Pharmacology

Objective: To examine trends in adverse drug reactions (ADRs) in people aged 60 years or over causing admission to or an extended stay in Western Australian hospitals between 1981 and 2002.Design and setting: Secondary data analysis of case series.Patients: 43 380 patients admitted to WA public and private hospitals with an (International Classification of Diseases) ICD external cause code for an ADR, identified by the population-based WA Hospital Morbidity Data System.Main outcome measures: Age-specific, age-standardised and drug-specific rates of ADR-related hospital stays.Results: The age-standardised rate of ADR-related hospital stays increased from 2.5 per 1000 person-years (py) in 1981 to 12.9 per 1000 py in 2002. The largest increases occurred in those aged 80 + years (tenfold in men and sevenfold in women). The most common drug group involved was cardiovascular agents (17.5%), while anticoagulants (7.5%), cytotoxics (7.4%) and antirheumatics (6.8%) were the more specific drug classes most often implicated. ADRs from the last three classes of drugs were still rising at the end of the study, whereas ADRs from corticosteroids and antihypertensives peaked in 1996 and from opioids in 2000.Conclusions: Increases in hospital admissions or extended lengths of stay due to ADRs in WA have continued despite programs to promote rational and safer use of medicines. The sharp increase in ADRs from anticoagulants warrants attention to revised clinical guidelines.

Christel L Burgess BHlthSc(Hons) · C D’Arcy J Holman MB BS, MPH, PhD · Anthony G Satti BEd

An elevated concentration of low-density-lipoprotein cholesterol (LDL-C) plays a causal role in the development of coronary heart disease and ischaemic stroke. Placebo-controlled intervention studies of statin drugs for lowering LDL-C provide clear evidence of cardiovascular disease prevention. LDL-C concentration below 2.5 mmol/L is an arbitrary goal, and recent trials support the benefit of achieving this goal, or even lower levels. Pharmacological treatment is warranted in patients with high absolute risk of future cardiovascular events. Effective monotherapy is available for predominant hypercholesterolaemia and predominant hypertriglyceridaemia, but combination therapy may be required for severe cases or in those with mixed hyperlipidaemia. Side-effects are infrequent and usually mild, but widespread use of lipid-modifying medication demands caution because of the possibility of muscle or liver dysfunction or drug interactions.

Leon A Simons MD, FRACP · David R Sullivan FRACP, FRCPA

Alexandra A Bennett,* Jo-anne E Brien,† Peter S Macdonald‡ * PhD Candidate, † Professor of Clinical Pharmacy, University of Sydney, Sydney, NSW (address for correspondence: Therapeutics Centre, St Vincent's Hospital, Darlinghurst, NSW 2010); ‡ Associate Professor of Medicine, and Cardiologist, St Vincent's Hospital, Sydney, NSW. sashabATpharm.usyd.edu.au To the Editor: We wish to add our perspective to the article by Phillips et al. 1 Needs identified by GPs included education about the effectiveness and target dosing of angiotensin-converting enzyme (ACE) inhibitors and β-blockers, and improved communication. We wish to highlight the potential roles hospital and community pharmacists have in supporting GPs caring for patients with heart failure. It is expected that by 2010 there will be at least 25 patients with heart failure per GP and 100 per community pharmacy in Australia. A recent review of 100 patients with heart failure discharged from St Vincent’s Hospital (SVH) in New South Wales showed they were taking an average of 9.5 regular medications, two-thirds of which were cardiac medications. 2 Their average age was 70.5 years. They had an average of 7.3 diagnoses, including ischaemic heart disease, atrial fibrillation and osteoarthritis. They were commonly taking amiodarone, warfarin and digoxin. Six per cent of patients had taken cyclooxygenase-2 (COX-2) inhibitors before they were admitted to hospital. 2 While rates of ACE inhibitor (or angiotensin-II-receptor antagonist) and β-blocker use at discharge were high in patients with systolic dysfunction (84% and 65%, respectively), only a minority of patients were taking target doses (27% and 15%, respectively). This highlights the need for good communication between healthcare providers. Discharge letters are often illegible and do not necessarily prioritise issues or detail future management, such as stating whose responsibility it is to up-titrate the dose of ACE inhibitor or β-blocker. Electronic entry of medical information, including e-prescribing (currently being trialled in some hospitals), may assist. Some patients have typed medication cards from a pharmacist on discharge. However, this is not routine practice. Ideally, all patients should receive such cards with supporting information. Copies of this information should be provided for the GP and pharmacist. Such a system would support Australian Pharmaceutical Advisory Council guidelines for continuity of care. Since 2002, a pharmacist has consulted with patients in the SVH Heart Failure Clinic regarding medication and lifestyle issues. Problems identified are referred to the treating cardiologist. A pilot study of this service showed high patient satisfaction (T Hargraves, Pharmacist, St Vincent’s Hospital, personal communication). Such a service could also be provided by community pharmacists, perhaps linked to home medicines review. A pharmacist is also employed by the community multidisciplinary heart failure service based at SVH. These positions support patients and their carers as well as healthcare providers, including GPs, community and hospital pharmacists and nurses. Evidence for such roles for pharmacists is supported by US and UK data. 3 We propose that designs for future models of care for patients with heart failure should incorporate pharmacists.

Alexandra A Bennett · Jo-anne E Brien · Peter S Macdonald

CorrectionRe: “Bilateral acute angle closure caused by supraciliary effusions associated with venlafaxine intake” by de Guzman M H P, Thiagalingam S, Ong P Y and Goldberg I in the 7 February 2005 issue of the Journal (Med J Aust 2005; 182: 121-123). In the second paragraph of the “Clinical record”, the number “3” appears, instead of a multiplication symbol, in two places. The second sentence should read “Spectacle correction revealed compound hypermetropic astigmatism (right eye, +1.00 + 1.50 × 75°; left eye, +1.75 + 2.25 × 110°).” In the same article, the initial capital letter (“V”) of the first paragraph after the clinical record box is missing: the first word should be “Venlafaxine”. Similarly, in the article by Ng C V T [page 120] in the same issue, the initial capital letter (“M”) is missing: the first word of the first paragraph should be “Myasthenia”. The html and pdf versions of these articles were correct when published online.

Maria Hannah Pia de Guzman MD, DPBO · Sureka Thiagalingam MPH, MB ChB · Poh Yan Ong MD, MS · Ivan Goldberg MB BS, FRANZCO, FRACS

Clinical records Patient 1 In 2004, a 63-year-old woman presented to the emergency department with a 1-month history of nausea and intermittent vomiting. Three weeks before presentation she was empirically prescribed esomeprazole for management of dyspepsia. A week before presentation, she stopped taking this medication, as she suspected it was exacerbating the malaise, nausea and vomiting. On presentation, she was pale, with blood pressure of 160/60 mmHg and no signs of fluid overload. Dipstick urinalysis showed blood +, protein ++, and leukocytes. Serum creatinine level was 1878 μmol/L (reference range [RR], 60–125 μmol/L), and serum urea level, 42 mmol/L (RR, 2.5–6.5 mmol/L). A normochromic, normocytic anaemia was present (haemoglobin level, 87 g/L; RR, 130–180g/L), with no eosinophilia. Urine microscopy revealed isomorphic red blood cells, some white blood cells, but no casts. Urine culture showed no growth. On admission, the patient’s remaining medications (irbesartan [150 mg daily] and atorvastatin [40 mg at night]) were also withdrawn as a precautionary measure. As acute interstitial nephritis was suspected, she was treated with methylprednisolone (500 mg daily for 3 days) followed by oral prednisone (50 mg daily). Supportive haemodialysis was begun. On Day 4 of admission, a renal biopsy was performed; results were consistent with acute interstitial nephritis. Prednisolone therapy was continued for a total of 4 weeks on a tapering dose. Supportive dialysis was required for 4 days, by which time renal function had improved. However, at follow-up 8 months later, serum creatinine level remained abnormal at 187 μmol/L (Box 1). Patient 2 In the same year, a 63-year-old man presented to the emergency department with a 3-week history of nausea, vomiting, weight loss and oliguria. Five weeks before presentation, he was prescribed rabeprazole by his family physician as empirical treatment for nausea and dyspepsia. This was replaced by esomeprazole a week later, as symptoms had not resolved. The patient discontinued the latter after 2 weeks’ therapy (12 days before presentation), as he had still gained no relief of symptoms. Medications on presentation were irbesartan/hydrochlorothiazide (300/12.5 mg daily), amlodipine (10 mg daily) and rofecoxib (12.5 mg daily) as required. He had been taking these medications for the previous 3 years, but used rofecoxib infrequently. On presentation, the patient was pale, with no signs of fluid retention. Dipstick urinalysis showed blood ++, protein +, and trace leukocytes. Serum creatinine and urea levels were 1110 μmol/L and 31 mmol/L, respectively. Six months previously, serum creatinine level had been 109 μmol/L. The patient also had normochromic, normocytic anaemia (haemoglobin level, 90 g/L), with no eosinophilia. Urine microscopy revealed isomorphic red blood cells, granular casts, hyaline casts, some white blood cell casts, but no red blood cell casts. Urine culture showed no growth. A clinical diagnosis was made of acute interstitial nephritis induced by a proton-pump inhibitor (PPI). The patient was admitted to hospital and treated with prednisolone (60 mg daily). Renal biopsy 2 days later confirmed acute interstitial nephritis (Box 2). Renal function improved after admission, and serum creatinine level was 600 μmol/L on discharge 5 days after presentation. Subsequently, renal function declined slowly, and, 9 months after presentation, long-term peritoneal dialysis was begun. In these two cases of acute interstitial nephritis, esomeprazole was implicated as the likely causative agent (although Patient 2 was also briefly exposed to rabeprazole). In both cases, renal function improved after esomeprazole was withdrawn and corticosteroid treatment begun, although Patient 2 went on to require long-term dialysis. Omeprazole was first implicated as a cause of acute interstitial nephritis in 1992.1 Since then, 22 case reports of omeprazole-induced acute interstitial nephritis have been referenced in Medline. 2-7 Recently, pantoprazole and lansoprazole have also been implicated as causes of acute interstitial nephritis, 3,8 along with rabeprazole (unpublished data from our centre). Before the cases reported here, the Adverse Drug Reactions Advisory Committee (ADRAC) had been notified of four cases of acute interstitial nephritis induced by esomeprazole, along with six cases of acute renal failure and two of renal impairment. In October 2004, the manufacturer of esomeprazole, AstraZeneca, reported being aware of at least 15 cases worldwide of acute interstitial nephritis possibly induced by esomeprazole, and at least 200 cases worldwide induced by omeprazole (data on file, Astra-Zeneca). Two of these esomeprazole cases and 20 of the omeprazole cases were from Australia (it is unclear whether these two esomeprazole cases were included in those notified to ADRAC). MIMS online lists acute interstitial nephritis as a complication of omeprazole but not esomeprazole.9 A recent hospital series reported drug-induced acute interstitial nephritis as the cause of biopsy-proven acute renal failure in 8% of cases, with PPIs accounting for eight of the 14 cases. 2 The diagnosis of acute interstitial nephritis is most common when renal biopsy is performed for unexplained renal impairment, with a reported prevalence in this setting of 27%.10 PPI-induced acute interstitial nephritis poses a particularly difficult diagnostic challenge, as symptoms are non-specific and may mimic the original indications for which the PPI was prescribed. Most patients diagnosed with PPI-induced acute interstitial nephritis recover renal function, but some fail to recover fully and, in extreme cases, require long-term renal replacement therapy, 2 as in Patient 2. Little is known about the relationship between the risk of PPI-induced acute interstitial nephritis and duration and dosage of PPI therapy, delay in diagnosis, or other factors. In addition, it is not clear whether the prognosis differs between acute interstitial nephritis induced by PPIs and that induced by other drugs. Although both our patients were treated with corticosteroids, evidence for their use remains anecdotal and is not derived from randomised controlled trials. A recent report of the largest retrospective series published to date found no statistically significant difference in outcome, as determined by serum creatinine level, between patients who received corticosteroid therapy and those who did not at 1, 6 and 12 months after presentation.11 PPIs are now the third most commonly prescribed drug in Australia. Although acute interstitial nephritis is a rare complication, it is a potentially catastrophic cause of acute and chronic renal failure. All medical practitioners need to be aware of this potential class reaction. Early recognition may prevent the development of irreversible renal injury. Lessons from practice Acute interstitial nephritis is a rare but serious adverse effect of proton-pump inhibitor (PPI) therapy, which may potentially lead to chronic kidney failure. Acute interstitial nephritis has now been described in association with all PPIs currently marketed in Australia. The initial symptoms of PPI-induced acute interstitial nephritis are usually non-specific, often mimicking the symptoms of dyspepsia for which the PPI was initially prescribed. A high index of suspicion is needed, and serum creatinine level should be checked promptly if the diagnosis is suspected. 1 Serum creatinine level over time after presentation in Patient 1 Shaded area indicates the reference range, 60–125 μmol/L. 2 Renal biopsy specimen in Patient 2 Biopsy specimen from the renal cortex taken 2 days after presentation, showing an interstitial inflammatory infiltrate composed of lymphocytes and eosinophils (I), with mild acute tubular necrosis and a cellular cast (C). (Original magnification × 40; haematoxylin–eosin stain.)

