Pharmacology

The need for stimulant treatment must be assessed regularly In a United States legal action in 2000 about educational neglect, Albany County judge G E Maney ordered the parents to resume administering methylphenidate to 7-year-old Kyle Carroll.1 At the time, this controversial ruling was understandable, because controlled trials of stimulant treatment (dexamphetamine and methylphenidate) for attention deficit hyperactivity disorder (ADHD) had consistently shown that stimulants reduce ADHD symptoms. The catch is that trials have examined short-term effectiveness (usually over less than 6 months), while ADHD is a chronic condition. In 1992, the US National Institute of Mental Health funded the Multimodal Treatment Study of Children with ADHD (MTA) to examine the long-term effects of routine community management versus carefully delivered treatments. Children with ADHD, combined type (that is, showing symptoms of inattention, impulsivity and hyperactivity), were randomly allocated to medication, psychosocial treatment, a combination of both, or standard community care. The medication group received treatment with methylphenidate in which an optimal dose was titrated, with blinding, to achieve maximum benefit. The psychosocial group received a variety of interventions that consisted of parent training, a summer treatment camp and classroom management. Those in the routine care group were given information about services and left to their own devices. In total, 579 children with a mean age of 8.5 years were randomly allocated to the four groups, about 145 in each. After 14 months, children in both the medication groups showed greater improvement than those in the behavioural treatment and community care groups, leading the authors to conclude that “carefully crafted medication management was superior to the behavioral treatment and to routine clinical care that included medication”.2 The results were influential in treatment guidelines3 and clinical practice. Participants were naturalistically followed up 1 and 2 years after the end of the trial. The results of the last follow-up (3 years from the onset of treatment), of 84% of the original sample of children (then aged 10–13 years), showed that none of the treatment groups differed on any of the five clinical and functional outcomes (parent- and teacher-rated ADHD and oppositional symptoms, reading achievement scores, social skills, and functional impairment).4 Also, there were no differences in substance use or delinquency, with the exception of a slightly lower rate of substance use among those in the psychosocial treatment group.5 While improvement had been steepest during the first 14 months (mostly in the methylphenidate group), this levelled off, and at 3 years, all groups showed a similar improvement; the methylphenidate group had not deteriorated but the other groups had caught up.4 Speculation is bound to follow these results, which have many ambiguities and nuances. For example, this follow-up was not part of the controlled trial and, as happens in practice, children switched on and off their medication over time in the various groups, with consequent difficulties for analysis and interpretation. The results highlight several issues. First, it suggests the Rolls-Royce model (medication plus psychosocial treatment involving the child, family, and school) is not more effective in the long run than any of the other treatments, including the often maligned community care. The combined treatment is seen as the ideal, but is rarely delivered in practice, because of high cost and the burden for parents and schools.6 Second, there seems to be a “growing out of” or developmental factor at work. Epidemiological7 and follow-up8 data have consistently reported a reduction in ADHD symptoms with increasing age — although some individuals continue to show problems. This is also consistent with findings that brains of children with ADHD, rather than developing abnormally (as in autism), mature later.9 The MTA did not include a placebo group, which might have led to the conclusion that regression to the mean or maturation itself were the reasons for improvement. If that was the case, it is possible that helping families and schools contain children’s ADHD behaviour during the middle and late primary school years with minimal interventions (eg, parent management training) may be enough for a proportion — but not all — of these children to get better, or for medication to be required mostly during this developmental period. Finally, the MTA confirmed that medication can cause retardation of growth, including weight, particularly during the first year of treatment.10 While results of one study rarely justify drastic changes of practice, the findings underscore the complexity of ADHD, show that stimulant drugs are far from being a silver bullet, and that there is much that we do not yet know. This does not mean that stimulants no longer have a place in the treatment of ADHD. However, that place has shrunk, and clinicians should be circumspect when assessing the need for ongoing treatment (eg, through medication breaks). Much needs to be done to clarify who benefits the most from medication, at what developmental point stimulants are most useful, and for how long they should be taken. It is also not known whether these results apply to the slow-release formulations (which may enhance adherence) and to atomoxetine (a non-stimulant drug with antidepressant activity, which is thought to act by inhibition of the presynaptic noradrenalin transporter). Parents, often caught in the bind of concerns about their children taking medication and fear of the consequences of not treating them, might be comforted by these findings. One wonders whether Judge Maney would have issued the same order to Kyle Carroll’s parents had he been aware of this information.

Joseph M Rey MB BS, PhD, FRANZCP

Objective: To identify and analyse factors underlying intern prescribing errors to inform development of specific medication-safety interventions.Design: A prospective qualitative study that involved face-to-face interviews and human-factor analysis.Setting: A tertiary referral teaching hospital, Brisbane, Queensland, February–June, 2004.Participants: Fourteen intern prescribers involved in 21 errors.Method: A structured questionnaire was used to identify factors causing the errors. Transcripts were analysed on the basis of human-error theory to identify underlying themes.Main outcome measures: Factors underlying prescribing errors.Results: Errors were multifactorial, with a median of 4 (range, 2–5) different types of performance-influencing factors per error. Lack of drug knowledge was not the single causative factor in any incident. The factors in new-prescribing errors included team, individual, patient and task factors. Factors associated with errors in represcribing were environment, task and number of weeks into the term. Defences against error, such as other clinicians and guidelines, were porous, and supervision was inadequate or not tailored to the patient, task, intern or environment. Factors were underpinned by an underlying culture in which prescribing is seen as a repetitive low-risk chore.Conclusion: To reduce the risk of prescribing errors, a range of strategies addressing patient, task, individual, team and environment factors must be introduced.

Ian D Coombes BPharm(Hons), MSc · Danielle A Stowasser BPharm, PhD · Judith A Coombes BPharm, MSc · Charles Mitchell MB BS, FRACP

To the Editor: In Australia, the rising cost of the Pharmaceutical Benefits Scheme (a comprehensive system for subsidising prescription medicines for the whole population) has led to the Australian Government instituting a number of cost-saving strategies. One of these strategies is to encourage the use of generic medicines. However, generic prescribing is a contentious issue among Australian prescribers. The debate has centred on issues related to bioequivalence, quality and safety.1,2 Further, previous studies have shown that changing existing prescribing behaviour is difficult.3,4 To avoid the difficulty of having to change existing prescribing behaviour, education about the benefits of generic prescribing should be aimed at medical students, who are the prescribers of the future.5 To explore and evaluate senior (final-year) medical students’ perceptions of and knowledge about generic medicines and generic prescribing, we undertook a nationwide, web-based survey of senior medical students in Australian universities from 18 June to 18 September 2004. Of 1497 senior medical students in 10 universities throughout Australia, 400 (26.7%) responded to the survey. The first part of the questionnaire required students to select the correct bioequivalence limits allowed by the Therapeutic Goods Administration when comparing a generic medicine with a brand-name medicine. We compared responses to detect differences according to sex, graduate (students with a Bachelor or higher degree on entry to medical school) versus non-graduate status, and between the 10 universities using Fisher’s exact test. For the first question, six options were given, with the correct answer being 80%–125%. Most respondents (64%) did not answer the question, and only three (0.8%) answered it correctly. Responses to other individual questions in the web survey are shown in the Box. Seventy-one per cent of respondents (287) thought that they needed more information on how bioequivalence tests are conducted. More than 90% of respondents did not believe that generic medicines registered in Australia are equal in terms of quality and efficacy to their brand-name counterparts. A similar proportion of respondents thought that generic medicines would cause more side effects than brand-name medicines. Eighty-seven per cent highlighted pharmacists as one of the most important health care professionals to advise them on generic medicines. Almost 92% of respondents agreed that their future prescribing habits would be likely to be influenced by their senior colleagues and medical consultants. More than 60% believed that their respective university did not adequately cover the topic of cost-effective prescribing in their medical curriculum. Our survey clearly shows that medical students in Australia need to be better taught about issues relating to generic medicines and generic prescribing. Modifying existing curricula to include education about generic medicines will be a critical strategy towards promoting rational use of generic medicines by medical practitioners. Responses to questions assessing knowledge and perceptions of senior medical students in Australia about generic medicines and bioequivalence Responses P (Fisher’s exact test) Survey question/statement Strongly agree Agree Neutral Disagree Strongly disagree Sex Graduate status* University† All generic products of a particular medicine that are rated as “generic equivalents” are: therapeutically equivalent to the innovator brand product 66 (16.5%) 276 (69.0%) 18 (4.5%) 36 (9.0%) 4 (1.0%) 0.692 0.094 0.096 therapeutically equivalent to each other 4 (1.0%) 49 (12.3%) 23 (5.8%) 263 (65.8%) 61 (15.3%) 0.846 0.998 0.107 I have not been introduced to the issues of bioequivalence for generic drugs during my medical education 120 (30.0%) 153 (38.3%) 47 (11.8%) 69 (17.3%) 11 (2.8%) 0.703 0.893 0.010 I need more information on how bioequivalence tests are conducted for generic medicines 73 (18.3%) 214 (53.5%) 74 (18.5%) 34 (8.5%) 5 (1.3%) 0.036 0.572 0.195 A generic medicine is bioequivalent to a brand-name medicine 79 (19.8%) 270 (67.5%) 18 (4.5%) 30 (7.5%) 3 (0.8%) 0.574 0.943 0.827 A generic medicine must be in the same dosage form (eg, tablet, capsule) as the brand-name medicine 27 (6.8%) 106 (26.5%) 52 (13.0%) 196 (49.0%) 19 (4.8%) 0.751 0.677 0.152 A generic medicine must contain the same dose as the brand-name medicine 47 (11.8%) 171 (42.8%) 44 (11.0%) 126 (31.5%) 12 (3.0%) 0.919 0.905 0.048 Generic medicines are of inferior quality to brand-name drugs 148 (37.0%) 226 (56.5%) 20 (5.0%) 5 (1.3%) 1 (0.3%) 0.006 0.944 0.054 Generic medicines are less effective than brand-name medicines 151 (37.8%) 228 (57.0%) 19 (4.8%) 1 (0.3%) 1 (0.3%) 0.029 0.124 0.010 Generic medicines produce more side effects than brand-name medicines 148 (37.0%) 222 (55.5%) 26 (6.5%) 3 (0.8%) 1 (0.3%) 0.052 0.619 0.023 Generic medicines are less expensive than brand-name medicines 165 (41.3%) 215 (53.8%) 9 (2.3%) 9 (2.3%) 2 (0.5%) 0.190 0.154 0.072 Brand-name medicines are required to meet higher safety standards than generic medicines 112 (28.0%) 219 (54.8%) 42 (10.5%) 22 (5.5%) 5 (1.3%) 0.747 0.843 0.162 * Comparing graduate (those with a Bachelor or higher degree on entry to medical school) with non-graduate students. † Differences between the 10 universities represented.

