 occasions over eight weeks), both amputation sites remained actively infected with MRSA and E. coli. On Day 120 (after 73 days' glycopeptide therapy), teicoplanin was ceased, and a new oxazolidinone, linezolid (600 mg intravenously, twice daily), was commenced in combination with oral ciprofloxacin and metronidazole. Over the next five days, dramatic improvement was noted in all infected wounds. After 11 days, intravenous linezolid was changed to oral linezolid (600 mg twice daily). MRSA was isolated from the amputation sites nine days after linezolid was begun, but was not detected again in any subsequent cultures. The patient continued to receive oral linezolid for 81 days. His condition improved steadily, and he was transferred to a rehabilitation unit on Day 179. Over the subsequent six months, he remained reasonably well, with no evidence of MRSA infection. Assessment of patient isolates After attending a presentation during which new laboratory methods for the accurate identification of VISA and hVISA were presented (Annual Conference of the Australian Society for Antimicrobials, Melbourne, April, 2001), we decided to further investigate stored MRSA isolates from the patient. Two MRSA strains obtained from the right below-knee amputation stump were retrieved from storage at -70ºC. These strains (AR1 and AR2) were isolated on hospital Day 104 (after 57 days of teicoplanin therapy) and Day 129 (nine days after changing from teicoplanin to linezolid therapy), respectively. The two strains were assessed for in-vitro antibiotic susceptibility using routine methods (agar dilution and broth microdilution).15 They were also assessed for glycopeptide-resistant subpopulations using methods described previously.5-7 These comprised: Colony morphology: Each isolate was examined macroscopically for the heterogeneous colony morphology typical of hVISA; pure cultures have been reported to produce a mix of both large and small colonies when cultured on Columbia agar with 5% horse blood (Oxoid, Basingstoke, UK) and other media.6,7 Colonies suspected of glycopeptide resistance were further assessed for vancomycin and teicoplanin resistance. Vancomycin gradient plates: Vancomycin resistance was assessed using vancomycin gradient plates prepared as described previously.6 Thirty mL of brain-heart infusion (BHI) agar (Oxoid, Basingstoke, UK) containing vancomycin (4 mg/L) was poured into a 10 cm square petri dish raised on one edge by 6 mm. After setting, the resultant wedge was overlaid with a 30 mL layer of BHI agar without antibiotic and allowed to set horizontally. Plates were stored for 24 hours at 4ºC to allow diffusion of vancomycin into the upper agar layer. Twenty-four-hour cultures of organisms in brain-heart infusion (BHI) broth were adjusted to a 0.5 McFarland standard, and 20 µL aliquots were spread on the gradient plates in an even line along the increasing antibiotic gradient. Plates were assessed after 48 hours' aerobic incubation at 37ºC.6 E test minimum inhibitory concentration: Both vancomycin and teicoplanin resistance was assessed by E test (AB Biodisk, Solna, Sweden), using methods and interpretations recommended in the United States7 and Europe.11 US methods use Mueller-Hinton agar (Oxoid, Basingstoke, UK) and an inoculum equivalent to the 0.5 McFarland standard, and define intermediate vancomycin resistance as MIC, 8-16 mg/L. European methods use BHI agar and a heavier inoculum (2 McFarland standard) and define intermediate vancomycin resistance as MIC ≥8 mg/L. Teicoplanin intermediate resistance is defined as MIC > 8 mg/L (US) or > 6 mg/L (Europe). Inoculated media were incubated aerobically for 24 hours at 37ºC.7,11 Population analysis profile: The proportion of cells in the population of each isolate that was resistant to a range of vancomycin and teicoplanin concentrations was assessed, using methods described previously.6,9 Assessment of nosocomial transmission As the presence of hVISA was first recognised five months after the patient's infection was cured empirically, screening was undertaken to ascertain whether hVISA had been transmitted nosocomially: Nose, groin, hand and wound specimens from the index patient were cultured to assess current MRSA and hVISA infection or colonisation. Nose and groin specimens were collected from all patients attending the in-centre haemodialysis units also attended by the index patient. These were assessed, along with multiple environmental samples from the units, for the presence of MRSA and hVISA. All patients in the Nephrology Department who had been diagnosed with MRSA infection or colonisation between October 2000 and May 2001 were identified from the hospital's microbiology database. Their clinical course was reviewed to identify those whose condition did not respond to vancomycin. Stored MRSA isolates from these patients were assessed for glycopeptide resistance, as described above. All MRSA isolates obtained at our institution since May 2001 were assessed prospectively for hVISA using a screening plate of BHI agar with vancomycin (4 mg/L).12 Results Antibiotic susceptibility of index isolate Routine antibiotic sensitivity testing: The two patient isolates, AR1 and AR2, were confirmed to be MRSA and to have identical susceptibility profiles. Both tested resistant to penicillin, methicillin, erythromycin, trimethoprim, cotrimoxazole, clindamycin and ciprofloxacin, but susceptible to tetracycline, chloramphenicol, mupirocin, fusidic acid, vancomycin (MIC, 2 mg/L) and teicoplanin (MIC, ≤ 8 mg/L) using agar dilution methods,15 and to linezolid (MIC, 1.5 mg/L) using the E test.15 Glycopeptide-resistant subpopulations: Both AR1 and AR2 displayed small and large colony variants, consistent with previous reports of hVISA, VISA and VRSA.6,7 By E test, both isolates had a vancomycin MIC of 6-8 mg/L (US method) and 8 mg/L (European method), and a teicoplanin MIC of 24 mg/L (US method) and 16-24 mg/L (European method). Repeated analysis of AR2 using vancomycin gradient plates demonstrated growth across the entire 4 mg/L vancomycin gradient, confirming the MIC to be > 4 mg/L, and the isolate to be hVISA. Population analysis profiles were also consistent with both isolates' being hVISA. In particular, detailed analyses of AR2 demonstrated that colony subpopulations were able to grow on 3 mg/L and 4-6 mg/L vancomycin plates at frequencies of 1 in 10 and 1 in 105-106, respectively (Box 2). In comparison, control organisms generated resistant colonies at a rate of < 1 in 108 at these concentrations. Similarly, population analysis of AR2 using 8 mg/L and 16 mg/L teicoplanin demonstrated presence of resistant subpopulations at frequencies of 1 in 103 and 1 in 105-106, respectively (Box 2). These findings are consistent with those for hVISA reported by Hiramatsu.5,6,9 Nosocomial transmission of hVISA MRSA, hVISA and VISA were not detected in cultures obtained from the index patient after completion of linezolid therapy. Similarly, hVISA was not detected from nose or groin cultures of 85 patients who were either current renal ward inpatients or undergoing in-centre haemodialysis. Also, hVISA was not detected in cultures of 28 environmental sites in the ward and haemodialysis units, suggesting that routine cleaning was effective in limiting significant hVISA colonisation and contamination. Twenty-six renal patients were identified from the microbiology database with MRSA infection during the eight months between October 2000 and May 2001. Six of these patients were considered by the Nephrology Department to have had a slow clinical response to anti-MRSA treatment. MRSA isolates were retrieved from frozen storage for all six patients, and the most recently obtained MRSA isolate was assessed for all (except one patient in whom the second most recent isolate was assessed). None of these MRSA strains were hVISA. Prospective screening of all MRSA isolates at our institution for hVISA began in July 2001. Of 315 isolates obtained from 128 patients, none were hVISA. Discussion This is the first report of clinical treatment failure caused by MRSA with reduced susceptibility to glycopeptides in Australia. Similar cases have been described in Europe, North America and South-East Asia,7,16 and a single strain of vancomycin-resistant S. aureus has been reported in Japan.17Slow clinical response, and even treatment failures, associated with glycopeptide therapy for MRSA infections have been described previously.1,18-20 This has generally been attributed to the characteristics of glycopeptides: their penetration into sites of established sepsis, which is generally inferior to that of other agents, such as β-lactams, and their slow bactericidal activity.20-22 Empirically, we attributed the clinical failure of teicoplanin in our patient to multiple factors, including his advanced vascular disease, and poor drug delivery (despite adequate serum teicoplanin levels), as well as the inherent characteristics of the drug.2 However, the patient's very rapid clinical improvement and the ultimate clearance of MRSA soon after commencement of linezolid is consistent with our later identification of the infecting strain as hVISA. Our detailed search did not detect hVISA contamination of the haemodialyis environment, or colonisation or infection of other haemodialysis patients, or any subsequent patients with MRSA at our hospital. Thus, we believe that hVISA is not widespread in our hospital, and that our case is unusual. Now that the microbiological methods to identify hVISA have been clearly described,6,7,14 it is likely that strains will be identified in Australia. However, it is a challenge to establish a laboratory screening protocol for hVISA and to determine what resources should be allocated to screening for hVISA. The Centers for Disease Control and Prevention in Atlanta recommend that routine screening of all MRSA isolates for vancomycin resistance is currently unnecessary and probably wasteful. Instead, attention should be focused on patients in whom glycopeptide therapy is failing, or those at increased risk of MRSA carriage and infection, such as patients undergoing haemodialysis or chronic ambulatory peritoneal dialysis.7,12 Our identification of hVISA may be the beginning of a new phase in the emergence of antibiotic resistance in Australia, when the glycopeptides vancomycin and teicoplanin will no longer be effective in some cases of MRSA infection.18-20,23 This raises challenges for clinical management, laboratory detection and infection control. Furthermore, while two recently available agents, linezolid and quinupristin-dalfopristin, appear active against hVISA, VISA, MRSA and vancomycin-resistant enterococci, resistance to linezolid has already been reported among strains of both MRSA and Enterococcus faecium.21,22,24 Thus, we may be approaching an era when there are no effective therapies for some strains of MRSA. Competing interests None declared. Acknowledgements We wish to acknowledge the invaluable assistance of the infection control practitioners and staff of the Microbiology and Nephrology departments. References Kucers A. Vancomycin. In: Kucers A, Crowe S, Grayson ML, Hoy J. The use of antibiotics. 5th ed. Oxford: Butterworth Heinemann, 1997: 763-790. Fekety R. Vancomycin, teicoplanin, and the streptogramins: quinupristin and dalfopristin. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. 5th ed. Philadelphia: Churchill Livingstone, 2000: 382-392. Turnidge JD, Bell JM. Methicillin-resistant Staphylococcus aureus evolution in Australia over 35 years. Microb Drug Resist 2000; 6: 223-229. Gottlieb T, Mitchell D. The independent evolution of resistance to ciprofloxacin, rifampicin and fusidic acid in methicillin-resistant Staphylococcus aureus in Australian teaching hospitals (1990-1995). Australian Group for Antimicrobial Resistance (AGAR). J Antimicrob Chemother 1998; 42: 67-73. Hiramatsu K, Hanaki H, Ino T, et al. Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. J Antimicrob Chemother 1997; 40: 135-136. Hiramatsu K. The emergence of Staphylococcus aureus with reduced susceptibility to vancomycin in Japan. Am J Med 1998; 104 Suppl 5A: 7S-10S. Tenover FC, Biddle JW, Lancaster MV. Increasing resistance to vancomycin and other glycopeptides in Staphylococcus aureus. Emerg Infect Dis 2001; 7: 327-332. Howe RA, Wootton M, Walsh TR, et al. Heterogeneous resistance to vancomycin in Staphylococcus aureus. J Antimicrob Chemother 2000; l45: 130-132. Trakulsomboon S, Danchaivijitr S, Rongrungruang Y, et al. First report of methicillin-resistant Staphylococcus aureus with reduced susceptibility to vancomycin in Thailand. J Clin Microbiol 2001; 39: 591-595. Wong SS, Ho PL, Woo PC, Yuen KY. Bacteremia caused by staphylococci with inducible vancomycin heteroresistance. Clin Infect Dis 1999; 29: 760-767. Walsh TR, Bolmstrom A, Qwarnstrom A, et al. Evaluation of current methods for detection of staphylococci with reduced susceptibility to glycopeptides. J Clin Microbiol 2001; 39: 2439-2444. Fridkin SK. Vancomycin-intermediate and -resistant Staphylococcus aureus: what the infectious disease specialist needs to know. Clin Infect Dis 2001; 32: 108-115. Wootton M, Howe RA, Hillman R, et al. A modified population analysis profile (PAP) method to detect hetero-resistance to vancomycin in Staphylococcus aureus in a UK hospital. J Antimicrob Chemother 2001; 47: 399-403. Centers for Disease Control and Prevention. Staphylococcus aureus with reduced susceptibility to vancomycin-Illinois, 1999. MMWR Morb Mortal Wkly Rep 2000; 48: 1165-1167. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing. Supplement M100 S11. Wayne, Pa: The Committee, 2001. Geisel R, Schmitz FJ, Thomas L, et al. Emergence of heterogeneous intermediate vancomycin resistance in Staphylococcus aureus isolates in the Dusseldorf area. J Antimicrob Chemother 1999; 43: 846-848. Hiramatsu K, Aritaka N, Hanaki H, et al. Dissemination in Japanese hospitals of strains of Staphylococcus aureus heterogeneously resistant to vancomycin. Lancet 1997; 350: 1670-1673. Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med 1991; 115: 674-680. Wood CA, Wisniewski RM. Beta-lactams versus glycopeptides in treatment of subcutaneous abscesses infected with Staphylococcus aureus. Antimicrob Agents Chemother 1994; 38: 1023-1026. Small PM, Chambers HF. Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users. Antimicrob Agents Chemother 1990; 34: 1227-1231. Drew RH, Perfect JR, Srinath L, et al. Treatment of methicillin-resistant Staphylococcus aureus infections with quinupristin-dalfopristin in patients intolerant of or failing prior therapy. J Antimicrob Chemother 2000; 46: 775-784. Prystowsky J, Siddiqui F, Chosay J, et al. Resistance to linezolid: characterization of mutations in rRNA and comparison of their occurrences in vancomycin-resistant enterococci. Antimicrob Agents Chemother 2001; 45: 2154-2156. Hanaki H, Kuwahara-Arai K, Boyle-Vavra S, et al. Activated cell-wall synthesis is associated with vancomycin resistance in methicillin-resistant Staphylococcus aureus clinical strains Mu3 and Mu50. J Antimicrob Chemother 1998; 42: 199-209. Tsiodras S, Gold HS, Sakoulas G, et al. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet 2001; 358: 207-208. (Received 10 Sep, accepted 26 Sep, 2001) Authors' details Austin and Repatriation Medical Centre, Melbourne, VIC. Peter B Ward, BAppSc, PhD, Senior Scientist, Microbiology Department; Paul D R Johnson, FRACP, PhD, Deputy Director, Infectious Diseases Department, and Associate Professor, Department of Medicine, University of Melbourne, VIC; Elizabeth A Grabsch, BSc, MPH, Infection Control Scientist, Microbiology Department; Barrie C Mayall, FRACP, FRCPA, Medical Microbiologist, Microbiology Department; M Lindsay Grayson, FRACP, FAFPHM, MD, Director, and Professor, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, and Department of Medicine, University of Melbourne, Melbourne, VIC. Reprints: Dr P B Ward, Microbiology Department, Austin and Repatriation Medical Centre, Studley Road, Heidelberg, VIC 3084. Peter. WardATarmc.org.au Make a comment 1: Glossary (adapted from references 7 and 12) MRSA: Methicillin-resistant Staphylococcus aureus. An isolate of S. aureus, resistant to methicillin, with minimum inhibitory concentration (MIC) to vancomcyin ≤2mg/L. MRSA does not produce vancomycin-resistant subpopulations during routine laboratory susceptibility tests. hVISA: Heteroresistant vancomycin-intermediate S. aureus. An isolate of MRSA which produces subpopulations with vancomycin MICs ≥4mg/L, typically at a rate of 1:105 to 1:106 resistant:sensitive colonies. Antibiotic-resistance detection methods that use large inocula, such as E test, are needed to screen for hVISA. VISA: Vancomycin-intermediate S. aureus. An isolate of MRSA which produces colonies with vancomycin MICs of 8-16mg/L at high frequency, and is detectable as "intermediate resistant" using standard low-inocula susceptibility tests. VRSA: Vancomycin-resistant S. aureus. An isolate of MRSA which produces populations of colonies with vancomycin MICs >32mg/L at high frequency. Back to text 2: Number of colonies resistant to defined concentrations of vancomycin and teicoplanin among subpopulations of a Staphylococcus aureus strain, AR2, isolated from the index patient. A range of inocula (103-109) were used to measure viable subpopulations at each antibiotic concentration. Back to text

