Pharmacology

To the Editor: A 50-year-old man presented with gynaecomastia and galactorrhoea, reporting diminished libido and energy over 12 months. Previous medical and psychiatric histories were unremarkable. The patient had a tender increase of the right breast tissue. His testes appeared normal. He had markedly elevated prolactin levels (410 μg/L; reference range [RR], < 15 μg/L) and decreased testosterone levels (5.6 nmol/L; RR, 10–33 nmol/L); results of other biochemical tests were unremarkable. Pituitary magnetic resonance imaging (MRI) showed a microadenoma. Cabergoline 0.5 mg twice weekly was commenced. One year later, the patient had normal prolactin (8 μg/L) and testosterone (14 nmol/L) levels. His libido and sexual function had improved — he claimed his “mates are envious”. MRI demonstrated no changes to the tumour. He was lost to follow-up. Five years after his last review, the patient re-presented with his estranged wife, who was concerned about changes to his behaviour after starting cabergoline. He had engaged in excessive casino and horse-racing gambling, resulting in financial losses (> $100 000), and excessive libido had led to hypersexual activities and divorce proceedings. His prolactin levels were normal (10 μg/L), but testosterone levels were low (8 nmol/L). Cabergoline was ceased. On review 3 months later, the patient’s change in behaviour was dramatic. All gambling and hypersexuality issues had ceased, and divorce proceedings were on hold. His prolactin levels had increased (78 μg/L); testosterone levels were unchanged (8 nmol/L). No changes were seen on MRI. Pathological gambling has been reported in patients with Parkinson’s disease who take dopamine agonists — particularly pramipexole but also cabergoline (4.5% of published cases).1 Most were also prescribed levodopa.1 A minority had concomitant hypersexuality.1 The prevalence of pathological gambling in patients with Parkinson’s disease has been estimated at 6.1%, compared with 0.25% in age- and sex-matched controls.2 There has been one published case report of pathological gambling (but not hypersexuality) following use of a dopamine agonist (cabergoline 0.25 mg weekly) for prolactinoma.3 However, the dose of cabergoline normally used in Parkinson’s disease is higher (0.5–6 mg/day).4 Normalising prolactin levels usually leads to increased libido and vitality, but not pathological gambling and hypersexuality. Our patient had not engaged in these activities before commencing cabergoline, and there was no personal or family history of psychiatric illness. Moreover, his testosterone concentrations during treatment ranged from low to low–normal, never high. His Naranjo score was 6, indicating a “probable” adverse drug reaction.5 No reduction in tumour size was seen, raising the question of a partial non-functioning pituitary adenoma. Cabergoline-induced pathological gambling and hypersexuality are probably under-reported, and physicians should consider screening for these in patients treated with dopamine agonists.