Mohamed Azmi Ahmad Hassali · Kay Stewart · David C M Kong

We seldom identify the holiday season with medical matters, but perhaps we have been remiss in not doing so. Many holiday customs have medical significance — some positive, some negative. Christmas and the following 2 weeks host the highest cardiac and non-cardiac mortality of the major holidays,1 but few people seem to dread the approach of December as a threat to their physical health. On the positive side, some ancient kinds of Christmas gifts turn out to have modern medical applications, while, not so positively, some modern decorations cause a fair degree of morbidity. Here, solely to amuse and pique curiosity, not to provide an exhaustive review, we explore the pharmacology of the first Christmas gifts, as well as the potential benefits and hazards of some modern Christmas decorations. Ancient gifts that keep on giving today The first holiday custom we thought might have a medical application is the giving of Christmas gifts. This apparently originated with the arrival of the Magi, the three wise men, some time around the year 1 CE. Given the apostle Luke’s vocation as a physician, we felt it only fitting to use his biblical account of the three wise men bearing gifts to the baby Jesus. But, alas, his gospel includes no account of this exchange, so we were forced to quote Matthew, a tax collector: “Then they opened their treasure chests and gave him gifts of gold, frankincense and myrrh”.2 Interestingly, all three of these items have modern medical applications. Gold is the most obvious. As sulfhydryl-containing organic gold compounds, it has been used for rheumatoid arthritis and tuberculosis since the early 1920s, although elemental (metallic) gold was used for many centuries before. Elemental gold is largely inert, not reacting to any chemicals it encounters inside the body; however, it can be deposited in the soft tissue of the skin and eye, leading to a condition known as chrysiasis. Unfortunately, the gold deposits are actually an unappealing grey–blue, rather than the metallic gold glow that might be considered festive. Although the use of gold is not as common today as it was in previous years, exposure to modern therapeutic technology, such as the Q-switch laser, or even ultraviolet light, has resulted in chrysiasis many years after gold therapy was discontinued.3 Gold also causes its share of problems when combined with another holiday tradition: ethanol. Case reports indicate that Goldschlager, a liquor that contains gold flakes, has been associated with lichen planus.4 Although frequently having a lacy white pattern, known as Wickham’s striae, lichen planus too is unappealing, rather than festive. The next gift of the Magi, frankincense, has several medical uses. This substance is obtained from trees of the genus Boswellia, by slashing the tree trunk longitudinally and harvesting the liquid released after it has dried to “tears”.5 It has been valued greatly since ancient times, although its mechanism of action has only recently been discovered. Frankincense inhibits leukotriene synthesis via the inhibition of 5-lipoxygenase, but, interestingly, it does not block cyclo-oxygenase or 12-lipoxygenase.6 This mechanism is similar to that of the leukotriene-receptor antagonist, monteleukast, and indeed frankincense has been shown to prevent exacerbations of asthma much more efficiently than placebo in a small study.7 Frankincense also appears to be bacteriostatic and larvicidal, and may yet prove beneficial as an antimicrobial.8 Further, it seems to have activity against skin cancer as an escharotic agent and stimulates apoptosis in colon cancer cells.5 It has also shown some cytotoxic activity against meningioma.5 Finally, myrrh, a secretion of plants of the genus Commiphora,9 is proving to have its own set of medical benefits. It appears to have an analgesic effect through action on opioid receptors.9 It also seems to have antimicrobial activity, and has recently been touted as a highly effective treatment for schistosomiasis in Egypt.10 Myrrh extracts have shown antibacterial activity against common pathogens such as Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus.11 On a more practical level, myrrh combined with bee propolis (a hive sealant used as an alternative to beeswax) and, paradoxically, honey has been used to treat wounds in patients with diabetes mellitus, with great success in limited trials.12 Another product of plants of the genus Commiphora, guggulipid, is purported to have a favourable effect on lipids — causing a modest decrease in low-density lipoprotein (LDL) cholesterol concentration, but a profound increase in high-density lipoprotein (HDL) cholesterol.13 However, randomised trials have failed to show this effect.14 Traditional decorationsMistletoe, a plant popular as a decoration around the Christmas holidays, is also finding a myriad of medicinal uses. This tree parasite, thought to have been sacred to the Druids, and blamed for the death of the Norse god Balder, is commonly used as an excuse for stealing a kiss during the Christmas season. But mistletoe does not, to our knowledge, have any aphrodisiac qualities. However, it has been found to inhibit peristalsis, and has been suggested as a treatment for colic.15 A mistletoe extract has shown antihypertensive effects in rats, although safety in humans has not been established.16 Mistletoe extracts also apparently have activity against bladder carcinoma in both mice and rats.17 In humans, mistletoe has been used to treat prostate cancer.18 Modern decorations or dealers of disease?The humble Christmas tree can be a source of disease, as well as providing pleasure. A young man in Molokai, Hawaii, contracted ophthalmomyiasis while unloading a Christmas tree.19 Perhaps the larvicidal effect of frankincense would have been of benefit to him in this situation (as it might be to a herd of reindeer — flying or otherwise — infested by botfly larva). As might be expected, children are not immune from the dangers of Christmas trees. A 2-year-old Canadian child with recurrent pneumonia eventually underwent a thoracotomy and right lower lobectomy for the disorder. The pathology examination revealed a 3 cm by 0.5 cm foreign body resembling the distal branch of an evergreen tree.20 Similarly, a 2-year-old Australian child apparently inhaled an ornament shaped like a Christmas tree, which caused asthma-like symptoms until it was removed laryngoscopically.21 Even artificial trees have been the source of disease. A 44-year-old English woman had a relapse of bird fancier’s lung a long time after she got rid of her fine, feathered friend.22 Apparently, her symptoms were triggered by an artificial Christmas tree that had been her bird’s favourite perch — protein deposits left on the branches were enough to cause the recurrence. Christmas trees have also been — unfairly — blamed for sporotrichosis. It seems that, although Christmas-tree farming has been associated with this disorder, it is actually the sphagnum moss used to wrap the roots of the trees, rather than the trees themselves, that are the culprit.23 Christmas trees are not the only unfairly maligned plant of the Christmas season. Perhaps the most notable medical feature of a common Christmas decorative plant — the poinsettia (Euphorbia pulcherrima) — is actually the lack of any adverse events associated with it. This festive red and green plant is used throughout the United States as both a Christmas gift and a holiday decoration, despite the widespread public notion that it is highly toxic. Recent investigations failed to show any fatalities — and indeed very few adverse events at all — associated with poinsettia ingestion.24 Likewise, that common Christmas plant, holly (Ilex aquifolium), is traditionally thought of as poisonous, but a PubMed search of this genus and species revealed no reports of ill effects associated with traditional European holly. That said, there were also no reports on the safety of European holly ingestion either, so it is probably a dish best avoided. Other members of this species have been shown to have toxic effects when ingested in tea form.25 So, as families and friends gather this Christmas holiday season, they can delight in the fact that most of the decorations in their homes are medically relevant. The traditional biblical gifts of gold, frankincense and myrrh are all doing their part to stamp out disease. The humble tree parasite, mistletoe, despite its toxic nature, has its place in the medical pharmacopoeia. Parents need not fear their toddlers drifting too close to the poinsettia, because the plants are pretty much harmless. On the other hand, they should keep an eye on that Christmas tree . . .