Peter B Ward · Elizabeth A Grabsch · Barrie C Mayall

Position Statement Anticoagulation in pregnancy and the puerperium A Working Group on behalf of the Obstetric Medicine Group of Australasia MJA 2001; 175: 258-263 Abstract - Management and prophylaxis of venous thromboembolism in pregnancy and the puerperium - Acute venous thromboembolism - Prophylaxis of venous thromboembolism - General - Previous thromboembolism - Previous single VTE and no recognised thrombophilia - Previous recurrent VTE or idiopathic VTE - Familial thrombophilia - Hyperhomocysteinaemia - Antiphospholipid syndrome and VTE - Management and prophylaxis of obstetric problems associated with uteroplacental thrombosis - References - Authors' details - - More articles on Obstetrics & gynaecology and women's health Abstract For the management of acute thrombotic events in pregnancy therapeutic doses of low molecular weight heparins (LMWH) may be used, unless the shorter half-life of intravenous unfractionated heparin (UH) and predictable reversibility by protamine are important. Treatment should be continued up until delivery and into the puerperium. Pregnant women who have had an acute thrombotic event should be delivered by a specialist team. In the case of recent thrombosis, delivery should be planned and the time during which anticoagulation therapy is ceased around the time of delivery should be minimised. Therapeutic doses of LMWH contraindicate the use of regional anaesthesia, and a switch to intravenous UH before delivery may allow greater flexibility in this regard. Prophylactic doses of LMWH can be used to reduce the risk of recurrent thromboembolic events in pregnancy. The regimen used will depend on the previous history, the family history and the presence of risk factors, including the genetic and acquired causes of thrombophilia. Women with mechanical heart valves are at high risk during pregnancy and require therapeutic anticoagulation throughout pregnancy under the direction of experienced specialists. Low-dose aspirin can reduce the risk of recurrent pre-eclampsia by about 15%, but the role of UH and LMWH in the prevention of recurrent miscarriage or obstetric complications associated with uteroplacental insufficiency is still uncertain. Low molecular weight heparins (LMWH) are being used increasingly as standard treatment for venous thrombosis, replacing unfractionated heparin (UH) for both therapeutic and prophylactic anticoagulation. Compared with UH, LMWH have increased bioavailability and a longer half-life. They also have the benefits of ease of administration, often as a single daily dose, have reduced requirements for monitoring, and are associated with less heparin-induced thrombocytopenia, reduced bleeding complications and improved patient acceptability.1Heparins do not cross the placenta, whereas warfarin does.2,3 By contrast, warfarin is teratogenic between six and 12 weeks' gestation, and may cause fetal and neonatal bleeding if used during the second or third trimester. Except perhaps in women with mechanical heart valves, there is general agreement that UH or LMWH should be substituted for warfarin as soon as pregnancy is diagnosed. Long-term treatment with UH carries risks of maternal osteoporosis4-6 and heparin-induced thrombocytopenia. Consistent, long term therapeutic anticoagulation can be hard to achieve with subcutaneous UH, because of low bioavailability and the changing anticoagulant response to UH as pregnancy progresses, often requiring close laboratory monitoring. LMWH require much less monitoring and appear to carry a smaller risk of heparin-induced thrombocytopenia, bleeding, and probably osteoporosis.7-9 Data on the effectiveness and safety of LMWH in pregnancy are limited but systematic reviews are becoming available.10 Given the convenience of LMWH and doctors' increasing familiarity with their use, there is growing opinion that LMWH have a role in pregnancy in preference to UH. In this position paper we summarise current views and make consensus recommendations for anticoagulation in pregnancy and the puerperium. The consensus process followed for this article is summarised in Box 1. Management and prophylaxis of venous thromboembolism in pregnancy and the puerperium Acute venous thromboembolism Antenatal management: Clinical trials in non-pregnant patients show that LMWH are at least as effective and safe as UH in the initial management of acute proximal or calf deep venous thrombosis (DVT).1 Recurrence of thromboembolism is reduced by ongoing warfarin therapy and, in the case of proximal DVT, treatment should be continued for at least six months (C1). The standard initial treatment for pulmonary embolism, whether during pregnancy or not, remains intravenous UH (C2). For an antenatal DVT, treatment should start with a LMWH at the therapeutic dose recommended by the manufacturers9(Box 2) (C1). Intravenous UH may be preferred in situations where its short half-life and predictable reversibility by protamine sulfate are important (eg, when delivery or surgery may be imminent). Calf DVT should be treated in the same way as proximal DVT in pregnancy because of ongoing hypercoagulability during pregnancy (C2). If intravenous UH is used for the initial treatment of pulmonary embolism, therapeutic doses of LMWH may be commenced once the patient is haemodynamically stable (C1). Anticoagulation therapy should then be maintained until delivery (C1). It is generally recommended that therapeutic doses of UH or LMWH be continued throughout pregnancy.9,11,12 In practice, some clinicians change to a prophylactic dose of LMWH after 12 weeks of therapy if the woman is still pregnant, and continue with this dose until labour (Box 2) (C3). The rationale for this approach includes a declining risk of recurrence with time after acute venous thromboembolism (VTE),13 a desire to reduce osteoporosis associated with LMWH, and the suggestion from small trials in non-pregnant patients that lower prophylactic or intermediate doses of LMWH may be as effective as warfarin in preventing secondary recurrence of VTE.14-16 The safety of such a reduction of LMWH dose before 12 weeks after acute VTE in pregnancy needs to be established in clinical trials. Monitoring: There is no need to use an anti-factor Xa assay to monitor either therapeutic or prophylactic doses of LMWH (C2). Therapy with UH can be monitored and managed according to the activated partial thromboplastin time (APTT). Management of labour and delivery: Women requiring therapeutic anticoagulation should be counselled before delivery, which should be planned under the care of a specialist team (C1). Elective delivery allows for dose adjustment to minimise the opposing risks of bleeding at delivery and of further thrombosis.13 Vaginal delivery is preferable, as there is less risk of haemorrhage than with caesarean section. Delivery by caesarean section should be determined on the basis of obstetric indications (C1). The use of regional anaesthesia requires special consideration, and is outlined in Box 3. The intensity of anticoagulation therapy required during delivery depends on how recently the VTE occurred. If within the last month, each day without anticoagulation therapy is associated with a 1% absolute increase in the risk of recurrence.13 It is therefore important to minimise the time off anticoagulation. Intravenous UH should be substituted for LMWH 24-36 hours before obstetric intervention, aiming to maintain the APTT at 1.5-2 times baseline. After induction, UH therapy is ceased once labour is established, allowing the APTT to return to normal, usually within 4-6 hours. Women requiring elective caesarean section should cease UH therapy six hours before surgery to allow for the full range of obstetric and anaesthetic options (C1). If the VTE occurred between one and three months previously, therapeutic LMWH can be reduced to a prophylactic dose for 24-48 hours and labour can then be induced. The last dose of LMWH is given the night before induction. In women whose cervical assessment suggests that labour is likely to be established within a few hours of induction, the last dose of LMWH before induction may be withheld (C2). Women who have had a VTE more than three months previously and who are still receiving a therapeutic dose of LMWH can be switched to a prophylactic dose at 38 weeks' gestation, allowing spontaneous labour to occur. Again, LMWH are withheld at the onset of labour (C2). Alternatively, if a woman wishes to be assured of access to epidural anaesthesia, induction of labour can be offered, with the last dose of LMWH on the day before the day of induction (C2). Anti-embolism stockings, compression devices and electrical calf stimulators may be used and continued postpartum, especially if caesarean delivery is undertaken (C1). In all women in whom anticoagulants have been used, the third stage of labour should be managed actively with oxytocic therapy and controlled cord traction to minimise the risk of postpartum haemorrhage (C1). Postpartum management: Postpartum, anticoagulation therapy is usually recommenced at the same intensity as that used antenatally. Prophylactic doses can be recommenced within 2-6 hours of both vaginal and caesarean deliveries (C1). This may be prophylactic doses of LMWH or low-dose (12 000 U/24 h) UH infusion, if rapid reversal of anticoagulation may be required. Therapeutic doses of UH or LMWH may be reintroduced 24 hours after vaginal delivery (C2). Caution should be exercised in recommencing therapeutic doses of LMWH earlier than 24 hours after operative delivery because of the risk of surgical bleeding, but most women can be receiving therapeutic doses by 36-48 hours after caesarean section (C1). Warfarin therapy can then be initiated and, once therapeutic levels have been achieved, continued in place of LMWH to complete the six months of therapy and for at least six weeks postpartum. Neither medication contraindicates breastfeeding (C1). Prophylaxis of venous thromboembolism General VTE remains a major cause of maternal mortality in Australia, the United Kingdom and in the United States, occurring at a rate of approximately one death per 100 000 maternities.11,12,18 The rate is much higher in older women; in the UK, women aged over 39 years had a mortality rate of 1 per 3300 pregnancies.19 VTE can occur at any time during pregnancy; its prevalence is approximately equally distributed between the three trimesters.20 Although two-thirds of events occur antenatally, the day-by-day risk is greatest in the first weeks after delivery.20Major known risk factors for VTE in pregnancy and postpartum include caesarean section (particularly in labour), obesity, prolonged bed rest and immobility, pre-eclampsia, nephrotic syndrome, current infection and other recent surgery, in addition to previous VTE and thrombophilia. These risk factors often coexist and reinforce each other. A risk-assessment profile may be constructed, as suggested in the consensus report from the Royal College of Obstetricians and Gynaecologists,21 which recommends that: all "at risk" women should be monitored for symptoms and signs of VTE during the first week postpartum; hydration should be maintained and early mobilisation encouraged; graduated compression stockings with or without calf stimulation should be used during and after caesarean section in women at moderate risk (one or two risk factors); in women at high risk (three or more risk factors), LMWH or UH prophylaxis should be used and continued for at least five days. The efficacy or benefit of these interventions is unknown, as no high grade evidence is available. Previous thromboembolism In women who have had previous VTE, the risk of recurrence will be influenced by a number of factors, including whether the index event was spontaneous or provoked, the presence or absence of a family history of VTE, the presence of a known thrombophilia, or whether there has been more than one episode of VTE. The decision as to whether VTE prophylaxis is required throughout pregnancy or only postpartum may be based on this information (Box 4).22Women requiring prophylaxis during pregnancy can be managed with low-dose LMWH (Box 2). They can then be allowed to come into spontaneous labour (C2). LMWH are withheld at the onset of labour (C2). Alternatively, if such a woman wishes to be assured of access to regional anaesthesia, induction of labour can be offered, with the last dose of LMWH on the day before the day of induction (Box 3) (C2). Previous single VTE and no recognised thrombophilia Both earlier and more recent cohort data suggest that most pregnant women with a past history of a single precipitated thrombotic event in or out of pregnancy, or associated with the combined oral contraceptive pill, and who have no underlying thrombophilia, can be safely managed by careful observation before delivery and postpartum thromboprophylaxis for six weeks23 (C2). Previous recurrent VTE or idiopathic VTE Women who have either recurrent VTE, previous idiopathic VTE, or a previous VTE and a strong family history of VTE but with no demonstrated cause for thrombophilia, may be given thromboprophylaxis throughout pregnancy and for six weeks postpartum23,24 (C1). Familial thrombophilia Thromboembolism is a multifactorial disease, in many cases developing as a result of a thrombotic tendency (a thrombophilia) interacting with other factors, such as pregnancy.25,26 Situations in which such a thrombophilia may require consideration during pregnancy are: previous personal thromboembolic disease and known thrombophilia; no previous VTE, but a strong family history (ie, one or more first-degree relatives affected) and known thrombophilia; no previous VTE, strong family history, no previous investigations; no previous VTE, weak family history (ie, incidental finding of thrombophilia in a family member); and no personal or family history of VTE, but known thrombophilia detected after screening (eg, after obstetric complications or before starting to take the combined oral contraceptive pill). The known causes of familial thromboembolism differ in their risk of associated thrombosis.27 The prevalence of such thrombophilic disorders varies between populations.28 A combination of any two or more inherited factors substantially increases the risk of thromboembolism. Box 4 summarises the risk profiles of the various genetic thrombophilias and offers guidelines for therapy. Box 5 describes management during pregnancy of medical problems requiring anticoagulation outside pregnancy. Hyperhomocysteinaemia In women with a previous history of VTE and hyperhomocysteinaemia, it may be prudent to reduce plasma homocysteine concentrations by folate supplementation throughout pregnancy, in addition to other thromboprophylaxis (C2). Antiphospholipid syndrome and VTE The presence of a lupus anticoagulant or of moderately to strongly positive titres of anticardiolipin antibody (ACA) is a strong risk factor for recurrent VTE, especially in pregnancy. Suggestions for treatment are shown in Box 4. Unless there is an associated history of poor obstetric outcome (see below), low-dose aspirin therapy need not be added (C2). On the other hand, it is contentious whether women with a positive lupus anticoagulant with or without ACA with no previous history of VTE (eg, women with systemic lupus erythematosus) require any prophylactic treatment at all during pregnancy. Low-dose aspirin may be a reasonable option for such women (C1). Management and prophylaxis of obstetric problems associated with uteroplacental thrombosis A common pathophysiological link between various poor pregnancy outcomes, including recurrent miscarriage, stillbirth, placental abruption, fetal growth restriction and pre-eclampsia, is thrombosis in the uteroplacental circulation. Antiplatelet agents (especially low-dose aspirin) have been trialled, particularly for preventing pre-eclampsia. A recent systematic review has shown a 15% reduction in the incidence of recurrent pre-eclampsia when low-dose aspirin is used, less benefit for the prevention of preterm birth and no benefit for the prevention of fetal growth restriction.35 Whether LMWH or UH can be used safely and more effectively than just aspirin in placental vasculopathy, with or without thrombophilia, is currently under investigation. Only in the case of recurrent miscarriage associated with the antiphospholipid syndrome has the addition of UH to aspirin been shown to be beneficial.36 A number of small cohort studies in women with previous obstetric complications who were treated with LMWH showed a good outcome, but whether the outcome was related to the use of LMWH is uncertain.37,38While awaiting the results of further studies, and given the small numbers of affected women, no specific treatment recommendations can be made. We encourage clinicians to refer such patients to centres where randomised controlled trials are being carried out or where cohort studies are under way. Competing interests: The authors are grateful to Pharmacia Upjohn for an unrestricted financial grant towards the costs involved in the preparation of this article, although the company did not contribute in any way either to the analysis or to the recommendations. There are no other known conflicts of interest. Future research questions The working party identified further areas for research. These include: Comparison of LMWH versus intravenous UH in acute DVT and pulmonary embolism in pregnancy. High-dose versus low-dose LMWH therapy for secondary prophylaxis after acute DVT in pregnancy. The value of prospective blinded anti-Xa levels in the use of therapeutic LMWH in pregnancy. The timing, benefits and risks of any dose adjustment of LMWH/UH, particularly peripartum. Controlled longitudinal studies of bone density and fracture rates in women using long-term LMWH. Prevention of pregnancy-associated VTE: the risks and benefits of LMWH thromboprophylaxis during pregnancy and postpartum for specific groups. Prevention of adverse pregnancy complications related to placental insufficiency. Randomised studies to determine the efficacy of LMWH in improving subsequent pregnancy outcome in women with specific pregnancy complications and an underlying thrombophilia. A register of women being treated with anticoagulants during pregnancy. A register to determine the clinical significance of thrombophilias in particular patient groups. References Weitz J. Drug therapy: low molecular weight heparins. N Engl J Med 1997; 337: 688-698. Flessa H, Kapstrom AB, Glueck HI, Will JJ. Placental transport of heparin. Am J Obstet Gynecol 1965; 934: 570-573. Forestier F, Sole Y, Aiach M, et al. Absence of transplacental passage of fragmin (Kabi) during the second and the third trimesters of pregnancy. Thromb Haemostas 1992; 67: 180-181. Dahlman TC, Sjoberg HE, Ringertz H. Bone mineral density during long-term prophylaxis with heparin in pregnancy. Am J Obstet Gynecol 1994; 170: 1315-1320. Douketis JD, Ginsberg JS, Burrows RF, et al. The effects of long-term heparin therapy during pregnancy on bone density — a prospective matched cohort study. Thromb Haemost 1996; 75: 254-257. Barbour LA, Kick SD, Steiner JF, et al. A prospective study of heparin-induced osteoporosis in pregnancy using bone densitometry. Am J Obstet Gynecol 1994; 170: 862-869. Nelson-Piercy C. Heparin-induced osteoporosis in pregnancy. Lupus 1997; 6: 500-504. Farquharson RG. Heparin, osteoporosis and pregnancy. Br J Hosp Med 1997; 58: 205-207. Ginsberg J, Greer I, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 2001; 199: 122S-131S. Sanson BJ, Lensing AW, Prins MH, et al. Safety of low molecular weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 668-672. Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999; 353: 1258-1265. Toglia M, Weg J. Current concepts: venous thromboembolism during pregnancy. N Engl J Med 1996; 335: 108-114. Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997; 336: 1506-1511. Pini M, Aiello S, Manotti C, et al. Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis. Thromb Haemost 1994; 72: 191-197. Gonzalez-Fajardo J, Arreba E, Castrodeza J, Perez J, et al. Venographic comparison of subcutaneous low-molecular weight heparin with oral anticoagulant therapy in the long-term treatment of deep venous thrombosis. J Vasc Surg 1999; 30: 283-292. Das S, Cohen A, Edmonson R, et al. Low molecular weight heparin versus warfarin for prevention of recurrent venous thromboembolism: a randomized trial. World J Surg 1996; 20: 521-527. Tryba M. European practice guidelines: thromboembolism prophylaxis and regional anesthesia. Regional Anesthes Pain Med 1998; 23 (6 Suppl 2): 178-182. Maternal mortality committee. Maternal deaths in Australia 1991-1993. Canberra: NHMRC, 1998. Department of Health. Why mothers die. Report on confidential enquiries into maternal deaths in the United Kingdom 1994-1996. London: The Stationery Office; 1998. Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and the leg of presentation. Obstet Gynecol Surv 1999; 54: 265-271. Royal College of Obstetricians and Gynaecologists. Report of the RCOG Working Party on prophylaxis against thromboembolism in gynaecology and obstetrics. London: RCOG, 1995. McColl MD, Walker ID, Greer IA. The role of inherited thrombophilia in venous thromboembolism associated with pregnancy. Br J Obstet Gynaecol 1999; 106: 756-766. Brill-Edwards P, Ginsberg J, Gent M, et al. Safety of withholding antepartum heparin in women with a previous episode of venous thromboembolism. N Engl J Med 2000; 343: 1439-1444. Letsky EA. Peripartum prophylaxis of thrombo-embolism. Baillieres Clin Obstet Gynaecol 1997; 11: 523-543. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-1173. Preston FE, Rosendaal FR, Walker ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 913-916. Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000; 342: 374-380. Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222-1231. Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves — a systematic review of the literature. Arch Intern Med 2000; 160: 191-196. Arnaout M, Kazma H, Khalil A, et al. Is there a safe anticoagulation protocol for pregnant women with prosthetic valves? Clin Exp Obstet Gynecol 1998; 25: 101-104. Elkayam U. Pregnancy through a prosthetic heart valve. J Am Coll Cardiol 1999; 33: 1642-1645. Lee LH, Liauw PCY, Ng ASH. Low molecular weight heparin for thromboprophylaxis during pregnancy in 2 patients with mechanical mitral valve replacement. Thromb Haemost 1996; 76: 628-630. Sadler L, McCowan L, White H, et al. Pregnancy outcomes and cardiac complications in women with mechanical, bioprosthetic and homograft valves. Br J Obstet Gynaecol 2000; 107: 245-253. Rowan J, McCowan L, Raudkivi P, North R. Enoxaparin treatment in women with mechanical heart valves during pregnancy. Am J Obstet Gynecol. In press. Knight M, Duley L, Henderson Smart DJ, King JF. Antiplatelet agents for preventing and treating pre-eclampsia. Cochrane Database Syst Rev 2000; 2. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314: 253-257. Brenner B, Hoffman R, Blumenfeld Z, et al. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000; 83: 693-697. Riyazi N, Leeda M, de Vries J, et al . Low-molecular-weight heparin combined with aspirin in pregnant women with thrombophilia and a history of preeclampsia or fetal growth restriction: a preliminary study. Eur J Obstet Gynecol Reprod Biol 1998; 80: 49-54. The authors of the Position Statement are listed below Authors' details Department of Obstetrics, University of Adelaide, Women's and Children's Hospital, North Adelaide, SA. William M Hague, FRCP, FRCOG, Senior Physician in Obstetric Medicine and Clinical Senior Lecturer. National Women's Hospital, Auckland, New Zealand Robyn A North, PhD, FRACP, Associate Professor in Obstetric Medicine. Flinders Medical Centre, Bedford Park, SA. Alexander S Gallus, FRCPA, FRACP, Haematologist and Professor. King Edward Memorial Hospital, Subiaco, WA. Barry N J Walters, MB BS, FRACP, Physician in Obstetric Medicine and Clinical Associate Professor, Department of Obstetrics and Gynaecology, University of Western Australia. Christopher Orlikowski, MB BS, FANZCA, Anaesthetist. Monash University, Monash Medical Centre, Melbourne, VIC. Robert F Burrows, FACOG, FRANZCOG, Professor of Maternal-Fetal Medicine. Mater Mothers' Hospital, South Brisbane, QLD Robert B Cincotta, FRANZCOG, CMFM, Specialist in Maternal-Fetal Medicine. North Western Adelaide Health Service, Adelaide, SA. Gustaaf A Dekker, PhD, FRANZCOG, Professor of Obstetrics and Gynaecology. Mercy Hospital for Women, East Melbourne, VIC. John R Higgins, MD, FRANZCOG, Senior Lecturer in Obstetrics and Gynaecology (currently, Professor of Obstetrics and Gynaecology, University College, Cork, Ireland). Royal Hospital for Women, Sydney, NSW. Sandra A Lowe, MD, FRACP, Physician in Obstetric Medicine. Royal North Shore Hospital, Sydney, NSW. Jonathan M Morris, MD, FRANZCOG, Senior Lecturer in Obstetrics and Gynaecology. Nepean Hospital, Sydney, NSW. Michael J Peek, PhD, FRANZCOG, Professor of Obstetrics and Gynaecology. Reprints will not be available from the authors. Correspondence: Dr W M Hague, Department of Obstetrics, Women's and Children's Hospital, North Adelaide, SA 5006. bill.hagueATadelaide.edu.au Make a comment 1: Consensus process The authors of this position statement are members of the Obstetric Medicine Group of Australasia (OMGA), with a particular clinical and research interest in managing pregnant women with thromboembolic problems. The authors were all members of the working party, and include six obstetricians, four obstetric physicians, an obstetric anaesthetist and a clinical haematologist. We met collectively in October 1999 to discuss the broad issues of the use of low molecular weight heparins in pregnancy before producing a draft document; this was subsequently modified by written comments and refined at teleconferences in May, June and September 2000. The position statement is a consensus statement inasmuch as there is little high-grade evidence from either randomised trials or other cohort studies on which to make recommendations, especially for management. Our recommendations have been annotated to reflect the degree of agreement among us as follows: C1 Complete consensus; C2 Near-complete consensus (nine or more of the 12 authors); and C3 No consensus. Back to text 2: Doses of low molecular weight heparins Low molecular weight heparin Therapeutic dose Prophylactic dose Dalteparin (Fragmin) 100U/kg twice daily 5000U daily Enoxaparin (Clexane) 1 mg/kg twice daily 40mg daily or 1.5mg/kg daily Back to text 3: Suggested guidelines for regional anaesthesia and levels of consensus (Box 1) Regional anaesthesia (epidural or spinal block) is contraindicated during anticoagulation therapy because of the increased (although unquantified) risks of spinal haematoma17 (C1). If a regional anaesthetic is desired in women who require anticoagulation therapy, an elective delivery will allow for a planned reduction in dose or a change to intravenous unfractionated heparin (UH) (C1). Therapeutic subcutaneous injections of low molecular weight heparins (LMWH) or UH should be ceased at least 24 hours, and preferably 36 hours, before regional anaesthesia (epidural or spinal block) (C1). Intravenous UH (used to permit a rapid return of the APTT to normal after cessation of the infusion) should be discontinued at least six hours, and preferably 12 hours, before regional anaesthesia (C1). In women receiving prophylactic LMWH, an interval of more than 20 hours from the last dose should allow the placement of a regional block with minimal risk of complications (C2). A normal activated partial thromboplastin time (APTT) does not ensure minimal anticoagulant effect of LMWH, and the platelet count should be determined to exclude heparin-induced thrombocytopenia (C2). If caesarean section is being undertaken, further doses of LMWH should be delayed for at least four hours after placement of an uncomplicated regional block, and longer if the regional block has been complicated (C1). Low-dose LMWH therapy can be continued after delivery if there have been no complications in the siting of the regional block.17 An epidural catheter can be removed 12-20 hours after a prophylactic dose of LMWH, and the next injection should be delayed by at least four hours after removal (C1). Women should be closely monitored postpartum for any symptoms or signs of spinal haematoma, in particular for numbness and weakness in the lower limbs, severe back pain, and bladder or bowel incontinence (C1). Back to text Box 4 consists of 4a, 4b, 4c, 4d. 4a: Suggested management guidelines and levels of consensus (see Box 1) Thromboprophylaxis against recurrent venous thromboembolism (VTE) in pregnant women with previous VTE and no identified thrombophilia, according to estimated pregnancy-related risk of thrombosis Single episode of VTE Thrombosis history Recurrent VTE Spontaneous Probable cause* Family history of VTE in one or more 1st degree relatives PrA (option ThA) (C2) PrA (C2) Negot (C2) No family history of VTE PrA (C1) Negot (C2) Nil (C2) *Risk factors present such as surgery, combined oral contraceptive pill. Back to text 4b: Anticoagulation to prevent venous thromboembolism (VTE) in pregnant women testing positive for lupus anticoagulant or anticardiolipin antibodies (ACA), according to estimated pregnancy-related risk of thrombosis Lupus anticoagulant and/or ACA IgG ACA IgG weak moderate-strong positive,* ACA Thrombosis history positive* IgM positive Recurrent VTE in pregnancy despite prophylaxis ThA (C1) ThA (C1) Recurrent VTE outside pregnancy ThA (C2) ThA (C2) Previous VTE PrA (C1) Negot (C1) No previous VTE Nil (C1) Nil (C1) *Based on the highest-ever titre measured in the individual patient. Back to text 4c: Preventing venous thromboembolism (VTE) in pregnant women with established thrombophilias, according to estimated pregnancy-related risk of thrombosis Thrombosis history Antithrombin deficiency (Very rare) Protein C deficiency (Rare) Protein S deficiency (Rare) FVL* or PGM† homozygous (Uncommon) FVL* or PGM† heterozygous (Common) Personal history of VTE independent of family history ThA (C2) PrA (C1) PrA (C1) PrA (C1) Negot (C1) Family history of VTE in one or more 1st degree relatives ThA/PrA (C3) PrA (C1) PrA (C1) PrA (C1) Negot (C1) Family history of VTE in a distant relative ThA/PrA (C3) PrA (C1) Negot (C1) Negot (C1) Nil (C1) No personal or family history of VTE ThA/PrA (C3) PrA (C1) Nil (C1) Nil (C1) Nil (C1) *G1691A mutation in the factor V gene [Factor V Leiden] causing activated protein C resistance; †G20210A mutation in the prothrombin (factor II) gene. Back to text 4d: Key to management recommendations ThA Therapeutic anticoagulation necessary throughout pregnancy and postpartum - very high risk (>20%). PrA Prophylaxis necessary throughout pregnancy and puerperium - high risk (10%-20%). Negot Need for prophylaxis negotiable on a case-by-case basis until further data become available - moderate risk (3%-10%). Nil Postpartum prophylaxis or no prophylaxis - low risk (3%). Back to text 5: Management during pregnancy of medical problems requiring anticoagulation therapy outside pregnancy (consensus levels are described in Box 1) Women with mechanical heart valves require therapeutic doses of anticoagulant medication throughout pregnancy to prevent valve thrombosis or maternal thromboembolic events9 (C1). Women with mechanical heart valves should be managed under joint subspecialty care (C1). The maternal benefits of warfarin (prevention of valve occlusion and systemic embolism) must be balanced against hazards to the fetus (congenital anomalies, intracranial haemorrhage and fetal loss).29 Unfractionated heparin (UH) and low molecular weight heparins (LMWH) are safe for the fetus, but there is still debate as to their therapeutic efficacy in the mother compared with that of warfarin.29-33 UH is associated with higher rates of maternal thromboembolic complications, including fatal events.29,33 There are limited data on the efficacy of LMWH in mechanical valves during pregnancy, but valve thrombosis may occur.34 High rates of maternal valve thrombosis occur if subtherapeutic doses of UH or LMWH are used.9,30 Women should participate in the choice of anticoagulation therapy (C2). In women with other diseases (eg, dilated cardiomyopathy) who require anticoagulation therapy to prevent thromboembolic complications, the use of therapeutic or prophylactic doses of LMWH will depend on the perceived risk of thromboembolism (C1). Back to text

MJA 2001; 174: 650-651 Clinical record A 35-year-old man, previously well with no known allergies, presented to the emergency department 17 days after starting bupropion (Zyban) to assist him in giving up smoking. He had been taking no other medication before his presentation. Five days before presentation, he complained of discomfort in his throat, and two days later he developed an urticarial rash on his trunk and limbs, joint pain and swelling, and sweating. He had seen his general practitioner three times in the three days before presenting to the emergency department, and was treated with promethazine and prednisolone (50 mg Day 1, 25 mg Day 2, 25 mg Day 3) and cessation of bupropion. Despite this treatment, his symptoms progressed. His rash became more extensive and he started vomiting. At presentation to the emergency department, he had a temperature of 37.6ºC, a diffuse urticarial rash on his trunk and limbs, swelling of the metacarpophalangeal joints and interphalangeal joints, and tender wrists, knees and ankles. Testing with a urine dipstick showed red blood cells (RBC) and 5 g/L protein in his urine. Investigation revealed normal serum electrolyte, urea and creatinine levels. He had neutrophilia of 13.3 x 109/L (normal, 2-8 x 109/L), erythrocyte sedimentation rate of 18 mm/h (normal, < 15 mm/h), C-reactive protein level of 218 mg/L (normal, < 8 mg/L), and gamma glutamate transferase level of 72 U/L (normal, < 43 U/L), but results of other liver function tests were normal. Urine microscopy showed > 108 RBC/L (normal, < 107 RBC/L). Tests for antinuclear antibody, antibodies to dsDNA, antibodies to extractable nuclear antigens, antineutrophil cytoplasmic antibodies, immune complexes, and rheumatoid factor were negative. His immunoglobulin and complement levels were normal. An immunoelectrophoretogram showed raised acute phase reactants. A skin biopsy was consistent with urticaria. There was no evidence of vasculitis. The man was admitted to hospital and treated with prednisolone (50 mg/day) and antihistamines. A repeat urine analysis showed resolution of the haematuria and proteinuria. He developed angioedema of his lip which settled over two days. He was discharged two days after admission on a 10-day steroid taper and a non-steroidal anti-inflammatory drug, and he made a slow recovery over the following two weeks. Discussion of bupropion Bupropion hydrochloride (Zyban sustained-release tablets; GlaxoSmith Kline) has captured the imagination of prescribers and patients in Australia. This drug, which enhances the ability of patients to abstain from smoking, became available on private prescription in the Australian market in November 2000, and on the Pharmaceutical Benefits Schedule from 1 February 2001. By the end of March, 213 000 prescriptions had been approved by the Health Insurance Commission for dispensing for smoking cessation. These data suggest that 10% of all Australian smokers tried the drug in the first two months after it became available on the Pharmaceutical Benefits Scheme. Such rapid take-up of a newly registered drug has not been seen before in this country, and surpassed the manufacturer's ability to maintain supply — the drug allocation for use in Australia in the first year was used in two days. Bupropion hydrochloride is a selective inhibitor of neuronal uptake of catecholamines (noradrenaline and dopamine). The mechanism by which bupropion enhances the ability of patients to abstain from smoking is unknown; however, it is presumed that this effect is mediated in part by noradrenergic or dopaminergic mechanisms.1 Pharmacokinetic studies suggest that both bupropion and its major active metabolite, hydroxybupropion, bind to plasma and cell-surface proteins at a significant level (84% and 77%, respectively). The elimination half-life of bupropion and hydroxybupropion is about 20 hours, and steady-state levels for bupropion and its metabolites are reached within eight days (GlaxoSmith Kline, Therapeutic Goods Administration registration submission). A number of clinical trials have shown that bupropion leads to smoking abstinence for a four-week period in more patients than placebo or nicotine transdermal systems, with an optimal dose response at 300 mg/day.1,2 In addition, bupropion helps patients maintain continuous abstinence for six months, and reduces subjective symptoms of cigarette craving and nicotine withdrawal symptoms.1,2 It is also associated with less weight gain.1-4 Adverse reactions associated with bupropion include headaches, agitation, insomnia, dry mouth, and seizures.4 Bupropion should not be administered to patients with one or more conditions predisposing to a lower seizure threshold, such as a history of seizures, head trauma, tumour of the central nervous system, or other medications known to lower the seizure threshold. A less frequent but significant adverse event seen with administration of bupropion is a hypersensitivity reaction. This occurs at a rate of about 3% (GlaxoSmithKline, Therapeutic Goods Administration registration submission) and most commonly manifests as pruritus, urticaria and/or angioedema; however, some patients present with symptoms suggestive of a serum-sickness-like reaction. These patients usually develop symptoms about 10-20 days after starting bupropion. Their initial symptom is usually an urticarial rash. Over the following days they develop malaise, polyarthralgia/polyarthritis, and fever. Seven patients with the serum-sickness illness have been reported.5-9 There was no evidence of nephritis or complement pathway activation reported in these patients. A serum-sickness-like reaction to a drug is believed to be an immune-complex-mediated illness precipitated by the drug acting as a hapten in a protein-hapten complex. As a high proportion of bupropion binds to protein, it is possible that in some individuals the protein-hapten complex will provoke an immune response, with antibody production. The presence of urticaria in 3% of individuals receiving bupropion suggests the antibodies produced can activate anaphylatoxins such as C3a or C5a, which lead to mast cell and basophil degranulation. Alternatively, the drug might directly activate mast cells or induce specific IgE which activates the mast cells; however, skinprick testing with the drug in our patient provided no evidence for these pathways. It is surprising that we and others8 have not been able to find evidence of complement protein activation or immune complexes in these patients. The absence of circulating immune complexes may be due to the immune complexes being predominantly cell-bound. A serum-sickness-like reaction usually resolves after antigen withdrawal, over about 14 days. Some patients may require hospitalisation. The adverse events with bupropion highlight the importance of postmarketing surveillance of new therapeutic agents, especially those that are used in a large number of people in a short period, as is the case with bupropion. Key points for practice Bupropion (Zyban, GlaxoSmith Kline) is a new therapeutic agent for smoking cessation with rapid and significant market penetration in Australia. Relatively rare adverse events are occurring commonly because of the number of patients receiving treatment. Patients need to have the risk of a hypersensitivity reaction discussed with them and be advised to stop bupropion if symptoms develop. Hypersensitivity reactions can cause significant morbidity, and may require hospitalisation and treatment with prednisolone tapered over a few weeks. References Hurt RD, Sachs DP, Glover ED, et al. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 1997; 337: 1195-1202. Jorenby DE, Leischow SJ, Nides MA, et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999; 340: 685-691. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation (Cochrane Review). Cochrane Database Syst Rev 2000; CD000031. Holm KJ, Spencer CM. Bupropion: a review of its use in the management of smoking cessation. Drugs 2000; 59: 1007-1024. McLean SE, Pirie SD. A 30-year-old woman with a generalised rash. J Emerg Nurs 1999; 25: 575-576. Tripathi A, Greenberger PA. Bupropion hydrochloride induced serum sickness-like reaction. Ann Allergy Asthma Immunol 1999; 83: 165-166. Yolles JC, Armenta WA, Alao AO. Serum sickness induced by bupropion. Ann Pharm 1999; 33: 931-933. McCollom RA, Elbe DHT, Ritchie AH. Bupropion-induced serum sickness-like reaction. Ann Pharm 2000; 34: 471-473. Peloso PM, Baillie C. Serum sickness-like reaction with bupropion. JAMA 1999; 282: 1817. Make a comment ADRAC reports involving bupropion The Australian Adverse Drug Reactions Advisory Committee has received 780 reports in association with bupropion to mid-May 2001. The more commonly reported problems have involved skin reactions (307 reports), psychological disturbances (285) and nervous system disorders (268). Urticaria has been the most common event reported (167 reports). Other reactions commonly reported have included nausea (87 reports), dizziness/ataxia (78), other rashes (86), insomnia (78), headache (68), and tremor (57). There have been nine deaths involving suspected adverse reactions with bupropion, but it has not been possible to establish or exclude a causal link with bupropion. It should be kept in mind that a high proportion of patients taking bupropion are likely to be in age groups where sudden cardiovascular death occurs and that smoking increases that risk. Thirty-three reports describe a syndrome of a skin rash or urticaria with joint pain or swelling consistent with a serum-sickness-like reaction. This was only recognised by the reporter of the adverse reaction in 10 cases. The delayed onset, ranging from 5 to 37 days (median, 17 days) after commencement of bupropion, is also consistent with a serum-sickness-like syndrome. In at least 16 of the cases, steroids were required. I W Boyd, Executive Secretary, ADRAC, personal communication; <http://www.health.gov.au/tga/docs/html/zyban.htm>. Back to text