Nimeshan Geevasinga BSc · Lukas Kairaitis FRACP · Gopala K Rangan FRACP · Patrick L Coleman MRCI, FRACP

Vanessa M McDonald,* Peter G Gibson† * Clinical Nurse Consultant, † Professor, Department of Respiratory and Sleep Medicine, John Hunter Hospital, Locked Bag 1, Hunter Region Mail Centre, Newcastle, NSW 2310. Peter. GibsonAThunter.health.nsw.gov.au To the Editor: The delivery of asthma drugs via inhalation offers the best balance between efficacy and safety. However, poor inhalation technique limits the efficacy of this approach. In recent years, there has been a progressive increase in the types of inhalation devices used in asthma management. We questioned whether this would lead to “inhaler-device polypharmacy”, a situation in which an individual used multiple types of inhalation device to deliver his or her asthma medications. We conducted a novel investigation of this issue in 2004. We examined the computerised records of adults with asthma who had been enrolled in a standardised, evidence-based asthma management and education program1 between 2000 and 2004. We noted the number and type of inhaler devices used, as well as competence with each device (a trained asthma educator had observed and scored inhalation technique). We defined “inhaler-device polypharmacy” as the use of two or more different types of inhalation device. The devices assessed in the education program included a pressurised metered-dose inhaler (with and without a spacer), turbuhaler, accuhaler, aeroliser, autohaler, and handihaler. Nebuliser use was not included in the evaluation. We assessed a total of 511 patients: 278 (107 male; mean age, 37 years) between 1 January 2000 and 1 January 2002 (Period 1), and 233 patients (55 male; mean age, 40 years) between 2 January 2002 and 1 January 2004 (Period 2). Period 1 patients were distinct from Period 2 patients in that the latter began their treatment after the release of combination asthma therapy in a single inhaler, when polypharmacy may have been expected to diminish. Inhaler-device polypharmacy was present in 203 (73%; 95% CI, 68%–78%) patients during Period 1 and 164 (70%; 64%–75%) in Period 2 (P = 0.3) (Box). In Period 1, inhalation technique was inadequate with at least one device in 58 (29%) patients using inhaler polypharmacy and in 19 (25%) using only one device (Box). In Period 2, inhalation technique was inadequate with at least one device in 85 (52%) patients using inhaler polypharmacy and in 25 (36%) using only one device. In both Period 1 and Period 2 patients, inadequate inhaler technique with at least one device increased with the number of devices used (P values 0.02 and 0.05, respectively) (Box). We conclude that inhaler-device polypharmacy is a common problem among adults with asthma. Inadequate inhalation-device technique is also common, especially among patients using three or more delivery devices. Inhaler-device polypharmacy could lead to poor asthma control through inadequate delivery of medication. Patients with poor asthma control should be evaluated for their asthma management skills, including competency in using inhaler devices. These skills should be optimised before a new drug and/or device is added to their treatment regimen. We see no justification for the use of more than two inhalation delivery devices in asthma management. Number of asthma patients using single or multiple inhalation devices and proportion of those patients with inadequate technique, over two time periods One device Two devices Three or more devices Period 1* (n = 278) 75 (27%) 150 (54%) 53 (19%) Period 2† (n = 233) 69 (30%) 129 (55%) 35 (15%) Patients with inadequate inhalation-device technique Period 1* 19/75 (25%) 35/150 (23%) 23/53 (43%) Period 2† 25/69 (36%) 64/129 (50%) 21/35 (60%) * 1 Jan 2000–1 Jan 2002. † 2 Jan 2002–1 Jan 2004.

Vanessa M McDonald · Peter G Gibson

Luke R Bereznicki,* Shane L Jackson,† Gregory M Peterson‡ * PhD Candidate, † Research Fellow, ‡ Professor of Pharmacy, Unit for Medication Outcomes Research and Education, University of Tasmania, Private Bag 26, Hobart, Tasmania 7001. lberezniATutas.edu.au To the Editor: If a new drug such as ximelagatran is to be considered as a replacement for warfarin in preventing the thromboembolic complications associated with atrial fibrillation (AF), drug cost becomes an important issue. Brighton’s recent article in the Journal, 1 while comprehensive, does not discuss the cost-effectiveness of ximelagatran treatment. Ximelagatran was approved in several European countries for the prevention of venous thromboembolism associated with orthopaedic surgery. The cost of the drug for this indication (24 mg given twice daily) is 4.5 euros (A$7.7) per day.2 This represents the best available estimate of the cost of using ximelagatran for AF, although the dose is higher in AF (36 mg twice daily), and there are limitations in applying the drug cost in one country to another country. Routine monitoring of the antithrombotic effect of ximelagatran (ie, international normalised ratio [INR] testing) was not conducted in clinical trials. While this is potentially advantageous, frequent testing of alanine aminotransferase (ALT) levels is recommended at baseline and monthly for the first 6 months of therapy, every second month for the remainder of the first year, and every third month thereafter, for safety reasons.3 This is because some patients taking ximelagatran will develop elevated ALT levels (about 6.1% of patients to greater than threefold normal, and 3.4% to greater than fivefold normal) when ximelagatran therapy is commenced.3 The costs of INR and ALT tests are very similar (about $25 and $22, respectively). Although INR monitoring may be more frequent with warfarin than ALT testing with ximelagatran, the cost difference associated with therapeutic monitoring would remain far less than the likely cost of ximelagatran. We estimate the cost associated with treating 1000 patients with AF with ximelagatran instead of warfarin for 1 year, taking into account drug costs, monitoring costs and the slight difference in major bleeding rates, to be about $2.4 million (Box). A United States Food and Drug Administration advisory committee has recently raised concerns about the safety of ximelagatran (after episodes of severe liver damage), and has recommended that it not be granted any indication for use without further safety data. In particular, ALT monitoring did not prevent 3 deaths attributable to ximelagatran-associated hepatocellular necrosis.3 In light of the recent withdrawal of rofecoxib (Vioxx; Merck Sharp & Dohme), warfarin carries the intangible benefits of a long and proven track record. It certainly requires careful management and ongoing monitoring, but healthcare resources might be better spent on improving the use of warfarin rather than paying substantially increased costs for a drug with similar efficacy and an uncertain safety profile. Estimated costs of treating 1000 patients with atrial fibrillation (AF) with ximelagatran or warfarin for the first year of therapy. Ximelagatran* Warfarin† Total cost $2 803 821.00 $106 800.00 Cost per patient $2 803.82 $106.80 Monitoring Test (frequency/year) ALT (10)‡ INR (20)§ Total cost $217 000.00 $507 000.00 Cost per patient $217.00 $507.00 Major bleeding¶ Annual incidence** 1.6% 2.2% No. of expected events 16 22 Total cost $38 730.00 $53 253.00 Ischaemic stroke†† Annual incidence‡‡ 1.6% 1.6% No. of expected events 16 16 Total cost $101 936.00 $101 936.00 Overall cost Total $3 161 487.00 $768 989.00 Per patient $3 161.49 $768.99 Cost difference compared with warfarin Total $2 392 498.00 — Per patient $2 392.50 — ALT = Alanine aminotransferase. INR = International normalised ratio. * Cost of giving ximelagatran (24 mg twice-daily) to prevent venous thromboembolism post-surgery (German data; the dose for prevention of thromboembolism in AF is 36 mg twice-daily).3† Cost of warfarin taken from the Australian Pharmaceutical Benefits Scheme, December 2004. ‡ Monitoring cost derived from the cost of conducting ALT testing (Medicare Benefits Schedule, December 2004) according to the manufacturer’s directions (tests at baseline, monthly for the first 6 months, 2-monthly for remainder of the first year). § Cost derived from Medicare Benefits Schedule (December 2004) based on a frequency of 20 tests per annum. ¶ The cost of a hospital admission caused by a major bleed was $2420.60 in Australia for the years 2002–2003 (estimate based on 2002–2003 public hospital data).4 Intracranial haemorrhage may be associated with significant ongoing costs, but a smaller proportion of major bleeding incidents. ** No significant difference between warfarin and ximelagatran in either SPORTIF III5 or V;6 statistically significant when data from both trials were combined at P < 0.05. †† Cost ($6371) taken from the NEMESIS study7 and covers acute admission to an Australian hospital with ischaemic stroke only; this is an underestimate of the ongoing costs associated with ischaemic stroke. ‡‡ No significant difference between warfarin and ximelagatran in SPORTIF III5 and V;6 no significant difference when data from both trials were combined at P < 0.05.