Stuart M Smith MD · B James McCallum MD, FACP

To the Editor: I was part of a review of the Therapeutic Goods Administration (TGA)-approved product information (PI) monographs contained in MIMS (Monthly index of medical specialties) annual with respect to their poisoning management advice.1 We looked at the 10 most common poisonings presenting to Westmead Hospital and another 15 clinically important poisonings as determined by two of the authors, and compared the poisoning management advice given in MIMS to a “gold standard” derived from a consensus of five pharmacological resources. For the 25 drugs examined, 14 monographs contained inaccurate information, one contained a recommendation for ineffective treatments, and 14 omitted specific treatments or antidotes. Many of these errors could delay or even prevent patients receiving currently accepted and effective therapies for life-threatening poisonings if MIMS were used as the primary resource. The omission of sodium bicarbonate for ventricular conduction delay and hypotension in amitriptyline, quinine and thioridazine poisonings is particularly problematic. Ventricular conduction delay and hypotension is often refractory to other therapies, and delay in bicarbonate administration could result in avoidable deaths. The recommendation of sodium bicarbonate for ventricular conduction delay and hypotension was included in the TGA-approved monograph for amitriptyline in 1984, but was subsequently removed without qualification in 1990 and remains absent. Cyproheptadine, an important therapy for serotonin syndrome, is not included in the TGA-approved monograph for sertraline, and its delay could result in avoidable morbidity. Atropine for verapamil-induced bradycardia is a simple and intuitive therapy; however, its omission from the TGA-approved monograph could again result in avoidable morbidity and mortality. We also found potentially dangerous treatments recommended in the TGA-approved monographs not covered by the consensus opinion. These included intravenous amphetamine or intramuscular ephedrine to counter the sedative effects of promethazine poisoning, administration of enteric-coated ammonium chloride tablets to increase urinary excretion in chloroquine poisoning, and forced osmotic diuresis using a urea or mannitol infusion for lithium poisoning. These treatments are out of the Dark Ages, and their use should be considered negligent. Based on this and other reports in previous editions of the Journal, the TGA-approved PI monographs contain inaccurate, inadequate, out-of-date or potentially dangerous information relating to poisoning management advice, paediatric drug dosages,2 drug interactions,3 breastfeeding mothers,4 and various thyroid medications.5 How can we use MIMS for anything other than simple drug formulation information? Surely, to anyone who wishes to practise up-to-date, safe, evidence-based medicine, the answer must be that we cannot. It is time for the TGA to take up its role as regulator and insist on updated and accurate PI monographs from the pharmaceutical companies.

James L Mallows

In reply: An article by Stockigt1 and follow-up correspondence from Mallows raised concerns about the limitations of approved product information (PI). The purpose of PI needs to be realised. The document is not intended to act as a textbook of medicine or general management of patients, but is intended to contain sufficient information to allow a health professional, in average circumstances, to use the specified medicine safely and to refer to other sources of information and expertise should they be required. The PI covers uses of the medicine evaluated and approved by the Therapeutic Goods Administration (TGA). The sponsor of the medicine is responsible for maintaining the PI, and the TGA has procedures in place to support their timely updating. On occasions, the TGA initiates reviews of PI when a need is identified. Health professionals, especially specialists, are important in identifying possible improvements in PI, based on their experience, knowledge or awareness of current medical practice. The TGA encourages physicians who have suggestions to approach the sponsor of the medicine or the TGA. It is not possible to address in detail the article by Stockigt1 or the letter by Mallows. The thyroid PI documents have been reviewed by the sponsor companies, and changes have been made where evidence supports this. However, as indicated above, there are limitations on the role of PI. Mallows raises the issue of complex management instructions on overdosage, including the specifics of bicarbonate administration for potential metabolic acidosis. The PI documents for the named products do mention that overdose patients are likely to develop such complications, and that they require admission to hospital and management by appropriate specialists; intensive care admission is recommended in several of the documents. It is arguable how much further detail is required. The PI cannot replace careful consideration of the individual circumstances of the patient combined with expert knowledge of patient management. PIs are complex documents. The TGA is currently considering the format of the PI and whether it can be rearranged to better balance provision of basic messages and more complex material in separate presentations.

David T Graham

Excess serotonin in the central nervous system leads to a condition commonly referred to as the serotonin syndrome, but better described as a spectrum of toxicity — serotonin toxicity. Serotonin toxicity is characterised by neuromuscular excitation (clonus, hyperreflexia, myoclonus, rigidity), autonomic stimulation (hyperthermia, tachycardia, diaphoresis, tremor, flushing) and changed mental state (anxiety, agitation, confusion). Serotonin toxicity can be: mild (serotonergic features that may or may not concern the patient); moderate (toxicity which causes significant distress and deserves treatment, but is not life-threatening); or severe (a medical emergency characterised by rapid onset of severe hyperthermia, muscle rigidity and multiple organ failure). Diagnosis of serotonin toxicity is often made on the basis of the presence of at least three of Sternbach’s 10 clinical features. However, these features have very low specificity. The Hunter Serotonin Toxicity Criteria use a smaller, more specific set of clinical features for diagnosis, including clonus, which has been found to be more specific to serotonin toxicity. There are several drug mechanisms that cause excess serotonin, but severe serotonin toxicity only occurs with combinations of drugs acting at different sites, most commonly including a monoamine oxidase inhibitor and a serotonin reuptake inhibitor. Less severe toxicity occurs with other combinations, overdoses and even single-drug therapy in susceptible individuals. Treatment should focus on cessation of the serotonergic medication and supportive care. Some antiserotonergic agents have been used in clinical practice, but the preferred agent, dose and indications are not well defined.

Geoffrey K Isbister MB BS, MD, FACEM · Nicholas A Buckley BMed, MD, FRACP · Ian M Whyte MB BS, FRACP