Elizabeth Benson

Liang Han Ling, Colin Marchant, Nicholas A Buckley, Michael Prior and Rod J Irvine MJA 2001; 174: 453-455 Abstract - Methods - Results - Discussion - Acknowedgements - Authors' details - - More articles on Pharmacology - More articles on Drugs and alcohol Abstract Objective: To describe the clinical features of paramethoxyamphetamine (PMA; "death") poisoning and to compare these with those of people with self-reported "ecstasy" poisoning. Design: Retrospective casenote review. Participants and setting: 22 patients who presented to the Emergency Department of the Royal Adelaide Hospital (RAH), a major metropolitan teaching hospital, between 1 January 1996 and 31 December 1998 with PMA poisoning identified through urine drug screens; and 61 patients with self-reported ecstasy poisoning between 1 September 1997 and 31 December 1998 found through the hospital databases. Results: Patients with PMA poisoning presented with tachycardia (64%), hyperthermia (temperature > 37.5ºC; 36%), coma (41%), seizures (32%), arrhythmias (23%), and QRS intervals ≥ 100 ms (50%) with greater frequency and often greater severity than those with self-reported ecstasy poisoning. Two patients with PMA poisoning presented with severe hypoglycaemia (blood glucose level, < 1.5 mmol/L) accompanied by hyperkalaemia (K+ concentration, > 7.5 mmol/L). Conclusions: At our hospital, PMA poisonings accounted for most of the severe reactions among people who believed they had taken ecstasy. Hypoglycaemia and hyperkalaemia may be specific to PMA poisoning. PMA toxicity should be suspected with severe or atypical reactions to "ecstasy", and confirmed by chromatographic urine drug screens. The recreational use of amphetamine derivatives among young people is common, particularly at dance clubs and dance parties ("raves"). 3,4- Methylenedioxymethamphetamine (MDMA), popularly known as "ecstasy", was first identified in street use in 1972.1 Another amphetamine derivative, paramethoxyamphetamine (PMA), also appeared in recreational use during the 1970s. PMA, and other amphetamine derivatives, such as 3,4-methylenedioxyethylamphetamine (MDEA) and 3,4-methylenedioxyamphetamine (MDA), are known to have been sold on the street as ecstasy.2,3 Within a few years, PMA was associated with several fatalities in Canada and earned the street-name "death".4 Further fatalities associated with PMA toxicity have only been reported in significant numbers in South Australia,2,5,6 where at least eight deaths have occurred since September 1995, while no deaths from MDMA alone were reported in the same period (P D Felgate, Scientist, Forensic Science Centre, South Australia, personal communication). The toxic effects of MDMA are well described,7-10 and the few previous case reports of PMA poisoning showed similar toxic effects.2,4,5 Serotonergic and sympathomimetic symptoms include anxiety, agitation, nausea, and palpitations. Life-threatening adverse effects of MDMA include severe hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, multiorgan failure, arrhythmias, intracerebral haemorrhage, seizures, and hyponatraemia leading to cerebral oedema.3,11 While case reports of PMA deaths collectively suggest that PMA is more toxic than MDMA, the clinical effects of PMA have not yet been studied systematically. Here, we report a series of non-fatal, confirmed PMA poisonings, all in patients presenting to the emergency department of a metropolitan hospital in South Australia. Methods We conducted a retrospective casenote review of all PMA poisonings identified through urine drug screens of patients presenting to the Royal Adelaide Hospital (RAH) Emergency Department between 1 January 1996 and 31 December 1998. We included PMA poisonings involving the coadministration of MDMA or other substances. Urine drug screens had been performed by enzyme immunoassay, with confirmation of positive results by gas chromatography and mass spectrometry, according to Australian Standard 4308 (1995). Data were retrieved from casenotes by means of standardised forms and entered into a computer database. Findings were compared with those for all other patients presenting to the RAH between 1 September 1997 and 31 December 1998 because of adverse effects after the self-reported use of "ecstasy". These patients were identified by reviewing casenotes of all stimulant drug poisonings through admission diagnosis-related group coding and recorded in the RAH Emergency Department database; a few additional cases that had been wrongly coded were identified through urine drug screens. Confirmation of MDMA exposure by urine drug screens was not available for most patients in this comparison group. Ethical approval for this study was granted by the Royal Adelaide Hospital ethics committee. Results Twenty-two PMA poisonings were confirmed by urine drug screens between 1 January 1996 and 31 December 1998. These occurred in the first eight months and last eight months of the study period, with 16 months of no confirmed PMA poisonings in between. The casenotes of 15 of these 22 patients recorded that they believed they had taken ecstasy. No patient's records showed that he or she knowingly took PMA. Sixty-one patients with self-reported ecstasy (MDMA) poisoning presented to RAH between 1 September 1997 and 31 December 1998. Their characteristics and clinical features are compared with the PMA group in the Box. Eleven patients with PMA poisoning had only relatively minor symptoms (anxiety, agitation, delirium, hallucinations, headache, involuntary movements, vomiting). Frequent signs recorded in these patients included tachycardia (heart rate > 100 bpm), mild hyperthermia (temperature, > 37.5ºC) and a prolonged QRS interval on electrocardiogram, often with a right bundle branch block pattern. A much larger proportion of patients with ecstasy poisoning presented with relatively minor symptoms. The other 11 patients with PMA poisoning had life-threatening toxicity with coma, generalised seizures, severe hyperthermia (temperature, > 40ºC) or hypothermia (temperature, < 34.5ºC), and some had arrhythmias (atrial fibrillation [2], multifocal ventricular ectopic beats [2], supraventricular tachycardia [1]). Two patients with PMA poisoning presented with severe hypoglycaemia (blood glucose level, < 1.5 mmol/L; normal range, 3.8-5.5 mmol/L), accompanied by hyperkalaemia (K+, > 7.5 mmol/L; normal range, 3.1-4.2 mmol/L). Discussion PMA and MDMA are structurally and pharmacologically similar, producing their effects through serotonergic, dopaminergic, and noradrenergic mechanisms. The recent case reports of PMA-related deaths in South Australia5,6 suggest that PMA is more toxic than MDMA, but do not provide a clinical explanation for this difference. Our retrospective study showed that most people with PMA poisoning present with clinical features that are qualitatively similar to those of people with ecstasy poisoning (ie, hyperthermia, coma, and seizures), but that these symptoms occur more frequently and are more severe in those who took PMA. Certain features, such as QRS interval prolongation, hypoglycaemia and hyperkalemia, appear unique to PMA poisoning, suggesting there may be toxicological mechanisms different from those of MDMA contributing to PMA's adverse effects. Our patients with PMA poisoning did not have significant acidosis, haemolysis or tissue damage to explain the hyperkalaemia. The high frequencies of prolonged QRS intervals and seizure suggest that PMA may have sodium-channel-blocking properties. Severe hypoglycaemia has never previously been reported as an adverse effect of PMA. The affected patients did not have liver failure at the time, nor were other drugs detected that might explain the hypoglycaemia. However, PMA is a monoamine oxidase (MAO) inhibitor,12 and other MAO inhibitors have been reported to stimulate insulin release.13 There are only two human studies on PMA, neither of which provides an explanation for serious toxic effects. Sustained blood pressure elevation of up to 240/130 mmHg occurred in some people taking PMA at a dose of 1 mg/kg bodyweight,4 and PMA was found to be three times as potent as the amphetamine derivative MDA as a hallucinogen.14 Our retrospective study design makes direct comparison between PMA and MDMA impossible. As urine drug screens were not routinely performed in presentations involving stimulant use, it is impossible to determine the exact frequency of PMA and MDMA poisonings presenting over the study period, or to identify a large enough cohort of people poisoned with MDMA alone to serve as a control group. Coadministration of other drugs and inconsistencies in casenote reporting are further factors which would have confounded the comparison of PMA and MDMA poisonings. However, the coronial data and the unique toxicological features of the known PMA poisonings we identified are sufficient to demonstrate that PMA accounts for most severe adverse events after apparent ecstasy ingestion in Adelaide. As PMA does not account for the majority of ecstasy use, this implies that PMA is substantially more toxic than MDMA. The serious acute toxic effects of MDMA are generally related to hyperthermia, which results from a combination of temperature deregulation, excessive physical activity and high ambient temperatures.3 This knowledge has led to moderately successful public health and education programs to highlight these dangers and encourage users of MDMA at "rave" parties to ensure adequate hydration and to take breaks to cool down. However, much of the serious toxicity we describe with PMA, such as sudden collapse and seizures, may not be amenable to such harm-minimisation approaches. Although the actual doses ingested by our patients are not known, only one person reported taking more than two tablets and none were deliberate overdoses. Estimates of dose are unreliable, not only because of the difficulty in obtaining a reliable history of illicit drug use, but also because of variations in tablet strength. However, analysis of recently confiscated ecstasy capsules and tablets shows similar mean concentrations of the active ingredient in those containing PMA (73 mg) and MDMA (106 mg) (P D Felgate, Forensic Science Centre, South Australia, personal communication). Thus, the apparent greater toxicity of PMA is unlikely to be explained by the dose received. Despite the poor reputation of PMA, its use remains a continuing health concern in Australia. Deaths from PMA use have been reported most frequently in Adelaide, but also in Queensland and Western Australia.2 PMA toxicity should be suspected in patients presenting with severe or atypical reactions to ecstasy and the diagnosis can be confirmed by chromatographic urine drug screens. Acknowledgements We thank Dr Christopher Angley, Staff Consultant, RAH, for assistance with database searching, and the South Australian Forensic Science Centre for figures on illicit stimulant deaths in South Australia. References Buchanan JF, Brown CR. "Designer drugs". A problem in clinical toxicology. Med Toxicol Adverse Drug Exp 1988; 3: 1-17. Felgate HE, Felgate PD, James RA, et al. Recent paramethoxyamphetamine deaths. J Analyt Toxicol 1998; 22: 169-172. Milroy CM. Ten years of "ecstasy". J R Soc Med 1999; 92: 68-71. Cimbura G. PMA deaths in Ontario. CMAJ 1974; 110: 1263-1267. Byard RW, Gilbert J, James R, Lokan RJ. Amphetamine derivative fatalities in South Australia -- is "Ecstasy" the culprit? Am J Forensic Med Pathol 1998; 19: 261-265. Byard RW, James RA, Gilbert JD, Felgate PD. Another PMA-related fatality in Adelaide. Med J Aust 1999; 170: 139-140. Green AR, Cross AJ, Goodwin GM. Review of the pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA or "Ecstasy"). Psychopharmacol 1995; 119: 247-260. McCann UD, Slate SO, Ricaurte GA. Adverse reactions with 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy"). Drug Safety 1996; 15: 107-115. Rochester JA, Kirchner JT. Ecstasy (3,4-methylenedioxymethamphetamine): history, neurochemistry, and toxicology. J Am Board Family Pract 1999; 12: 137-142. Steele TD, McCann UD, Ricaurte GA. 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"): pharmacology and toxicology in animals and humans. Addiction 1994; 89: 539-551. Henry JA, Jeffreys KJ, Dawling S. Toxicity and deaths from 3,4-methylenedioxymethamphetamine ("ecstasy"). Lancet 1992; 340: 384-387. Ask AL, Fagervall I, Ross SB. Selective inhibition of monoamine oxidase in monoaminergic neurons in the rat brain. Naunyn Schmiedebergs Arch Pharmacol 1983; 324: 79-87. Stockley IH. Drug interactions. 4th ed. London: The Pharmaceutical Press; 1996. Galloway G, Shulgin AT, Kornfeld H, Frederick SL. Amphetamine, not MDMA, is associated with intracranial hemorrhage. J Accident Emerg Med 1995; 12: 231-232. (Received 20 Sep 2000, accepted 15 Feb 2001) Authors' details Department of Clinical and Experimental Pharmacology, Faculty of Medicine, University of Adelaide, SA. Liang Han Ling, 5th Year Medical Student; Colin Marchant, 6th Year Medical Student; Nicholas A Buckley, FRACP, MD, Senior Consultant; Rod J Irvine, PhD, Research Fellow. Institute of Medical and Veterinary Science, Adelaide, SA. Michael Prior, BAppSc, FAIMS, Senior Scientist, Toxicology. Reprints will not be available from the authors. Correspondence: Dr N A Buckley, Department of Clinical and Experimental Pharmacology, Faculty of Medicine, University of Adelaide, SA 5000. nbuckleyATmail.rah.sa.gov.au Make a comment Demographic and clinical data for patients confirmed to have ingested paramethoxyamphetamine (PMA) compared with others who reported ingesting "ecstasy" PMA (n=22) "Ecstasy" (n=61) % Difference (95% CI) P* Median age (range) 23 (18-32) 22 (17-35) 0.1115 Males 15 (68%) 33 (54%) 14% (-10% to 38%) 0.3176 Cardiovascular effects Median pulse (range) 118 (52-218) 88 (46-160) 0.0156 No. (%) with: Pulse ≥100bpm QRS interval ≥100ms Arrhythmias 14 (64%) 11 (50%) 5 (23%) 25 (41%) 3 (5%) 3 (5%) 23% (-1% to 46%) 45% (23%-67%) 18% (-1% to 36%) 0.0842 0.0278 Metabolic effects Median temperature Range 37°C 32-42°C 36°C 32-38°C 0.1185 No. (%) with: Temperature >37.5°C Temperature >40.0°C 8 (36%) 4 (18%) 3 (5%) 0 31% (11%-52%) 18% (2%-34%) 0.0008 0.004 Neurological effects Median Glasgow coma score Range 12.5 3-15 15 4-15 0.0018 No. (%) with: Glasgow coma score Seizures 9 (41%) 7 (32%) 4 (7%) 2 (3%) 34% (13%-56%) 29% (9%-49%) 0.0005 0.001 No. (%) with life-threatening toxicity† 11 (50%) 4 (7%) 43% (22%-65%) *Fisher's exact test or Mann-Whitney U test. †Seizures, temperature >40°C or Glasgow coma score <6. 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Colin Marchant · Nicholas A Buckley · Michael Prior · Rod J Irvine

Christmas Offerings MJA 2000; 173: 662-663 Introduction The proprietary names of new drugs not only lack imagination but, via the mindless assemblage of concatenated consonants, resemble the loser's board in a last round of Scrabble. Disenfranchised consonants, particularly Xs, Zs and Qs, appear in drug names with as much logic as their appearance in a cup of alphabet soup (albeit my second favourite after soup de jour). While prescribing doctors require no scientific proof that there has been a secular change to idioglossia, I explore this proposition scientifically, using the proprietary names of two classes of psychotropic drugs. Methods The database for my study was the list of oral antipsychotic and antidepressant drugs in the 1998 MIMS Annual.1 The proprietary names for all currently listed "older" and "newer" (ie, pre- and post-1990) drugs were examined for the relative frequency of vowels and consonants. (See Box for names compared.) Results Quantitative analyses I surveyed a total of 33 psychotropic drug names, but was unable to demonstrate a difference between "old" and "new" drugs by the chi-squared test (chi-squared = 0.008; df = 1; NS). It was time for a post hoc ad hoc ergo propter hoc hypothesis, viz., that there had been an increase in specific letters, such as V, I and Z. The latter (ie letter) analysis predictably revealed shifts, with the most notable changes being -- for the consonants -- a distinct increase in the representation of Cs (from 2% of the letter distribution in the "old" drugs to 5% in the "new" drugs) and, even more distinctly, increases in Xs (from 0 to 7%) and Zs (from 1% to 6%). For the vowels, Is had decreased from 6% to 1%, while Os had increased from 6% to 13%. I undertook a validity check by making a comparison with the distribution of these letters in Scrabble, where Cs = 2%, Xs = 1%, Zs = 1%, Is = 9% and Os = 8%. Thus, the older drugs had a distribution of those letters in accord with our Scrabble control, while their current distribution was quite out of kilter and thus, QED, seriously discordant with the English language, the games we play, the rules of sport and the Olympic ideal. Qualitative analyses I read the lists to all hospital support staff cleaning the doctors' corridor in spring 2000, with each (n = 2) asked to assess each drug name for resonance, melodiousness, assonance and assiness. Against expectation, they unanimously rated the "newer" drugs far higher. Post hoc analysis determined, however, that both were non-English-speaking, but they did express thanks for trying to talk to them in their own language. I then undertook a second study involving all unit registrars who had expressed (at their appointment interview) a keen interest in undertaking research if offered a position. These 23 registrars were similarly required to rate each drug set on the evaluative parameters. All three respondents rated the older psychotropic drug names as more attractive, with one noting that it was not the price -- but the excess of Xs -- that prevented her prescribing the new atypical antipsychotics, so rejecting the "null" hypothesis that "nothing succeeds like XS". Discussion My study demonstrated an increased use of discordant consonants in proprietary names for two psychotropic drug classes. Z is climbing up the alphabet, but its appeal is questionable, as any parent knows who has asked their child to eat a zucchini. The only Z that ever had any style belonged to the graffiti artist Zorro. But Zs for drug names? Perhaps a hypnotic? Zizzzz, or even Zizzzzzzzzzzzzzz. X has risen from near x-tinction, C is coming in, and O is on the rise as a leavening vowel. Current analyses allow the confident prediction that "XOCZ" will be the proprietary name to be launched next. But do we want the alphabet-ordered also-rans (the Xs, Ys and Zs) to run? Why not capture the beauty of the English language? How truly evocative then are the names for the new "atypical antipsychotic" drugs -- Clopixol, Clozaril, Risperdal and Zyprexa, which my computer spell-check renders as Claypool, Closure, Dispersal and Pyrexia. Surely, they lack the majestic evocation of the older drug names. Again my spell-check assists us -- Largactil "reframed" as "LargeAction", Anatensol as "Intensely", Navane as "Nirvana", Stelazine as "Stabilize", Anafranil as "Unafraid", Endep as "Endow" and Surmontil as "Surmountable" provide a subliminal message of hope, action and therapeutic success, like the lovely and pleasing word "placebo". Are the "new drug names" not building to treatment resistance? What's in a name? In the old days, lots. The alcohol deterrent drug Antabuse evocatively told us a story. It was anti-abusers and self-abusing, belonged to the right (ie left) end of the dictionary in being close to AA (so assisting prescribing doctors), and was nicely balanced in its mix of vowels and consonants. A fine achievement for a drug that made you vomit. Another example is the hypnotic, Halcion. Only when there was no wind and the waters were quiet and tranquil could the albatross take off, the so-called "halcyon days". Thus was the prescriber encouraged to prescribe Halcion for tranquillity, for wind and for plane phobia. But now we have drugs like Xanax (presumably a computer-driven palindrome). What next? A drug labelled ZZQQZZ? You wouldn't even accept that as a number plate. The rumbelow conjunction of compounding consonants presents the medical profession with a number of deceptively important problems. First, the written equivalent of "Chinese whispers". A handwritten script for Zantac may emerge, after some pharmacist confusion, as one for Zactin, or Zestril, or Zarontin. Second, we are now ankle deep in xenoglossia -- being required to understand a language we have never learned. Third, where is the placebo effect in offering a patient a new wonder drug named "Prozolox"? Fourthly, where is the appeal? What respectable canine, after years of eating affiliative, affirmative and affectionately labelled "Pal", would take a chunk out of a tin labelled Zbra or Quale? What are the marketing and advertising sections of the pharmaceutical companies doing? We know that recognition and verbal learning relate to the pleasantness and association value of words,2 with such research empirically establishing the high appeal of words like "caress", "Christmas", "comfort", "delight", "flower", "kindness", "pleasure" and "sunshine". Presuming that those companies wish us to use their product, are their marketing divisions out to lunch on this issue? If so, and before they get back from lunch, should we in the medical profession not show some leadership? Perhaps to get the ball rolling, I could offer some suggestions for the next "Drugs R Us" company that appreciates gratuitous advice. A search for appealing words can take many roads. James Joyce held that "cuspidor" was the most beautiful word in the English language, but, despite his genius, his inability to call a spittoon a spittoon confirms that beauty is in the eye of the beholder. We need, then, an author "of the people", someone who could sit comfortably with the "man on the Clapham bus". Barbara Cartland! Dame Barbara once listed the 12 "most beautiful" words in the English language as ecstasy, love, God, divine, pure, innocent, rapture, moonlight, shimmering, radiance, magical and mysterious. What an evocative list, and not a Q, X or Z to be seen! But, returning to psychiatry, we need psychotropic drug names that invoke the domain and the suggested impact, increase compliance, have a placebo component and make us all feel good. Cartland provides a semantic base for a thesaurus search. For an antidepressant, recognising that others have stolen Cartland's suggestion of "ecstasy", why not "Cloud9" or "BlissPill"? For anti-manic drugs, why not "Glidedown" or "Asymptote", and perhaps "Astoic", "Flatline" or "Earthbound" for a mood stabiliser. For antipsychotics, if not "SangFroid" (which might be misconstrued as "Sane Freud"), why not "Equanimity", or "Anodine" or "Chillout"? For an anxiolytic, "C-Rene", "Care-less" or "Earthed", perhaps. Of course, such concerns also hold for other classes of drugs. One of the most successful drug releases in the past decade was that of Viagra. But, as a treatment for erectile dysfunction, it has quite the wrong connotation. Viagra rhymes with Niagara. As in Niagara Falls. An unfortunate choice. How about "PeckUp" (note the neat diffusion into "Pickup" -- suggesting both a tonic and the means of acquiring a partner for the night). It would have been a real sales winner if the naming had been more prescient. I rest my case. References MIMS Annual. Sydney: MIMS Australia, 1998. Silverstein A, Dienstbier RA. Rated pleasantness and association value of 101 English nouns. J Verbal Learning Verbal Behav 1968; 7: 81-86. Authors' details School of Psychiatry, University of New South Wales, Sydney, NSW. Gordon B Parker, Professor, and Head. Reprints will not be available from the author. Correspondence: Professor G B Parker, School of Psychiatry, Prince of Wales Hospital, High Street, Randwick, NSW 2031. g.parkerATunsw.edu.au We appreciate your comments. Psychotropic drug names compared Oral antipsychotic drugs: Old: Anatensol, Largactil, Melleril, Navane, Neulactil, Orap, Serenace, Sparine, Stelazine New: Clopixol, Clozaril, Risperdal, Zyprexa Oral antidepressant drugs: Old: Allegron, Anafranil, Deptran, Endep, Nardil, Parnate, Pertofran, Prothiaden, Surmontil, Tofranil, Tolvon, Tryptanol New: Aropax, Aurorix, Cipramil, Efexor, Luvox, Prozac, Serzone, Zoloft Return to text