Luke R Bereznicki · Shane L Jackson · Gregory M Peterson

Objectives: To describe the tolerability of mefloquine in Australian soldiers for malaria prophylaxis, including a comparison with doxycycline.Design: Open-label, prospective study and cross-sectional questionnaire and interview.Setting and participants: Two contingents of Australian soldiers, each deployed to East Timor for peacekeeping duties over a 6-month period (April 2001–October 2001 and October 2001–May 2002).Outcome measures: Withdrawals during the study; adverse events relating to mefloquine prophylaxis; willingness to use mefloquine again on deployment.Results: Of 1157 soldiers starting on mefloquine, 75 (6.5%) withdrew because of adverse responses to the drug. There were three serious adverse events of a neuropsychiatric nature, possibly relating to mefloquine. Fifty-seven per cent of soldiers using mefloquine prophylaxis reported at least one adverse event, compared with 56% using doxycycline. The most commonly reported adverse effects of both drugs were sleep disturbance, headache, tiredness and nausea. Of the 968 soldiers still taking mefloquine at the end of their deployments, 94% indicated they would use mefloquine again. Of 388 soldiers taking doxycycline prophylaxis who were deployed with the first mefloquine study contingent, 89% indicated they would use doxycycline again.Conclusions: Mefloquine was generally well tolerated by Australian soldiers and should continue to be used for those intolerant of doxycycline.

Scott J Kitchener MB BS, DrPH, FAFPHM · Peter E Nasveld MB BS, BMedSci(Hons), FACTM · Robin M Gregory BAppSc, MBus · Michael D Edstein MSc, PhD

There has been a relentless increase in resistance of malaria parasites to conventional antimalarial drugs, including chloroquine, sulfadoxine–pyrimethamine and mefloquine. In response to this situation, short-course artemisinin-based combination therapies (ACTs) have been developed. The World Health Organization has endorsed ACT as first-line treatment where the potentially life-threatening parasite Plasmodium falciparum is the predominant infecting species. ACTs combine the rapid schizontocidal activity of an artemisinin derivative (artesunate, artemether or dihydroartemisinin) with a longer-half-life partner drug. Although the use of chloroquine and sulfadoxine–pyrimethamine as partners in ACT improves their efficacy, this may only have value as a short-term measure in patients with a degree of immunity to malaria. Alternative currently available partner drugs include mefloquine, lumefantrine and piperaquine. Artesunate–mefloquine is highly effective but is expensive and side effects (mainly neurotoxicity) can be problematic. Artemether–lumefantrine, the only ACT available in Australia, appears less effective than artesunate–mefloquine and needs to be administered with food to ensure adequate bioavailability. Dihydroartemisinin–piperaquine is highly effective, well tolerated and relatively inexpensive. The goal of potent, safe, easy-to-administer and inexpensive ACTs may see trioxolanes in place of artemisinin derivatives, as well as novel partner drugs such as pyronaridine or naphthoquine, in the future.

Timothy M E Davis DPhil, FRACP · Harin A Karunajeewa FRACP · Kenneth F Ilett PhD

Peter R Mansfield,* Agnés I Vitry,† James M Wright‡ * Research Fellow, Department of General Practice, University of Adelaide, 34 Methodist Street, Willunga, SA 5172; † Senior Lecturer, QUMPPRC, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide; ‡ Professor, Department of Pharmacology & Therapeutics and Medicine, University of British Columbia, Vancouver, BC, Canada. peter.mansfieldATadelaide.edu.au To the Editor: Langton et al claim that “the celecoxib studies have not demonstrated an increased risk of thrombosis”.1 However, the European Agency for the Evaluation of Medicinal Products concluded that “there is a trend towards a higher MI [myocardial infarction] risk associated with the use of celecoxib compared with naproxen and diclofenac”, and decided that a warning statement was required for all cycloxygenase 2 (COX-2)-selective drugs.2 It is surprising that celecoxib may be worse than diclofenac, because diclofenac is similarly COX-2-selective as celecoxib.3,4 A retrospective analysis of the full CLASS study data for people not taking aspirin found the rates of serious thromboembolic cardiovascular events were celecoxib 1.4% and diclofenac 1.6%, as against 0.7% for ibuprofen.5 These differences were not individually statistically significant, but CLASS was underpowered for cardiovascular events. However, pooling the results for the two similarly COX-2-selective drugs versus ibuprofen reveals a significant difference (relative risk [RR], 2.1; 95% CI, 1.1–3.9). In the full CLASS data, celecoxib did not have a lower rate of complicated ulcers (RR, 0.83; 95% CI, 0.46–1.5) and there was a trend towards more serious adverse events of all types (RR, 1.17; 95% CI, 0.99–1.39) than in the combined ibuprofen and diclofenac groups.3,6 We conclude that the case against all COX-2-selective drugs has not been proven beyond doubt because they have not been studied adequately. However, on the balance of probabilities, they are all likely to have a similar propensity to rofecoxib to increase thrombotic cardiovascular events to some extent. This prothrombotic effect may be reduced by combining them with aspirin, but then the main gastrointestinal benefit is likely to be lost,3,4 so use of such combinations is not justified. Overall, celecoxib is no more effective, more expensive, no safer (and possibly less safe) than non-selective drugs. Meloxicam has not been shown to be any better. COX-2-selective drugs should not be used unless a subpopulation can be identified for whom these drugs have an advantage over the non-selective drugs. In theory, COX-2-selective drugs may be useful for a tiny group of people who are at greater risk of serious harm from gastrointestinal injury than from vascular events. However, there is no proven way to identify such people and there are no relevant trials to guide us. For example, no trials have been done in patients with a history of peptic ulcer. All COX-2-selective drugs should be removed from the market until they have been properly evaluated.

Peter R Mansfield · Agnés I Vitry · James M Wright

Leslie G Cleland,* Michael J James† * Director, † Chief Medical Scientist, Department of Rheumatology, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000 lclelandATmail.rah.sa.gov.au To the Editor: Langton et al document the history of rofecoxib approval in 1999 and withdrawal in 2004. 1 They also provide an outline of the possible mechanisms for increased cardiovascular risk, which we detailed in the Journal in August 2001. 2 Their editorial raises the issue of whether the increased cardiovascular risk is a class effect of all selective cyclooxygenase 2 (COX-2) inhibitors and notes that no increased risk has been identified to date with celecoxib use. While this is correct, the editorial omits to state that, although several drugs are categorised as “COX-2 inhibitors”, the selectivity for COX-2 over COX-1 inhibition varies greatly between different drugs (see Box). 3 Selectivity for COX-2 for different “COX-2 inhibitors”3 Drug COX-1 / COX-2 (IC50 ratio) Aspirin <0.5 Ibuprofen 0.5 Meloxicam 18 Diclofenac 29 Celecoxib 30 Rofecoxib 267 It is potentially significant that celecoxib is only modestly COX-2 selective compared with rofecoxib. Because COX-2-selective inhibition can lead to selective inhibition of vascular prostacyclin synthesis with little or no effect on vascular or platelet thromboxane synthesis,1 a highly selective COX-2 inhibitor such as rofecoxib is expected to disrupt the balance between antithrombotic prostacyclin and prothrombotic thromboxane. The relatively modest COX-2 selectivity of celecoxib may be one explanation for the lack of adverse cardiovascular effects demonstrated to date. It would also explain its lack of upper gastrointestinal tract protection relative to diclofenac, as both drugs have similar COX-2 selectivity.4 The newer coxibs, like rofecoxib, are significantly more COX-2-selective than celecoxib and, if this selectivity is the basis for the adverse cardiovascular events, then caution is needed with these newer agents. Although the editorial states that trials have not shown increased risk with the newer coxibs, this is not correct. On 15 October 2004, Pfizer announced that valdecoxib, when used for pain management in coronary artery bypass surgery, caused an increased number of adverse cardiovascular events.5 As the editorial states, the VIGOR study with rofecoxib in treating rheumatoid arthritis revealed a greatly increased incidence of adverse cardiovascular events compared with naproxen, and yet rofecoxib sales continued for another four years at a high level. 1 Perhaps the most important question for prescribers arising from the experience with rofecoxib is not whether clinical trial results are conclusive, but how should prescribers respond to apparent conflicts in the medical literature. In such a situation, resort to ethical and legal obligations for disclosure of information will be the prudent approach, as we have detailed.6 For prescribers considering the loss of rofecoxib, some perspective is provided by the following. The number needed to treat (NNT) to cause an increase in one fatal or non-fatal cardiac event in the VIGOR study was 225 (average trial duration was 9 months). In trials with statins in which coronary heart disease was absent at enrolment, the NNT per year to prevent one fatal or non-fatal coronary event was 217 to 256.7

Leslie G Cleland · Michael J James

Hari Manev,* Radmila M Manev† * Professor, † Assistant Professor of Clinical Psychiatry, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, MC912, Chicago, Illinois, 60612, USA hmanevATpsych.uic.edu To the Editor: In their editorial on the rofecoxib controversy, Langton et al point out that large-scale but inconclusive studies failed to recognise an increased risk of heart attack and stroke in patients treated with this cyclooxygenase 2 (COX-2) inhibitor.1 Might something still be learned from these studies? Both COX-2 and 5-lipoxygenase (5-LOX) use the same substrate (arachidonic acid) to produce prostaglandins and leukotrienes, respectively. Overactive 5-LOX increases the risk of heart attack and stroke,2,3 and may be involved in the comorbidity of these disorders with anxiety and depression.4 In contrast, COX-2 appears to be cardioprotective. 5 Genetic diversity is responsible for overactive 5-LOX in some individuals and increases their risk for cardiovascular pathology.2,3 It is likely that patients with these alleles might be more susceptible to cardiovascular pathology in the absence of COX-2 activity — that is, be at increased risk of rofecoxib-provoked myocardial infarction and stroke. If possible, retrospective studies should be attempted to determine the genotype of subjects treated with rofecoxib for 5-LOX2 and 5-LOX-activating protein3 polymorphisms and to relate these findings to rates of myocardial infarction and stroke.