A woman in her 20s presented to the emergency department, malnourished and dehydrated, and with acute paralysis of the lower limbs. Over the previous 10 days, she had inhaled nitrous oxide from “whipped-cream bulbs” (10–20 per day) for pain caused by a sprained ankle. She had a history of intravenous drug use and was on a methadone program. The nitrous oxide misuse combined with the malnutrition, with low vitamin B12 levels, apparently resulted in subacute combined degeneration of the spinal cord — a rare complication of nitrous oxide misuse. Clinical recordA young woman in her 20s presented to the emergency department with a history of increasing difficulty in mobilising over the previous week. For the 3 days before presentation, she had been confined to the back seat of a car (from which she was extricated with difficulty on arrival at the emergency department). An estimated 60 empty “whipped-cream bulbs” were found on the floor of the car. She had a history of intravenous drug use and was on a methadone program, but there was no other significant medical history. She had sprained her ankle 10 days before presentation, and had been inhaling nitrous oxide from whipped-cream bulbs for the pain (10–20 per day). Further immobility and boredom had increased her usage. On examination, she was pleasant, but dishevelled and malnourished, with evidence of needle track marks from intravenous drug use on her extremities. She had a Glasgow Coma Scale score of 14/15 (best eye response, 4; best verbal response, 4; best motor response, 6); her respiratory rate was 20 breaths/min; heart rate, 95 beats/min; blood pressure, 95/63 mmHg; temperature, 35.6°C; and oxygen saturation in room air was 94%. She had a 1/5 flaccid proximal weakness of the lower limbs (Medical Research Council [United Kingdom] scale), with a flicker of power preserved distally, but absent plantar and knee-jerk reflexes. She had a patchy sensory level to T10, and absent vibration sense to her anterior superior iliac spines bilaterally. There was a proprioception deficit to her feet, knees and hips bilaterally. She was in urinary retention, and 1800 mL was drained through an indwelling urinary catheter. Rectal examination showed atony of the anal sphincter. There were mild pressure areas on the dorsal surfaces of her legs and buttocks, with diffuse oedema of the lower limbs. The rest of the examination was unremarkable. InvestigationsDifferential diagnoses included a space-occupying lesion of the spinal cord, transverse myelitis, HIV myelopathy, Guillain–Barré syndrome, and multiple sclerosis. We were concerned about the presence of a neurological toxin in the whipped-cream bulbs, given the history of neurological deterioration coinciding with the patient’s excessive use of the bulbs. Our diagnosis was initially delayed, as we were unable to ascertain the exact constituents of a whipped-cream bulb. Magnetic resonance imaging (MRI) of the whole spine and brain was performed and was initially reported as showing no abnormality. Initial laboratory investigations showed: a raised serum creatine kinase level of 9000 U/L (reference range [RR], < 150 U/L); acute renal failure, with a creatinine level of 490 μmol/L (RR, 80–140 μmol/L) and a urea level of 41 mmol/L (RR, 2.5–7.5 mmol/L); a troponin leak of 0.7 μg/L (RR, < 0.05 μg/L); and a normocytic anaemia, with a haemoglobin level of 83 g/L (RR, 120–140 g/L) and a mean cell volume of 95 fL. Vitamin B12 levels were 124 pmol/L (RR, > 210 pmol/L). A lumbar puncture was attempted but, on sitting the patient upright, she had a bradycardiac arrest and required cardiopulmonary resuscitation (CPR) for 30 s, resulting in spontaneous return to circulation and heart rate. Her arrested circulation was most likely the result of her being dehydrated (as evidenced by prerenal renal failure). Given her clinically demonstrated neuropathy, it is possible that a combination of autonomic neuropathy and reduced intravascular volume from dehydration, together with orthostatic stress on positioning, resulted in the precipitous fall in blood pressure, bradycardia, and arrest. This would explain the rapid return to cardiac output on return to a supine position, with only transient CPR. A Doppler ultrasound scan of the lower limbs showed bilateral deep venous thrombosis (DVT) to the level of the common femoral arteries. Indirect evidence of pulmonary embolus (PE) included a large alveolar–arterial gradient of > 100 mmHg (RR, 10–25 mmHg) and electrocardiogram changes — tachycardia and a right bundle branch block. It was decided not to perform a computed tomography pulmonary angiography, given the strongly supportive evidence for PE, and an intravenous contrast load was contraindicated given her acute renal failure. A further PE on upright positioning may also have contributed to her cardiac arrest; however, her rapid return to baseline clinical status on returning to a supine position does not support this. Clinical courseThe patient was resuscitated in the emergency department, with fluid loading for prerenal renal failure and as therapy for rhabdomyolysis. She was then transferred to the intensive care unit (ICU) for observation, and given vitamin B12 replacement therapy and methionine. Her acute prerenal failure resolved with rehydration, and she was given an intravenous heparin infusion as anticoagulation therapy for bilateral proximal DVT, and subsequently given warfarin for a target international normalised ratio of 2.0–3.0. Further imaging, such as a ventilation–perfusion scan for the presence of PE, was not performed as it would not have contributed to her management. After 2 days in the ICU, she was transferred to a general medical unit. An MRI scan on review 2 weeks after her admission showed an increased T2 signal within the posterior columns of the spinal cord. She slowly regained partial motor function of her limbs and normal sensory levels over the following 5 months. She was discharged after 7 months of rehabilitation and inpatient care. She was able to walk short distances, with the aid of a walking frame, but had residual neurological deficits affecting the distal lower-limb muscle groups. DiscussionNitrous oxide is a colourless, odourless gas with a weak anaesthetic but useful analgesic action.1 It is used during short, painful procedures. Because of its ability to elevate mood, nitrous oxide is colloquially known as “laughing gas”, and is a common drug of misuse. “Nagging” or “nanging” are terms used to describe the recreational use of nitrous oxide, derived from the repetitive sound distortions experienced by nitrous oxide users.2,3 In a New Zealand survey of first-year university students, 57% were aware of its recreational use and 12% used it regularly.2 Nitrous oxide is readily available from most supermarkets and online, as it is used as the aerator and propellant for whipped-cream dispensers. The average bulb used for aerating whipped cream contains 8 g of nitrous oxide. Pathophysiology and diagnosisSubacute combined degeneration of the spinal cord is a recognised complication of vitamin B12 deficiency or of nitrous oxide exposure (with or without pre-existing normal vitamin B12 levels). This complication is well documented in anaesthesia literature in relation to frequent nitrous oxide exposure in anaesthesia, such as during multiple operations, or analgesic use for repeated dressing changes for burns patients.4,5 Patients with long-term nitrous oxide recreational use are reported to have neurological symptoms ranging from paraesthesias to incoordination and autonomic dysfunction.6-9 There is no known neurological toxicity threshold for nitrous oxide exposure. Toxicity is related not to the frequency or level of nitrous oxide exposure, but to the patient’s levels of vitamin B12. Spinal cord degeneration resulting from a single short exposure to nitrous oxide anaesthesia, in association with vitamin B12 deficiency, has been reported.10,11 The neuropathological changes observed in the affected spinal cord include initial swelling and irregularity of the myelin sheath surrounding the nerve cell axons (reversible), followed by frank demyelination and loss of axons (irreversible).12 This occurs in the central regions of the posterior columns and, to a lesser extent, in the posterolateral regions of the spinal cord. The changes manifest as high-signal lesions on MRI T2-weighted scans caused by increased water content secondary to oedema.10,11 Nitrous oxide inhibits the active form of vitamin B12, rendering it unavailable to form the myelin sheath proteins, resulting in axonal swelling and eventual axonal loss. The mechanism of action is the inactivation of vitamin B12 (cobalamin) from its monovalent, active cobalt form (Co+) to the inactive, bivalent cobalt form (Co2+). The irreversibly inactivated vitamin B12 (Co2+) results in failure of methylation of proteins in the myelin sheaths4 and a loss of nerve cell axon integrity.12 Another contributing factor to the toxicity of nitrous oxide is the role of vitamin B12 as a cofactor of the methionine synthase reaction. The enzyme catalyses the reaction in which homocysteine is converted to methionine; tetrahydrofolate is also formed, which is a cofactor in the metabolism of nucleic acids (eg, DNA).9 Thus, nitrous oxide has a direct effect on DNA synthesis, as well as nerve axon integrity. Other postulated mechanisms of action for central nervous system toxicity of nitrous oxide include inhibitory effects on N-methyl-d-aspartate receptors, stimulatory effects on dopamine neurones, stimulation of descending noradrenergic neuronal pathways, provoked release of noradrenaline in dorsal horn neurones, and sympathetic action via α-1-adrenergic stimulation.8,9 A diagnosis of subacute combined degeneration of the spinal cord can be confirmed by MRI, in association with low serum vitamin B12 levels, but in some cases MRI scans show no abnormality.11 The differential diagnoses include demyelination, neoplasms, infections (eg, with Listeria spp., or HIV), myelopathy, and syringomyelia. Treatment and prognosisTreatment involves ceasing nitrous oxide use and giving vitamin B12 replacement therapy. Administration of methionine may also be required as an adjunct, given the direct effects of nitrous oxide on methionine synthase. Exogenous methionine would provide a direct substrate for methionine synthase, while the body slowly replaces the inactive vitamin B12 and commences repletion of endogenous methionine. Two patients receiving vitamin B12 replacement therapy experienced a worsening of their neurological symptoms until the addition of oral methionine, which halted the neurological decline and accelerated their recovery.9 Reported recovery periods vary from 1 week to 1 year. Partial versus full recovery will depend on the extent of the neuropathological damage to the spinal cord; spinal cord oedema and myelin sheath loss will resolve, but axon loss is permanent.

Michaela Cartner MB BS, FACEM · Michael Sinnott MB BS, FACEM, FRACP · Peter Silburn MB BS, PhD, FRACP

To the Editor: We report two cases of previously well male bodybuilders who presented with severe extrapyramidal reactions after intramuscular injection of the antipsychotic fluphenazine decanoate, in the mistaken belief that it was an anabolic steroid. The first patient, aged 31 years, obtained fluphenazine decanoate from a gym contact. He injected 50 mg intramuscularly on alternate days (Days 1, 3 and 5) to a total of 150 mg, then presented to two local hospitals on Days 7 and 11 with difficulty swallowing, generalised muscle stiffness and lethargy. He withheld the history of fluphenazine use, and was diagnosed with tonsillitis. On Day 14, he presented to our emergency department (ED) with marked dystonia, immobility, and inability to speak or swallow food. On examination, he was afebrile and haemodynamically stable. He was given a trial dose of benztropine 2 mg, but improvement was slight and, given the absence of relevant history, benztropine was not repeated. The neurology team raised the possibility of a conversion disorder, but the psychiatry team, noting the patient’s attempts to speak and an absence of recent stressors, believed that further investigation into an organic cause was required. When the patient’s wife learned that he had used fluphenazine and alerted the neurology team to this use, he was started on regular benztropine and his condition improved over the next 3 days. The dose of benztropine was reduced on discharge, but his dystonia recurred and required readmission to hospital for further treatment. The second, unrelated patient, also aged 31 years, openly admitted purchasing fluphenazine decanoate from “a friend of a friend”. After injecting two 50 mg depots, he had multiple presentations to three EDs, where he was treated for dystonia with immediate doses and then regular low doses of benztropine. On admission to our hospital 19 days after injection, he was afebrile and haemodynamically stable, with marked dystonia. His initial creatine kinase level was elevated (553 U/L; normal, < 204 U/L), but subsequently normalised and was not accompanied by autonomic dysfunction. His condition improved with regular oral diazepam and benztropine, but symptoms recurred when he inappropriately reduced his benztropine dose after discharge. On subsequent review, both patients’ dystonia was resolving, but they had significant akathisia. Inadvertent and inappropriate use of a long-acting phenothiazine not only required prolonged anticholinergic therapy for these men, but we believe placed them at risk of neuroleptic malignant syndrome. We have found no previous similar reports in the medical literature, but are aware anecdotally of at least one other case of a patient treated recently at a district hospital. The anabolic steroid nandrolone decanoate is referred to colloquially on numerous websites and by our patients as “deca” (from the Organon brand name Deca-Durabolin). We believe our patients and their supplier(s) have mistaken the “decanoate” in fluphenazine decanoate for the pharmacologically active component of the drug.