Gordon B Parker

Research Recent trends in the use of antidepressant drugs in Australia, 1990-1998 Peter McManus, Andrea Mant, Philip B Mitchell William S Montgomery, John Marley and Merran E Auland MJA 2000; 173: 458-461 For editorial comment, see Parker Abstract - Introduction - Methods - Results - Discussion - Acknowlegdements - References - Authors' details - - - More articles on General practice and primary care Abstract Objective: To determine the pattern of use of antidepressant drugs in the Australian community, 1990-1998, and to compare this with those of other developed countries. Design: Retrospective analyses of prescription and sales data, together with information about patient encounters for depression (from an ongoing survey of service provision by general practitioners) and population-based prevalence estimates for affective disorders (from community health surveys). Main outcome measures: National and international consumption of antidepressants, expressed in defined daily doses (DDDs) per 1000 population per day. Changes in both the frequency of general practice patient encounters for depression and population-based prevalence estimates for affective disorders. Results: Dispensing of antidepressant prescriptions through community pharmacies in Australia increased from an estimated 12.4 DDDs/1000 population per day in 1990 (5.1 million prescriptions) to 35.7 DDDs/1000 population/day in 1998 (8.2 million prescriptions). There has been a rapid market uptake of the selective serotonin reuptake inhibitors (SSRIs), accompanied by a decrease of only 25% in the use of tricyclic antidepressants (TCAs). In 1998, the level of antidepressant use in Australia was similar to that of the United States, while the rate of increase in use between 1993 and 1998 was second only to that of Sweden. In Australia, depression has risen from the tenth most common problem managed in general practice in 1990-91 to the fourth in 1998-99, and the number of people reporting depression in the National Health Surveys (1995 v 1989-90) has almost doubled. Of the prescriptions dispensed in 1998 for antidepressant drugs subsidised by the Pharmaceutical Benefits Scheme, 85% were written by general practitioners, and 11.2% by psychiatrists. Conclusions: As in most developed countries, antidepressant use increased between 1990 and 1998. The rapid market uptake of the new antidepressants, particularly SSRIs, is likely to have been driven by increased awareness of depression, together with availability and promotion of new therapies. Introduction The World Health Organization report on the global burden of disease placed major depression fourth among the leading causes of disease burden in the developing world in 1990, and predicted that it would rise to second by the year 2020.1 In parallel with the increasing awareness of depression as an important health issue, the past decade has seen an increase in the pharmacotherapy options for managing depression with the arrival of several new classes of antidepressants. To review trends in antidepressant use in Australia, the Drug Utilisation Sub-Committee (DUSC) of the Pharmaceutical Benefits Advisory Committee, Department of Health and Aged Care, convened a working group in 1998. The working group, which comprised representatives from the DUSC and from the Australian Pharmaceutical Manufacturers Association (APMA), reviewed Australian and international data on antidepressant sales and dispensing. The aim was to determine patterns of antidepressant use in Australia between 1990 and 1998 and to compare Australian patterns with those in similar developed countries. To assist in interpretation of Australian drug use trends, the group reviewed changes in both the frequency of general practice patient encounters for depression and in population-based prevalence estimates for affective disorders. Methods Prescription and sales data Prescription dispensing data were obtained from the database maintained by the DUSC that monitors the dispensing of prescription medicines through community pharmacies in Australia.2 No data on public hospital use are included in this database. The measurement units used are either prescription volumes or the number of defined daily doses (DDDs) per 1000 population per day. The DDD is based on the assumed average daily dose of the drug when used for its main indication by adults. It is the unit approved by the World Health Organization (WHO) for drug use studies, and allows for comparisons independent of differences in price, preparation and quantity per prescription.3 Within the data on dispensing of antidepressant drugs subsidised by the Pharmaceutical Benefits Scheme (PBS), it is also possible to determine the major specialty of the prescribing doctor. Data on total sales of antidepressants from wholesalers to retail and hospital pharmacies for all countries, except Sweden, were obtained from IMS Health Incorporated. IMS Health is the leading international provider of information on drug usage to the pharmaceutical and healthcare industries.4 Data were retrieved as kilograms of active ingredient and then converted to DDDs per 1000 population per day. Excluded were the use of lithium, Hypericum (St John's wort) or tryptophan, and combinations involving these drugs or their active constituents. Utilisation data for Sweden, where separate local arrangements apply, were supplied by the Swedish Association of the Pharmaceutical Industry (LIF). The 1999 WHO defined daily doses (DDDs) were used in calculations. Drugs unique to particular markets that did not have DDDs available were provisionally assigned values using standard references and information provided by drug information centres in the countries involved.5 Prescriber surveys Information related to general practice patient encounters for depression was obtained from the General Practice Statistics and Classification Unit of the Family Medicine Research Centre (FMRC), University of Sydney, which is conducting an ongoing survey of service provision by general practitioners (GPs).6 This involves 1000 randomly selected, active, recognised GPs per year, each recording details of 100 consecutive consultations on structured encounter forms. Rolling recruitment ensures that the recording weeks are distributed evenly over the year and that there is constant change in participants. These data can be compared with the findings of an earlier FMRC study of morbidity and treatment in general practice that used simpler but compatible methods.7 Information on prescribing by specialists is not included in these GP surveys. Community health surveys The 1995 National Health Survey was a household survey conducted by the Australian Bureau of Statistics to obtain national benchmark information on a range of health-related issues and to enable the monitoring of trends in health over time.8 A previous health survey, collecting broadly comparable data, was conducted in 1989-90.9The 1997 National Survey of Mental Health and Wellbeing of Adults was also conducted by the Australian Bureau of Statistics and used a representative sample of people aged 18 years or over living in private dwellings.10 The survey was interview-based with a diagnostic component administered through a modified version of the WHO Composite International Diagnostic Interview (CIDI). The CIDI translates the criteria of the Diagnostic and statistical manual of mental disorders, 4th edition (DSM-IV),11 and the International classification of diseases, 10th edition (ICD-10),12 into sets of questions that can be readily answered by the general adult population. Specific combinations of symptoms may indicate a specific mental disorder. Results Antidepressant use in Australia The dispensing of prescriptions for antidepressants through community pharmacies in Australia increased from an estimated 12.4 DDDs/1000 population per day in 1990 (5.1 million prescriptions) to 35.7 DDDs/1000 population per day in 1998 (8.2 million prescriptions). Trends in the use of the selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), moclobemide, venlafaxine and nefazodone between 1990 and 1998 are shown in Box 1. The market uptake of the SSRIs has been rapid and accompanied by a decrease of only 25% in the use of the TCAs. Other new agents included moclobemide (a reversible monoamine oxidase type A inhibitor), nefazodone (a 5-HT2 antagonist) and venlafaxine (a serotonin-noradrenaline reuptake inhibitor). The 10 most commonly dispensed antidepressants in Australia in 1998 were, in descending order, sertraline, dothiepin, paroxetine, amitriptyline, fluoxetine, doxepin, moclobemide, imipramine, venlafaxine and citalopram. Of these, only the four tricyclic antidepressants were on the market in 1990, with dothiepin alone maintaining or improving its position over this period. Of the PBS-subsidised prescriptions dispensed for antidepressants in 1998, 85% were written by GPs, while 11.2% were written by psychiatrists. International comparisons We compared retail and hospital sales of antidepressants in Australia and seven major developed countries for the years 1993 and 1998 (Box 2). In 1998, sales of antidepressants in Australia (34.2 DDDs/1000 population per day) were similar to those of the United States (34.2 DDDs/1000 population per day), less than in Sweden (37.1 DDDs/1000 population per day) and France (36 DDDs/1000 population per day) and higher than in Canada (30.8 DDDs/1000 population per day) and the United Kingdom (30.4 DDDs/1000 population per day). Germany and Italy had considerably lower usage levels (12 and 9.9 DDDs/1000 population per day, respectively). The rate of increase in Australia between 1993 and 1998 was second only to that of Sweden. For these same countries in 1998, Box 3 shows the percentage split (based on DDDs/1000 population per day) of the antidepressant market by drug class. There was considerable variability in the percentage that TCAs represented of overall antidepressant use, from a low level of 11% in Sweden through to a high of 67% in Germany. Australia, Canada and France had a similar profile, with TCAs representing about 20% of antidepressant use. Venlafaxine was marketed in all eight of the countries surveyed and ranged between 1.5% and 5.2% of the total use. Mianserin had a low level of use in most countries, except for France and Italy, where it represented about 4% of antidepressant use. It was not available in North America. Similarly, moclobemide had a low level of use in most countries, except in Australia, where it represented 12% of the antidepressant market. Prescriber surveys Surveys conducted in 1990-91 and 1998-99 by the Family Medicine Research Centre have shown the increasing prominence of depression as a problem managed in general practice.6,7 In 1998-99, depression ranked as the fourth most common general practice problem, compared with the tenth in 1990-91. The rate of patient encounters involving depression per 100 encounters has increased from 2.1 in 1990-91 to 3.5 in 1998-99. In 1998-99, compared with 1990-91, antidepressants were more likely to be prescribed per every 100 encounters for depression (58.4 prescriptions [95% CI, 56.1-60.8] v 52.3 prescriptions [95% CI, 49.2-55.5]). Comparisons with age and sex demographics for total general practice encounters (women, 58.7%) suggest that female patients were over-represented at encounters for depression. The most frequent patient age group in encounters at which a tricyclic antidepressant was prescribed was 45-64 years (38%), whereas for encounters at which SSRIs were prescribed it was 25-44 years (43%). Sex distribution was similar for both drug groups, with about a third of the patients being men. Depression was the most common problem for which TCAs and SSRIs were prescribed in 1998-99, although the proportion of TCAs prescribed for depression (48.8% [95% CI, 44.3%-53.3%]) was lower than that of SSRIs (81.9% [95% CI, 79.7%- 84.1%]). Other specific problems managed with TCAs were sleep disturbance (7%), anxiety (5%) and back complaints (4.5%). For the SSRIs, these were anxiety (5.8%) and phobia/compulsive disorder (1.7%). When used for depressive disorders, TCAs had a prescribed daily dose consistently lower than the WHO DDD. The prescribed daily doses and DDDs for the most commonly dispensed TCAs were amitriptyline (mean, 59 mg; median, 50 mg; DDD, 75 mg), doxepin (mean, 61 mg; median, 50 mg; DDD, 100 mg) and dothiepin (mean, 85 mg; median, 75 mg; DDD, 150 mg). The prescribed daily doses for the most commonly dispensed SSRIs were much closer to the DDD: fluoxetine (mean, 24 mg; median, 20 mg; DDD, 20 mg), paroxetine (mean, 23 mg; median, 20 mg; DDD, 20 mg) and sertraline (mean, 72 mg; median, 50 mg; DDD, 50 mg). Community health surveys The 1997 National Mental Health and Wellbeing Profile of Adults identified a 5.8% prevalence of affective disorders (depression, 5.1%; dysthymia, 1.1%) during the 12 months before the survey among people aged 18 years or over.10 Women were more likely than men to have experienced affective disorders (7.4% compared with 4.2%). Although based on self-reports, household surveys conducted by the Australian Bureau of Statistics in 1989-90 and 1995 identified marked changes in the number of people reporting current or previous depression. In the 1995 National Health Survey, 8.1 persons per 1000 population reported depression as a long term condition, compared with 2.8 persons per 1000 in the 1989-90 survey. For depression as a recent illness, 11.4 per 1000 population reported this in 1995, compared with 5.8 per 1000 in 1989-90.8,9 Discussion The past decade has seen a remarkable change in the number of people recognised with and managed for depression, in the range of drug therapy options available, and in the volume of antidepressants prescribed. Previously, depression had been reported as under-recognised and undertreated.13-15Prominent among the likely reasons for this change are increased community awareness of depression as an important health issue, and attempts, most notably through government and community campaigns, to reduce the stigma of mental illness and the gaps in professional expertise inhibiting adequate recognition and treatment of depression.16,17 Coincident with these campaigns, important treatment recommendations were released in the United Kingdom in 1992 (the Royal College of General Practitioners and the Royal College of Psychiatrists) and, in the United States, in 1993 (Agency for Health Care Policy and Research).13,18 In Australia, the Psychotropic drug guidelines19 are the endorsed national standard, and the National Health and Medical Research Council has published clinical practice guidelines for managing depression in young people.20,21 The 1995 Australian National Health Survey showed that the number of people reporting depression as a recent and/or long term condition had nearly doubled compared with the earlier survey conducted in 1989-90. Such a change in the true underlying prevalence of disease is unlikely over a relatively short period of time, and the increase is far more likely to reflect a greater awareness of depression, with patients being more comfortable about coming forward for help and doctors, particularly in general practice, being more willing to provide it. This increased awareness of depression by doctors and patients, together with the availability and promotion of new drug therapy options (between 1990 and 1998, five SSRIs have been approved for PBS subsidy together with moclobemide, venlafaxine and nefazodone), accounts for the rise from the tenth to the fourth most common problem managed in general practice between 1990-91 and 1998-99. In 1998-99, encounters for depression were also more likely to generate a prescription for an antidepressant. This change is reflected in drug utilisation statistics. The market uptake of the SSRIs has been rapid and, remarkably, accompanied by only a relatively small decrease in the use of the TCAs. As a result, the overall antidepressant market has expanded greatly, with utilisation (as defined by DDDs/1000 population per day) being nearly three times greater in 1998 than in 1990. Prescription rates, however, have risen only 60% over that time, as the newer antidepressants are more likely to be dosed closer to the DDD than the older tricyclic antidepressants. TCAs are prescribed for sleep disturbance in a small proportion (7%) of patients, which is not the case for SSRIs. Most developed countries have seen similar trends, with sales in Australia consistent with US sales and slightly higher than those in the UK. The percentage that the SSRIs represented of total antidepressant use in Australia in 1998 was similar to that in the United Kingdom. The considerably lower levels of antidepressant use in Germany are probably related to Germany's strong tradition of use of complementary medicines (substantial use of Hypericum preparations [St John's wort] were not included in the comparisons); and the lower levels in Italy may be because, in 1994-98, SSRIs were not reimbursed by the national health system in Italy, but were fully paid for by the patient (Dr Alberto Vaccheri, Associate Professor, Department of Pharmacology, University of Bologna, personal communication, June 1999). Although there are interesting differences between countries, the rapid uptake of the new antidepressants is likely to have been driven by increased awareness, together with the availability and promotion of new therapies. The drug utilisation patterns, supported by evidence from population and general practice surveys, showed that there has been growth in the actual market rather than just redistribution within the market. Public health benefits of this major change in drug use (eg, reductions in suicide rates) are anticipated in the long term, but measuring population-level outcomes from changes will not be easy. Acknowledgements Other members of the Antidepressants Working Group who helped prepare these data were the Australian Pharmaceutical Manufacturers Association and the pharmaceutical industry (Susan Alexander, Mark Bradley, Michelle Burke, Liz Campbell, Victoria Croker, Marnie Firipis, Deborah Monk, Michael Ortiz, Ruth Stokes, Nick Williams). Drug Utilisation Sub-Committee secretariat (John Dudley). General Practice Statistics and Classification Unit, Family Medicine Research Centre, University of Sydney (Helena Britt and Geoff Sayer, who conducted the analyses of the depression data from BEACH). Disclosure: Philip B Mitchell has been a member of scientific advisory boards for Eli Lilly, SmithKline Beecham and Wyeth. References Murray CJ, Lopez AD. The global burden of disease: summary. Cambridge, Mass: Harvard School of Public Health, Harvard University Press (on behalf of the World Health Organization and the World Bank), 1996. Edmonds DJ, Dumbrell DM, Primrose JG, et al. Development of an Australian drug utilisation database: a report from the Drug Utilization Sub-Committee of the Pharmaceutical Benefits Advisory Committee. PharmacoEconom 1993; 3: 427-432. World Health Organization Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC classification and DDD assignment. 2nd edition. Oslo, Norway: WHO, 1998. Hurley SF, McNeil JJ, Berbatis CG. Sources of Australian pharmacoepidemiology data. Commun Health Stud 1988; 12(1): 82-96. World Health Organization Collaborating Centre for Drug Statistics Methodology. ATC Index with DDDs, 1999. Oslo, Norway: WHO, 1998. Britt H, Sayer GP, Miller GC, et al. BEACH (Bettering the Evaluation And Care of Health): a study of general practice activity, six-month interim report. AIHW Catalogue No. GEP 1. Canberra: Australian Institute of Health and Welfare (General Practice series no.1). Bridges-Webb C, Britt H, Miles D, et al. Morbidity and treatment in general practice in Australia 1990-1991 [Errata in Med J Aust 1993; 158: 72, 652]. Med J Aust 1992; 157 (Suppl Oct 19): S1-S56. Australian Bureau of Statistics. 1995 National Health Survey: use of medications, Australia. Canberra: ABS, 1995. (Catalogue No. 4377.0.) Australian Bureau of Statistics. 1989-90 National Health Survey: summary of results, Australia. Canberra: ABS, 1991. (Catalogue No. 4364.0.) Australian Bureau of Statistics. 1997 Mental Health and Wellbeing: profile of adults. Canberra: ABS, 1997. (Catalogue No. 4326.0.) American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th edition (DSM-IV). Washington, DC: APA, 1994. World Health Organization. International classification of diseases, 10th edition (ICD-10). Geneva: World Health Organization, 1993. Paykel ES, Priest RG. Recognition and management of depression in general practice: a consensus statement. BMJ 1992; 305: 1198-1202. Hirschfeld RMA, Keller MB, Pamico S, et al. The National Depressive and Manic-Depressive Association consensus statement on the undertreatment of depression. JAMA 1997; 277: 333-340. Kendrick T. Prescribing antidepressants in general practice: watchful waiting for minor depression, full dose treatment for major depression. BMJ 1996; 313: 829-830. Paykel ES, Tylee A, Wright A, et al. The Defeat Depression Campaign: psychiatry in the public arena. Am J Psychiatry 1997; 154 (6 Suppl): 59-65. The National Mental Health Strategy. Community Awareness Program: a review. Canberra: Commonwealth Department of Health and Aged Care, November 1998. US Department of Health and Human Services. Agency for Health Care Policy and Research (AHCPR). Depression in primary care: Vol 11. Treatment of major depression. Rockville, Md: AHCPR, 1993. Psychotropic drug guidelines. 4th edition. Melbourne: Therapeutic Guidelines, 2000. National Health and Medical Research Council. Depression in young people. A guide for general practitioners. Canberra: NHMRC, 1997. National Health and Medical Research Council. Depression in young people. A guide for mental health professionals. Canberra: NHMRC, 1997. (Received 5 May, accepted 31 Aug, 2000) Authors' details Drug Utilisation Sub-Committee, Department of Health and Aged Care, Canberra, ACT. Peter McManus, MMedSc, BPharm, Secretary. South Eastern Sydney Area Health Service, Sydney, NSW. Andrea Mant, MD, FRACGP, MA, Area Adviser, Quality Use of Medicines; and Associate Professor, School of Community Medicine, University of New South Wales, Sydney, NSW. School of Psychiatry, University of New South Wales, NSW. Philip B Mitchell, MD, FRANZCP, FRCPsych, Professor; and Administrative Director, Mood Disorders Unit, Prince of Wales Hospital, Sydney, NSW. Health Economics and Outcomes Research, Eli Lilly Australia Pty Ltd, Sydney, NSW. William S Montgomery, BPharm, DipHospPharm, GradCertHealthEcon, Health Outcomes Research Manager. Department of General Practice, University of Adelaide, Adelaide, SA. John Marley, MD, MB ChB, Professor. Health Economics and Pricing Department, SmithKline Beecham (Australia) Pty Ltd, Melbourne, VIC. Merran E Auland, PhD, Health Economist. No reprints will be avaliable from the authors. Correspondence: Mr P McManus, Secretary, Drug Utilisation Sub-Committee, Mail Drop Point 83, Department of Health and Aged Care, GPO Box 9848, Canberra, ACT 2601. peter.mcmanusAThealth.gov.au Make a comment Back to text Back to text Percentage split of antideprssant sales (based on defined daily doses per 1000 population per day) by drug class in 1998 (data for all countries, except Sweden, from IMS Health; Swedish data from the Swedish Association of the Pharmaceutical Industry). SSRI = selective serotonin reuptake inhibitor. TCA = tricyclic antidepressant. Back to text

Peter McManus · Andrea Mant · Philip B Mitchell · William S Montgomery · John Marley · Merran E Auland