Hari Manev · Radmila M Manev

Richard O Day,* Garry G Graham† * Professor of Clinical Pharmacology, University of New South Wales and St Vincent’s Hospital, Victoria Road, Darlinghurst, NSW 2010; † Emeritus Professor of Pharmacology, University of New South Wales, Sydney, NSW r.dayATunsw.edu.au To the Editor: We consider that it is important to comment on the views expressed by Langton et al on the limited value of paracetamol in the treatment of musculoskeletal pain.1 Langton et al recognise that paracetamol is widely recommended as first-line therapy to reduce chronic pain, but they largely dismiss its usefulness, noting that: . . . when used alone paracetamol appears to be less effective than NSAIDs and there are no studies of the safety of the long-term intake of paracetamol.1 However, paracetamol is widely recommended as the first-line drug treatment in the management of osteoarthritis. This is based on its efficacy and safety as compared with nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase 2 (COX-2) inhibitors. This position is supported by published guidelines, including those of the American College of Rheumatology2 and the European League of Associations of Rheumatology (EULAR).3 In these guidelines, NSAIDs are recommended for use in moderate to severe osteoarthritis pain (American College of Rheumatology guidelines) or where the pain is unresponsive to paracetamol (EULAR guidelines). Our own Australian Therapeutic Guideline series and National Prescribing Service publications similarly recommend paracetamol as first-line treatment in osteoarthritis4 (see National Prescribing Service, Fact Sheet 8, October 2004 <www.nps.org.au>). The efficacy of paracetamol in comparison with NSAIDs in patients with osteoarthritis has been demonstrated in patients treated for periods ranging from 3 weeks to 2 years, with total daily doses of paracetamol ranging from 2.6 g to 4.0 g,5 but this has been contentious.6,7 In a 2-year study involving 66 patients with osteoarthritis, Williams et al noted a higher withdrawal rate due to side effects in the naproxen group than in the paracetamol group, and slightly less efficacy in the paracetamol group.5 Pincus and colleagues reported that a third of patients receiving paracetamol continued on this treatment for more than 24 months, and that paracetamol was significantly less likely to be discontinued because of toxicity than NSAIDs.8 Thus, although paracetamol is on average less effective in pain reduction compared with NSAIDs,6 the difference in efficacy is small and a substantial proportion of patients can be treated satisfactorily and safely with paracetamol alone.9 Paracetamol remains the appropriate initial treatment for the management of osteo-arthritis. Other medications, such as NSAIDs or COX-2 inhibitors, can be added if patient response is unsatisfactory and the risk–benefit ratios are acceptable. When considering alternative options to rofecoxib, prescribers should also review the non-drug options, such as weight loss, physiotherapy, orthotics, and, where possible, opt for paracetamol first.10 Prescribers need to continue to be mindful of the potential for adverse effects with NSAIDs, particularly in high-risk patients or patients taking concomitant medications. The serious public health problem of upper gastrointestinal tract bleeding caused by NSAIDs is a major consideration in the management of patients with osteoarthritis and becomes more of an issue in the elderly, many of whom have osteoarthritis.

Richard O Day · Garry G Graham

Paul Langton,* Graeme Hankey,† John Eikelboom‡ * Cardiologist, Hollywood Private Hospital, Nedlands, WA; † Neurologist, Stroke Unit, ‡ Haematologist, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847 john.eikelboomAThealth.wa.gov.au In reply: Mansfield, Vitry and Wright take issue with our statement that the celecoxib studies have not shown an increased risk of thrombosis, but provide no data to support their claims, while Cleland and James highlight differences in COX-2 selectivity as a potential explanation for differences in the cardiovascular safety of coxibs. Recently published clinical data confirm an increased risk of cardiovascular events with rofecoxib but not celecoxib, 1 which is consistent with in-vivo studies suggesting that celecoxib but not rofecoxib improves endothelial function,2,3 as well as a significantly lower incidence of oedema and hypertension with celecoxib compared with rofecoxib.4 Nevertheless, we reiterate that it remains incumbent on drug manufacturers and regulatory authorities to demonstrate cardiovascular safety for all new and existing coxibs, including celecoxib. The published coronary artery bypass graft surgery randomised trial referred to by Cleland and James did not report a significant excess of adverse cardiovascular events with valdecoxib,5 nor did two recently published meta-analyses.6,7 However, unpublished data from a second coronary artery bypass graft surgery trial, as well as meta-analyses presented at the American Heart Association meeting in New Orleans in November 2004, indicate that valdecoxib compared with placebo significantly increases the risk of adverse cardiovascular events.8 This is reflected in the recently revised US prescribing information for valdecoxib. 9 Manev and Manev propose enhanced 5-lipoxygenase activity as a mechanism for increased cardiovascular risk in patients treated with COX-2-selective inhibitors. We agree that this important hypothesis merits further study. Day and Graham emphasise paracetamol as first-line drug treatment in the management of osteoarthritis, referring to recently published American, European and Australian guidelines to support their position. We do not dispute the effectiveness of paracetamol to reduce chronic pain. However, data from the 2004 systematic review quoted in our editorial10 demonstrate that nonsteroidal anti-inflammatory drugs are better than paracetamol for pain relief and are often preferred by patients, despite a higher incidence of adverse effects. Only one of the 10 randomised controlled trials included in this systematic review followed patients beyond 3 months; this study reported the primary efficacy outcome only during the first 6 weeks and was not powered for safety.

Paul Langton · Graeme Hankey · John Eikelboom

We describe a patient with myasthenia gravis and thymoma who developed recurrent severe myasthenic crises associated with the use of combination chemotherapy. Myasthenia gravis (MG) is an uncommon immunological disorder of the neuromuscular junction that is characterised by abnormal weakness and fatigability of some or all striated voluntary muscles. It is the most common autoimmune disorder in patients with thymoma, in whom the incidence is 30%–50%. 1 In patients with MG, up to 90% of their acetylcholine receptors may be destroyed by autoantibodies, predisposing them to disease exacerbation by any agent that impedes neuromuscular transmission.2 Clinical recordIn February, a 49-year-old self-employed builder developed MG and was subsequently found to have invasive thymoma. This was incompletely excised. The surgical procedure was complicated by left phrenic nerve palsy. In May, the patient commenced his first cycle of chemotherapy, which was to comprise doxorubicin 50 mg/m2 Day 1, cisplatin 100 mg/m2 Day 1 and etoposide 120 mg/m2 Days 1, 3 and 5, with dexamethasone 20 mg, ondansetron 8 mg and metoclopramide 10 mg administered before chemotherapy to control nausea. His MG had been well controlled on pyridostigmine 60 mg twice daily. However, within 24 hours of the first dose of chemotherapy, he developed a severe myasthenic crisis with respiratory failure requiring intubation. This was managed with dexamethasone 8 mg daily and plasmapheresis, and was thought to be due to the high-dose dexamethasone given prior to chemotherapy. In addition, he had developed a chest infection a couple of days before starting chemotherapy, which may have contributed to the respiratory failure. A methicillin-sensitive Staphyloccus aureus was isolated from sputum cultures. This was managed upon hospitalisation with intravenous ceftriaxone 1 g daily for 7 days. In June, the patient received his second cycle of chemotherapy, this time without dexamethasone. Within several hours, he developed increasing breathlessness with bulbar dysfunction and generalised weakness. Despite treatment with steroids and intravenous neostigmine, his respiratory state continued to deteriorate, necessitating intubation and subsequent plasmapheresis. No further cycles of chemotherapy were administered. A restaging computed tomography scan at the time revealed minimal residual tumour and mediastinal lymphadenopathy. In August, he completed a course of mediastinal radiotherapy that was complicated by mild radiation pneumonitis. DiscussionA review of the literature revealed no previous report of MG unmasked or aggravated by chemotherapeutic agents. However, several other classes of drugs have been associated with exacerbation of pre-existing MG. Aminoglycosides have been most frequently associated with drug-induced neuromuscular blockade. However, agents most likely to cause aggravation of MG when overused are anticholinesterase drugs, high-dose prednisolone, anaesthetic agents and neuromuscular blockers. Immunosuppressive drugs have also been implicated,3 and transient worsening of MG by high-dose corticosteroids is commonly encountered.4 Miller and colleagues5 found a positive correlation between serum methylprednisolone sodium succinate concentrations and deterioration in neuromuscular transmission. No effect on acetylcholine-receptor antibodies was noted. They speculated that the effects of steroids on MG arise from dissociation of nerve excitation and muscle contraction. Our patient developed recurrent severe myasthenic crises despite the omission of steroids in his second cycle of chemotherapy. It is highly likely that at least one of the three chemotherapeutic agents used had a direct inhibitory effect on neuromuscular transmission, aggravating pre-existing MG. The adverse drug reaction was assessed as “probable” based on a score of 5 on the Naranjo Adverse Drug Reaction Probability Scale.6 The exact mechanism for the neuromuscular blockade is uncertain, but may be due to disrupted calcium entry into the presynaptic nerve terminal, inhibiting presynaptic acetylcholine release. Alternatively, it may be due to postsynaptic blockade, the drugs may bind competitively to the acetylcholine, or may interfere with ionic conductance across the muscle membrane.7 A combination of pre- and post-synaptic blockade may also occur.