Elizabeth A S Giugni · Rachel S Boddy · Natalie G Limet

To the Editor: Bajorek et al1 did not address two aspects of compliance that may be an issue in community care of patients with atrial fibrillation taking warfarin: time of dose, and point-of-care testing. There is no pharmacological reason requiring warfarin administration in the evening. This practice arose to facilitate dose adjustment on the day of testing, initially in hospitals, and subsequently flowed on to community care. We know that compliance is better with once-daily administration re-gimens, and this patient group invariably needs other medications, such as diuretics, that require morning doses. Concomitant morning administration of warfarin would be logical. In addition, it would reduce attendances by domiciliary nurses to cognitively impaired patients, who may otherwise require twice-daily visits for administration of medications. This would alleviate a significant burden on this stretched resource. The implementation of point-of-care testing at the general practitioner’s surgery by a registered nurse can be of great benefit in the liaison required to manage therapy, and facilitates instant dose adjustments by the doctor, who has comprehensive knowledge of the patient’s pharmaceutical and health circumstances.2

Peter W Ford · Angela Close

In reply: I thank Ford and Close for highlighting additional points regarding the optimal management of anticoagulants in general practice. Indeed, neither of these points was raised by our study participants. Regarding the timing of doses, for medication safety reasons, in many hospitals the warfarin dose is listed for mid-evening administration; the recently introduced National Inpatient Medication Chart (NIMC), which incorporates a designated “warfarin section”, nominates 16:00 as the time. In the hospital setting, this timing is necessary to enable the treating medical team (rather than after-hours staff) to review the day’s blood test results, and subsequently prescribe the appropriate dose. The process ensures that treatment is optimally managed by those most knowledgeable about the patient’s regimen, prevents dose omissions, and reduces the time to dose stabilisation (and potentially, time to discharge). Ford and Close appropriately point out that this timing may not always be convenient for patients once they are discharged to the community setting. The optimal regimen should facilitate the patient’s adherence to treatment, and therefore should coordinate with the rational use of existing support services. This needs to be more carefully considered in discharge planning when warfarin therapy is involved. Point-of-care testing is an efficient mode of monitoring anticoagulation therapy, but we were unable to expand on this in our previous discussion (due to word limits). Internationally, point-of-care testing underpins many comprehensive monitoring services, whereby allied health professionals (eg, trained nurses or pharmacists) perform the blood tests, monitor results, adjust doses, and/or prescribe therapy, as well as educate patients, under the guidance of a medical officer. Such services are conventionally offered on an outpatient basis (eg, the Antithrombosis Center, University of Illinois Medical Center, Chicago, Ill, USA) or within the general practice setting, and are effective and safe models of care. Patient self-management using point-of-care testing devices has also been studied overseas,3 with reports of good control of international normalised ratio (INR) and high patient satisfaction. Locally, point-of-care testing has been trialled within community pharmacies. In a Sydney-based study, trained community pharmacists monitored INRs using point-of-care testing, reviewed doses according to standardised nomograms, and subsequently liaised with GPs regarding dose adjustments. The results showed that collaborative management effectively maintained INRs within the therapeutic range.4 There is scope to develop such models further, and we are currently investigating GPs’ preferences for models of care, as well as opportunities for mobile anticoagulation services.

Beata V Bajorek

To the Editor: The Guidelines for the management of acute coronary syndromes 20061 state: “Enoxaparin may be used in conjunction with fibrin-specific fibrinolytic agents in patients under the age of 75 years, provided they do not have significant renal dysfunction. An intravenous bolus dose of 30 mg followed by a 1 mg/kg subcutaneous injection every 12 hours in combination with tenecteplase is the most comprehensively studied therapy.”1 In Australia, enoxaparin is not licensed for intravenous use (Tony Hall, Team Leader, High Risk Medications and Systems, and Christine Maclean, Associate Director, Safe Medication Practice Unit, Queensland Health, personal communication) and there is no recommendation for the intravenous use of enoxaparin in the drug product information.2 Are the authors recommending “off-label” use of intravenous enoxaparin, or do they wish to modify the guidelines to reflect what the management should be if clinicians are unable to use intravenous enoxaparin?

Mark Little · Chris Johnstone

In reply: The guidelines were published to provide clinicians with the most contemporary information on the management of acute coronary syndromes based on the international literature, and may include treatments which are not currently available, officially licensed or available through the Pharmaceutical Benefits Scheme in Australia. In the context of adjuvant therapy for patients with ST-segment-elevation myocardial infarction (STEMI), the guidelines recommend that antithrombin therapy should be used with fibrin-specific fibrinolytic agents.1 Based on the best evidence available at the time, the guidelines mention two antithrombins, unfractionated heparin and enoxaparin, to be considered for use in this setting. The recommendation for enoxaparin is based on comprehensive evidence of clinical benefit with the regimen of an initial intravenous (IV) bolus dose followed by subcutaneous injections every 12 hours. It is up to individual practitioners to determine whether the IV dose should be provided “off-label” or omitted, based on the evidence and the circumstances of the individual patient and setting. The issue of superiority of enoxaparin over unfractionated heparin as adjuvant therapy for patients with STEMI is currently being evaluated in light of recent evidence,2 and will be included in a future update of the guidelines.

Constantine N Aroney · Philip Aylward

Reform is needed, but will the current Bill enact the best options? Two articles in this issue of the Journal1,2 comment on a complex but important piece of legislation put forward by the Minister for Health and Ageing — the National Health Amendment (Pharmaceutical Benefits Scheme) Bill 2007 (the Bill).3 The Bill splits the Pharmaceutical Benefits Schedule into two formularies: “one part for single brand drugs [F1], the other part for drugs that have multiple brands or that are interchangeable at the patient level with drugs with multiple brands [F2]”.3 The Bill allows reference pricing of drugs within each formulary but disallows an ongoing link in the price of drugs between formularies. The Bill institutes progressive mandatory price reduction and price disclosure by the sponsors of multiple brand (generic) medicines for drugs on F2. The aim of this is to ensure that the price the government pays for Pharmaceutical Benefits Scheme (PBS) medicines more closely reflects discounted prices paid by pharmacists and international prices for generic medicines. A support package will be provided to help community pharmacists adjust to the new arrangements. Authority approvals will be streamlined, a public awareness campaign is promised to promote the use of generic medicines, and a working group will be established to consider issues of continued access to innovative medicines through the PBS. The government argued in the Bill that dual delinked formularies were required to tackle a problem caused by reference pricing: price reductions imposed on multiple brand generic medicines that were being discounted to pharmacies would, in many cases, flow directly on through price linking to single brand patented medicines that were not being discounted. This was said to cause difficulties for the innovative pharmaceutical industry and to place patients at risk of losing subsidised access to many worthwhile medicines.4 The government believes patients will not be disadvantaged by the proposed changes, as out-of-pocket costs to patients would remain unchanged. In some cases, patients should pay less. It is estimated that the mandatory price reductions for drugs in the F2 formulary will result in patients paying between 20 cents and $4.65 less for about 400 drugs that will fall below the current copayment amount of $30.70 (for general patients), or that were already below this amount. The articles by Searles et al1 and Faunce2 raise three concerns about the Bill. First, eliminating global reference pricing could result in Australia paying more for a new medicine in F1 that is no better than those already available in F2. Second, these changes appear to reflect ongoing pressure from the United States through the Medicines Working Group established by the Australia–US Free Trade Agreement to weaken the PBS system of evidence-based reference pricing. Third, mandatory price reductions and price disclosure for drugs on the F2 formulary, while saving the government money, provide little financial relief to patients and are unlikely to stimulate the Australian generic medicine industry. Reference pricing is a means of negotiating a lower price by tying the subsidy to the differential effectiveness of the drug — its comparative clinical outcome rather than its cost of production. This principle applies both at the time of initial subsidy and later, when new competitors arrive on the scene. The proposed changes may not change the initial pricing mechanism, which will continue to use comparative effectiveness as a criterion for pricing. What they will do is lessen the “downward pressure” on single brand (patented) drug prices over time. With the new dual formulary system, there will no longer be an automatic price reduction when different drugs of similar effectiveness for the same condition are listed on the PBS at a lower price. The problem with the current system, as Searles et al make clear, is that we are paying too much for drugs that are out of patent, where the company has already made its profit on the initial investment. We need a means to reduce the price of generic drugs in a system where fixed out-of-pocket costs to consumers and historic negotiated prices with suppliers provide no incentive to switch to generics, and where there are no competitive forces to reduce prices to government. The Bill does provide one mechanism to do so. It will mandate price reductions to government for out-of-patent medicines over time. This will lower the cost of generic drugs in Australia — a much needed reform. The problem is that it relies on annual administrative rule changes that do little to encourage the generic medicine industry and may have the effect of maintaining high prices for patented medicines, even when similar non-patented drugs are falling in price. The unforeseen result might be that we will pay more for the health gains from many new expensive medicines over time. Searles et al suggest one alternative — maintain a single formulary, but have closed-bid, competitively tendered contracts with generic medicine suppliers to provide key drugs outside of the PBS. Another option would be to increase competition for generic drugs (within a single or dual formulary) by allowing generic drug manufacturers to discount to government rather than wholesalers or pharmacies. A generic-brand price discount to consumers could be seen as an extension of the current brand price premium scheme — instead of consumers paying more than the regular copayment for a particular brand, they could pay a lower price if they choose a particular generic. Using a market price signal of a copayment reduction for consumers is likely to be more effective in stimulating generic medicine use than the proposed government advertising campaign, possibly a lot cheaper, and is consistent with the aim of the National Medicines Policy to provide timely access to the medicines that Australians need, at a cost patients and the community can afford. Fine-tuning such a system so that the expected increase in market share would be enough to encourage a local industry, or to ensure the kind of continuous price reductions that the Bill imposes, is something that the government could experiment with — without serious disruption to the system. A Senate Committee inquiry into the Bill held a public hearing on Friday 15 June 2007, and was required to report the following Monday. The Committee recorded that this provided insufficient time to analyse specific concerns raised in evidence, especially in relation to possible long-term impact of these reforms. The Senate Committee recommended that the Minister report to the Senate 12 months after implementation of the reforms on their impact, par-ticularly on the cost of medicines to consumers.5 The Bill was amended accordingly.