Medicine and the community Anabolic-androgenic steroids: medical assessment of present, past and potential users Anthony J O'Sullivan, Michael C Kennedy, John H Casey Richard O Day, Brian Corrigan and Alex D Wodak MJA 2000; 173: 323-327 Abstract - Methods - Results - Discussion - Acknowedgements - References - Authors' details - - More articles on Drugs and alcohol Abstract Objective: To document adverse effects of anabolic-androgenic steroid (AAS) use in community-based users attending a medical clinic. Design and setting: Prospective recruitment, questionnaire-based interview, physical examination and investigations, with follow-up, of people who attended, anonymously, an inner-city hospital clinic established specifically to examine AAS use. Participants: 58 men, comprising 27 past AAS users, 14 present users and 17 potential users (who formed the control group). Main outcome measure: Clinical adverse effects and abnormal laboratory findings. Results: Cyclical use of oral and intramuscular, human and veterinary AASs were reported. The most commonly reported source of AASs was friends (59%), gymnasiums (25%) and doctors (14%). The most common reported adverse effects were alterations in libido (61%), changes in mood (48%), reduced testis volume (46%) and acne (43%). Although mean systolic and diastolic blood pressure was not significantly different between groups, five present (29%), 10 past (37%) and one potential user (8%) were hypertensive. Gynaecomastia was found in 10 past users (37%; P < 0.01 v. potential users), two present users (12%) and no potential users. Mean testis volume was significantly smaller in present users (18 mL; P < 0.02) than in the other groups. Twenty past users (83%), eight present users (62%) and five potential users (71%) had abnormal liver function test results (P = 0.5). After discussion of test results, only 11 participants (19%) reported they would not use AASs in the future. Conclusions: Adverse effects were reported by or detected in most of the AAS users who attended the clinic. Despite awareness of adverse consequences, most participants planned future use of AASs. The actions of testosterone are generally divided into androgenic (virilising) and anabolic (tissue building).1 Synthetic derivatives of testosterone, androgenic-anabolic steroids (AASs) were synthesised to improve oral absorption,2 and to dissociate the anabolic and androgenic actions;3 however, AASs bind to the one receptor.4AASs increase muscle size and probably strength,5,6 and athletes believe that they can enhance performance.7,8 Performance enhancement is presumed by sporting bodies in their banning of these substances to ensure fair competition;9 performance enhancement is also supported by "underground" anabolic steroid guides and the media.10 Widespread and much-publicised AAS use continues at all levels of sport,5 having spread from elite athletes to recreational bodybuilders, adolescents and amateur athletes.11 AAS use has been reported by 0.9%-7.6% of school-age males in the United States,11-12 and 3.2% in young Australians.13 In the United States, 0.9% of adult males and 0.1% of females have reported AAS use;14 the prevalence in the Australian general population is not known. There is a very high reported prevalence (38%-58%) in particular subgroups worldwide, such as bodybuilders and weightlifters.15 Despite widespread AAS use, documentation of adverse effects in community users is usually based on questionnaires16 and case studies.2 Clinical studies in which AASs are prescribed generally report a low rate of adverse effects.6,17 This is a difficult area of research because the illicit status of AAS use impedes data collection. Further, those who use AASs to enhance their sporting performance should be compared with groups with similar dietary and exercise patterns rather than with population norms. Thus, we established a medical clinic which people taking AASs or considering taking them in the future could attend anonymously to undergo a medical assessment and laboratory investigations to provide data on adverse effects. Methods The AAS clinic was conducted from 1 September 1994 to 31 August 1997 in the Department of Alcohol and Drug Services, St Vincent's Hospital, Sydney. Participants were recruited from the general population by advertisements in local newspapers, posters in local gymnasiums, and a New South Wales Health Department newsletter. Names were not recorded; a code number was given to each participant to protect anonymity. Each participant attended initial (90 minutes) and follow-up (30 minutes) consultations conducted by one practitioner (A O'S). A questionnaire was used to ask a series of open questions about medical history and history of AAS use. Participants underwent physical examination and investigations, including an electrocardiogram and blood tests. All results were discussed and follow-up of abnormal results was encouraged. Adverse effects of AAS use and the risks of parenteral drug use were discussed. AASs were not prescribed, nor was their use supported. Participants were encouraged to enquire about adverse effects and information provided was based on published clinical research. Participants were divided into three groups: past users were those who had ceased AAS use at least three weeks before being seen; present users, those who had used AASs within the past seven days; and potential users, those who reported they had never used AASs. The potential users (who formed our control group for the clinical, biochemical and hormonal parameters) were not asked questions about adverse effects of AASs. Statistical analysis involved analysis of variance (ANOVA) for continuous variables, and all three groups were compared individually. For proportions, the χ2 test was used. Results Fifty-eight participants, all male, attended -- 27 past users, 14 present users and 17 potential users. One past and two potential users returned during the study period, having begun to use AASs. Thus, 17 participants were regarded as present users in the statistical analyses (Box 1). The age range for the 58 participants was 16-36 years. Forty-five participants (24 past, 13 present and 8 potential users) consented to blood tests. Thirteen participants reported male-to-male sexual activity. Androgenic-anabolic steroid use Cyclical AAS use, for between six weeks and six months, was reported by all past and present users. The number of cycles ranged from one to nine. Oral and intramuscular human and veterinary AASs were used (see Box 2), either individually or in combination. Dosage was usually increased for the first half of the cycle, maintained, then tapered off. The most common reason for AAS use was to increase bulk (muscle mass), followed by increased strength and definition. Seven participants reported taking tamoxifen to treat or prevent gynaecomastia, and the use of clenbuterol, thyroxine, human chorionic gonadotropin, growth hormone and diuretics was also reported. Six of the past or present users (14%) reported obtaining AASs through a medical practitioner, 11 (25%) through a gymnasium, and 26 (59%) through friends. The average daily expenditure on AASs was $5.10 (range, $1-$21). After discussion of the adverse effects of AASs and of any abnormal findings, 30 participants (10 past, 13 present, 7 potential users) planned future AAS use, 11 (8 past, 0 present and 3 potential users) decided against further use and 17 (6 past, 4 present and 7 potential users) participants were undecided. Adverse effects of androgenic- anabolic steroid use Box 3 shows the adverse effects described by participants. Twenty-five participants reported mood changes during AAS use (Box 3). Although four reported feelings of increased well being, and one, feelings of increased self-confidence, 14 reported aggression, paranoia or anxiety and four reported depression (some who reported mood changes could not qualify their feelings). Among past and present users, 16 participants reported increased libido, six decreased libido, and five noticed increased and reduced libido in the same cycle. Nine participants reported erectile dysfunction towards the end of a cycle or after ceasing AAS use. Mean testis volume was reduced and gonadotropins suppressed in the present users compared with the other groups and with population norms (Boxes 1 and 4). Gynaecomastia (usually tender) was detected in two present and 10 past users (P < 0.01 v. potential users), and varied from 5 mm to 50 mm in diameter. Six participants were referred for surgical review, five proceeding to bilateral excision. One past user had previously had surgery for gynaecomastia. Nineteen participants reported acne, usually involving the face and back, during AAS use. We detected no significant difference in mean systolic and diastolic blood pressures (Box 1). Ten past users (37.0%; P = 0.02 v. potential users), five present users (29.4%) and one potential user (8.3%) were hypertensive (systolic pressure > 140 mmHg or diastolic pressure > 90 mmHg). Electrocardiograms (reported by M C K, who was blinded to AAS use) showed no evidence of myocardial ischaemia or previous myocardial infarction. No participants had signs of chronic liver disease. Twenty participants declined serological testing for hepatitis B and C (10 past, 1 present and 9 potential users). Three present users and one potential user reported positive tests for hepatitis B, of whom one present and one potential user also reported positive tests for hepatitis C (excluded from the liver function analysis). No new cases of hepatitis B or C were detected among the 38 participants tested. There were no significant differences in the mean values of liver function tests in the three groups (Box 4). Twenty past (83.3%), eight present (61.5%) and five potential users (71.4%) had one or more abnormal liver function test results (P = 0.5). Creatine kinase levels were not significantly different between groups, but the increased values reflect increased muscle bulk and recent exercise. Thirty-two of the 44 participants who consented to blood tests consented to HIV antibody testing; all results were negative. Of the 12 participants who declined HIV testing, seven gave no specific reason, and five reported a recent negative HIV antibody test. Discussion Our findings show that some people who use or plan to use AASs will attend a medical clinic, thereby enabling documentation of patterns of AAS use and adverse effects. Nonetheless, the rate of attendance was low and does not reflect the prevalence of AAS use. Attendance may have been limited by insufficient awareness of the clinic's existence, AAS use not being supported or prescribed, and the clinic being located in an inner-city hospital. Our participants were self-selected, and may not be representative of AAS users in general. The higher than expected prevalence of male-to-male sexual activity may have resulted from the clinic being located in an area with a large gay population. The reported cyclical use of AASs was similar to patterns of use reported in the US1,4 and detailed in unofficial steroid books.10 We found that use of parenteral and oral, veterinary and human preparations was reported; reports from Sydney,16 Belgium,15 and the US20 all describe similar patterns. AASs suppressed the hypothalamic-pituitary-gonadal axis, producing reversible suppression of gonadotropins and a reversible reduction in testis volume similar to that observed with androgens used for contraception.21 AAS use caused changes in libido, with decreased libido towards the end of a cycle or soon after cessation, presumably reflecting transient hypogonadism. Some participants reported erectile dysfunction, but psychological factors may have contributed. Our finding of gynaecomastia in 12 participants (21%) was similar to proportions reported in some other studies (24%-31%;20 34%16). However, a proportion of 47% has been reported with chronic high-dose AAS use,22 and low prevalence (2%) has also been reported.17 Six of our participants were sufficiently worried about the cosmetic appearance to seek treatment, which involved surgical excision in five. Users took tamoxifen in combination with AASs in an attempt to resolve or prevent gynaecomastia.17,23 One study reported resolution of gynaecomastia in three participants with tamoxifen.17 Time constraints precluded our attempting detailed psychological assessments. However, mood changes were reported in 48% of participants during AAS use, findings consistent with other reports.16 The psychological effects of AASs may represent an important public health problem.20,24 One study of 41 AAS users reported that major psychiatric symptoms were common (44%),25 while another reported no significant psychological side effects in AAS users taking moderate doses.26 However, the dose and pattern of illicit AAS use differs from AAS use in a controlled clinical environment. On balance, it appears that these medications can have major psychological effects in some users which may be related to their prior psychological state.20,24,26 Although mean blood pressure was not different between groups, we found that approximately a third of past and present users were hypertensive. The failure of blood pressure to return to normal after cessation of AAS use may relate to longer-term effects on vascular function.27 Slight elevations in blood pressure have been reported previously following AAS use,28 while other studies have reported no change in blood pressure.27 Acute vascular events, including myocardial infarction and intracerebral haemorrhage, as well as cardiac arrhythmias, have been reported following AAS use.27,29 The effects of AASs on cardiac function are discussed in a recent comprehensive review.27 Abnormal results in liver function tests with AAS use have been reported previously,2,4 although one study using weekly 600 mg intramuscular testosterone injections showed no change in liver function test results.6 Severe cholestasis, peliosis hepatis (blood-filled cysts in the liver4) and primary hepatocellular carcinoma have been reported after AAS use.2 It is possible that hepatic damage may not manifest as elevated liver enzyme levels and that other means of hepatic assessment may be required. Although all results and potential adverse effects were discussed with participants, only 11 were confident they would not start or recommence AAS use. Reasons for continuing to use AASs despite the presence and knowledge of risks are unknown, but may relate to self-esteem, body-image dissatisfaction,30 or even opiate-like dependence.31 Compared with a control group, we found adverse effects on blood pressure and the development of gynaecomastia in AAS users, while results of liver function tests were not significantly different. Adverse effects may have been over-represented in our sample as participants may have presented because of symptoms. Long-term adverse effects may not have been identified in this study. More detailed investigations of AAS use on hypothalamic, hepatic, prostatic and cardiac function are required. How best to approach the public health problem of AAS misuse is yet to be determined. Information about AASs should be made readily available to educate the general public and medical practitioners.32 Data obtained should aid further policy decision-making into methods of reducing AAS use. Further research into the reasons why people self-administer AASs, and into methods of reducing AAS use in the community, is required. Acknowledgements The Androgenic-Anabolic Steroids Clinic was supported by a grant from the New South Wales Health Department. We would like to thank Sterling McCorby for help in establishing the Clinic, and SydPath, St Vincent's Hospital, for performing the laboratory investigations. References Yesalis CE, Bahrke MS. Anabolic-androgenic steroids. Sports Med 1995; 19: 326-340. Kennedy MC. Anabolic steroid abuse and toxicology. Aust N Z J Med 1992; 22: 374-381. Kashkin KB. Anabolic steroids. In: Lowinson JH, Ruiz P, Millman RB, Langrod JG, editors. Substance abuse: a comprehensive textbook. 2nd ed. Baltimore: Williams and Wilkins, 1992. Wilson JD. Androgen abuse by athletes. Endocr Rev 1988; 9: 181-199. Kennedy MC, O'Sullivan AJ. Do anabolic-androgenic steroids enhance sporting performance? Med J Aust 1997; 166: 60-61. Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 1996; 335: 1-7. Bagatell CJ, Bremner WJ. Androgens in men -- uses and abuses. N Engl J Med 1996; 334: 707-714. Wade N. Anabolic steroids: doctors denounce them, but athletes aren't listening. Science 1972; 176: 1399-1403. Skolnick AA. Tougher drug tests for Centennial Olympic Games. JAMA 1996; 275: 348-349. Grunding P, Bachmann M. World anabolic review 1996. Houston, TX: MB Muscle Books, 1995. Buckley WE, Yesalis CE, Friedl KE, et al. Estimated prevalence of anabolic steroid use among male high school seniors. JAMA 1988; 260: 3441-3445. Komoroski EM, Rickert VI. Adolescent body image and attitudes to anabolic steroid use. Am J Dis Child 1992; 146: 823-828. Handelsman DJ, Gupta L. Prevalence and risk factors for anabolic-androgenic steroid abuse in Australian high school students. Int J Androl 1997; 20: 159-164. Yesalis CE, Kennedy NJ, Kopstein AN, Bahrke MS. Anabolic-androgenic steroid use in the United States. JAMA 1993; 270: 1217-1221. Delbeke FT, Desmet N, Debackere M. The abuse of doping agents in competing body builders in Flanders (1988-1993). Int J Sports Med 1995; 16: 66-70. Copeland J, Peters R, Dillon P. A study of 100 anabolic-androgenic steroid users. Med J Aust 1998; 168: 311-312. Millar AP. Licit steroid use -- hope for the future. Br J Sports Med 1994; 28: 79-83. Australian Bureau of Statistics and Commonwealth Department of Health and Aged Care. National Nutrition Survey: Nutrient intakes and physical measurements, Australia 1995. Canberra: ABS, 1998. Baker HWG. Male infertility. In: DeGroot LJ, editor. Endocrinology. 3rd ed. Philadelphia: WB Saunders, 1995: 2409. Pope HG, Katz DL. Psychiatric and medical effects of anabolic-androgenic steroid use. Arch Gen Psychiatry 1994; 51: 375-382. Schurmeyer T, Knuth UA, Belkien L, Nieschlag E. Reversible azoospermia induced by the anabolic steroid 19-nortestosterone. Lancet 1984; 1: 417-420. Jin B, Turner L, Walters WAW, Handelsman DJ. Androgen or estrogen effects on human prostate. J Clin Endocrinol Metab 1996; 81: 4290-4295. Spano F, Ryan WG. Tamoxifen for gynaecomastia induced by anabolic steroids. N Engl J Med 1984; 311: 861-862. Corrigan B. Anabolic steroids and the mind. Med J Aust 1996; 165: 222-226. Pope HG, Katz DL. Affective and psychotic symptoms associated with anabolic steroid use. Am J Psychiatry 1988; 145: 487-490. Tricker R, Casaburi R, Storer TW, et al. The effects of supraphysiologic doses of testosterone on angry behaviour in healthy eugonadal men -- a clinical research study. J Clin Endocrinol Metab 1996; 81: 3754-3758. Sullivan ML, Martinez CM, Gennis P, Gallagher EJ. The cardiac toxicity of anabolic steroids. Prog Cardiovasc Dis 1998; 41: 1-15. Bretza JA, Novey HS, Vaziri ND, Warner AS. Hypertension. A complication of danazol therapy. Arch Intern Med 1980; 140: 1379-1380. Kennedy MC, Corrigan AB, Pilbeam ST. Myocardial infarction and cerebral haemorrhage in a young body builder taking anabolic steroids. Aust N Z J Med 1993; 23: 713. Blouin AG, Goldfield GS. Body image and steroid use in male bodybuilders. Int J Eat Disord 1995; 18: 159-165. Tennant F, Black DL, Voy RO. Anabolic steroid dependence with opioid-type features. N Engl J Med 1988; 319: 578. Kennedy MC, Baume P, Corrigan AB, et al. Drugs in sport. A position paper. Fellowship Affairs 1997; 16: 27-28, 37-38. (Received 19 Aug 1999, accepted 11 Jul 2000) Authors' details Departments of Medicine and Endocrinology, St George Hospital, Sydney, NSW. Anthony J O'Sullivan, FRACP, MD, Senior Lecturer in Medicine. St Vincent's Hospital, Sydney, NSW. Michael C Kennedy, FRACP, MD, Consultant Physician, Richard O Day, AM, FRACP, Professor of Clinical Pharmacology; John H Casey, FRACP, PhD, Consultant Endocrinologist, Department of Endocrinology; Alex D Wodak, FRACP, FAFPHM, Director, Department of Alcohol and Drug Services. Institute of Sport, Concord Hospital, Sydney, NSW. Brian Corrigan, AM, FRACP, Director. Reprints will not be available from the author(s). Correspondence: Dr A J O'Sullivan, Department of Medicine, St George Hospital, Belgrave Street, Kogarah, NSW, 2217. Make a comment 1: Clinical parameters of androgenic-anabolic steroid users, divided into potential users, present users, and past users (mean and 5th-95th percentiles) Potential users (n=17) Present users (n=17) Past users (n=27) Population norm for age18 P Height (cm) Weight (kg) Age (years) Body mass index (m2/kg) Systolic blood pressure (mmHg)† Diastolic blood pressure (mmHg)† Mean testis volume (mL) No. with gynaecomastia 179 (171-185) 82.8 (61.8-103.2) 26 (19-34) 25.8 (20.5-32.1) 128 (114-142) 74 (69-82) 25 (21-29) 0 179 (169-187) 80.8 (64.5-104.7) 23 (17-32)* 25.4 (20.9-31.6) 133 (110-160) 80 (69-86) 18 (10-25)‡ 2 180 (173-186) 83.8 (69.5-96.8) 27 (22-34) 25.7 (22.3-29.5) 134 (112-160) 80 (70-97) 23 (14-30) 10§ 178 (166-190) 78.3 (59-104.4) 24.6 (19.4-32.3) 124 (106-142) 71 (54-88) 15-3019 0.66 0.76 0.05 0.93 0.42 0.12 0.02 0.004 *P=0.05 present users v. past users (analysis of variance [ANOVA]). †10 (37.0%) of the past users (P=0.02 v. potential users), 5 (29.4%) of the present users and 1 potential user (8.3%) were hypertensive as defined by systolic pressure >140mmHg or diastolic pressure >90mmHg. ‡P=0.02 present users v. past users and potential users (ANOVA). §P=0.004 past users v. potential users ( χ2). Back to text 2: Summary of commonest anabolic steroids reportedly used Brand name Chemical name Form Human or veterinary No. of users Anapolon* Andriol* Boldebal H Deca 50 Deca-durabolin* Dianabol Dynabol-50 Primobolan* Primobolan depot* Supertest Sustanon* Stanazol Testosterone cypionate Testo LA Tribolan Oxymetholone Testosterone undecanoate Boldenone undecylenate Nandrolone decanoate Nandrolone decanoate Methandrostenolone Nandrolone cypionate Methenolone acetate Methenolone enanthate Testosterone propionate Testosterone esters Stanozolol Testosterone cyclopentyl propionate Nandrolone decanoate Methandriol dipropionate 50mg tablets 40mg tablets 50mg/mL 50mg/mL 50mg/mL 5mg tablets 50mg/mL 5mg tablets 100mg/mL 50mg/mL 100, 250mg/mL 50mg/mL 100, 200mg/mL 100mg/mL 35mg, 75mg/mL 40mg H H V V H H V H H V H V V V V 10 5 3 15 8 8 4 6 3 5 14 15 5 3 3 *Human preparations registered in Australia. Back to text 3: Adverse effects reported by 44 past and present users of androgenic-anabolic steroids Side effect No. (%) users affected Change in libido Mood changes Reduction in testis volume Acne Erectile dysfunction Headaches Hair growth Oedema, fluid retention Prostatitis Parotid swelling Nipple discharge on cessation Sleeplessness Rash Cutaneous boils Lower back pain Stomach cramps Muscle cramps Increased appetite 27 (61%) 25 (57%) 20 (46%) 19 (43%) 9 (21%) 4 (9%) 2 (5%) 2 (5%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) Back to text 4: Biochemical and hormonal parameters of androgenic-anabolic steroid users and potential users Potential users (n=8) Present users (n=16) Past users (n=24) P Reference interval Sodium (mmol/L) Potassium (mmol/L) Chloride (mmol/L) Bicarbonate (mmol/L) Urea (mmol/L) Creatinine (µmol/L) Glucose (mmol/L) Albumin (g/L) Bilirubin (µmol/L) Alkaline phosphate (U/L) Alanine aminotransferase (U/L) Gamma glutamyl transferase (U/L) Creatine kinase (U/L) Cholesterol (mmol/L) Triglycerides (mmol/L) Follicle stimulating hormone (IU/L) Luteinising hormone (IU/L) 140.4±0.6 3.8±0.1 101±1 27.6±1.0 5.5±0.5 93±3 4.3±0.2 47±1 11±2 93±13 32±7 19±5 212±68 4.5±0.5 1.1±0.2 5.1±1.1 3.8±1.1 140.0±0.5* 4.2±0.1 102±1 28.3±0.7 5.3±0.3* 100±4 4.4±0.2 46±1 12±1 78±7 37±7 12±1* 673±235 4.6±0.5 1.2±0.1 1.3±0.3‡ 1.4±0.4‡ 141.3±0.3 4.3±0.1 102±1 29.1±0.5 6.8±0.5 107±4† 4.3±0.2 45±1 12±1 84±7 43±5 19±2 526±175 4.3±0.2 1.2±0.2 4.0±0.5 4.0±0.5 0.10 0.21 0.65 0.36 0.08 0.11 0.96 0.31 0.91 0.57 0.52 0.07 0.45 0.89 0.97 0.002 0.002 137-146 3.5-5.0 95-105 24-31 3.0-8.5 60-120 4.0-7.8 36-47 < 18 30-100 < 30 < 35 130 6.5 2.0 0.9-8.1 1.5-14.0 *P < 0.05 present users v. past users. † P < 0.05 past users v. potential users. ‡ P < 0.003 present users v. past and potential users (analysis of variance). Four participants with previous viral hepatitis B were excluded from the liver function test analysis, and two with Gilbert's syndrome were excluded from the bilirubin analysis. Back to text

Anthony J O'Sullivan · Michael C Kennedy · John H Casey · Richard O Day · Brian Corrigan · Alex D Wodak

Editorial Migraine treatment and mistreatment: primum non nocere Triptans can provide wonderful relief from migraine, but must not be overused as "pseudo-preventives" MJA 2000; 172: 412-413 If the 1990s was the decade of the brain for neuroscientists, then it was the decade of new treatments and renewed hope for sufferers of neurological diseases. Neurology, long the bastion of diagnosis, has become the specialty of the physician that we would all like to be -- one who is able to take a careful history and conduct a meticulous physical examination leading to a diagnosis and management plan. For headache patients, and perhaps neurological patients in general, it is the latter development in neurology, the move to more effective management of the conditions, that has been truly marvellous. We have started to identify the genes involved in causing the problem,1 and by so doing have begun to understand the episodic nature of the attacks in terms of ion-channel dysfunction. We have finally begun to image the primary headaches with functional/anatomical methods that have pointed to the brainstem, in migraine,2 and the posterior hypothalamus, in cluster headache,3 as likely candidates for the basic pathophysiological process. What is misuse and when is good medicine slipping into overtreatment? Best of all, from a clinical perspective, neurotherapeutics leapt ahead. The advent of the triptans (serotonin agonists) was to migraine and cluster headache almost the equivalent of penicillin to bacterial infection! It seems almost outrageous to liken the development of triptans to the discovery of penicillin, but this analogy has been used by at least three of my patients, themselves general practitioners who suffer migraines, to describe the change in their lives. Migraine never threatens life, but, as Professor Jim Lance, the Australian doyen of migraine, taught me, it simply "makes it hell". Disability is the key word to understanding the impact of migraine: inability to work effectively, care for dependants, enjoy recreation or participate in the myriad responsibilities that the non-migraineur takes for granted. What have we learnt from the developments of the past decade and what should we expect for the next decade in terms of therapeutics? The first triptan to be released was sumatriptan, developed in considerable part through the pioneering work of Lance and Anthony at Prince Henry Hospital in Sydney.4 This compound burst on to the clinical scene in the late 1980s,5 proving to be highly efficacious in clinical studies.6 Its development was marked by careful clinical trials methodology and spurred the widespread adoption of the International Headache Society Diagnostic Criteria7 for use in clinical studies. These criteria have been a boon for the clinical scientist and, if more widely used and adapted for primary care, could be useful for both doctors and patients more generally. As it became obvious that sumatriptan heralded a major advance in therapy, other researchers became interested in the field and triptan sons and cousins were soon in gestation. Naratriptan and zolmitriptan are now available in Australia and in Europe we also have rizatriptan; in late development or close to registration are almotriptan, eletriptan and frovatriptan. Do we have enough? For patients who respond to the triptans already available, obviously yes; for those who still suffer, confined like children to a room without a view for no sin other than their parents' genetic gifts, obviously not.8 Triptans are not perfect: a third of patients taking them have recurrence of headache within 24 hours; for some they do not work at all; and for those with significant risk factors for cardiovascular disease they are inappropriate. It has been at once heartening to find patients who show no improvement with one triptan yet respond to another, and disheartening that we have not been able to dissect what it is about the compounds9 that makes such profound differences in their clinical performance in individuals. In medicine almost every sunny day has a cloud on the horizon, and headache therapeutics is no exception. Ten years after the release of sumatriptan for clinical use, we have begun to appreciate the problems of mistreatment with triptans, reinforcing previous observations on mistreatment with other acute attack medications such as ergotamine or compound analgesics. In this context, "mistreatment" implies the inappropriate use of acute attack therapies by patients, either acting independently or under their doctors' instructions. This is referred to in the literature variously as "abuse", "overuse" or "misuse". Patients seldom misuse medications for any gain other than to attempt to function normally, to get to work or to look after their families. Given that acute medicines were designed for relatively infrequent use, and indeed that the triptans were studied explicitly in people having migraine frequencies of six or less per month, I believe that frequent use is a misuse of the medicine and a mistreatment of migraine. Reports of triptan misuse10,11 come as no surprise given the problems with ergotamine over the years,12 and this has sparked renewed interest in the subject of analgesic misuse.13 While the extent to which analgesics, particularly compound analgesics such as those containing codeine, can induce headache is not yet established, it seems clinically plausible that they block the frequency-reducing benefits of headache preventive therapy. What is misuse and when is good medicine slipping into overtreatment? With regard to ergotamine, a recent European consensus statement recommends, with some clearly stated exceptions, that the maximum usage should be 4-6 times a month.14 The tool with which to define this problem is the diary: a simple record of the number of days on which headache is experienced, and which prescription or over-the-counter medications are taken, will soon reveal whether excess medication is being consumed and whether management, including neurological referral, is appropriate. What are the prospects for the future? An understanding of migraine neurobiology will build on what has been done; more genes will be identified; functional imaging will better define and elaborate on the brain areas responsible for the disorder; and experimental laboratory work will put these observations under the modern anatomical and physiological microscope, returning more questions to the clinical scientists. In terms of treatment we need to do both more and less. We need to treat more patients who could benefit from medication but are not receiving adequate treatment. We need to develop new preventives to treat the sufferer of frequent headache whose disability load is truly dreadful, while at the same time guarding against using medications designed for intermittent acute use (triptans, ergotamine and analgesics) as pseudo-preventives -- primum non nocere! Lastly, we must spread the message that migraine is a genetically determined problem which is reasonably well characterised neurobiologically. Migraine involves dysfunction of brainstem and diencephalic areas normally involved in controlling pain and other sensory information and results in activation of very specific trigeminovascular pain pathways which are well defined and understood. The future is bright -- a good history, meticulous physical examination, clear diagnosis and explanation, and management directed at restoring ability to function is exactly what we can offer and, I think, exactly what patients want. Peter J Goadsby Professor of Clinical Neurology, Institute of Neurology University Department of Clinical Neurology National Hospital for Neurology and Neurosurgery Queen Square, London, UK Disclosure statement: In recent times the author has advised, collaborated with, and spoken at meetings organised by various companies, including Allergan, Almiral-Prodesfarma, AstraZeneca, BristolMyersSquibb, GlaxoWellcome, MSD, Pfizer, Pharmacia-Upjohn, Sandoz, and SmithKlineBeecham, which manufacture compounds referred to in this article or have an interest in developing compounds for the treatment of various primary headache syndromes. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNLA4. Cell 1996; 87: 543-552. Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nat Med 1995; 1: 658-660. May A, Bahra A, Buchel C, et al. Hypothalamic activation in cluster headache attacks. Lancet 1998; 351: 275-278. Anthony M, Hinterberger H, Lance JW. Plasma serotonin in migraine and stress. Arch Neurol 1967; 16: 544-552. Doenicke A, Brand J, Perrin VL. Possible benefit of GR43175, a novel 5-HT1-like receptor agonist, for the acute treatment of severe migraine. Lancet 1988; 1: 1309-1311. Ferrari MD. The Subcutaneous Sumatriptan International Study Group. Treatment of migraine attacks with sumatriptan. N Engl J Med 1991; 325: 316-321. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8(Suppl 7): 1-96. Goadsby PJ. A triptan too far. J Neurol Neurosurg Psychiatry 1998; 64: 143-147. Goadsby PJ. 5-HT1B/1D agonists in migraine: comparative pharmacology and its therapeutic implications. CNS Drugs 1998; 10: 271-286. Kaube H, May A, Diener HC, Pfaffenrath V. Sumatriptan misuse in daily chronic headache. BMJ 1994; 308: 1573-1574. Limmroth V, Kazarawa S, Fritsche G, Diener HC. Headache after frequent use of new serotonin agonists zolmitriptan and naratriptan. Lancet 1999; 353: 378. Friedman AP, Brazil P. Ergotamine tolerance in patients with migraine. J Am Med Assoc 1955; 157: 881-884. Diener HC. A personal view of the classification and definition of drug dependence headache. Cephalalgia 1993; 13: 68-71. Tfelt-Hansen P, Saxena PR, Dahlof C, et al. Ergotamine in the acute treatment of migraine - a review and European consensus. Brain 2000; 123: 9-18. Make a comment