Christina V T Ng MB BS,FRACP

Clinical record A 35-year-old man presented to the emergency department complaining of right visual blurring and discomfort overnight. Over the previous 2 years, similar episodes had occurred, mostly at night or in dim lighting, affecting one eye at a time and resolving spontaneously each time. The patient was not using any type of medication at the time when the episodes began to occur. Although infrequent initially, these episodes had increased to two or three times a week after mirtazapine, a tetracyclic antidepressant, had been prescribed for depression and anxiety 5 months previously. Symptoms persisted despite treatment being changed to sertraline, a selective serotonin reuptake inhibitor (SSRI). Ten days before presentation, the sertraline was replaced by venlafaxine 75 mg once a day. Symptoms were occurring about every other day. There was no other significant ocular or family history. Spectacle correction revealed compound hypermetropic astigmatism (right eye, +1.00 + 1.50 × 75° left eye, +1.75 + 2.25 × 110°). On presentation, the patient’s visual acuity was 6/24, improving, with a pinhole before the eye, to 6/9 (right eye) and 6/6 (left eye). The right pupil was fixed and mid-dilated and the cornea was mildly oedematous. Both anterior chambers were axially shallow, with forward displacement of the iris–lens diaphragm (ie, the plane formed by the iris and the anterior surface of the lens at the pupil). Intraocular pressures were 69 mmHg (right eye) and 62 mmHg (left eye) (intraocular pressure > 21 mmHg is generally considered as being elevated). Gonioscopy revealed bilateral completely closed angles. The patient was given intravenous mannitol 100 g over 40 minutes, oral acetazolamide 500 mg, topical timolol 0.5%, apraclonidine 1% and pilocarpine 2%. Intraocular pressures fell to 13 mmHg and 5 mmHg in the right and left eyes, respectively. Gonioscopically, the angles could now be opened with indentation of the cornea; however, the anterior chambers remained shallow. Bilateral laser peripheral iridotomies were performed on the day of presentation (left eye) and on the next day (right eye) to eliminate pupil block. Post-iridotomy gonioscopy showed no change in the angle configuration or anterior chamber depth. The patient was sent home with instructions to take oral acetazolamide 250 mg three times a day, topical timolol 0.5% once a day, pilocarpine 2% four times a day, and brimonidine 2% twice a day. Venlafaxine was discontinued. The patient refused alternative antidepressant medication and requested referral to a psychiatrist or psychologist for counselling. On Day 4 after the patient presented with acute angle closure, ultrasound biomicroscopy showed bilateral supraciliary effusions and anterior chamber shallowing (Box 1). Manifest refraction (ie, manual subjective measurement of refractive error) at this time revealed a myopic shift of about 3 dioptres in each eye. Over several weeks, medications to lower intraocular pressure were withdrawn one by one. Follow-up ultrasound biomicroscopy showed gradual resolution of the supraciliary effusion, which was complete some 5 weeks after the acute attack. The anterior chambers deepened slightly and the patient’s usual hypermetropic refraction returned. Gonioscopy at this time still showed easily occludable angles. Bilateral laser peripheral iridoplasties were performed to reduce the risk of future angle closure. Venlafaxine is described as a safe and effective antidepressant that is chemically distinct from other antidepressants.1 It is a non-selective inhibitor of the reuptake of serotonin, norepinephrine and dopamine and has no anticholinergic activity in vitro. Because of their relative lack of anticholinergic effects, venlafaxine and similarly acting selective serotonin reuptake inhibitors (SSRIs) are preferred over tri- and tetracyclic antidepressants for patients who are at risk of angle closure. We report the case of a young patient taking venlafaxine who developed simultaneous bilateral acute angle closure secondary to supraciliary effusions. Angle closure and/or acute transient myopia possibly caused by supraciliary effusion has been reported for many drugs, including sulfonamides, tetracycline and some diuretics.2 Supraciliary effusions causing secondary angle closure in patients taking topiramate3-5 and sulfonamides6 have been documented by ultrasound biomicroscopy by various authors. The postulated mechanisms by which supraciliary effusions produce angle-closure glaucoma and transient myopia are illustrated in Box 2. There have been reports in the literature of angle closure or increased intraocular pressure in patients taking venlafaxine8,9 or SSRIs.5,10-15 We found one previous report of bilateral acute angle-closure glaucoma in a patient taking venlafaxine8 and one report of raised intraocular pressure in two known glaucoma patients with narrow angles taking venlafaxine.9 Eleven cases of raised intraocular pressure in patients taking SSRIs have been reported to the Australian Adverse Drug Reactions Advisory Committee.10 However, the mechanisms for the raised intraocular pressure in these cases are not mentioned. To our knowledge, ours is the first reported case of acute angle closure in a patient taking venlafaxine in which the presence of a supraciliary effusion precipitating the secondary angle closure has been identified by ultrasonography. Furthermore, our patient was taking only venlafaxine at the time of presentation. The patient in the abovementioned case of acute angle closure8 had taken four other medications immediately before starting or during treatment with venlafaxine. There is a case report of secondary angle closure due to supraciliary effusions in a patient taking topiramate who was also taking venlafaxine, but the authors attributed the effusions to the topiramate.4 It is possible that the mirtazapine and sertraline taken previously by our patient contributed to his condition, as did his underlying hypermetropic status. It may be that the weak anticholinergic or mydriatic effects of serotonergic drugs are sufficient to precipitate angle closure by a mechanism similar to that of the cyclic antidepressants.6,8 The serotonergic effects of these drugs may also have a role in angle closure.11,14,16 Serotonin and serotonin receptors have been found in the human ciliary body, and serotonin, its agonists and antagonists do affect intraocular pressure.17 The supraciliary effusions documented here are evidence of the serotonergic effects of venlafaxine causing angle closure, although the precise cause for the effusions is unknown. Lessons from practice Use venlafaxine (and antidepressants in general) with caution in patients who are at risk of angle-closure glaucoma. Patients at risk are those with hypermetropic refraction (ie, whose distance spectacles magnify objects) and those with symptoms of angle closure (intermittent blurring of vision associated with seeing coloured rings around lights, eye redness, or eye pain). Such symptoms should not be dismissed as “migrainous”. Patients at risk of angle closure should undergo ophthalmological screening, particularly gonioscopy, before starting antidepressant drugs. Because any patient could develop a supraciliary effusion in response to various drugs (especially antidepressants), it is prudent to include symptoms of angle closure when educating patients about possible side effects of these drugs. They should seek ophthalmological care if they experience symptoms of angle closure or a myopic shift in their vision. 1 Ultrasound biomicroscopy images, Day 4 after the patient presented with acute angle closure A: Supraciliary effusion, right eye (arrow). (C = cornea; CB = ciliary body; I = iris; S = sclera.) B: Shallow anterior chamber, left eye. The large area of iris–lens apposition indicates forward displacement of the lens. Pupil block has already been relieved by peripheral iridotomy (not shown). (AC = anterior chamber; C = cornea; I = iris; L = lens.) 2 Postulated mechanisms by which supraciliary effusions produce angle-closure glaucoma and transient myopia * Based on information from Craig et al.7

Maria Hannah Pia de Guzman MD, DPBO · Sureka Thiagalingam MPH, MB ChB · Poh Yan Ong MD, MS · Ivan Goldberg MB BS, FRANZCO, FRACS