Ken J Harvey MB BS, FRCPA · Anthony H Harris MA, MSc · Liliana Bulfone BPharm, MBA, GradCertHealthEco

Draft legislation introduced to Parliament on 24 May 2007 proposes changes to the Pharmaceutical Benefits Scheme (PBS), including the creation of two formularies. The F1 formulary will contain single brand drugs that are not considered “interchangeable on an individual patient basis”, while the F2 formulary will contain mainly older drugs (many of them generic) for which there is at least one alternative product considered to be clinically interchangeable. Drugs in F1 will not be compared with those in F2 for pricing purposes, even if clinical trial data show them to be equivalent (or even inferior) for the same clinical indication. This undermines the evidence-based approach to reference pricing currently used in the PBS. Other changes require compulsory price disclosures and price cuts for generic medicines. While positive, these amendments are unlikely to deliver generic medicine prices as low as those in other developed countries. This is important, in view of growing evidence of the unaffordability of prescription medicines in the Australian community.

Andrew Searles BEc, DipEd, MMedStat · Susannah Jefferys BA LLB(Hons) · Evan Doran BA, GradDipHealthSocSci, PhD · David A Henry MB ChB, MRCP, FRCP

Unless the federal government changes the course of our medicines policy with intention, Australia’s pricing of patented pharmaceuticals is likely to follow inequitable US trends Proposed amendments to the National Health Act 1953 (Cwlth) are currently being considered by the Australian federal government. The National Health Amendment (Pharmaceutical Benefits Scheme) Bill 2007 (the Bill) includes several changes that will limit reference pricing under the Australian Pharmaceutical Benefits Scheme (PBS). Here, I argue that these amendments have been influenced by the Australia–United States Free Trade Agreement (AUSFTA) and, further, that if US influence on Australian medicines policy continues, there are likely to be adverse consequences for all Australians, involving the erosion of scientific objectivity and equity in PBS processes and, eventually, the end of public-funded medicines. What is reference pricing?The PBS is an internationally respected system under which the federal government uses public funds to reimburse pharmacists (and thence manufacturers) the “health innovation” value of listed medications, as proven by scientific evidence assessed by pharmacoeconomic experts on the Pharmaceutical Benefits Advisory Committee (PBAC). This allows Australian patients to generally pay a relatively low standardised copayment (currently $30.70 for non-concessional patients) for all PBS medicines, patented and generic alike. Under the current PBS system, once expert assessment has established that a new patented drug has better efficacy or safety than a different off-patent comparator for the same clinical indication, it is recommended by the PBAC for listing. The submission price is then further negotiated by the Pharmaceutical Benefits Pricing Authority (PBPA). If the PBAC’s analysis merely establishes equal effectiveness, then, in a fundamental cost-minimisation process, the newly listed drug’s initial reimbursement price is linked to the lowest in the relevant price reference group. Reference pricing, in its most fundamental sense however, applies post-listing when new competitors (with lower prices) enter six groups presently established under the Therapeutic Group Premium (TGP) Policy. In this TGP system, the unusual criterion of “individual interchangeability” assists patients wishing to obtain an alternative to a drug in one of these groups whose price has a high additional premium. Readily expanding categories of TGP reference pricing are a fundamental institutional manifestation of the evidence-based distributional justice — seeking a fair balance between price and proven community benefit — required to underpin public expenditure on medicines under section 101(3B[a]) of the National Health Act, as well as the principle of equity of access under the Australian National Medicines Policy.1 What are the amendments influencing reference pricing? The Bill proposes amendments (new sections 85AB, 85AC) to the National Health Act that will divide the current PBS formulary into two. Medicines will be listed on the F1 formulary if there are no “bioequivalent” brands or drugs in reference pricing groups subject to the TGP Policy — these will mostly be patented or “innovative” medicines. The F2 formulary will cover generic medicines. Once adopted, specific price cuts and disclosures will be imposed only on F2 generic medicines. New reference pricing groups subject to the TGP (in addition to the existing six) will have to meet the additional high standard (undefined in legislation) that they are “interchangeable on an individual patient basis” (proposed sections 84AG and 101[3BA]). Reference pricing — as it now operates after PBS listing to produce “flow-on” price drops — will be problematic when the trigger drug is in the F2 formulary (although the latter’s existence may cause the F1 comparator to be redefined as an F2). What lies behind these changes?I am concerned that at least some of the impetus for this alteration of PBS fundamentals may have come from multinational patented-pharmaceutical companies through mechanisms established by the AUSFTA. Annex 2C of the AUSFTA,2 which focuses on the PBS and pharmaceuticals, has led to some positive changes, including public summary documents of PBS drug-listing decisions.3 However, it also produced a new review mechanism that is triggered after PBAC rejection decisions,4 with increased opportunities for industry pre-hearings and consultations with technical staff, as well as a Medicines Working Group (MWG) comprising high-level officials on medicines policy from both Australia and the US.5 Further, in the past few months policies have been produced for full PBS cost-recovery from industry6 — despite such “user fees” and increased liaison mechanisms being criticised as creating conflicts of interest for the US Food and Drug Administration that significantly endanger public safety.7 Perhaps most significantly with respect to the Bill, Annex 2C.1 of the AUSFTA emphasises the principle of valuing pharmaceutical innovation through either the operation of “competitive markets” (the US position) or by “adopting or maintaining procedures that appropriately value the objectively demonstrated therapeutic significance of a pharmaceutical” (the Australian position).8 The potential importance to Australian medicines policy of this ambiguous definition of innovation has been highlighted in this Journal9 and elsewhere.10 We should not forget that the US negotiators to the AUSFTA, who previously worked very closely with senior members of the US patented-pharmaceutical industry on the Industry Functional Advisory Committee on Intellectual Property Rights for Trade Policy Matters, had an explicit legislative mandate to seek the “elimination” of PBS reference pricing (see Box).11 The same legislation also required the US Department of Commerce to investigate the possible future dismantling of reference pricing in OECD (Organisation for Economic Co-operation and Development) countries.12 In December 2005, in Paris, the US sought to implement this agenda through the OECD Project on Pharmaceutical Pricing Policies and Innovation.13 Australian AUSFTA negotiators provided reassurances about the Annex 2C.1 innovation principle before a Senate Select Committee on 21 June 2004: ... we went into these negotiations with an absolutely clear mandate to protect and preserve the fundamentals of the PBS. That is what this agreement does ... there is nothing in the commitments that we have entered into in Annex 2C or the exchange of letters on the PBS that requires legislative change.14 However, when the AUSFTA MWG met for the first time in Washington, DC on 13 January 2006, Australia’s Minister for Trade, Mark Vaile, stated that: . . . the core principle that we both agree on in this area . . . is recognising the value of innovation . . .15 To my way of thinking, this represents a restatement of Australia’s position on objective, evidence-based assessment of health innovation, in accord with the National Medicines Policy. Documents obtained under a Freedom of Information application (organised by Pat Ranald, Australian Fair Trade and Investment Network, 2007) reveal almost nothing of what was said at the first AUSFTA MWG meeting. One disclosed document, presumably discussed, was an opinion editorial in The Australian, which argued that: “Truly innovative cures should be referenced against innovation in other classes, rather than against generics”16 — an approach that seems to reflect the US “competitive markets” method of valuing innovation. The second meeting of the MWG on 30 April 2007 discussed the new F1 category, which had now been structured along the same lines proposed in the editorial the MWG had discussed at their previous meeting (International Trade Law Symposium, Canberra, 4 May 2007, personal communication). The official Australian Government website only disclosed that the MWG “discussions were constructive and informative”.17 I believe this evidence suggesting a possible, non-transparent link between the definition of innovation in AUSFTA Annex 2C.1, the MWG, and the new F1 PBS category, with its sequestration from post-listing reference pricing against generic medicines, has disturbing implications for sovereignty over Australian public health policy. The PBS beyond AustraliaIn its recent free trade negotiations with the US, the South Korean Government demanded a process similar to Australia’s current system of evidence-based cost-effectiveness and reference pricing.18 Article 5.2 of the Republic of Korea–United States Free Trade Agreement, after recognising each nation’s differing approach to medicines policy, indicates that if South Korea establishes a reimbursement system for pharmaceuticals or medical devices where the amount paid is not based on “competitive market-derived prices”, then it has to “appropriately recognize the value of patented pharmaceutical products” (Article 5.2 [b][i]). Article 5.1 (c) and (e) respectively mention PBS-type “sound economic incentives” as a method of facilitating access to patented medicines and PBAC-style “transparent and accountable” procedures as a means of promoting health innovation. However, Article 5.7 creates a Medicines and Medical Devices Committee, similar to the AUSFTA MWG. Will the parallels continue? The end of public-funded medicines?In Australia, it is likely that creating an F1 PBS category where patented drugs are insulated from post-listing reference pricing against generics and required price drops may, in the short term, tempt governments to increase the extent of patient cost-sharing (perhaps through differential means-tested copayments) for high-cost patented medicines. If the proposed amendments are adopted, the incentives for pharmaceutical products to remain within the price-protected F1 class are likely to lead to much more aggressive pharmaceutical patent battles in Australia (taking advantage of intellectual property changes introduced by Chapter 17 of the AUSFTA) that could delay the introduction of cheaper generic medicines.19 The consequent widening discrepancy between initial listing prices for patented medicines and their therapeutically equivalent generic comparators may become unconscionable. The evolving higher prices for F1 patented medicines could also provide additional arguments for patented-pharmaceutical industry lobbyists to claim that the PBS is “unsustainable” and that we need to move to a privately financed prepaid insurance system, such as medical savings accounts (a form of medicines superannuation).20 If, however, a future Australian government wants to retain public funding of patented medicines and contain PBS expenditure, it could remove, or rigorously define according to established PBAC records, the criteria of “interchangeable on an individual patient basis”. It also needs to be clarified that this concept will not interfere with the initial choice of cost-effectiveness comparator, initial cost-minimisation, or the creation of therapeutic relativity sheets that are used by the PBPA to assess post-listing industry requests for price rises. Without such clarification, and a robust mechanism for shifting F1 drugs to the F2, the proposed changes to the PBS threaten a shift away from the fundamentally evidence-based method of valuing the health innovation of a patented pharmaceutical after listing. They may, instead, push it more towards valuing F1 products through the operation of markets that are nominally competitive, but readily distorted by collusion and advertising. Much will depend on whether the government protects and supports the independence of officials involved in pharmacoeconomic analysis and vigorous price negotiations with patented pharmaceutical manufacturers (both at first listing and over time), in the MWG and, if necessary, in AUSFTA Chapter 21 dispute resolution procedures. My concern is that the haste with which this legislation is progressing might lead to this policy choice being delegated to technical experts in finance, or working groups with private interests, rather than being made part of a systematic public debate about the kind of health care system all Australians want to have, and the trade-offs they are prepared to make against strategic objectives of trade or international public policy. If the Australian regulatory and policy environment for medicines continues to further resemble the inequitable US system, we will similarly have unaffordable innovative products and worse health outcomes (despite low-cost generics) for citizens lacking private insurance with extensive coverage. United States AUSFTA negotiators’ instructions on Pharmaceutical Benefits Scheme reference pricing The US Trade Representative, the Secretary of Commerce, and the Secretary of Health and Human Services were obliged to: Bear in mind the negotiating objective set forth in the Bipartisan Trade Promotion Authority Act of 2002 to achieve the elimination of government measures such as price controls and reference pricing which deny full market access for United States products. In so doing, the agencies shall provide periodic and timely briefings for the Committees of the House and Senate listed above, with an interim briefing no later than 90 days after enactment to address negotiations to establish a US–Australia Free Trade Agreement and, as appropriate, other current negotiations.11 [emphasis added] AUSFTA = Australia–United States Free Trade Agreement.