Peter J Goadsby

Abstract Cardiovascular risk factors are commonly associated with erectile dysfunction and should be identified and treated. Patients with cardiovascular diseases should be assessed and counselled regarding their fitness for sexual activity. The danger of concurrent use of sildenafil and nitrates under any circumstances, regardless of age and sex, must be highlighted at all levels of the community. Sildenafil is absolutely contraindicated in patients receiving treatment with long-acting nitrates for ischaemic heart disease. Patients who need sublingual short-acting nitrates infrequently should not be precluded from taking sildenafil, provided they are aware that sildenafil is not to be taken within 24 h of taking the nitrate. There has been concern about the use of sildenafil (Viagra; Pfizer) for the treatment of erectile dysfunction (ED), particularly with regard to its possible role in the reported deaths and other serious cardiovascular events. Although sildenafil attracted considerable free media publicity in its debut in Australia and ranks as the most publicised new product this decade,1,2 consumer interest has been subdued and partly overshadowed by reports of 130 deaths involving sildenafil users in the United States between late March and mid-November 1998.3 It is therefore important that the association between sildenafil and these deaths be examined critically, so that the nature and the degree of risk may be identified and proper guidelines may evolve for the use of sildenafil. Cardiovascular disease and erectile dysfunction Cardiovascular disease and ED are known to be associated. In the Massachusetts Male Ageing Study,4 moderate or complete ED was 31% more prevalent among people with heart disease than in an age-matched cohort without heart disease. In a study in Perth, WA, the prevalence of complete ED among patients with hypertension, ischaemic heart disease and peripheral vascular disease was 26%, 38% and 57%, respectively, compared with 18.6% for the whole study.5 Reported ED in patients hospitalised for myocardial infarct or coronary artery surgery is of the order of 57%-64%.6,7 Conversely, in patients with severe ED, there is a 16% risk of severe, clinically occult ischaemic heart disease.8 Indeed, a statistically significant correlation has been shown between ED and the number of occluded coronary vessels.9 A significant number of patients requesting treatment for ED will have known or undiagnosed ischaemic heart disease, leading to considerable potential for adverse cardiovascular events. Moreover, many medications used for the treatment of cardiovascular disease may aggravate ED or complicate its treatment.10 Sildenafil and erectile dysfunction Sexual stimulation leads to the release of nitric oxide in the corpus cavernosum and results in an increase of cyclic guanosine monophosphate (cGMP), which produces smooth muscle relaxation and increased blood flow. Sildenafil is a selective inhibitor of cGMP-specific type 5 phosphodiesterase (PDE), the enzyme responsible for the degradation of cGMP in the corpus cavernosum. Thus, it enhances the effects of cGMP and permits an erectile response to be achieved or sustained (Box 1). The relevant pharmacodynamic and pharmacokinetic characteristics of sildenafil are summarised in Box 2.11-13 The efficacy of sildenafil in the treatment of ED has been demonstrated in 21 randomised, double-blind, placebo-controlled trials involving more than 3000 patients aged 19-87 years with ED of various aetiology.11 Sildenafil has been studied in men with ischaemic heart disease and with a wide range of other risk factors.14 A low incidence of serious or clinically significant adverse events, including cardiovascular events, was reported, comparable to that in patients with no known history of cardiovascular disorders. In Phase II-III studies involving 349 placebo patient-years and 693 sildenafil patient-years in randomised studies and 4220 patient-years in open-label studies, the incidence of myocardial infarction was lower in the sildenafil group than in the placebo group, although the difference was not statistically significant. The incidence of adverse events attributable to lowering of blood pressure in patients taking sildenafil was also low and no higher than in those receiving placebo. It was similar in patients taking concomitant antihypertensives and in those not taking these medications.14 There were reports of 26 deaths in about 5000 sildenafil patient-years, including 14 people with myocardial infarction and sudden death. None of the deaths was considered to be treatment related.14 Sildenafil and adverse cardiovascular events The unprecedented hype generated by the launch of sildenafil in the United States was dampened by reports of cardiovascular events, including deaths, allegedly associated with its use. A summary of reports of death among sildenafil users was posted by the Food and Drug Administration (FDA), with the pertinent remark that, in interpreting these reports, consideration should be given to the limitations of spontaneous reporting, such as under-reporting, duplication, marketing and medicolegal factors, incomplete or inaccurate clinical information, and the assumption of a cause-effect relationship.3 An overview of the FDA's updated summary of 130 reports of death between late March and mid-November 1998 is shown in Box 3. Deaths have also been reported in the Netherlands15 and Australia.16 Did sildenafil cause or contribute to the reported deaths? Sexual activity remains a potential trigger for myocardial infarction and sudden death may result from ischaemia or arrhythmia, although the relative and absolute risks are apparently low (Box 4). In the US general population with an age distribution similar to that of sildenafil users, there are about 400 deaths per million per week, and about 150 of these have a cardiovascular cause.29 In Australia, there are about 250 myocardial infarctions (50 fatal) per week affecting men aged 35 to 69 years.30,31 More than 70% of the deceased subjects in the FDA summary had overt or occult cardiovascular disease. Considering the high prevalence of risk factors for sudden cardiac death in users of sildenafil, the reported 130 deaths need to be viewed in the context of patient exposure to about 50 million sildenafil tablets, or more than 6 million prescriptions, during the same period. Pharmacologically, the action of sildenafil as a type 5 PDE inhibitor is highly specific. Potential for disaster seems to lie in the concurrent use of sildenafil and organic nitrates, as sildenafil potentiates the effect of nitrates and may lead to life-threatening hypotension (Box 1). Among the deaths reported in the FDA summary, there were 16-19 sildenafil users who had allegedly used or received glyceryl trinitrate or a nitrate-containing medication. In this subset of individuals, the concurrent use of nitrates would provide the possible causal link between sildenafil and death. Therefore, it is not unlikely that sexual activity in a vulnerable person and adverse drug interaction caused or contributed to the reported deaths. Recommendations Box 5 shows the recommended strategy for treating ED. To minimise adverse consequences, it is important that a patient's fitness for sexual and physical activity be assessed when treatment of ED is considered, and that the patient be appropriately counselled if sexual activity is inadvisable. In general, sexual intercourse should be safe if a patient can perform an activity equal to 5-6 metabolic equivalents (METS), such as climbing 20 stairs in 10-15 seconds without distress.32 Postinfarction patients who reach 5-6 METS on stress testing without ischaemia or arrhythmia can resume their normal sexual activity without risk.33 In one study, patients with a negative exercise test result did not demonstrate ischaemia on Holter monitoring during sexual intercourse.26 The frequent use of short-acting nitrates and ongoing therapy with long-acting nitrates are absolute contraindications to the use of sildenafil. The only option for patients in this situation is to avoid the use of sildenafil. A policy of refraining totally from the use of sildenafil in all patients receiving nitrates in whatever form and regardless of frequency would, of course, quarantine patients from the risk of drug interaction. Nevertheless, patients who have only an infrequent need for short-acting nitrates, such as sublingual glyceryl trinitrate, should not be precluded from the use of sildenafil. However, doctors need to ensure that patients fully understand the implications of the potential interaction of these therapies. Patients whose only exposure to nitrate therapy is infrequent use of sublingual glyceryl trinitrate tablets or spray should be advised that at least 24 hours from the last use of the short-acting nitrates should be allowed to elapse before the use of sildenafil. It is not definitely known when nitrates can be safely administered after a dose of sildenafil. Certainly, patients should be cautioned against the use of any form of nitrates for at least 24 hours after sildenafil. In elderly patients, and in those with hepatic and renal impairment or receiving medications which may inhibit the cytochrome P450 3A4 isoenzyme (eg, erythromycin, fluconazole, fluoxetine, cimetidine), consideration must be given to decreased sildenafil clearance. If a patient should develop angina within 24 hours of taking sildenafil, nitrates should be totally avoided. Doctors should ensure that their patients follow this advice carefully. If necessary, an increase in the dose of alternative anti-anginal agents should be considered. If a patient requires hospital admission, non-nitrate anti-anginal preparations such as ß-blockers or calcium-channel blockers can be used with due regard to the risk of hypotension. If complications should develop from the inadvertent concurrent use of a nitrate, the recommendations of the American College of Cardiology and the American Heart Association34 should be followed. These include resuscitative measures such as fluid infusion and judicious use of intravenous vasopressors to maintain blood pressure, as well as appropriate non-nitrate anti-anginal agents. If adherence to such guidelines is difficult, the alternative is to avoid sildenafil in favour of other therapeutic options for ED. Clinical judgement and discretion must prevail over generalisation, bearing in mind the risk and benefit and the priority of the therapeutic interventions involved. There are no established data on the safety and efficacy of sildenafil in patients with myocardial infarction or life-threatening arrhythmia within the preceding six months; patients with systolic blood pressure < 90 mmHg; or patients with cardiac failure or coronary artery disease causing unstable angina. Caution must be exercised in prescribing sildenafil for these patients and for patients receiving complicated multidrug antihypertensive therapy.34 Where appropriate, monitoring of blood pressure at the initiation of sildenafil therapy would identify patients with a hypotensive response to sildenafil. An appropriate educational program will reduce the risk of drug interaction by alerting pharmacists and doctors to the potential danger. Pharmaceutical companies marketing nitrate-containing medications should specify sildenafil as a contraindication in their product information. Paramedics, nursing staff, patients and the community at large should be instructed on the danger of the concurrent use of sildenafil and nitrates, and of the undesirable practice of sharing medication with relatives and friends (Box 6). It is important that a warning be given to every patient, regardless of sex or age. Women have been known to use sildenafil to heighten sexual arousal and young people may use amyl nitrite inhalation for recreational pursuit. Cardiovascular diseases affect an estimated 2.3 million Australians.35 The risk of angina increases with age, affecting 12.4% of men and 11.7% of women aged 65-69 years.36 These proportions are likely to be greater among patients with ED. A request for treatment of ED provides a window of opportunity to assess the patient for cardiovascular and other risk factors, including diabetes and abnormal lipid profile. Cardiovascular risk factors, if identified, should be vigorously treated according to established guidelines.37,38 The sildenafil controversy continues.39 It has been reported that the FDA continues to believe that sildenafil remains safe.39 However, continuing postmarketing surveillance is essential for sildenafil, as for any recently marketed drug. Disclosure B G A Stuckey has served as a principal investigator in clinical studies of sildenafil. K K Chew and B G A Stuckey have received sponsorship to attend conferences from Pfizer Aust Pty Ltd. P L Thompson serves on the international steering committee of a Pfizer-sponsored clinical trial of lipid lowering in the elderly. K K Chew, B G A Stuckey and P L Thompson have been invited to present papers at Pfizer-sponsored meetings. References Kiely M. Viagra saturates media. Marketing Globe. Marketing 1998; Dec: 58. Jones A. When the thrill has gone. Business Rev Weekly 1999; June 25: 90-95. US Department of Health, Food and Drug Administration. Postmarketing safety of sildenafil citrate (Viagra) and summary of reports of death in Viagra users received from marketing (late March through mid-November 1988). 24 November 1988. Feldman HA, McKinlay JB, Goldstein I, Longcope C. Erectile dysfunction, cardiovascular disease and cardiovascular risk factors: prospective results in a large random sample of Massachusetts men. J Urol 1998; 159 Suppl 5: 91 abstract 347. Chew KK, Earle CM, Stuckey BGA, et al. Erectile dysfunction in general medical practice: prevalence and clinical correlates. Int J Impot Res 2000; 12: 1-5. Wabrek AJ, Burchell RC. Male sexual dysfunction associated with coronary heart disease. Arch Sex Behav 1980; 9: 69-75. Gundle MJ, Reeves BR, Tate S, et al. Psychosocial outcome after aortocoronary artery surgery. Am J Psychiatry 1980; 137: 1591-1594. Anderson M, Nicholson B, Louie E, Mulhall JP. An analysis of vasculogenic erectile dysfunction as a potential predictor of occult cardiac disease. J Urol 1998; 159 Suppl 5: 30 abstract 118. Greenstein A, Chen J, Miller H, et al. Does severity of ischaemic coronary disease correlate with erectile function? Int J Impot Res 1997; 9: 123-126. Slag MF, Morley JE, Elson MK, et al. Impotence in medical clinic outpatients. JAMA 1983; 249: 1736-1740. Morales A, Gingell G, Collins M, et al. Clinical safety of sildenafil citrate (Viagra) in the treatment of erectile dysfunction. Int J Impot Res 1998; 10: 69-74. Viagra -- approved product information. Pfizer, 1998. Boolell M, Allen MJ, Ballard SA, et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 1996; 8: 47-52. Zusman RM, editor. Cardiovascular data on sildenafil citrate. Am J Cardiol 1999; 83(5A). Feenstra J, van Drie-Pierik RJHM, Lacle CF, Stricker BHC. Acute myocardial infarction associated with sildenafil. Lancet 1998; 352: 957-958. Viagra is here! Australian Adverse Drug Reactions Bulletin 1998; 17(4). Hellerstein HK, Friedman EH. Sexual activity and the postcoronary patient. Arch Intern Med 1970; 125: 987-999. Bohlen Y, Held JP, Sanderson MO, Paterson RP. Heart rate, rate-pressure product, and oxygen uptake during four sexual activities. Arch Intern Med 1974; 144: 1745-1748. Willich SN, Klatt S, Arntz HR. Circadian variation and triggers of acute coronary syndromes. Eur Heart J 1998; 19 Suppl C: C12-23. Nalbangtil I, Yigitbasi O, Kiliccioglu B. Sudden death in sexual activity. Am Heart J 1976; 91: 405-406. Ueno M. The so-called coital death. Jpn J Legal Med 1963; 17: 330-340. Renshaw DC, Karstaedt A. Is there (sex) life after coronary bypass? Comp Ther 1988; 14: 61-66. Lecomte D, Fornes P, Nicolas G. Stressful events as a trigger of sudden death: a study of 43 medico-legal autopsy cases. Forensic Sci Int 1996; 79: 1-10. Muller JE, Mittleman MA, Maclure M, et al. Triggering myocardial infarction by sexual activity. JAMA 1996; 275: 1405-1409. Johnston BL, Fletcher GF. Dynamic electrocardiographic recording during sexual activity in recent post-myocardial infarction and revascularization patients. Am Heart J 1979; 98: 736-741. Drory Y, Shapira I, Fisman EZ, Pines A. Myocardial ischaemia during sexual activity in patients with coronary artery disease. Am J Cardiol 1995; 75: 835-837. Kavanagh T, Shephard RJ. Sexual activity after myocardial infarction CMAJ 1977; 116: 1250-1253. Paolillo V, Marra S, Spadaccini F, Angelino PF. Dynamic electrocardiographic recording during sexual activity in recent post-myocardial infarction and revascularization patients [letter]. Am Heart J 1980; 100: 763. Health United States. 1998. Hyattsville, Maryland: US National Center for Health Statistics, 1998. Australian Institute of Health and Welfare. Heart, stroke and vascular diseases, Australian facts. Canberra: AIHW and the Heart Foundation of Australia, 1999. (Cardiovascular Disease Series No. 10. AIHW Cat. No. CVD 7.) Australian Bureau of Statistics. Causes of death, Australia. Canberra: ABS, 1997. (Cat No. 3303.0.) Cardiac rehabilitation: sex after a heart attack. In: Zaret BL, Moser M, Cohen LS, editors. Yale University School of Medicine Heart Book. New York: Hearst Books, 1992; 351. Tardif GS. Sexual activity after a myocardial infarction. Arch Phys Med Rehabil 1989; 70: 763-766. Summary statement of the American College of Cardiology and the American Heart Association on the use of sildenafil (Viagra) in patients at clinical risk from cardiovascular effects. 10 August 1998. <http://www.americanheart.org/ Whats_News/AHA_Science_Advisories/viagra.html>. Accessed 18 February 2000. Fact sheet for prevention of myocardial infarction. National Heart Foundation of Australia. Curr Ther 1999; 39: 52. Fact sheet for angina. National Heart Foundation of Australia. Curr Ther 1999; 39: 63. Grundy SM, Balady GJ, Criqui MH, et al. Guide to primary prevention of cardiovascular diseases. A statement for healthcare professionals from the Task Force on Risk Reduction. Circulation 1997; 95: 2329-2331. Heart Foundation of Australia. Guide for the use of lipid lowering drugs in adults. Canberra: Heart Foundation of Australia, 1999. Available at <http://www. heartfoundation.com.au/include/defaultStory.asp?OwnerUID=200&Content Type=tblcategory>. Mitka M. Some men who take Viagra die -- why? [news]. JAMA 2000; 283(5). <http://jama.ama-assn.org/issues/v283n5/full/jmn0202-2.html>. Accessed 18 February 2000. (Received 8 Oct 1999, accepted 14 Feb 2000) Authors' details Keogh Institute for Medical Research, Perth, WA. K Kim Chew, FRCP(Edin), FRCP(Glas), Senior Clinical Fellow; Bronwyn G A Stuckey, MB BS, FRACP, Medical Director, and Consultant Endocrinologist, Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, WA. University of Western Australia, Perth, WA. Peter L Thompson, FRACP, FACP, Clinical Professor of Medicine, University of Western Australia, and Consultant Cardiologist, Sir Charles Gairdner Hospital, Perth, WA. Reprints will not be available from the authors. Correspondence: Dr B G A Stuckey, Keogh Institute for Medical Research, 3rd Floor A Block, Queen Elizabeth II Medical Centre, 2 Verdun Street, Nedlands, WA 6009. rmriATwt.com.au 2: Pharmacodynamic and pharmacokinetic characteristics of sildenafil11-13 Sildenafil is about 4000-fold more selective for type 5 phosphodiesterase (PDE5) than for PDE3, which is involved in cardiac contractility. In healthy volunteers, sildenafil produced a modest decrease in blood pressure (up to 8.4 mmHg systolic and 5.5 mmHg diastolic), but no consistent orthostatic effects and no clinically relevant electrocardiographic changes. In patients receiving medications containing nitrates, the hypotensive effects of sildenafil can be severe. In a US study with isosorbide mononitrate 20 mg twice daily, 50 mg sildenafil produced maximal blood pressure reductions of 40.9 mmHg systolic sitting and 51.6 mmHg systolic standing, and 25.8 mmHg diastolic sitting and 29.3 mmHg diastolic standing, about one hour after dosing and lasting up to 6 h. Similar haemodynamic interaction occurred for about two hours after a dose of 500 µg sublingual glyceryl trinitrate (maximum reductions: systolic, 36.0 mmHg sitting; diastolic, 20.5 mmHg sitting). Sildenafil has a half-life of about 4 h. After an oral dose of 100 mg, the plasma level peaks at about 440 ng/mL within 30-120 min, and drops to about 2 ng/mL at 24 h. Sildenafil is predominantly metabolised in the liver by the cytochrome P450 3A4 system, and 18% of the dose is excreted in the urine. Increased plasma levels may result from concomitant use of a cytochrome P450 3A4 inhibitor (eg, erythromycin, fluconazole, fluoxetine, cimetidine) or reduced clearance in elderly persons (>65 years) and in those with significant hepatic and renal impairment (creatine clearance <30 mL/min). 3: US Food and Drug Administration summary of reports of death in sildenafil users Number of deaths reported130Number with cause not mentioned or unknown48Number from homicide or drowning2Number from stroke3Number from cardiovascular events Definite or suspected myocardial infarction Cardiac arrest Cardiac symptoms Coronary artery disease77 41 27 6 3Use of nitrates Took or were administered a nitrate medication Found with nitrate in their possession16 3Time of death after use of sildenafil Not stated or unknown Within 4-5 hours of using sildenafil (includes 27 during or immediately after sexual intercourse) Later the same day Next day Two days later Three to seven days later61 44 6 8 5 4Cardiovascular risk factors One or more risk factors No identified risk factors, but severe coronary artery disease found at autopsy No history of cardiac disease or risk factors No risk factors and no sexual activity Not specified 90 3 12 2 23 4: Sexual activity and adverse cardiovascular events Sexual activity, like any other physical effort, increases cardiac work and myocardial oxygen demand.17 Heart rate and blood pressure rise to an energy expenditure of 2.0-5.4 metabolic equivalents.18 Sexual activity may trigger an adverse cardiovascular event.19,20 Coital death has been reported to account for 0.6% of sudden deaths,21 although it is said to be rare in a stable sexual relationship.22 In a study of 43 cases, sudden death was found to occur primarily in patients with severe heart disease, especially coronary heart disease, and in only three cases was sexual activity involved.23 In another study, 9% of patients reported having had sexual activity in the 24 hours, and 3% in the two hours, preceding myocardial infarction. The relative risk of myocardial infarction occurring in the two hours after sexual activity was estimated to be 2.5, and was not increased in patients with a history of previous angina pectoris or myocardial infarction. The absolute risk increase was low, at one chance in a million for a healthy individual.24 Electrocardiographic abnormalities during sexual activity have been reported in 12 of 24 patients with recent myocardial infarction or revascularisation.25 In another study, 31% of men with ischaemic heart disease had ischaemia on Holter monitoring during sexual intercourse, although only 7% were symptomatic.26 However, the frequency of angina pectoris and ventricular premature beats is less during sexual intercourse than during standard laboratory exercise, and sexual relations are thought to carry no special risk for the average postinfarction patient.27 Sexual activity in the early posthospital phase of myocardial infarction is not a stronger stimulus than other activities for cardiac electrical instability.28 Anxious sexual preoccupation, frustration and avoidance may actually be greater risk factors than coitus or coital alternatives.22