We report an outbreak of a “rash” syndrome in patients attending methadone clinics in New South Wales. It presents with a pruritic, exanthematous or purpuric rash involving the trunk, limbs, palms and soles, which develops over a week and proceeds in most patients to desquamation (mainly of palms and soles) persisting for 3–4 weeks. Mucosae are not involved, and patients are generally systemically well. To date, the rash has affected 22% of 316 patients attending one methadone clinic in western Sydney, as well as patients in clinics elsewhere in Sydney and rural NSW. The aetiology is as yet unknown. We report an outbreak of a “rash” syndrome in patients attending a number of methadone clinics across New South Wales during October and November 2004. The syndrome first came to our attention when, over a week, two patients presented to a methadone clinic in western Sydney and three to the Westmead Hospital emergency department with a distinctive rash. Subsequent enquiries and patient surveillance revealed that 70 of 316 patients (22%) at the methadone clinic had developed a similar “rash” syndrome in October and November. All were prescribed methadone syrup. Clusters of patients have also been increasingly reported at other methadone clinics across metropolitan Sydney and some regional and rural areas in NSW. To date, informal communication with interstate methadone clinics has identified small numbers of patients with the “rash” syndrome outside NSW. In the first western Sydney case reliably identified by history, symptoms developed in August 2004. The principal features of the “rash” syndrome are a pruritic, exanthematous or purpuric rash that typically develops over 2 to 4 days on the hands, feet, trunk and lower limbs and persists for up to 7 days. It is usually followed by a desquamative phase that particularly involves the hands and feet and lasts up to 3 to 4 weeks. Some patients develop only the desquamative phase. The condition appears relatively benign, with few, if any, systemic symptoms, although the palms and soles of the feet can become painful with pressure after desquamation. In several patients, the rapidly developing purpuric nature of the presenting rash raised initial concern about meningococcal disease or a systemic vasculitic syndrome sufficient to warrant referral for specialist assessment. We describe four illustrative cases. Clinical recordsPatient 1A man aged in his 30s presented to a hospital emergency department with a 3-day history of a petechial and purpuric rash. He was an intravenous drug user who had been in a methadone treatment program for 7 years. He intermittently injected his oral methadone intravenously, most recently 24 hours before onset of the rash. This initially involved the lower limbs, but spread over 24 hours to affect the buttocks, lower back and abdomen. Associated but relatively mild symptoms included malaise and nausea for a week before rash onset, followed by sore throat, myalgia, ankle arthralgia, abdominal and chest pain and vomiting. At presentation, the patient was afebrile. Blood pressure was 120/60 mmHg, and pulse 70 bpm. A sparse petechial and purpuric rash was present on lower limbs, feet, buttocks and lower abdomen. There was no pedal oedema, joint effusion or tenderness. There were no abnormalities on respiratory and cardiovascular examination, no clinical evidence of endocarditis, no lymphadenopathy, and mucosae were normal. The right upper abdominal quadrant was tender, but the liver and spleen were not enlarged, and no renal masses were palpable. Investigations were uninformative (Box 1). Inpatient progress was unremarkable, and, 10 days after presentation, all symptoms had resolved, despite ongoing oral and intravenous methadone use. Patient 2A middle-aged man presented with a 2-day history of an erythematous, pruritic rash over his trunk and limbs which was now beginning to desquamate. He was also an intravenous drug user in a methadone treatment program. In addition to taking prescribed oral methadone, he intermittently injected both methadone and stimulants, such as amphetamine, intravenously. There was no history of fever, oropharyngeal, genital, eye or systemic symptoms. On examination, he was afebrile, looked well and had a generalised exanthem, with erythema and significant desquamation of soles and palms (Box 2, A and B). There were no oral, mucosal or eye signs, and no lymphadenopathy or hepatosplenomegaly. Results of investigations were unremarkable (Box 1). He was treated for 2 days with oral prednisolone and an antihistamine, and then discharged. The rash settled over a week, although he continued to have desquamation of the soles and palms 2 weeks later. Patient 3A young man who was an intravenous drug user in a methadone treatment program presented to the same hospital with a 2-day history of a purpuric lower-limb rash. In addition to taking prescribed oral methadone, he intermittently injected both heroin and methadone intravenously. Five days before presentation, he developed bilateral calf pain and generalised myalgia. He was initially seen at another hospital, where he was treated with broad-spectrum intravenous antibiotics for presumed sepsis. He discharged himself after 24 hours and was admitted to our hospital about 12 hours later because of his concern about the rash. On admission, he was afebrile, with blood pressure of 115/65 mmHg and pulse of 75 bpm. He had a prominent purpuric rash involving both lower limbs (Box 2C), with sparse lesions on both forearms. Mucosae were normal, and there was no meningism, lymphadenopathy, hepatosplenomegaly, joint swelling or tenderness, no abnormalities on respiratory and cardiac examination, and no stigmata of endocarditis. Results of investigations were once again unremarkable (Box 1). The patient remained well despite the rash and was discharged from hospital 24 hours after admission. Patient 4A young woman who was an intravenous drug user in a methadone treatment program presented to the methadone clinic with a 4-day history of an erythematous, pruritic rash over her trunk, limbs and hands. Other than oral methadone, she was taking no drugs and was otherwise well. Examination revealed an extensive exanthem over her trunk, hands and legs. She had no fever, and blood pressure was normal. She was reviewed a week later and still had an extensive generalised erythematous exanthem, as well as finger and palm desquamation (Box 2, D and E). Results of investigations were unremarkable (Box 1). DiscussionThe aetiology of this “rash” syndrome is yet to be elucidated. Currently, it appears to be restricted to people using methadone syrup, with no reports of rash in over 100 patients in western Sydney prescribed buprenorphine for treatment of opioid dependence, nor among non-methadone-using family members of patients with the rash, nor among healthcare workers in contact with these patients. To date, all patients with the “rash” syndrome who have been assessed for hepatitis C exposure are seropositive, but not all are viraemic. Some patients with the “rash” syndrome smoke cannabis and intermittently inject methadone or other drugs. However, these characteristics are not universal among affected patients, nor more frequent than in unaffected patients on the methadone program, among whom they are also common. Similarly, the use of prescription or complementary medicines does not seem to be associated with the “rash” syndrome. Similar rashes and associated desquamation are common in staphylococcal and streptococcal toxin-induced illnesses, such as toxic shock syndrome and scalded skin syndrome,1-3 and in some viral illnesses, such as parvovirus infection and measles.4 However, the patients in the current outbreak did not give a history of bacterial or viral illness, and family members not taking methadone do not appear to have developed the syndrome. HIV antibody testing has been performed in some affected patients and has been negative. Throat swabs taken in some patients have grown only normal respiratory flora. Markers of streptococcal infection, such as antideoxyribonuclease B antibodies and anti-streptolysin O titre, are positive in some but not all patients. Skin biopsy performed in a number of patients has failed to help define the aetiology of the rash. Histological examination often shows focal and mild spongiosis with superficial perivascular chronic inflammation, while direct immunofluorescence examination shows deposition of IgM and complement 3 in dermal capillaries. These findings are consistent with an immunological reaction in the skin, but do not clarify whether it is the primary cause of the rash or a secondary phenomenon. A hypersensitivity reaction to a contaminant in the methadone syrup could present with such a picture. The fact that, to date, all the patients identified in western Sydney had been taking methadone syrup from a single manufacturer raises the possibility of batch contamination; however, batches are distributed nationally, so more widespread involvement would probably be expected if this was the basis of the syndrome. In addition, examination of the methadone syrup has failed to detect any contamination. The possibility of alternative sources of contamination, such as methadone storage or delivery devices, remains to be explored. We believe it is important for physicians to be aware of this newly emerging syndrome, both to assist with more accurate delineation of its epidemiology and pathogenesis, and to permit more effective investigation and treatment of affected patients. State public health units and the Therapeutic Goods Administration are investigating this outbreak to try to determine the cause of this new syndrome. 1 Results of investigations in four patients with rash Investigations Reference range Patient 1 Patient 2 Patient 3 Patient 4 Full blood count and film Normal; platelet aggregates on film Normal apart from WBC 10.8 x 109/L; occasional reactive lymphocytes Normal Normal, apart from Hb 107 g/L Haemoglobin (Hb) (g/L) 115–161 White blood cell count (WBC) (x 109/L) 3.7–9.5 ESR (mm/h) 0–15 4 11 5 38 C-reactive protein (mg/L) 0–11 20 27 22 15 Liver function tests Normal Abnormal Abnormal Normal γ-Glutamyltransferase (U/L) 8–43 47 48 Alanine aminotransferase (U/L) 10–47 88 157 Aspartate aminotransferase (U/L) 12–45 104 154 ANA, ANCA, ENAs, rheumatoid factor, complement C3 and C4 Normal nd Normal nd Cryoglobulins Absent nd Detected nd Prothrombin time (s) 11–18 Normal Normal Normal nd APTT (s) 25–36 Normal 39 Normal nd Hepatitis C virus IgG-positive; undetectable viral load (< 600 IU/mL) IgG-positive; viral load not assessed IgG-positive; viral load > 850 000 IU/mL IgG-positive; refused viral load assay HIV antibody Negative nd nd nd Urinalysis Trace protein (39 mg/24 h); no casts/red cells Normal Normal nd Blood culture Negative Negative Negative nd Throat swab Nd Normal flora nd nd Electrocardiogram Normal nd nd nd Chest x-ray Normal Normal Normal nd Echocardiogram Transthoracic normal; transoesophageal not tolerated by patient nd nd nd ESR = erythrocyte sedimentation rate. nd = not done. ANA = antinuclear antibody. ANCA = antineutrophil cytoplasmic antibody. ENAs = extractable nuclear antigen antibodies. APTT = activated partial thromboplastin time. 2 Features of the rash in four patients ↑A. Generalised exanthem on trunk and limbs in Patient 2. ↑B. Palm desquamation in Patient 2. ↑C. Purpuric rash involving lower limbs, with areas of confluence on the lower calf in Patient 3. ↓D. Extensive erythematous exanthem over trunk and limbs in Patient 4. ↑E. Palm desquamation in Patient 4.

Jon N Currie FRACP, FAChAM · Jimmy Chien BMed · Lisa Snell RN · Margaret Cluff RN · Karen Scrivener RN · Lucinda Wallman PhD, FRACP, FRCPA · Elizabeth M Benson FRACP, FRCPA