Thomas A Faunce BA LLB, BMed, PhD

To the Editor: Walker and colleagues recently reported a series of patients with interstitial pneumonitis following use of statin cholesterol-lowering drugs.1 They state that other investigators have previously reported biopsy findings resembling amiodarone-induced pulmonary toxicity in pneumonitis associated with statin therapy. We believe this observation is pivotal to understanding the authors’ findings. Amiodarone produces mitochondrial toxicity, which is recognised to be a potential initiating event in amiodarone-induced pulmonary toxicity.2 Statins also produce mitochondrial toxicity in vulnerable individuals. Adverse effects of statins on muscle have been linked to mitochondrial abnormalities,3 and other clinical manifestations of statin mitochondrial toxicity have been reported. Mitochondrial respiratory chain disease is famously protean in its manifestations, but most classically produces a mitochondrial encephalomyopathy — with muscle, brain, or both affected. Consistent with this, muscle and cognitive symptoms are the most widely reported adverse effects in our reporting database of statin adverse effects (comprising 2478 patients to date), and these symptoms frequently occur together, consistent with a common mechanism. Statin–amiodarone combinations have produced heightened toxicity relative to each agent alone. Interference with cytochrome P450 metabolism has been the presumed mechanism,4 but additive or synergistic mitochondrial toxicity may also be a factor. The occurrence of amiodarone-like interstitial pulmonary disease in statin users adds to concerns that a range of clinical presentations of mitochondrial toxicity may ultimately be reported with statins in susceptible individuals, with mitochondrial heteroplasmy and threshold effects determining the specific manifestations.5

Beatrice A Golomb · Marcella A Evans

To the Editor: In an ironic clinician–academic dichotomy, in the same month that the Royal Australian and New Zealand College of Psychiatrists published a survey showing that 79% of Australian psychiatrists combine antidepressants and 75% of psychiatrists believe that general practitioners should be given information on this topic,1 Keks et al chose a non-psychiatric journal to “mandate that combinations be used as a last resort, and only in specialist settings”.2 Specialists have voted with their prescription pads. That a large majority of Australian psychiatrists feel ethically and clinically obliged to use combination antidepressants speaks volumes about the poor results from the suggestions outlined by Keks et al. The multiple clinical reports and reviews of the benefits of combination antidepressants,3 the suffering and death from depression, and the very low rate of complications reported to the Adverse Drug Reactions Advisory Committee from combination antidepressants do not allow the luxury of awaiting combination therapy research which may never happen. Many combinations of antihypertensives or anti-asthma medications similarly lack such rigorous proof, but are widely used. Isolated case reports of medication complications must be seen as such. Access to psychiatrists for combination antidepressant therapy is a well intentioned but currently impractical suggestion. Most psychiatrists have massive waiting lists, and research confirms treatment resistance and progressive cell death in the hippocampus of depressed patients while awaiting effective treatment. Australian GPs are just as capable of using combination antidepressant therapy as their international colleagues, if given the same simple information and training. Canadian GPs read in their journals advice about using combination antidepressants. Anecdotally, many Australian GPs combine antidepressants, but express the wish that the issue could be discussed openly, without them feeling intimidated. Even textbooks of psychiatry, drafted some years ago, teach about combination antidepressants. In the United States, the National Institute of Mental Health STAR*D study of 4000 patients approved combination antidepressants such as venlafaxine with mirtazapine years ago, with no safety concerns.4 Keks et al refer to treatments that today are unacceptable to many, ranging from electroconvulsive therapy to tricyclic antidepressants, despite GPs and psychiatry trainees having been warned for years by academics that tricyclics are outdated, “dirty” and dangerous. Informed consent requires that patients be informed of all therapies that are relevant to their care and survival, and 88% of psychiatrists believe patients should be informed of combination antidepressants.1 Recent results from the STAR*D study demonstrate the superiority of modern combination antidepressants, with no statistically based evidence that they should not be used.5

David P Horgan

To the Editor: Keks et al make a number of important points about the place of combination antidepressant strategies in the pharmacotherapy of depression.1 However, it is important for readers to note that the vigorous repudiation of combination treatments is a peculiarly Australian preoccupation. Our colleagues in Europe and North America are not nearly so troubled. Combination antidepressant treatments are widely used by specialists. A recent survey of Australian doctors working in psychiatry reported that 79% of respondents had used combination antidepressants and that 75% believed that general practitioners should be given information on their use.2 There is emerging evidence for the use of combination antidepressant strategies — from case series, open clinical trials, and randomised controlled trials (RCTs). The largest summation of the data is a meta-analysis which found that combination antidepressant treatment produced a 62% response rate when monotherapy had failed.3 Although this finding alone cannot be convincing because of the acknowledged lack of large sample RCTs, it is quite another matter to decry combination prescribing as clinically unsound based only on the history of augmentation treatments such as lithium and, to a lesser extent, thyroid hormone treatment when, anecdotally, they provide such clinically disappointing results. It is not unreasonable to assert the primacy of good clinical reasoning, including sensible prescribing of combination antidepressants, over rigid adherence to evidenced-based algorithms. This sort of thinking is allowable because the evidence base for the treatment of depression is poor. Meaningful guidelines cannot be produced while the evidence is predicated on the flawed proposition that depression is an “it” (a homogenous construct).4 GPs might well be puzzled by the zeal in academic psychiatry for monotherapy. They are advised to “optimise” monotherapy, but not told what this means. They are very familiar with models of staged polypharmacy for common chronic illnesses such as hypertension, epilepsy, diabetes, and asthma, but in psychiatric pharmacotherapy this is apparently unwise or too risky. The way such admonishments are usually framed is by reference to serious but rare adverse reactions (like the serotonin syndrome), without proper attention to the equally serious and probably more common problems with the current “simple” psychotropic drug options already used by GPs. Failure to contextualise these risks leads to a distortion of risk–benefit prescribing decisions and an unnecessary restriction of treatment choices. We must have a commonsense approach to the treatment of depression that recognises the proper context of our knowledge base. Combination antidepressant treatments may be “beyond the evidence”, but this alone is not a sufficient justification to stop using them.