Peter L Thompson

Position Statement Use, misuse and abuse of androgens The Endocrine Society of Australia consensus guidelines for androgen prescribing Ann J Conway, David J Handelsman, Douglas W Lording, Bronwyn Stuckey, Jeffrey D Zajac on behalf of the Endocrine Society of Australia MJA 2000; 172: 220-224 Abstract - Use of androgens - Misuse of androgens - Abuse of androgens - Key references - Authors' details - - More articles on Endocrinology Abstract Androgen replacement therapy (ART) is usually life-long, and should only be started after androgen deficiency has been proven by hormone assays. The therapeutic goal is to maintain physiological testosterone levels. Testosterone rather than synthetic androgens should be used. Oral 17α-alkylated androgens are hepatotoxic and should not be used for ART. There is no indication for androgen therapy in male infertility. Although androgen deficiency is an uncommon cause of erectile dysfunction, all men presenting with erectile dysfunction should be evaluated for androgen deficiency. If androgen deficiency is confirmed, investigation for the underlying pathological cause is required. Contraindications to androgen therapy are prostate and breast cancer. Precautions include using lower starting doses for older men and induction of puberty. Intramuscular injections should be avoided in men with bleeding disorders. Androgen-sensitive epilepsy, migraine, sleep apnoea, polycythaemia or fluid overload need to be considered. Competitive athletes should be warned about the risks of disqualification. ART should be initiated with intramuscular injections of testosterone esters, 250 mg every two weeks. Maintenance requires tailoring treatment modality to the patient's convenience. Modalities currently available include testosterone injections, implants, or capsules. Choice depends on convenience, cost, availability and familiarity. There is no convincing evidence that, in the absence of proven androgen deficiency, androgen therapy is effective and safe for older men per se, in men with chronic non-gonadal disease, or for treatment of non-specific symptoms. Until further evidence is available, such treatment cannot be recommended. Androgens are hormones that are based on the structure of testosterone, the major male sex hormone, and are capable of developing and maintaining masculine sexual characteristics (including the genital tract, secondary sexual characteristics, and fertility) and the anabolic status of somatic tissues. All androgens have similar biological effects because they all act through the single androgen receptor. Their effects in different tissues are diversified by metabolism of testosterone to its active metabolites by the enzymes 5α reductase (which converts testosterone to 5α-dihydrotestosterone, an androgen with enhanced potency acting on the androgen receptor) and aromatase (which converts testosterone to oestradiol, which acts on the oestrogen receptor). Use of androgens The main medical use of androgens (Box 1) is as androgen replacement therapy (ART) for established androgen deficiency.1-3 Classical androgen deficiency occurs in about 1 in 200 men, due to testicular disorders that directly reduce testosterone output, or hypothalamic-pituitary disorders that reduce pituitary luteinising hormone (LH) secretion, which is the main drive to testosterone production by the interstitial (Leydig) cells of the testes. Although classical androgen deficiency is relatively easy to recognise, diagnosis of less severe androgen deficiency can be more difficult. Owing to its subtle and variable clinical features, the diagnosis may easily be missed, denying patients simple and effective medical treatment with often striking subjective benefits. Potential extensions of classical indications to partial androgen deficiency remain to be fully evaluated for clinical safety and efficacy. These indications include age, androgen deficiency secondary to a chronic medical condition or its treatment, hormonal male contraception, and postmenopausal symptoms.4-6 Until more definitive objective evidence is available regarding the safety and efficacy of prescribing androgens for these indications, they remain suitable for carefully monitored, controlled clinical research trials, but not for routine medical treatment. Pharmacological applications of androgens (Box 1) usually represent second-line therapy where more specific treatments are not yet available or have failed. Androgen treatment can evoke a strong placebo response. In men without genuine androgen deficiency, this placebo effect invariably wanes with time, leading to confusion and dissatisfaction with treatment. In addition, once androgen therapy has commenced, the biochemical changes can cloud further interpretation of results for months. Therefore, androgen replacement therapy should be commenced only after androgen deficiency is clearly established.2,3 Diagnosis of androgen deficiency1-3 Diagnosis of androgen deficiency involves the recognition of appropriate clinical features, with confirmation by biochemical testing. Important clinical features required to evaluate testicular function include reproductive history (including pubertal development), fertility status, changes in sexual function and body hair growth, known testicular pathology, drug use, and occupation. Physical examination should record androgenisation (secondary sexual characteristics, especially body hair distribution, musculature and gynaecomastia) and testis volumes (by orchidometry). Serum LH, follicle-stimulating hormone and testosterone levels should be measured, on at least two separate days and preferably in the morning, to minimise the effects of random and laboratory fluctuations and diurnal rhythms. Direct measurements of free testosterone, if available, may help establish the diagnosis of androgen deficiency, but require extensive validation. Indirect measurements of free testosterone, such as the free androgen index (testosterone/sex hormone binding globulin [SHBG] ratio), correspond poorly with direct measurements and lack empirical validation as a diagnostic test. Additional tests that may be required to identify underlying disorders include karyotyping, pituitary radiology and measurement of prolactin levels, serum ferritin levels, iron saturation and, increasingly, genetic diagnosis. Androgen deficiency is unlikely in men with mean testis volume > 20 mL without atrophy, with a plasma testosterone level consistently above 20 nmol/L, or presenting with erectile dysfunction and a plasma testosterone level consistently above 8 nmol/L (Box 2). Where the diagnosis is not clear, referral to a clinical endocrinologist with experience in this area is recommended.1 Androgen replacement therapy1-3 ART is indicated to rectify androgen deficiency of any cause sufficient to cause clinical consequences. After puberty, there is no age limit to ART. Androgen-deficiency effects may manifest as changes in one or more androgen-sensitive functions; for example, psychosexual function, or loss of anabolic effects on bone, muscle, blood-forming marrow and other androgen-responsive tissues. Apart from decreased spermatogenesis, ART can rectify all clinical features of androgen deficiency, which usually respond within 1-2 months of starting therapy, although the full effect may take longer. Dosage: Standard ART is either testosterone enanthate (Primoteston in castor oil; Schering) or mixed testosterone esters (Sustanon in arachis oil; Organon) as 250 mg in 1 mL oil at 14-day intervals. Deep intramuscular injections are usually given into the upper and outer quadrant of the buttock, although some patients prefer the deltoid or lateral thigh muscle sites. Few men can manage self-injection with the viscous oil vehicle. For all ART, testosterone and its esters should be used in preference to synthetic androgens, because of their established safety and efficacy, as well as ease of dose-titration and assay monitoring. Lower starting doses may occasionally be needed, especially in previously untreated elderly men and during first induction of puberty. Less frequent dosing intervals (eg, every three weeks) are occasionally necessary for those unable or unwilling to have standard dosage, but are accompanied by more extreme peaks and troughs in blood testosterone levels, which may exaggerate symptom fluctuations. An inadequate clinical response raises doubt about androgen deficiency as the cause of recalcitrant symptoms. Rarely, an inadequate clinical response may require increased dosage. If suboptimal symptomatic benefit is supported by biochemical evidence of inadequate maintenance of androgen levels (low trough testosterone levels with or without persistently supranormal LH levels in primary hypogonadism), the same dose may be injected at 10-day intervals. Persistently inadequate responses indicate that unresponsive symptoms are not due to androgen deficiency; further escalation in dose or frequency is not warranted. Men with mild or partial androgen resistance due to androgen-receptor mutations may benefit from high-dose androgen therapy. As the underlying disorders are almost always permanent, life-long ART after the age of puberty is usually necessary. Long term therapeutic compliance depends on an acceptable regimen. Crossover studies indicate that patients strongly prefer the stable testosterone levels and smoother clinical effects provided by implants or transdermal formulations, compared with the wide fluctuations in testosterone levels and symptoms during intramuscular testosterone ester injections. Thus, although ART should commence with injections, alternative modalities (Box 3) may improve compliance. Factors to consider include cost, convenience, availability, familiarity with alternatives, and tolerance for frequent injections. Monitoring: Monitoring of ART is mainly to ensure effective androgen replacement by a regimen tailored to the patient's needs, aiming to maintain adequate therapeutic compliance by continuation of treatment. Serial clinical observation of clinical well-being and major symptoms of androgen deficiency, together with limited numbers of hormonal assays, is usually adequate. Restoration of sexual function has a low threshold for androgen action, so adequate libido and potency is a necessary, but not sufficient, indication of clinically adequate androgen replacement. Blood hormone assays have limited utility in optimising an ART regimen at the start of treatment and in evaluating androgen replacement. Trough blood testosterone levels (ie, before the next scheduled dose) within the eugonadal reference range can be a valuable guide to the adequacy of parenteral androgen replacement, but random blood testosterone levels are not useful for monitoring with either oral or injectable testosterone. In men with hypergonadotropic hypogonadism, suppression of blood LH levels into the eugonadal reference range indicates adequate ART, whereas persistent non-suppression of LH after 3-6 months of regular treatment indicates inadequate dosage or compliance. In hypogonadotropic hypogonadism, blood gonadotropin levels are uninterpretable. Serial evaluation of bone density (especially vertebral trabecular bone) by dual-photon absorptiometry at 1-2-year intervals may be useful in evaluating the adequacy of long-term androgen effects on bone. Other biochemical indices of androgen action, such as haemoglobin, SHBG, and high density lipoprotein cholesterol levels, reflect only supraphysiological effects and are too insensitive for routine monitoring of ART. Androgen deficiency is protective against prostate disease, and ART may restore the risks to those equivalent to, but no more than, eugonadal men of similar age. Screening of men receiving ART for cardiovascular and prostate disease need be no more intensive than for men of similar age not on ART. Precautions and side effects14-17 Adverse effects of androgen treatment are uncommon. Virilisation may occur with androgen therapy in women or children; androgen therapy in these settings requires expert management. Truncal acne and hair growth, weight gain, gynaecomastia and male-pattern hair loss may be observed, and should be managed symptomatically. Certain side effects are characteristic of specific therapeutic modalities (eg, discomfort from intramuscular injections, extrusion of subdermal implants, gastrointestinal disturbance from oral testosterone undecanoate). Polycythaemia may occur disproportionately often in older men treated with testosterone ester injections. In addition, certain testosterone formulations have distinctive effects due to their pharmacokinetic features (eg, reduced levels of SHBG, high density lipoprotein cholesterol and other hepatic proteins due to supraphysiological hepatic testosterone exposure). This may be due to injectable testosterone esters (via high peak blood testosterone concentrations) or oral testosterone undecanoate (via high first-pass portal testosterone concentrations), whereas more steady formulations (transdermal, implants) exhibit fewer or no such effects. Oral synthetic androgens that have a 17α-alkyl substituent (oxandrolone, fluoxymesterone, danazol) are inherently hepatotoxic, causing cholestatic hepatitis, peliosis hepatis and hepatic tumours. Other classes of synthetic androgen, such as 19-nortestosterone derivatives (nandrolone, MENT) and the 1-methyl androgens (mesterolone, methenolone), are not hepatotoxic. Absolute contraindications to androgen therapy are prostate or breast cancer in men. Androgen therapy should be started in men over the age of 40 only after exclusion of undiagnosed prostate disease. Precautions are required for: older men starting androgen treatment, where it may precipitate urinary obstruction or unfamiliar increases in libido; pubertal boys, in whom excessive dosage may accelerate epiphyseal closure, leading to shortened final stature; parenteral androgen therapy in men with bleeding disorders; competitive athletes, who may be disqualified; androgen-sensitive epilepsy, migraine, sleep apnoea or polycythaemia; and cardiac or renal failure or severe hypertension susceptible to fluid overload from sodium and fluid retention. Misuse of androgens Medical misuse of androgens involves prescription with no acceptable medical indication. Some common examples of misguided prescribing of androgens in the absence of established androgen deficiency include: Male infertility: There is no indication for androgen therapy in male infertility. The only likely consequence is an adverse effect of suppressing spermatogenesis. Male sexual dysfunction or impotence: Androgen deficiency (with or without hyperprolactinaemia) is an uncommon (< 5%) cause of men presenting with erectile dysfunction. In such men, excluding androgen deficiency as a readily treatable underlying cause is essential. In the unusual event of severe androgen deficiency presenting with erectile dysfunction, the underlying cause needs to be identified, and plans for life-long ART need to be established. "Male menopause" or "andropause": There is still no evidence that the modest decreases in circulating blood testosterone levels which commence during mid-life have any clinical importance. The risks and benefits of androgen supplementation for partially androgen-deficient older men require further evaluation by placebo-controlled studies. Androgen treatment may be inappropriate, wasteful, and involve placebo effects. Terms such as "male menopause" and "andropause" are misleading; they have little place in meaningful medical or scientific discourse. Elderly men (> 65 years):18 There is no basis for androgen therapy based on age per se. Further controlled clinical trials are needed to evaluate the potential role of androgen supplementation in ageing. While some preliminary placebo-controlled studies suggest short-term benefits for muscle, bone and quality of life, findings are not yet consistent and the identification of appropriate treatment objectives and target subgroups, as well as overall analyses of risks, benefits and costs, are lacking. Specifically, it remains to be determined whether androgen supplementation has significant and sustained clinical benefits in older men with low-normal plasma total testosterone and normal LH levels. At present, there is no basis for androgen treatment outside properly designed clinical trials. Treatment of non-specific symptoms: There is no basis for androgen therapy based on symptoms in the absence of established androgen deficiency. In addition to the unproven safety and efficacy, the placebo effect of androgen injections may be confusing to both doctor and patient. When placebo effects wane, further confusion and dissatisfaction with treatment may be expected. Abuse of androgens Illicit use of androgens19-24 ("anabolic steroids") depends largely on obtaining androgens without legal prescription to be used in the absence of any medical indication. Illicit androgen use became epidemic over the past four decades, since androgens were reportedly first used in elite competitive power sports. A recent placebo-controlled study has shown that high-dose androgen administration does improve muscle size and strength in healthy eugonadal men. Whether these changes enhance athletic performance, whether they are sustained, and whether they apply to older men remains to be clarified. Medical prescription appears to support only a small proportion of illicit androgen use, but such activity has been formally ruled as a breach of professional standards by medical boards in most States and by the Royal Australasian College of Physicians. Highly motivated young men can be very sophisticated in manipulating and pressuring general practitioners while attempting to obtain prescriptions for androgens. The doctor is often led to believe that other practitioners are prescribing androgens for young men, and that he or she is being uncaring or negligent by not acceding to the patient's wishes. We recommend that general practitioners resist these pressures. Fortunately, most people appear ultimately to lose interest in this form of drug abuse. Background and evidence basis of recommendations The Endocrine Society of Australia (ESA) Consensus Guidelines for Androgen Prescribing were written on behalf of the Endocrine Society of Australia. The ad hoc Writing Committee commissioned by the ESA's Council was Dr A J Conway, Professor D J Handelsman (Chair), Associate Professor D W Lording, Dr B Stuckey, and Associate Professor J D Zajac. The draft guidelines were extensively circulated for comment to active members of the ESA with clinical expertise or interests in male reproductive endocrinology. Comments were incorporated into the final document, which was ratified by the ESA's Council. Androgen therapy, in regular clinical use for over 60 years, is one of the oldest hormonal regimens in modern therapeutics. As a long established standard and effective form of hormone replacement for many decades, placebo-controlled studies are unavailable and now unacceptable. Consequently, the NHMRC Quality of Evidence Ratings for these recommendations are those appropriate to an expert committee reviewing all available evidence from controlled experimental and observational studies as well as clinical experience. Key references Diagnosis and management of androgen deficiency Behre HM, Yeung CH, Nieschlag E. Diagnosis of male infertility and hypogonadism. In: Nieschlag E, Behre HM (eds): Andrology: Male Reproductive Health and Dysfunction. Berlin:Springer, 1997: 87-111. Plymate SR. Male Hypogonadism. In: Becker KL (ed): Principles and Practice of Endocrinology and Metabolism. 2nd ed. Philadelphia: J B Lippincott Company, 1995: 1056-1082. Nieschlag E, Wang C, Handelsman DJ, et al (eds) (1992). Guidelines for the use of androgens in men. Geneva, Special Programme of Research, Development and Research Training in Human Reproduction of the World Health Organisation. Male contraception Cummings DE, Bremner WJ. Prospects for new hormonal male contraceptives. In: Bremner WJ (ed): Clinical Andrology. Philadelphia: W B Saunders Company, 1994: 893-922. Handelsman DJ. Contraception in the male. In: DeGroot LJ (ed): Endocrinology. 3rd ed. Philadelphia: W B Saunders, 1994: 2449-2458. Androgen therapy in systemic disease Liu PY, Handelsman DJ. Androgen therapy in non-gonadal disease. In: Nieschlag E, Behre HM (eds):Testosterone: Action, Deficiency and Substitution. 2nd ed. E Nieschlag, Behre HM (eds), Berlin, Springer-Verlag, 1998. Comparative pharmacology of androgen formulations Bals-Pratsch M, Langer K, Place VA, Nieschlag E. Substitution therapy of hypogonadal men with transdermal testosterone over one year. Acta Endocrinologica 1988; 118: 7-13. Behre HM, Oberpenning F, Nieschlag E. Comparative pharmacokinetics of androgen preparations: application of computer analysis and simulation. In: Nieschlag E, Behre HM (eds): Testosterone: Action, Deficiency and Substitution. Berlin: Springer-Verlag, 1990: 115-135. Cantrill JA, Dewis P, Large DM et al. Which testosterone replacement therapy? Clin Endocrinol (Oxf) 1984; 24: 97-107. Conway AJ, Boylan LM, Howe C, Ross G, Handelsman DJ. A randomised clinical trial of testosterone replacement therapy in hypogonadal men. Int J Androl 1988; 11: 247-264. Handelsman DJ, Conway AJ, Boylan LM. Pharmacokinetics and pharmacodynamics of testosterone pellets in man. J Clin Endocrinol Metab 1990; 71: 216-222. Meikle AW, Mazer NA, Moellmer JF, et al. Enhanced transdermal delivery of testosterone across nonscrotal skin produces physiological concentrations of testosterone and its metabolites in hypogonadal men. J Clin Endocrinol Metab 1992; 74: 623-628. Snyder PJ, Lawrence DA. Treatment of male hypogonadism with testosterone enanthate. J Clin Endocrinol Metab 1980; 51: 1335-1339. Safety of androgens Alexandersen P, Haarbo J, Christiansen C. The relationship of natural androgens to coronary heart disease in males: a review. Atherosclerosis 1996; 125: 1-13. Barrett-Connor E. Testosterone, HDL-cholesterol and cardiovascular disease. In: Bhasin S, Gabelnick HL, Spieler JM et al (eds): Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. New York: Wiley-Liss, 1996: 215-223. Behre HM, Bohmeyer J, Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxf) 1994; 40: 341-349. Gooren LJ, Polderman KH. Safety aspects of androgen therapy. In: Nieschlag E, Behre HM (eds): Testosterone: Action, Deficiency and Substitution. Berlin: Springer-Verlag, 1990: 182-203. Androgen and the ageing male Tenover JL. Androgen therapy in aging men. In: Bhasin S, Gabelnick HL, Spieler JM, et al (eds): Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. New York: Wiley-Liss, 1996: 309-318. Androgen abuse Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 1996; 335: 1-7. Handelsman DJ, Gupta L. Prevalence and risk factors for anabolic-androgenic steroid abuse in Australian secondary school students. Int J Androl 1997; 20: 159-164. Lin GC, Erinoff L (eds). (1990). Anabolic Steroid Abuse. National Institute on Drug Abuse Research Monograph Series. Rockville, US Department of Health and Human Services. Wilson JD. Androgen abuse by athletes. Endocr Rev 1988; 9: 181-199. Yesalis CE, Kennedy NJ, Kopstein AN, Bahrke MS. Anabolic-androgenic steroid use in the United States. JAMA 1993; 270: 1217-1221. Young NR, Baker HWG, Liu G, Seeman E. Body composition and muscle strength in healthy men receiving testosterone enanthate for contraception. J Clin Endocrinol Metab 1993; 77: 1028-1032. Authors' details Endocrine Society of Australia, Sydney, NSW. Ann J Conway, MB BS, FRACP; David J Handelsman, MB BS, PhD, FRACP; Douglas W Lording, MB BS, FRACP; Bronwyn Stuckey, MB BS, FRACP; Jeffrey D Zajac, PhD, FRACP. Reprints will not be available from the authors. Correspondence: Associate Professor J D Zajac, Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC 3050. j.zajacATmedicine.unimelb.edu.au Make a comment 1: Use, misuse and abuse of androgens Use Physiological (androgen deficiency) 1-3 Classical androgen deficiency ("hypogonadism") Age-related partial androgen deficiency Micropenis (neonatal) Delayed puberty Aged men* Androgen deficiency secondary to chronic disease* Induced androgen deficiency Hormonal male contraception* Pharmacological (non-androgen deficiency)4-6 Osteoporosis Anaemia due to marrow or renal failure Advanced breast cancer Excessively tall stature in boys Misuse Inappropriate indications In absence of proven androgen deficiency: Male infertility Sexual dysfunction/impotence "Male menopause", "andropause" Older men (>65 years) Non-specific symptoms Abuse19-24 Absence of medical indication Sporting Competitive power sports (athletics, weightlifting, football, swimming, rowing, boxing) RecreationalBodybuilding Cosmetic"Body beautiful" subculture OccupationalSecurity, police, armed forces, professional sports * These indications remain to be fully evaluated for safety and efficacy in controlled clinical trials. Back to text 2: Biochemical evaluation of the diagnosis of androgen deficiency in men with clinical features consistent with hypogonadism* Testosterone level†Luteinising hormone level†Diagnosis<8 nMHigh‡Androgen deficiency (hypergonadotropic hypogonadism§)<8 nMNot highAndrogen deficiency (hypogonadotropic hypogonadism§)8-15 nMHigh‡Androgen deficiency (Leydig cell failure)8-15 nMNot highAndrogen deficiency not confirmed: unproven therapeutic benefit of androgen replacement therapy>20 nMAnyExcludes androgen deficiency>30 nM**High‡Androgen resistance*There is necessarily an arbitrary component to this type of table. It is based on current experience and should be subject to changes according to further clinical evidence. †Blood sample classification based on at least two separate morning blood samples. ‡"High" luteinising hormone level is defined as > 1.5 times the upper limit of the eugonadal reference range for young men. §Hypergonadotropic and hypogonadotropic hypogonadism are also referred to as primary and secondary hypogonadism, respectively. Compensated Leydig cell failure is a form of partial androgen deficiency in which androgen replacement is often beneficial. **Elevated testosterone is defined as above the upper limit of the eugonadal reference range for young men. Back to text 3: Androgen treatment modalities7-13 Testosterone implants Fused cylindrical pellets of pure crystalline testosterone that form a subdermal depot Provide stable, physiological levels of testosterone for 4-6 months following a single implantation of four 200 mg (800 mg) implants Implantation uses a trochar and cannula technique under office sterile conditions, and requires local anaesthesia Main adverse effect is extrusion of implants via the insertion site 1-2 months after implantation Extrusion rate (about 10%) depends on operator experience and patient's physical activity Minor adverse effects related to the minor office surgery (bleeding, infection) are infrequent (<5%) Should only be used for patients who have demonstrated satisfactory tolerance of androgen effects with shorter-acting preparations Transdermal testosterone Administered daily via androgen-impregnated adhesive skin patches or hydroalcoholic gels (not yet available in Australia) Other depot testosterone formulations Newer injectable esters (testosterone undecanoate, testosterone buciclate) Testosterone-laden biodegradable microspheres Both these formulations deliver stable, physiological testosterone levels for 2-3 months following injection Oral testosterone undecanoate Useful where parenteral testosterone is undesirable (eg, bleeding disorders or anticoagulation) or poorly tolerated Administered as 160-240 mg (four to six 40 mg capsules), divided into 2-4 doses per day Second-line formulation for routine ART, because of frequency of administration, high hepatic load, gastrointestinal intolerance, and higher cost Back to text

Ann J Conway · David J Handelsman · Douglas W Lording · Bronwyn Stuckey · Jeffrey D Zajac

New Drugs, Old Drugs Osteoporosis prevention and treatment Phillip N Sambrook and John A Eisman MJA 2000; 172: 226-229 Abstract - Introduction - Overview of the evidence - Recommendations - Disclosure - References - Authors' details - - More articles on Endocrinology Abstract Patients with low bone density or any prior low trauma fracture should be considered for therapeutic intervention. Oestrogen replacement therapy remains the first choice for prevention of bone loss in early postmenopausal women with low bone density In postmenopausal women with existing fractures, the rank order of treatments is firstly alendronate, secondly raloxifene and thirdly less potent bisphosphonates, such as etidronate, or active vitamin D metabolites, such as calcitriol. For men with osteoporosis, if hypogonadism is present, it should be treated with testosterone replacement therapy. Despite limited data, a bisphosphonate should then be considered in conjunction with calcium. Supplementation with simple vitamin D should be considered in elderly patients who are housebound or live in institutions, as they are at risk of vitamin D deficiency and osteomalacia. Introduction The prevention and treatment of osteoporosis (low bone density) was reviewed at the Australian Consensus Conference on Osteoporosis, held in 1996, and a series of position statements about its management were developed.1 For the treatment of postmenopausal osteoporosis, these statements ranked hormone replacement therapy (HRT) with oestrogen as first-line therapy for most patients, but in those intolerant or unable to take this medication the rank order of choice was considered to be alendronate, followed by etidronate or calcitriol. Since that meeting, the results of new trials with drugs such as raloxifene, further efficacy data for bisphosphonates, and postmarketing safety data for alendronate and calcitriol have become available. Moreover, increased dietary calcium intake and phyto-oestrogens are promoted in the media. The benefit of all these various agents versus their risk of side effects in this epidemic condition is gradually becoming clearer. Overview of the evidence Drugs used for treating and preventing osteoporosis, and the relevant evidence for this, are discussed below, and brief drug profiles, including recommended doses, are given in Box 1. Calcium Controlled trials6 have shown that calcium supplementation can prevent bone loss in postmenopausal women (E1) (see Box 2 for an explanation of level-of-evidence codes) and this has been associated with a modest reduction in fracture risk in longer-term studies (E2). There is also evidence (E1) to suggest calcium supplementation augments the effect of oestrogen on bone density.8 Gastrointestinal absorption appears to be similar from milk or soy-drink products and supplements. As most controlled trials of new agents have used calcium as baseline therapy, it is appropriate to add a calcium supplement to most active agents described below. Calcium supplements have a better bone-sparing effect when taken at night. Vitamin D A study in institutionalised elderly people in France showed treatment with calcium plus vitamin D significantly reduced the rate of hip fractures (E2),9 but a similar effect could not be shown in those who lived in the community.10 Australian data also indicate a substantial proportion of institutionalised (or housebound) elderly people may be vitamin D deficient,11 and the observed reduction in fractures in the French study may have reflected treatment of subclinical osteomalacia. Hence, vitamin D supplementation is recommended in institutionalised or housebound elderly people who have limited exposure to sunlight. Calcitriol Calcitriol is the active hormonal form of vitamin D. Controlled trials of its effect on bone density have shown conflicting effects,12,13 with studies showing increases, no change or even apparent loss of bone density with calcitriol therapy (although suboptimal doses may account for some of these discrepancies). A recent larger study suggests the effect on bone density is less than that seen with oestrogen.14 One large controlled trial addressing the efficacy of calcitriol in preventing fractures found a threefold difference in vertebral deformity rates favouring calcitriol15 (E2), but used a less strict fracture criterion than in more recent studies. In that study, fracture rates remained stable in calcitriol-treated patients but increased in the calcium-treated patients. Calcitriol treatment may be appropriate in patients with known or presumed calcium malabsorption. Although calcitriol is approved for osteoporosis in men in Australia, a recent small study suggested that calcitriol may be less effective than calcium supplementation alone.16 Etidronate Etidronate was the first bisphosphonate developed for clinical use, and there is extensive experience of its use in Paget's disease. There have been a number of relatively small controlled trials with etidronate, showing increases in bone density averaging 5% over 2-3 years17 and suggesting a 50% reduction in vertebral fracture rate (E1). However, these trials also used fracture criteria less strict than those used in more recent clinical trials.18-21 Non-randomised studies based in general practice suggest its effectiveness increases with duration of use.3 Alendronate Several controlled clinical trials of the bisphosphonate alendronate have shown a reduction of vertebral, and even peripheral, fracture rates by about 50%18-20 (E1). Some, but not all, studies have shown a reduction in hip fracture rates.4,19 Reduction of fracture rates was apparent in individuals with bone mineral density (BMD) T scores below - 2.5 (T scores are multiples of the standard deviation from the population mean, based on a young, healthy, sex-matched reference population), even without prior fractures,20 suggesting an important threshold at which to consider intervention. Oestrogen While calcium supplementation may reduce bone loss, a number of controlled clinical trials with oestrogen have shown long-term increases in bone density averaging 5% over three years (E1).22 Lower doses may be effective with concomitant calcium.8 Although only a few randomised clinical trials have addressed the effect on fractures,23,24 epidemiological studies indicate antifracture efficacy at all sites for oestrogen is comparable to that of other agents (E32).25 Epidemiological studies also suggest primary cardioprotective effects of oestrogen. However, this was not observed in a recent trial of the effects of oestrogen on secondary prevention of cardiovascular mortality and morbidity, despite improvements in surrogate measures of efficacy such as total and low density lipoprotein cholesterol levels.26 Raloxifene This selective oestrogen-receptor modulator, as well as acting to decrease bone resorption, improves lipid profiles (thought to be surrogates for cardiovascular risk) and reduces breast cancer incidence (in studies at 3.5 years).27 Importantly, raloxifene does not cause breast or uterine symptoms. Controlled clinical trials have shown modest increases in bone density, generally somewhat less than those seen with hormone replacement therapy.28 However, a 50% reduction in vertebral, but not as yet peripheral, fractures has been observed (E2).21 This may be a statistical power effect and longer-term studies are ongoing. Anabolic steroids Forearm bone mass has been shown to increase modestly after treatment with nandrolone decanoate (E33), but at higher dosages and shorter intervals than are generally used in Australia. The effect on spinal bone density is unclear.29 Although nandrolone is commonly used in general practice in Australia, and may have a beneficial effect on muscle mass which may help to reduce the risk of falls in the elderly, there have been no studies showing antifracture efficacy. "Natural therapies" A variety of so called "natural" therapies, including soy, red clover (Promensil [Novogen]), black cohosh (Remifemin [Scinat]), wild yam and topical progesterone, are frequently used for treating menopausal symptoms in Australia. Soy products have been associated with small effects on bone density in animal studies.30 There are no studies addressing either their efficacy on fractures or long term safety in humans at this time. The risk of adverse events with these agents is unclear, as there have been no controlled studies of long-term safety. The efficacy and safety of these agents are yet to be documented in controlled clinical trials. Topical progesterone does not provide protection from endometrial changes of unopposed oestrogen in a woman with an intact uterus. Recommendations Adequate dietary calcium intake, regular exercise and avoidance of risk factors, such as smoking and excessive alcohol intake, are important lifestyle recommendations for preventing osteoporosis, but they have only modest efficacy. For people with low BMD, and particularly those with any prior low trauma fracture, these measures will be insufficient to prevent further osteoporotic fractures and pharmacological therapy must be considered. Box 3 shows an appropriate approach to managing osteoporosis in postmenopausal women. HRT remains the mainstay of therapy for osteoporosis, particularly in early postmenopause. Although most women are at relatively low risk of osteoporotic fracture for the first five to 10 years after menopause, this will vary according to their bone density and other risk factors, such as propensity to falls. Although "natural" therapies may have some effect on menopausal symptoms, there is currently no evidence for their efficacy or safety in the prevention or treatment of osteoporosis. Older postmenopausal women, especially those with existing fractures, are at high risk of further osteoporotic fractures. The rank order of treatments of osteoporosis in this group, based on the current published evidence, is alendronate, followed by raloxifene, before less potent bisphosphonates, such as etidronate, or active vitamin D compounds, such as calcitriol. Simple vitamin D should be considered in house-bound or institutionalised elderly people, who are at risk of vitamin D deficiency and osteomalacia. Dietary calcium supplementation should be used in conjunction with all of the above therapies except calcitriol, with which overall calcium intake should be limited. For men with osteoporosis, hypogonadism, if present, should be treated with testosterone replacement therapy. In the absence of hypogonadism, although there are limited data, the rank order of treatment of osteoporosis in men is a bisphosphonate and calcium supplementation. Most importantly, the benefit in fracture prevention from treatment increases progressively with worsening osteoporosis. As a result, while it is never too early to consider prevention, it is never too late to start treatment. Failure to at least consider therapeutic options in a patient who has sustained an osteoporotic fracture is not reasonable medical practice. As in many other chronic diseases, no therapy can be effective without long term compliance. This is strongly dependent on regular positive feedback to patients from their general practitioners. Important messages for patients are given in Box 4. Disclosure The authors act as advisers to, and receive funding from, Roche; Merck, Sharpe & Dohme; Lilly; Pharmacia & Upjohn; Aventis; Novartis; and the Australian Dairy Corporation. References O'Neill S, Eisman JA, Glasziou P, et al. The prevention and treatment of osteoporosis [consensus statement]. Med J Aust 1997; 167 (Suppl): S4-S15. Calcitriol and hypercalcaemia. Aust Adverse Drug React Bull 1997; 16: 2. Van Staa T, Abenheim L, Cooper C. Upper gastrointestinal adverse events and cyclical etidronate. Am J Med 1997; 103: 462-467. A gut feeling for alendronate. Aust Adverse Drug React Bull 1999; 18 (3): 11. Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. New Engl J Med 1995; 332: 1589-1593. Nordin BEC. Calcium and osteoporosis. Nutrition 1997; 13: 664-686. National Health and Medical Research Council. A guide to the development, implementation and evaluation of clinical practice guidelines. Canberra: NHMRC, AusInfo 1999. Nieves JW, Komar L, Cosman F, Lindsay R. Calcium potentiates the effect of oestrogen and calcitonin on bone mass: review and analysis. Am J Clin Nutr 1998; 67: 18-24. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. New Engl J Med 1992; 327: 1637-1642. Lips P, Graafmans WC, Ooms ME, et al. Vitamin D supplementation and fracture incidence in elderly persons. Ann Intern Med 1996; 124: 400-406. Brock KE, Reid JF, Greenoak GG, Fraser DR, The effect of sunlight on 25-hydroxy vitamin D plasma levels in an elderly Sydney population [abstract]. Australian and New Zealand Bone and Mineral Society Proceedings, 1997, Abstract No. 38. Gallagher JC, Goldgar D. Treatment of postmenopausal osteoporosis with high dose synthetic calcitriol. Ann Intern Med 1990; 113: 649-655. Ott SM, Chestnut CH. Calcitriol is not effective in postmenopausal osteoporosis. Ann Intern Med 1989; 110: 267-274. Gallagher JC, Fowler S. Effect of estrogen, calcitriol and a combination of estrogen and calcitriol on bone mineral density and fractures in elderly women [abstract]. J Bone Mineral Res 1999; 14: Abstract no. T364. Tilyard MW, Spears GF, Thomson J, Dovey S. Treatment of postmenopausal osteoporosis with calcitriol or calcium. New Engl J Med 1992; 326: 357-362. Ebeling PR, Yeung S, Poon C, et al. Effects of baseline active calcium absorption on bone mineral density responses to calcitriol or calcium treatment in men with idiopathic osteoporosis [abstract]. J Bone Mineral Res 1999; 14: Abstract no. SA419. Storm T, Thamsborg G, Steiniche T, et al. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in postmenopausal osteoporosis. New Engl J Med 1990; 322: 1265-1271. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. New Engl J Med 1995; 333: 1437-1443. Black DM, Cummings SR, Karpf D, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348: 1535-1541. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures. JAMA 1998; 280: 2077-2082. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3 year randomised controlled trial. JAMA 1999; 282: 637-645. Writing group for the PEPI trial. Effects of hormone therapy on bone mineral density. JAMA 1996; 276: 1389-1396. Lufkin EG, Wahner HW, O'Fallon WM, et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med 1992; 117: 1-9. Windeler J, Lange S. Events per person year -- a dubious concept. BMJ 1995; 310: 454-456. Cauley JA, Seeley, Ensrud K, et al. Estrogen replacement therapy and fractures in older women. Ann Intern Med 1995; 122: 9-16. Hulley S, Grady D, Bush T, et al. Randomised trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280: 605-613. Cummings SR, Eckert S, Krueger KA. The effect of raloxifene on risk of breast cancer in postmenopausal women. JAMA 1999; 281: 2189-2197. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effect of raloxifene on bone mineral density, serum cholesterol concentrations and uterine endometrium in postmenopausal women. New Engl J Med 1997; 337: 1641-1647. Flicker L, Hopper JL, Larkins RG, et al. Nandrolone decanoate and intranasal calcitonin as therapy in established osteoporosis. Osteoporosis Int 1997; 7: 29-35. Arjmandi BH, Birnbaum R, Goyal NV, et al. Bone sparing effect of soy protein in ovarian hormone deficient rats is related to its isoflavone content. Am J Clin Nutr 1998; 68 (Suppl): 1364S-1368S. Authors' details The Institute of Bone and Joint Research, University of Sydney, Royal North Shore Hospital, Sydney, NSW. Phillip N Sambrook, MD, FRACP, Professor of Rheumatology. Garvan Institute, St Vincent's Hospital, Sydney, NSW. John A Eisman, PhD, FRACP, Professor of Medicine, and Head of Bone and Mineral Research Program. Reprints will not be available from the authors. Correspondence: Professor P N Sambrook, The Institute of Bone and Joint Research, Level 4, Block 4, Royal North Shore Hospital, St Leonards, NSW 2065. sambrookATmed.usyd.edu.au Make a comment 1: Profiles of agents for prevention and treatment of osteoporosis Calcium Action: Calcium is weakly antiresorptive and supplementation may reduce negative calcium balance and so reduce bone resorption, particularly in older patients. Dosing: Balance studies suggest a daily intake of 1500mg per day is required in postmenopausal women not using hormone replacement therapy. Adverse effects: Calcium is a relatively safe medication but may cause mild gastrointestinal intolerance. The risk of renal calculi is very low except in those at risk. Vitamin D Action: Vitamin D undergoes several metabolic steps in the body, so it is important to distinguish between simple vitamin D and its active metabolites (such as calcitriol), which have distinctly different pharmacological profiles. Simple vitamin D can be converted to calcitriol, and has a similar, but less potent, effect on increasing gastrointestinal absorption. Dosing: Simple vitamin D is mainly available in Australia as ergocalciferol (1000IU per capsule; Ostelin 1000; Boots Healthcare Australia). It is no longer available on the Pharmaceutical Benefits Scheme, but is a relatively inexpensive over-the-counter medication. Small amounts of vitamin D are contained in some calcium and vitamin supplements (eg, Caltrate + Vitamin D [Whitehall Laboratories] contains 200IU per tablet and cod liver oil tablets approximately 400IU). An appropriate dose for supplementation is 1000IU daily. Adverse effects: Chronic ingestion of large doses of vitamin D, usually at doses in excess of 50000 to 100000IU per day, is required to produce hypercalcaemia in normal patients. Thus, given the amounts of vitamin D contained in available preparations, intoxication is practically impossible. Calcitriol Action: The primary action of calcitriol is thought to be to increase gastrointestinal calcium absorption, and so indirectly reduce bone resorption. It may also increase bone formation, but at higher doses that may increase bone resorption. Dosing: The usual dose is 0.5mg daily. Adverse effects: Hypercalcaemia and hypercalciuria are uncommon in patients treated with the usual dose (above), but may occur in patients who increase their calcium intake substantially. Hence, calcium supplements should be avoided and dietary intake should be limited to less than 800mg daily. The Adverse Drug Reactions Advisory Committee (ADRAC) reported four cases of calcitriol-related hypercalcaemia in four years of postmarketing surveillance up to 1997.2 Etidronate Action: Etidronate is a first-generation bisphosphonate, and is relatively less potent in its effects on inhibiting bone resorption than later bisphosphonates. The balance of these effects can result in osteomalacia if the drug is used continuously in doses effective on bone resorption for osteoporosis. Dosing: In osteoporosis, etidronate is used in a cyclical regimen at 400mg daily usually for two weeks every three months to reduce the risk of mineralisation defects. Adverse effects: Etidronate has been associated with lower, but not upper, gastrointestinal events.3 The risk of mineralisation defect with the cyclical regimen is very low. Alendronate Action: This aminobisphosphonate is a potent inhibitor of bone resorption at doses that do not affect bone formation or mineralisation. Dosing: 10mg daily. Adverse effects: Clinical trials with alendronate have repeatedly shown no increase in adverse effects compared with control groups. However, there have been reports of oesophagitis after alendronate therapy, and recent postmarketing surveillance by ADRAC listed 331 adverse event reports among approximately 49000 patients in Australia taking alendronate.4 These included dyspepsia (44), nausea (43) and abdominal pain (37), and ulceration or stricture was confirmed endoscopically in 26 of 52 reports of oesophagitis. Although a causal relationship remains unproven, there appears to be a real but low incidence of upper gastrointestinal problems with alendronate. This is consistent with precautions in its administration requiring the patient to stay in an upright position and to fast for half an hour after taking it in the morning (as is required for adequate absorption). Oestrogen Action: Oestrogen is an antiresorptive drug, possibly mediated by effects on local release of various cytokines and growth factors in bone. Dosing: Conjugated equine, 0.625mg daily; piperazine oestrone sulfate, 1.25mg daily; transdermal oestradiol, 4mg patch. Adverse effects: Breast tenderness and abdominal swelling are not uncommon, but these problems usually settle, and starting with low doses can minimise them. Hormone replacement therapy has been associated with an increased risk of deep venous thrombosis. Transdermal routes of administration may reduce this risk. Controversy exists as to whether there may be an increased risk of breast cancer with long term oestrogen use. Studies that do suggest a small increase in risk indicate that they show no increase in risk in the first five years of treatment.5 Raloxifene Action: Like oestrogen, raloxifene is a selective oestrogen receptor modulator (SERM) which acts to decrease bone resorption, but, unlike oestrogen, it does not stimulate the breast or uterus. Dosing: 60mg daily. Adverse effects: An increased risk of venous thrombosis has been reported with raloxifene users, similar in extent to that seen with hormone replacement therapy. Unlike hormone replacement therapy, raloxifene is not useful for control of, and may worsen, menopausal symptoms. Anabolic steroids Action: Anabolic steroids are weak androgens and appear to exert a weak inhibitory effect on bone resporption. However, any effect on bone mass may in fact be secondary to effects on muscle mass. Dosing: Nandrolone decanoate, 50mg intramuscular injection every three weeks. Adverse effects: There is a high incidence of virilisation with these dosages and there are no long term safety data. Back to text 2: Level-of-evidence codes Evidence for the statements made in this article is graded according to the NHMRC system7 for assessing the level of evidence: E1Level I: Evidence obtained from a systematic review of all relevant randomised controlled trials. E2Level II: Evidence obtained from at least one properly designed randomised controlled trial. E31Level III-1: Evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or some other method). E32Level III-2: Evidence obtained from comparative studies with concurrent controls and allocation not randomised (cohort studies), case-control studies, or interrupted time series without a parallel control group. E33Level III-3: Evidence obtained from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group. E4Level IV: Evidence obtained from case-series, either post-test or pre-test and post-test. Back to text Back to text 4: Important messages for patients It is never too late to start treatment. A number of new therapies have been shown to significantly reduce fracture risk. The overall risk of gastrointestinal problems with bisphosphonates is low. The effects of natural therapies in preventing osteoporosis are unproven. Back to text