A man who had been taking prescribed methadone for many years presented with a desquamating rash (predominantly affecting the hands and feet) complicated by cellulitis of the right leg. There have now been multiple reports of a similar rash among methadone users in Sydney. The cause remains unknown. We report a man attending a methadone program in south-east Sydney who presented with a distinctive rash complicated by lower-leg cellulitis. This case adds to the widespread reports of a similar rash in methadone users around Sydney. The cause is under investigation by the New South Wales Department of Health. Clinical record In October 2004, a middle-aged man was referred to a hospital in south-east Sydney with a 14-day history of a painful, swollen, erythematous right lower leg and fever. Two days before onset of the leg symptoms, he had noticed a non-pruritic rash which started on his legs and feet and spread to abdomen and arms; it was accompanied by swelling, and then desquamation of the hands and feet. He had been diagnosed with cellulitis of the right lower leg 7 days before presentation and was prescribed oral flucloxacillin, but his condition did not improve significantly. Duplex ultrasound examination of the right leg 2 days before presentation excluded deep vein thrombosis. He was admitted to hospital for intravenous antibiotic treatment. The patient was a former intravenous heroin user and had been in a methadone program at a local pharmacy for the previous 8 years. He denied recreational drug use or injecting or sharing the oral methadone. His past medical history included previous right-leg deep vein thrombosis, chronic hepatitis B and C infection, gastro-oesophageal reflux, as well as melanoma excision several years before, and cholecystectomy a month previously. He had been taking griseofulvin for about 3 months for onychomycosis. He was taking methadone syrup (160 mg daily), griseofulvin (500 mg daily) and, when required, diazepam (5 mg three times daily), codeine/paracetamol (30/500 mg three times daily) and oxycodone (40 mg twice daily). He had recently started using, when required, cyproheptadine (4 mg at night), hyoscine (20 mg four times daily) and triamcinolone acetonide (0.02% cream topically) for the rash, and metoclopramide (10 mg three times daily) for mild nausea. On physical examination, the patient was haemodynamically stable and looked well. His temperature was 37.2°C. There was erythema, tenderness and warmth below the right knee, consistent with cellulitis. There was desquamation of the skin of both his lower legs, soles of feet (Box, a) and palms and fingers (Box, b), as well as non-pitting oedema of the feet and hands. There was hyperkeratosis of the soles, with xerosis and an erythematous maculopapular rash of the arms. The skin condition did not appear typical of disorders causing hyperkeratosis and desquamation, which usually do not present concurrently. He had no mucosal ulceration. Differential diagnoses included the early phase of an exfoliative erythroderma, psoriasis triggered by infection, early pityriasis rubra pilaris, bacterial toxin-mediated exfoliation, viral exanthem, sarcoidosis and syphilis. Rash in a patient who used oral methadone A: Hyperkeratosis and desquamation of the soles of the feet. B: Desquamation of the palms. C: Biopsy specimen from the maculopapular rash on the left arm, showing a slightly thickened epidermis with focal parakeratosis (P), and mild perivascular lymphocytic infiltrate (I). (Original magnification, × 20; haematoxylin–eosin stain.) Measurement of serum electrolyte, urea and creatinine levels and liver function tests all gave normal results. A full blood count revealed haemoglobin level of 125 g/L (reference range [RR], 130–180 g/L) and slight eosinophilia (0.48 × 10 9/L; RR, 0.04–0.44 × 10 9/L), but total white cell count was within the reference range (6.2 × 109/L; RR, 3.5–11.0 × 10 9 /L). Erythrocyte sedimentation rate was 10 mm/h (RR, 1–10 mm/h) and C-reactive protein level was 24 mg/L (RR, < 3 mg/L). Blood cultures showed no growth. A test for Treponema pallidum antibody was negative. Chest x-ray was normal, and HIV antibody test negative. Skin biopsy of the red macules on his left arm (Box, c) and the right-leg biopsy revealed non-specific histological changes, suggestive of chronic dermatitis. Periodic acid–Schiff staining for fungi was negative. Empirical treatment was begun with mometasone cream (0.1%), calcipotriol ointment (0.005%) and sorbolene cream twice daily to affected areas, and coal tar (5%) and salicylic acid (5%) in sorbolene base cream at night to the feet. Intravenous cephazolin (1 g three times daily) and oral clindamycin (300 mg four times daily) were begun for the cellulitis. The patient was discharged on Day 4 with the above topical preparations and oral cephalexin (500 mg three times daily), after both the rash and right-leg cellulitis abated significantly. He failed to attend a follow-up appointment, but reported by telephone that the rash had gradually resolved over several weeks. Discussion This case raises the alert to a possible adverse reaction to a methadone preparation. The cause may be methadone itself, another component of the preparation, or a contaminant. Previously reported cutaneous reactions to methadone include angioedema, facial oedema, flushing, pruritus, purpura, rash and urticaria.1 To our knowledge, no cases have been reported of a desquamating rash associated with methadone or other opioids. The cause of the rash in our patient did not appear infectious. He had no clinical evidence of staphylococcal toxic shock syndrome; he remained clinically well and did not develop the diffuse confluent erythema typical of this syndrome. Nor was the rash typical of a viral exanthem, in which a widespread morbilliform eruption predominates, without confluent erythema (as occurred on the lower legs), hyperkeratosis or desquamation. A reaction to a medication other than methadone seems less likely, as there had been no recent change. We are aware of other patients with a similar rash, oedema and desquamation of the hands and feet, all taking methadone: six patients in a methadone program at the same pharmacy as our patient, 20 from a local methadone clinic, and others at other methadone centres in Sydney (Mary Anne Ford, Registered Nurse, Bayside Clinic, Sydney, NSW, personal communication). We know of no patient with a similar rash who is not using methadone, and we believe all affected patients were taking the same brand and formulation of the drug. Most cases have been mild, and close contacts have not been affected. All patients appear to have continued using methadone from their usual dispensing clinic, and the rash has resolved over several weeks. The cause of the reaction remains unknown, and is possibly even an illicit drug available on the street. However, as all affected patients appear to have been taking methadone, this is perhaps the most likely agent. Marijuana has been reported, albeit rarely, to cause allergic reactions, and occasionally becomes contaminated with biological or chemical substances that might cause a reaction.2 -4 However, in that situation, one would expect cases to be more widely distributed outside the methadone-using population. In addition, at least one client with this rash from the local methadone clinic had a negative urine test for cannabinoids (Mary Anne Ford, as above, personal communication). Further investigation of these cases is required to determine the aetiology. Variables to be considered include the brand and batch of methadone used, storage, dose, mixing of batches in the dispensing pump, and other solutions included in the preparation to increase palatability. Pharmacists often mix batches of methadone and are not required to record the batch number dispensed to each patient, which makes tracing difficult. Also important to consider are any other prescription or non-prescription medications taken by patients, illicit drugs used, and sharing of methadone between patients from different methadone clinics. Many more cases may have been unreported and unrecognised, as most affected patients have had relatively mild and self-limiting symptoms. An investigation is now under way by the New South Wales Department of Health. Methadone clinics, pharmacists, dermatologists, general practitioners and emergency medicine staff need to be aware of the possibility of these reactions.

Natalie Kordjian BPharm, MB BS · Annabelle D Donaldson MB ChB · Steven A Krilis PhD, FRACP · Dedee F Murrell MA, BM BCh, FAAD(USA)

Re: “Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Haemostasis and Thrombosis”, by Ross I Baker, Paul B Coughlin, Alex S Gallus, et al on behalf of the Warfarin Reversal Consensus Group (Med J Aust 2004; 181: 492-497). In Box 5, an asterisk in the Box title should have attributed Prothombinex-HT to CSL Limited, the manufacturer of all plasma-derived therapeutic products fractionated from Australian plasma. The error only appeared in the printed edition. The html and pdf versions of the article published in the eMJA were correct on publication.

Ross I Baker PhD, FRACP · Paul B Coughlin PhD, FRACP, FRCPA · Hatem H Salem MD, FRACP, FRCPA · Alex S Gallus FRACP, FRCPA, FRCP · Paul L Harper MD, FRACP, FRCPA · Erica M Wood FRACP, FRCPA

Angelo Labate,* Mark R Newton,† Graeme M Vernon,‡ Samuel F Berkovic§ * Research Fellow, Brain Research Institute, † Neurologist, § Director, Epilepsy Research Centre, ‡ Drug Information Pharmacist, Austin Health, Heidelberg West, VIC 3081. s.berkovicATunimelb.edu.au To the Editor: Tramadol is a synthetic, centrally acting analgesic that was approved for use in Australia in 1998. Seizures have been reported in patients receiving the drug in overdose and, rarely, at the recommended dose.1-4 Over a one-year period, we observed a number of tramadol-associated seizures in the First Seizure Clinic at Austin Health, an outpatient service for rapid evaluation and diagnosis of patients with new-onset seizures.5 We evaluated 197 patients from April 2003 to April 2004. One hundred had alternative diagnoses to epileptic seizures: syncope (n = 56), convulsive syncope (n = 27), panic attacks (n = 3) and other events (n = 14). Of 97 patients with confirmed seizures, 8 (5 male; median age, 34 years [range, 18–51 years]) were associated with tramadol (Box). Two patients who had received high doses of tramadol (600–750 mg/day [maximum recommended dose, 400 mg/day]) had developed seizures within 24–48 hours. Among the other six patients, who had received tramadol in the recommended dose range (50–300 mg/day), seizures had occurred 2–365 days after commencing therapy. Long-term psychotropic medication was taken by two patients. Seizures were generalised tonic–clonic seizures, without auras or focal features. No patient had a prior history of seizures, and none had a recurrence after they had ceased taking tramadol for a median of 9 months’ follow-up (range, 2–14 months). Electroencephalographic studies were normal in seven patients, with only one isolated sharp slow-wave in one patient. Computed tomography scans were all normal, and magnetic resonance imaging was normal in five patients. Previous US studies suggest a relatively low risk of seizures with tramadol, unless it is taken by people with epilepsy or taken with other drugs that reduce the seizure threshold.2-4 Tramadol is now widely prescribed in Australia, with 1.65 million prescriptions for oral tramadol issued under the Pharmaceutical Benefits Scheme in 2003.6 The Australian Adverse Drug Reactions Advisory Committee had received 83 reports of convulsions associated with tramadol to March 2004, although in only three cases was the association classified as “certain”. In our First Seizure Clinic, tramadol is the most frequently suspected cause of provoked seizures. We cannot calculate the exposure risk in our population, but the frequency of tramadol-related seizures suggests that they may be under-reported. It is important to consider tramadol as a possible cause of seizures — even when used at recommended doses. This may avoid inappropriate use of anti-epileptic drugs and unnecessary restrictions on driving and choice of vocation that might apply in cases of new-onset epilepsy. Details of eight patients with tramadol-related seizures at the First Seizure Clinic, Austin Health, April 2003–April 2004 Patient 1 2 3 4 5 6 7 8 Age (years) 18 35 31 33 48 51 25 45 Sex M F F M M M F F Tramadol dosage (mg/day) 750 600 100 300 100 50 100 300 Treatment duration (days) 1 2 7 365 21 90 2 180 Concomitant psychotropic drug taken No No No Yes* Yes† No No No Duration of follow-up (months) 12 9 14 9 9 3 3 2 * Chlorpromazine hydrochloride 200 mg/day. † Haloperidol 1 mg/day.