Murray J Walters · Alston M Unwin · Sean B Gills

In reply: The letters by Horgan and Walters et al underline our motive for reviewing antidepressant combinations. The conclusions of the survey are at least questionable, given that the response rate was only 36%, 18% of respondents were not psychiatrists, and affirmative responders may have only used combination antidepressants once.1 In any case, should clinical popularity substitute for evidence? If so, once popular but now research-discredited treatments such as insulin coma therapy would still be used. Equating combination antidepressants to combination drugs for asthma and hypertension is misleading. How often are two β-blockers given together in maintenance treatment? Major depression causes severe suffering, but this does not justify the use of unproven treatments ahead of those supported by evidence. General practitioners should be informed about antidepressant combinations, but the information must be evidence-based. We described the process of dose optimisation, and stand by our advice that complex cases that require unproven treatment (such as combination antidepressants) be referred to a psychiatrist. Patients should also be informed about combination antidepressants, including the paucity of evidence concerning efficacy and safety, the absence of information about consequences of long-term treatment, and that some combinations are lethal and others frequently unsafe. Published data from the STAR*D study provide equivocal support for the combination of citalopram and bupropion, as we noted. Evidence of modest effectiveness (remission rate, 13.7%) for the combination of mirtazapine and venlafaxine has appeared.2 Our conclusion was that some antidepressant combinations could be used in certain clinical situations where evidence-based treatments have failed, with safeguards. Given that 17% of respondents to the survey1 observed serious complications with combination antidepressants, this is good advice.

Nicholas A Keks · Graham D Burrows · David L Copolov · Richard Newton · Nick Paoletti · Isaac Schweitzer · John W G Tiller

Re: “Ototoxic ear drops with grommet and tympanic membrane perforations: a position statement”, the letter by Robert J Black, Vince C Cousins, Peter Chapman, Zoran Becvarovski, Harvey L C Coates, Stephen J O’Leary, Christopher F Perry and Brian J Williams, in the 4 June issue of the Journal (Med J Aust 2007; 186: 605-606). The competing interests statement incorrectly states that “Zoran Becvarovski, Harvey Coates, Stephen O’Leary, Chris Perry and Brian Williams received honoraria for attendance at scientific meetings sponsored by Alcon Laboratories, which manufactures ciprofloxacin ear drops”. In fact, Brian Williams and Stephen O’Leary had no competing interests and their names appeared in this statement in error. The html and pdf versions of this letter have been corrected.

Robert J Black · Vince C Cousins · Peter Chapman · Zoran Becvarovski · Harvey L C Coates · Stephen J O’Leary · Christopher F Perry · Brian J Williams

To the Editor: With the proposed formation of the Australia New Zealand Therapeutic Products Authority (ANZTPA), the recent viewpoint article1 and accompanying editorial2 on systems of evaluating medicines were timely. Both reports provided interesting comments on existing systems and proposals for improving these in the future. However, I would like to comment on some omissions and errors in these articles. In their viewpoint article, Kelman et al stated that “there are as yet no overseas examples of ‘routine’ medicines monitoring”.1 This is not correct. The New Zealand Intensive Medicines Monitoring Programme (IMMP) has been undertaking routine monitoring of selected medicines since 1977. The IMMP collects nationwide prescription data to form cohorts of patients who are subsequently monitored for adverse events.3 These patient cohorts provide accurate denominator populations, which, as noted by Kelman et al,1 is important for risk quantification by measurement of incidence. The IMMP uses prescription-event monitoring (PEM) methods to perform active postmarketing surveillance of new medicines in New Zealand, and has been successful in identifying numerous new signals of adverse drug reactions and in quantifying risk.4 The IMMP has developed ways of enhancing PEM methodology by linking records with national morbidity and mortality databases.3 This methodology was recently successfully applied in a study of the safety and usage of atypical antipsychotic medicines in a nationwide paediatric population.5 In their editorial, Stanley and Meslin commented that none of the health care data linkage systems in England, Scotland, the United States or Canada “are nationwide or have the routine ability to link health care records with drug prescription data”.2 As described above, the IMMP has both these abilities. It was somewhat surprising that, although discussions regarding pharmacovigilance in the ANZTPA are now well underway, current systems in New Zealand were not mentioned in either of these Journal articles. I would encourage Australia to develop pharmacovigilance systems similar to those established in New Zealand. Of course, these will need to be adequately funded to achieve the expected outcomes. The formation of the ANZTPA is a great opportunity to improve pharmacovigilance in both countries.

Mira L Harrison-Woolrych

To the Editor: Systemic ototoxicity secondary to the use of aminoglycosides is well known in clinical medicine, and appropriate monitoring measures to prevent vestibulo-cochlear ototoxicity are routinely performed. Less well known is the potential for topical ear drops, particularly the aminoglycoside group, to cause both vestibular and cochlear damage when introduced through a patent grommet or tympanic membrane perforation for the treatment of infection.1 Although the incidence of aminoglycoside ototoxicity with ear drops is uncommon (for cochlear toxicity, in the order of one in 10 000 patients treated2), individual susceptibility and patient compliance problems may lead to inner ear damage. Concerns with the potential ototoxicity of aminoglycoside ear drops has led to American,3 British4 and Canadian5 expert committees providing guidelines on the use of potentially ototoxic ear drops in patients with tympanic membrane perforations or patent grommets. The Consensus Panel of the Australian Society of Otolaryngology Head and Neck Surgery (ASOHNS) unanimously agreed on the recommendations shown in the Box, which are based on the American guidelines. Broadly speaking, the Consensus Panel recommends avoiding the use of ototoxic ear drops in patients with perforated tympanic membranes where possible. The Australian National Aboriginal Community Controlled Health Organisation study showed that the non-ototoxic fluoroquinolone drops were more effective than commonly used ototoxic ear drops.1 An application to the Therapeutic Goods Administration for introduction of ciprofloxacin drops to the ear has recently been approved, and has been placed on the Pharmaceutical Benefits Scheme as an authority prescription for Aboriginal and Torres Strait Islander children with chronic suppurative otitis media as of February 2007. However, clinical circumstance may dictate that potentially ototoxic agents need to be used if culture/sensitivity testing suggests that fluoroquinolone drops would not be appropriate, are unavailable, or if previous treatment with fluoroquinolone ear drops failed. The Consensus Panel did not believe routine auditory/vestibular monitoring was warranted by the risks of ototoxicity, provided the treatment was short (5–10 days). The full document outlining the Consensus Panel’s recommendations is available from ASOHNS. Recommendations of the Consensus Panel of the Australian Society of Otolaryngology Head and Neck Surgery on ototoxic ear drops and tympanic membrane perforation Non-ototoxic eardrops are preferable in the presence of tympanic membrane perforations or grommets. If potentially ototoxic antibiotic ear drops are used, they should only be used in infected ears and discontinued immediately the infection has resolved. If potentially ototoxic antibiotic ear drops are prescribed for use in the open middle ear or mastoid, the reason for their use and a warning to the patient/parent of the risk of ototoxicity should be given and documented. If potentially ototoxic antibiotics are prescribed, the patient should be specifically instructed to return to the doctor if he or she develops vertigo, hearing loss or tinnitus. If the tympanic membrane is known to be intact and the middle ear and mastoid are closed, then the use of potentially ototoxic preparations presents no risk of ototoxic injury.

Robert J Black · Vince C Cousins · Peter Chapman · Zoran Becvarovski · Harvey L C Coates · Stephen J O’Leary · Christopher F Perry · Brian J Williams

Re: “Medicines and breastfeeding: information is available on safe use”, by Lisa H Amir, in the 7 May issue of the Journal (Med J Aust 2007; 186: 485). In the editing process, the last two sentences of the letter were altered, including removal of the author’s original emphasis on several words. The sentences should read “Medicines used during pregnancy are given safety ratings and the information is available online.5 Australian clinicians need similar guidance in relation to safe prescribing for breastfeeding women.” The author’s position at La Trobe University was also incorrectly given as “Lactation Consultant” rather than “Health Professional Research Fellow”. Her other positions (not included in the original letter) are General Practitioner at the Women’s Clinic on Richmond Hill, Melbourne, and Medical Officer at Breastfeeding Education and Support Services, Royal Women’s Hospital, Melbourne. The html and pdf versions of this letter have been corrected.

Lisa H Amir

To the Editor: The National Prescribing Service recently reviewed drug interaction information in a range of prescribing and dispensing software systems and reference sources, including the Therapeutic Goods Administration (TGA)-approved product information (PI). Our findings support those of Stockigt1 regarding the quality of information in PI. An expert panel (see Acknowledgements) assessed 40 pairs of potentially interacting drugs (20 clinically important and 20 minor interactions) by examining the “Interactions” section of 80 PI monographs. The panel assessed both detection and content, using a range of parameters considered to be important in clinical decision making. For the clinically important drug interactions, these included useful management information (defined as sufficient information to proceed without looking elsewhere), pharmacological mechanism of interaction, clinical effects of the interaction, and time frame (onset, duration). For clinically important interactions, 38 of 40 PI monographs listed the potential interaction; however, there were considerable shortcomings in the amount and quality of information provided. Only five of 38 monographs (13%) provided useful information about management. The mechanism was described in 15 monographs (39%) and clinical effects in 19 (50%); time frame was mentioned in only one (3%). In addition, there were many inconsistencies between any two monographs for a particular drug pair — not surprising given that the information is usually developed by different drug manufacturers at different times. The results of our study suggest that in many cases the PI for a drug does not provide useful information about potential drug interactions. For decision support to be useful to health practitioners, information must be sufficiently detailed and relevant. Poor quality, irrelevant or inconsistent information is at best unhelpful or a waste of time, and at worst may prompt an inappropriate management decision, potentially compromising patient care. While epidemiological evidence for drug interactions is limited, good quality information and practical advice is available in a number of specialised drug interactions reference sources. This issue will be discussed in more detail with the full results of our study, which will be submitted for publication later this year.

Michelle Sweidan · James F Reeve