Phillip N Sambrook · John A Eisman

Healthcare Accidental paracetamol overdosing and fulminant hepatic failure in children Fiona K Miles, Ramananda Kamath, Stuart F A Dorney, Kevin J Gaskin and Edward V O'Loughlin MJA 1999; 171: 472-475 See also Hynson Abstract - Introduction - Methods - Results - Discussion - References - Authors' details - - More articles on Pathology Abstract Objective: To delineate clinical characteristics useful for identifying children with liver failure due to accidental paracetamol overdose. Design: Retrospective review of medical records of all patients admitted from 1985 to 1998 with fulminant hepatic failure. Setting: Royal Alexandra Hospital for Children, a tertiary referral centre for paediatric liver transplantation. Main outcome measures: Contribution of paracetamol to liver failure; other risk factors for liver failure; comparison of clinical features of paracetamol group and others. Results: 18 patients were identified. Eight were considered to have accidental paracetamol hepatotoxicity. In a further three, other risk factors were present but paracetamol was considered a major contributor to liver failure. The seven remaining patients had other risk factors for liver failure. Patients with paracetamol-induced liver failure usually had an acute prodromal illness with prolonged fasting and, at presentation, had encephalopathy, coagulopathy, very high transaminase levels, but disproportionately low total bilirubin levels. Five patients had hypoglycaemia. End-stage liver failure occurred in 4/11 of the paracetamol group compared with 7/7 of the others. Conclusion: Accidental paracetamol overdose is associated with fulminant hepatic failure in infants and children. Patients present with high transaminase levels and liver synthetic failure out of proportion to the level of serum bilirubin. Prompt identification of such patients is important as many recover with supportive therapy. Introduction Paracetamol is a commonly used antipyretic and analgesic medication; in 1996, it was the second most common drug used in Australia, with 4.75 million units dispensed.1 There is a large range in the preparations of doses available, and the potential for accidental overdose due to confusion over concentration and frequency of dosing is high.2Intentional paracetamol overdose is a well-recognised cause of fulminant liver failure.2 However, there are few reports of accidental overdose due to recurrent ingestion of high therapeutic doses in children.3-6 Alonso et al reported seven children with fulminant liver failure without obvious cause.5 All patients had ingested paracetamol, but serum paracetamol levels were not in the toxic range. The authors postulated that, although paracetamol may have contributed to the liver injury, it was not causative. Two other reports describe accidental multiple dosing causing liver failure in children, with many patients receiving doses in the recommended therapeutic range.3,6 Prodromal illness associated with prolonged fasting was also recognised as potentially important in the development of liver injury.4,5 Since 1985, the Royal Alexandra Hospital for Children has been a tertiary referral centre for paediatric liver transplantation. Over this period, 19 patients have presented with acute liver failure. Our aims were to review all cases of acute liver failure, to identify patients with accidental (overdose with therapeutic intent) paracetamol-induced liver failure, and to define clinical features which may be useful in identifying such cases. Methods All patients at the Royal Alexandra Hospital with fulminant hepatic failure -- severe acute liver injury with no pre-existing liver disease resulting in encephalopathy within eight weeks of onset -- are managed by members of the liver transplant service. We reviewed case records of such patients for a history of liver disease, presenting symptoms, pre-existing history of paracetamol ingestion, clinical status at presentation, laboratory investigations and outcome. Paracetamol hepatotoxicity was considered likely if patients with liver failure had: a history of paracetamol ingestion over several days, confirmed by the finding of paracetamol in the blood; and exclusion (by routine laboratory testing) of other known causes of acute liver failure, such as viral hepatitis (A, B, C, Epstein-Barr virus, cyto-megalovirus, HSV-6, varicella or adenovirus), drug- or toxin-induced hepatotoxicity, inborn errors of metabolism (Wilson's disease, α1-antitrypsin deficiency, and fatty acid oxidation abnormalities). Approval for our study was obtained from the hospital's institutional ethics committee. Results Ninteen patients were identified, aged 6-165 months. One adolescent developed liver failure from suicidal overdose (30 g), and made a complete recovery with conservative treatment; this patient was excluded from the study. Paracetamol hepatotoxicity Eleven of the remaining 18 patients had presumed paracetamol hepatotoxicity. The patient data shown in the Table represent peak levels of study parameters or stage of encephalopathy. All patients had coagulopathy, elevated transaminase levels, and abnormal total serum bilirubin. Eight patients (numbers 1-8, Table) were identified as having paracetamol overdose as the only risk factor for liver failure. All eight patients had a history of a prodromal illness for which they received paracetamol for 4-21 days prior to the identification of liver disease. Reported paracetamol intakes ranged from 20 to 200 mg/kg per day. Paracetamol was detected in the blood of all eight patients, and all were encephalopathic (stage I-III) at presentation. Patients 1, 2, 3, 5 and 7 were hypoglycaemic (blood glucose levels < 3 mmol/L) at admission. Liver failure resolved with supportive treatment in six of these patients; Patients 2 and 6 died while awaiting liver transplants. Patient 5 survived, but had severe neurological sequelae as a result of protracted hypoglycaemia and stage IV encephalopathy. Patient 4 was admitted to the intensive care unit, but was not initially recognised as having liver failure. Patients 9, 10 and 11 had probable paracetamol hepatotoxicity, but also had other risk factors for liver injury. Patient 9 had Ewing's sarcoma and had been receiving chemotherapy. Multiple doses of paracetamol had been administered in hospital before the onset of liver failure. At postmortem, hepatic centrilobular necrosis consistent with paracetamol hepatotoxicity was found. Patient 10 also had a history of paracetamol ingestion, although the quantity could not be determined from the history. However, a high level of paracetamol was detected in the blood. The patient had had one previous admission with mumps encephalitis, which resulted in epilepsy and mental retardation. He had also been taking sodium valproate for seizures for several years, with no evidence of liver abnormalities. The patient died of end-stage liver failure and post-mortem revealed severe centrilobular necrosis consistent with paracetamol- rather than valproate-induced liver injury. Patient 11 had a mild prodromal illness due to Epstein-Barr virus infection, but ingested large quantities of paracetamol and presented with the clinical picture as described for Patients 1-8. Coagulopathy precluded liver biopsy in this group of patients. Metabolic studies: Urinary metabolic studies failed to reveal abnormal metabolites indicative of fatty acid oxidation defects in Patients 1, 2, 5, 6, 7 and 8, and skin fibroblast assays for fatty acid oxidation defects were normal in Patients 3, 6, 7 and 8. For Patient 4, no metabolic studies were performed. Other causes of liver failure Seven patients presented with fulminating liver failure from other causes, including Wilson's disease (1), cytomegalovirus infection (1), hepatitis B virus infection (1), presumed viral hepatitis (3), and an adverse reaction to dapsone (1). All patients presented with evidence of severe synthetic failure (coagulopathy and hypoalbuminaemia) and hepatic encephalopathy. Distinguishing paracetamol hepatotoxicity The Figure compares the serum bilirubin levels plotted against alanine transaminase levels in both groups of patients. In contrast to patients with other causes of acute liver failure, patients with presumed paracetamol hepatotoxicity all had serum bilirubin levels less than 200 µmol/L, and most had alanine transaminase levels greater than 4000 IU/L. Hypoglycaemia was not detected in any of the patients with liver failure from causes other than paracetamol, and all patients in this group either died or received transplants. Discussion Clinical features Accidental paracetamol overdose was the likely cause of acute liver failure in most children in this series presenting to a single paediatric institution. Eight of the 18 patients had likely paracetamol-induced liver failure due to accidental overdose, and in a further three paracetamol was a major risk factor. A distinct clinical pattern emerges when the patients with definite or presumed paracetamol toxicity are compared with patients with other causes of fulminant hepatic failure. Patients with paracetamol toxicity presented with a non-specific prodromal illness, often with fasting and/or vomiting. At the time of hospitalisation they had evidence of severe synthetic failure, often with associated hypoglycaemia, coagulopathy and mild encephalopathy, but with disproportionately low bilirubin levels. Moreover, most patients recovered with supportive therapy. A history of paracetamol ingestion over several days is important in establishing the diagnosis of paracetamol toxicity. In our study, reported ingestion of as little as 20 mg/kg per day over a protracted period was associated with liver failure. Similar toxic dosage ranges have been reported in other studies of children,3,5 raising the question of whether some susceptible children could suffer acute liver failure as a result of therapeutic doses of paracetamol ingested over several days. However, it is important to emphasise that the paracetamol intake data reported in this study, as in previous published reports, rely on history alone. The dosages reported by parents could not be verified by other means. Whether therapeutic doses of paracetamol could result in liver failure in susceptible children remains unresolved owing to the poor quality of the existing paediatric data. Serum paracetamol levels Paracetamol was detected in the serum of patients with presumed paracetamol hepatotoxicity. Although other investigators have used a level of 0.04 mmol/L3,4 as indicative of toxicity, it is not clear that this is a meaningful level in an individual with repeated ingestions over several days. A level of 40 µmol/L or greater at 24 hours after the ingested dose is thought to predict the likely development of liver failure, as portrayed in the nomogram adapted by Rumack and Matthews.7 However, this nomogram was derived from adult patients presenting with liver failure from a single suicidal overdose. No studies have addressed the question of serum levels likely to predict hepatic failure after repeated doses. We observed that the possible role of paracetamol was, on occasion, discounted because paracetamol levels were lower than those predictive of the development of liver failure from the nomogram. Poor correlation between paracetamol levels and liver toxicity with accidental overdose has been observed in a large series of adult patients in whom less than 50% had peak serum levels greater than 10 µg/mL (40 µmol/L).4 Similarly, low levels were reported in a small series of children.5 Nevertheless, serum paracetamol levels should be measured routinely in the investigation of children presenting with acute liver failure as soon as possible after assessment, but should be interpreted with caution. A recent study of paracetamol toxicity in adults by Schiodt et al identified a distinct group of patients who developed liver dysfunction after accidental poisoning with therapeutic intent.4 This group of 21 patients had ingested frequent doses of paracetamol for pain relief. Toxicity may have been compounded by prior starvation.2 Mortality in that study (4/21) was similar to ours, but was substantially higher than in a group of adult patients with non-accidental overdose. Some doubts about the role of paracetamol in causing fulminant hepatic failure in the study by Schiodt et al have been raised, as a high proportion of patients had a history of concurrent alcohol abuse and dosage levels were considered by some to be too low to cause toxicity.8-11 In contrast to that study of adults, studies in children raise considerable concern that accidental paracetamol overdose causes liver failure in this age group.3,5 However, it is important to note that all the reported series in children (including our own) are anecdotal reports. No studies have included a control group or undertaken a case-control study design, although liver biopsies were performed in six of seven patients in one series.5 While one could argue that the association between accidental overdose and liver failure in children is speculative, several arguments support the likely association with paracetamol: Suicidal overdose in adults produces acute liver failure with a clinical and biochemical picture very similar to that reported in our study of overdose due to repeated ingestion. The presence of severe liver synthetic failure and encephalopathy with the pattern of liver function tests we describe (see Figure) is a very atypical presentation for most diseases which produce liver failure in children. In our study, four children had centrilobular necrosis on postmortem examination, a finding consistent with paracetamol hepatotoxicity. While some of the clinical characterisics, such as prodromal illness, hypoglycaemia, high transaminase levels and coagulopathy, would be consistent with Reye's syndrome,12 it is not likely that this diagnosis would explain the abnormalities which we attribute to paracetamol toxicity. Recent in-vitro and animal studies indicate that paracetamol or its metabolites impair mitochondrial metabolism, and this effect occurs before hepatocyte necrosis.13-15 In this regard, paracetamol hepatotoxicity demonstrates some remarkable clinical and biochemical similarities to some inborn errors of fatty acid oxidation which can present with fulminant liver failure.16 Despite several attempts to define a safe therapeutic regimen, there is still no consensus as to the appropriate dose, or even efficacy, in children. One report recommended single doses of 10-15 mg/kg four-hourly as a "safe maximum".17 However, Nahata et al demonstrated that paracetamol may accumulate substantially, with raised concentrations after therapeutic doses for two to three days, even with doses of 13 mg/kg 24-hourly.18 One study which did review the potential for chronic overdose in children was done by Penna et al,19 in which 190 of 299 paediatric inpatients received paracetamol for indications of fever and postoperative pain. Most were prescribed four-hourly doses, with potential for greater than 90 mg/kg per day. Nearly a quarter of the high doses were for children under 12 months of age. Although it can be argued that paracetamol "is commonly administered to children . . . for most febrile illnesses",5 and thus can be a frequent coincidental association, there is evidence that accidental overdose while ingesting high therapeutic doses of paracetamol for pain and fever relief may cause fulminating liver failure in children. Clinicians should be alerted to the possibility of paracetamol toxicity in an infant or child presenting with a prodromal illness associated with fasting and the regular ingestion of paracetamol over several days. Hypoglycaemia, severe synthetic failure and encephalopathy with very high transaminase levels (above 4000 IU/L) and a serum bilirubin level less than 200 µmol/L would support the diagnosis. It is important to distinguish this group of patients, as the prognosis for recovery is good with conservative therapy. If N-acetylcysteine is instituted early, liver transplantation may be avoided. References Commonwealth Department of Health and Family Services. Top 10 drugs. Australian Prescriber 1997; 20: 92. Vale JA, Proudfoot AT. Paracetamol (acetaminophen) poisoning. Lancet 1995; 346: 547-552. Heubi JE, Barbacci MB, Zimmerman HJ. Therapeutic misadventures with acetaminophen: hepatotoxicity after multiple doses in children. J Pediatr 1998; 132: 22-27. Schiodt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med 1997; 337: 1112-1117. Alonso EM, Sokol RJ, Hart J, et al. Fulminant hepatitis associated with centrilobular hepatic necrosis in young children. J Pediatr 1995; 127: 888-894. Rivera-Penera T, Gugig R, Davis J, et al. Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity. J Pediatr 1997; 130: 300-304. Rumack BH, Matthews H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55: 871-876. Walker AM. Acetaminophen toxicity in an urban county hospital [letter]. N Engl J Med 1998; 338: 543. Avorn J. Acetaminophen toxicity in an urban county hospital [letter]. N Engl J Med 1998; 338: 543-544. Rao RB, Hoffman RS. Acetaminophen toxicity in an urban county hospital [letter]. N Engl J Med 1998; 338: 544. Makin AJ, Williams R, Bernal W. Acetaminophen toxicity in an urban county hospital [letter]. N Engl J Med 1998; 338: 544. Diagnosis and treatment of Reye's syndrome. JAMA 1981; 246: 2441-2444. Burcham PC, Harman AW. Acetaminophen toxicity results in site-specific mitochondrial damage in isolated mouse hepatocytes. J Biol Chem 1991; 266: 5059-5054. Vendemiale G, Grattagliano I, Altomare E, et al. Effect of acetaminophen administration on hepatic glutathione compartmentation and mitochondrial energy metabolism in the rat. Biochem Pharmacol 1996; 52: 1147-1154. Nazareth WM, Sethi JK, McLean AE. Effect of paracetamol on mitochondrial membrane function in rat liver slices. Biochem Pharmacol 1991; 42: 931-936. Tyni T, Palotie A, Viinikka L, et al. Long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency with the G1528C mutation: clinical presentation of thirteen patients. J Pediatr 1997; 130: 67-76. Temple AR. Pediatric dosing of acetaminophen. Pediatr Pharmacol 1983; 3: 321-327. Nahata MC, Powell DA, Durrell DE, Miller MA. Acetaminophen accumulation in pediatric patients after repeated therapeutic doses. Eur J Clin Pharmacol 1984; 27: 57-59. Penna AC, Dawson KP, Penna CM. Is prescribing paracetamol "pro re nata" acceptable? J Paediatr Child Health 1993; 29: 104-106. (Received 25 Jun, accepted 2 Sep, 1999) Authors' details The Royal Alexandra Hospital for Children, Sydney, NSW. Fiona K Miles, MB ChB, Fellow in Intensive Care; Ramananda Kamath, MD, FRACP, Associate Professor and Staff Specialist, Department of Gastroenterology; Stuart F A Dorney, MB BS, FRACP, Staff Specialist, Department of Gastroenterology; Kevin J Gaskin, MD, FRACP, Professor and Staff Specialist, Department of Gastroenterology; Edward V O'Loughlin, MD, FRACP, Staff Specialist, Department of Gastroenterology. Reprints: Dr E V O'Loughlin, Department of Gastroenterology, The Royal Alexandra Hospital for Children, PO Box 3515, Parramatta, NSW 2124. tedoATnch.edu.au Clinical characteristics of 11 patients with liver failure due to paracetamolPatient: 1Age (months): 21Paracetamol dosage (mg/kg per day): 20 (21 days) & 171 (last day)Serum:Paracetamol level (µmol/L): 10 (D2)*Bilirubin level (µmol/L): 123Alanine transaminase level (IU/L): 9618PT INR: 3.3Hepatic coma stage: IIOutcome: ResolvedPatient: 2Age (months): 63Paracetamol dosage (mg/kg per day): 100 (6 days)Serum:Paracetamol level (µmol/L): 560 (D1)*Bilirubin level (µmol/L): 87Alanine transaminase level (IU/L): > 10 000PT INR: 9.7Hepatic coma stage: IVOutcome: Died (PM: centrilobular necrosis)Patient: 3Age (months): 36Paracetamol dosage (mg/kg per day): Very frequent oral and rectal dosesSerum:Paracetamol level (µmol/L): 30 (D2)*Bilirubin level (µmol/L): 70Alanine transaminase level (IU/L): > 10 000PT INR: 4Hepatic coma stage: IIOutcome: ResolvedPatient: 4Age (months): 77Paracetamol dosage (mg/kg per day): 200 (11 days)Serum:Paracetamol level (µmol/L): 30 (D6)*Bilirubin level (µmol/L): 19Alanine transaminase level (IU/L): 1216PT INR: 1.4†Hepatic coma stage: IIIOutcome: ResolvedPatient: 5Age (months): 31Paracetamol dosage (mg/kg per day): 71 (4 days)Serum:Paracetamol level (µmol/L): 160 (D1)*Bilirubin level (µmol/L): 143Alanine transaminase level (IU/L): > 10 000PT INR: > 20Hepatic coma stage: IVOutcome: Resolved, severe brain damagePatient: 6Age (months): 129Paracetamol dosage (mg/kg per day): 20 (7 days)Serum:Paracetamol level (µmol/L): 180 (D1)*Bilirubin level (µmol/L): 82Alanine transaminase level (IU/L): > 10 000PT INR: 5Hepatic coma stage: IVOutcome: Died (PM: centrilobular necrosis)Patient: 7Age (months): 6Paracetamol dosage (mg/kg per day): UnknownSerum:Paracetamol level (µmol/L): 160 (D1)*Bilirubin level (µmol/L): 94Alanine transaminase level (IU/L): 9 170PT INR: 6.9Hepatic coma stage: IIIOutcome: ResolvedPatient: 8Age (months): 54Paracetamol dosage (mg/kg per day): 74mg/kg/day (5 days) & 150mg/kg/day (final day)Serum:Paracetamol level (µmol/L): 900 (D1)*Bilirubin level (µmol/L): 57Alanine transaminase level (IU/L): 8 300PT INR: 5.4Hepatic coma stage: IIOutcome: ResolvedPatient: 9Age (months): 79Paracetamol dosage (mg/kg per day): Unknown (frequent dosing over several days)Serum:Paracetamol level (µmol/L): 70 (D1)*Bilirubin level (µmol/L): 185Alanine transaminase level (IU/L): 4 300PT INR: 3.1Hepatic coma stage: IVOutcome: Died (PM: centrilobular necrosis)Patient: 10Age (months): 132Paracetamol dosage (mg/kg per day): UnknownSerum:Paracetamol level (µmol/L): 180 (D1)*Bilirubin level (µmol/L): 195Alanine transaminase level (IU/L): 3 620PT INR: 4.2Hepatic coma stage: IVOutcome: Died (PM: centrilobular necrosis)Patient: 11Age (months): 106Paracetamol dosage (mg/kg per day): 175 (7 days)Serum:Paracetamol level (µmol/L): 80 (D3)*Bilirubin level (µmol/L): 102Alanine transaminase level (IU/L): 6 700PT INR: 2.4Hepatic coma stage: IIIOutcome: Resolved* Days post admission to hospital. †Alanine transaminase level and INR measured on admission to hospital but not subsequently, despite deterioration of coma stage. PM = postmortem. OD = overdose. PT-INR = international normalised ratio (of prothrombin time). Normal ranges: serum bilirubin, 1-15 µmol/L; alanine transaminase, 10-50 IU/L; INR, 1-1.2. Back to textBack to text

Fiona K Miles · Ramananda Kamath · Kevin J Gaskin · Edward V O'Loughlin