Angelo Labate · Mark R Newton · Graeme M Vernon · Samuel F Berkovic

Barbara A Hawkshaw,* Yeqin Zuo† * Planning and Evaluation Officer, Health Promotion Unit, Central Sydney Area Health Service, Level 9 North, King George V Building, RPAH, Missenden Rd, Camperdown, NSW 2050; † Currently Tobacco Control Program Coordinator, Cancer Institute NSW, Sydney, NSW barbara.hawkshawATemail.cs.nsw.gov.au To the Editor: The World Health Organization recommends that hospital staff ask about the smoking status of every patient, and offer brief quit advice and pharmacotherapy.1 These effective strategies2 underlie the Central Sydney Area Health Service (CSAHS) Smoke Free Environment Policy,3 which specifies the use of nicotine replacement therapy (NRT) in managing nicotine dependence of inpatients. Recording quit advice is yet to become a regular feature of medical records, but documentation of smoking status and NRT prescribing is evidence of compliance with the policy. To monitor the implementation of this policy in CSAHS, we examined the medical records of smokers for evidence of NRT prescribing in hospital or at discharge. A small sample was chosen to provide a “snapshot” of NRT use. First, we identified 2718 patients admitted to Royal Prince Alfred Hospital and Canterbury Hospital between 1 July 2001 and 30 June 2002 who were single admissions, stayed 48 hours or longer, and were current smokers (ICD-10 code Z720).4 Current smokers were defined as those who had smoked any tobacco in the past month.4 Sixty medical and 60 surgical patients from each hospital were selected randomly by random number generation (medical/surgical status was based on the specialty of the admitting doctor). After excluding 33 patients who were either ex-smokers or smokers who died during admission, the sample included 207 patients. Records were examined for smoking history, NRT prescribing during hospitalisation, and documentation of smoking status or NRT prescribing on discharge summary. NRT was prescribed to 13 patients (6.3%) during their hospitalisation (Box). All 13 received patches. A larger proportion of medical patients than surgical patients had NRT prescribed in hospital (8.1% v 4.6%) and at discharge (7.1% v 2.8%). In 8% of records, smoking was identified on the discharge summary. Most records (80%) provided numerical information about daily cigarette consumption. Seventy per cent of our sample smoked more than 10 cigarettes per day. Other records described consumption in subjective terms only, such as “heavy”. We believe that this is the first study in Australia to estimate the NRT prescribing rate for inpatients using medical record audit. Very few patients who were smokers were prescribed NRT. It is encouraging that most patients who were prescribed NRT were given a supply of patches at discharge. The NSW Health Department’s Guide for the management of nicotine dependent inpatients is a commitment to assisting people to quit.5 Implementation of the CSAHS Smoke Free Environment Policy3 by hospital staff requires a greater knowledge of the barriers to prescribing NRT and documenting quit activities at all levels of the hospital system. Nicotine replacement therapy (NRT) prescribing and smoking history Medical* Surgical* Total NRT prescribing (n = 99) (n = 108) (n = 207) During hospital stay 8 5 13 (6%) At discharge 7 3 10 (5%) Smoking history (n = 99) (n = 108) (n = 207) Number of cigarettes recorded 76 90 166 (80%) Years of smoking recorded 26 41 67 (32%) Cigarettes per day (n = 76) (n = 90) (n = 166)† 1–10 25 24 49 (30%) > 10 51 66 117 (70%) * Admission categorised according to specialty of admitting doctor. † Only 80% of total sample indicated number of cigarettes per day.

Barbara A Hawkshaw · Yeqin Zuo

Erica L Mann Managing Director, Wyeth Australia and New Zealand, 17-19 Solent Circuit, Norwest Business Park, Baulkham Hills, NSW 2153. To the Editor: Wyeth Australia welcomes the opportunity to comment on Lu and colleagues’ discussion of whether rheumatoid factor status is a predictor of tumour necrosis factor-α (TNFα)-inhibitor response in rheumatoid arthritis (RA).1 Wyeth provided the data used by the Pharmaceutical Benefits Advisory Committee (PBAC) to originally exclude patients who test negative for rheumatoid factor from access to TNF-α inhibitors. Although Wyeth agreed with the PBAC’s interpretation that only patients with positive rheumatoid factor status may benefit from etanercept, efficacy in those testing negative for rheumatoid factor was not clearly established because of the small number of patients in these subgroups. Importantly, the subgroup analysis divided all study participants into two groups depending on their rheumatoid factor status and only included ACR 20 response (a standard from the American College of Rheumatology which requires at least 20% reduction in swollen joint count, tender joint count, and in three out of five of patient’s assessment of pain, patient’s assessment of disease activity, investigator’s assessment of disease activity, acute phase reactant levels and patient’s assessment of disability). This analysis may not represent the likely response of patients who test negative for rheumatoid factor, but who develop severe, progressive rheumatoid arthritis and otherwise meet the stringent eligibility criteria associated with Pharmaceutical Benefits Schedule listing (excluding positive rheumatoid factor status). It is possible that the small number of unique rheumatoid-factor-negative patients who have severe disease will not have a different response to etanercept from similar patients who are rheumatoid-factor positive. More recent data are available from a large multicentre study that compared treatment with etanercept in combination with methotrexate to either monotherapy alone for control of RA disease activity.2 Subgroup analysis for the effect of rheumatoid factor on treatment responses showed that the presence of rheumatoid factor in the circulation of study patients did not significantly affect the responses to therapy among treatment groups. Although these new data have yet to be presented to the PBAC for reconsideration, a submission on this matter is under way.

Erica L Mann

Objective: To assess effectiveness and side effects of thiazolidinediones (TZDs) as adjunctive therapy in suboptimally controlled patients with type 2 diabetes.Design and setting: Review of a prospectively recorded database at the Royal Melbourne Hospital diabetes clinic.Participants: 203 patients with type 2 diabetes who received pioglitazone or rosiglitazone between 1 May 2000 and 31 October 2002.Outcome measures: Response in glycohaemoglobin (HbA1c) level, lipid profile changes and side effects, including hypoglycaemia, weight gain, oedema and precipitation of cardiac failure.Results: Both pioglitazone and rosiglitazone improved glycaemic control, with a reduction in the HbA1c level of 1.02% (range, 0.85%–1.19%) and 0.96% (range, 0.81%–1.11%), respectively, in the first 6 months of therapy. Rosiglitazone was associated with a 0.45 mmol (range, 0.31–0.59 mmol) increase in cholesterol level and 0.99 mmol (range, 0.60–1.38 mmol) increase in triglyceride level, while pioglitazone was associated with insignificant declines in cholesterol and triglyceride levels. There was reduced requirement for insulin, but not for oral hypoglycaemic agent (OHA), in most patients who used these agents. Pioglitazone and rosiglitazone were associated with increased rates of hypoglycaemia (17% and 11% of patients, respectively), significant weight gain (48% and 58%) and oedema (33% and 21%). There were four cases of acute left ventricular failure and two cases of reversible liver dysfunction in patients treated with TZDs.Conclusions: Adding pioglitazone or rosiglitazone therapy to OHA or insulin in patients with type 2 diabetes significantly improved glycaemic control. However, the use of these drugs in routine clinical practice was associated with more frequent adverse events than previously reported in clinical trials.

Zanariah Hussein MB BS · John M Wentworth MB BS, PhD · Alison J Nankervis MD, FRACP · Joseph Proietto FRACP, PhD · Peter G Colman FRACP, MD

The emergence and spread of multidrug-resistant pathogens has increased substantially over the past 20 years. Over the same period, the development of new antibiotics has decreased alarmingly, with many pharmaceutical companies pulling out of antibiotic research in favour of developing “lifestyle” drugs. Reasons given for withdrawing from antibiotic development include poor “net present value” status of antibiotics, changes in regulations requiring larger drug trials and prolonged post-marketing surveillance, clinical preference for narrow-spectrum rather than broad-spectrum agents, and high new-drug purchase costs. Major improvements in infection control in Australia are needed to prevent further spread of resistant clones, buying some time to develop urgently needed new antibiotic agents. Perpetuating a culture of “pharma bashing” will simply lead to more pharmaceutical companies withdrawing from the market. A change in the health and research culture is needed to improve cooperation between public, academic and private sectors.

Patrick G P Charles MB BS, FRACP · M Lindsay Grayson MD, FRACP, FAFPHM

To the Editor: There is no substitute for injectable thiamine in the treatment and prevention of Wernicke’s encephalopathy, for which the oral form of thiamine is considered inadequate.1 If the condition is not treated promptly with parenteral thiamine, permanent brain damage can occur. A shortage of injectable thiamine noted in a South Australian hospital led us to enquire into the extent of the problem in Australia. In the first week of July 2004, we undertook an Australia-wide survey of major teaching hospital pharmacies. Sixteen hospitals were contacted by phone, and 15 chief hospital pharmacists provided information about thiamine stock, normal thiamine usage over a 6-month period, shortages of other drugs, and reasons for shortages. Data on thiamine are shown in the Box. Most hospitals (11/15) were unable to provide injectable thiamine for periods ranging from a few weeks to 5 months. Rationing reduced the use of injectable thiamine in 13/15 hospitals. There was a total shortfall of 2000 ampoules per month for the 13 hospitals. Given an average of six ampoules used per admission, we estimate that 330 patients a month were untreated or inadequately treated. Half the hospitals surveyed obtained some ampoules either directly from suppliers or through the Special Access Scheme (SAS) protocol of the Therapeutic Goods Administration (TGA). This protocol is time-consuming and cumbersome, while the non-SAS system is expensive (10 times the usual price per ampoule). Pharmacists reported having many other drugs (40–60) on back order. The pharmacists stated that drug shortages were caused by scarcity of raw materials and TGA restrictions. However, the current shortage of thiamine in Australia was foreseeable in 2003, when the main manufacturer stopped thiamine production. The TGA did not alert pharmacists or doctors to the potential shortage in writing, nor provide comprehensive help to prevent or alleviate the shortages. The public health response to shortages of essential medicines should include surveillance and a systematic analysis of the causes. Better communication between pharmacists, clinicians and government authorities, and the formation of contingency plans and guidelines, are needed. It was only through informal networking and the quick thinking of hospital pharmacists that a crisis was averted in Australia. It is unconscionable that an inexpensive essential medicine is not available to those Australians who may need it. In this respect, our public health system has failed. Because injectable thiamine has been unavailable or rationed, an increase in the incidence of alcohol-related brain damage may have occurred. Australian health ministers should act immediately to prevent critical shortages of essential medication, which could be tragic and costly. Stocks and usage of injectable thiamine in 15 Australian hospitals, as at 3 July 2004* Number of vials Use/month Hospital Lowest Current Previous 2 months Usual 1 0 0 0 16 2 0 0 0 50 3 0 0 0 50 4 0 0 0 65 5 0 12 0 20 6 0 10 0 35 7 0 25 0 20 8 0 200 0 130 9 0 120 0 1200 10 0 25 25 70 11 0 10 10 150 12 1 35 40 120 13 5 160 17 180 14 25 86 100 100 15 30 90 30 30 * The table compares the level of stock at its lowest during the shortage with the level at July 2004, along with estimates of use at July 2004 and before the shortage.

Simon Spedding · Matt D Gaughwin