Henrik Falhammar · Jennifer Y Yarker

To the Editor: The recent case report by Chow and colleagues raises questions about the causal link between black cohosh use and hepatotoxicity.1 The authors state that the patient had no history of “significant alcohol consumption”, but a presumably related adverse drug reaction report available from the Therapeutic Goods Administration reveals her alcohol use was “3–4 units [of] alcohol per day, [with] 1–2 alcohol-free days per week”.2 Alcohol misuse is a known risk factor for severe liver disease, as is gastric bypass surgery for obesity,3 also in the patient’s history. Unfortunately, because histological examination of the liver 6 weeks after first presentation found no recognisable residual hepatocytes, the diagnoses of alcoholic steatohepatitis, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis cannot be excluded. Without this, the specific conclusion of the liver biopsy that the “Massive hepatocellular necrosis [was] associated with herbal medication”2 cannot be substantiated. The patient “was not taking any other medications, including other herbal preparations”, but the use of multivitamins was disclosed,2 without further information on ingredients, indication, dosage and duration of use. Notably, an overdose of vitamin A can cause severe liver disease. Finally, discontinuation of black cohosh failed to reduce the patient’s bilirubin levels, suggesting ongoing liver cell destruction by the as-yet unknown agent. Chow et al state “Extensive investigations to exclude other causes of acute liver failure gave negative results”.1 It is unclear whether rare liver diseases were excluded, notably herpes infection, which has been reported to cause severe herpetic hepatitis. Nor was polymerase chain reaction testing performed for hepatitis viruses. The authors mentioned other published case reports of hepatotoxicity potentially linked with black cohosh.1 A recent assessment of 42 cases by the European Medicines Agency (EMEA) concluded that most were insufficiently documented, or were otherwise inappropriate for analysis.4 A case in the United States initially described as “probable” (> 1000% of the recommended dosage of black cohosh), based on the report that the patient “did not drink alcohol or use illicit drugs and was not taking any medications”, was later corrected.5 The patient testified under oath that she drank wine regularly and used other drugs, and a US court judged there was no evidence to establish that black cohosh had caused her liver disease.6 There is no apparent credible evidence that black cohosh caused liver failure in the patient described by Chow et al.1 A daily alcohol consumption of 30–40 g should be considered principally in any causality assessment. In addition, idiopathic reasons, rare or unclear liver diseases, and other medications should be considered as possible causes. Even in patients with liver disease who consume little or no alcohol and have no exposure to other toxic agents, the cause of the disease remains unclear in up to 30%. In view of this, reliable and sufficient reporting of adverse drug reactions is a necessary precondition to any reliable assessment of causality.7

Belal Naser · Eckehard Liske

To the Editor: The case reported by Chow and colleagues of liver failure associated with the use of black cohosh1 requires comment regarding causality. The case has also been the subject of an adverse drug reaction report by the Therapeutic Goods Administration (TGA), and a possible causality has been proposed.2 At presentation on 23 May 2006, the patient was aged 50 years (TGA),2 not 51 as stated by Chow et al.1 Her bodyweight was 88 kg (TGA)2 after gastric bypass for obesity.1 She had been taking black cohosh (20 mg daily) intermittently for 3 years. The subsequent temporal course is essential for assessing causality. According to the TGA report,2 the patient increased the dose of black cohosh to 40 mg daily on 31 March 2006 and stopped taking it on 31 May 2006. The case report describes a 2-month history of lethargy, nausea and arthralgia,1 obviously reported at first presentation. Back calculation shows symptom onset around 23 March 2006. Thus, symptoms emerged 1 week before the dose increase, suggesting a lack of temporal, and hence causal, association. The patient had several risk factors for severe liver disease.1 Risky use of alcohol for women is defined as more than seven standard drinks per week or more than three drinks on a single occasion.3 The patient had a daily intake of 3–4 units of alcohol, with 1–2 alcohol free days per week (reported by the TGA),2 rendering her at some risk of alcoholic liver disease. Moreover, gastric bypass with partial resection reduces gastric mucosal alcohol dehydrogenase and consequent gastric ethanol metabolism. In combination with rapid gastric passage of alcohol into the jejunum, this leads to high blood ethanol concentrations, another risk factor for liver disease. Risk factors for possible non-alcoholic steatohepatitis and cirrhosis are obesity and gastric bypass. Other causes were not excluded, including Wilson’s disease (by 24 h urinary copper measurement), hepatitis E, herpetic liver disease and infection by varicella zoster virus, parvovirus B19, parainfluenza virus, adenovirus and cytomegalovirus (by assessing for a change in IgG titre after disappearance of IgM). The marked hepatic mononuclear infiltrate is compatible with some viral infections. Certainly, various herbal products may cause liver disease. A good example is kava,4 but not black cohosh.5,6 The European Medicines Agency examined 42 cases of liver disease with a suspected association with black cohosh, and found that only four patients had some grades of causality.5 Reassessment showed that two of these patients had herpetic hepatitis, one had autoimmune hepatitis, and the fourth was not assessable.6 Further studies are necessary to show clearly whether black cohosh is potentially hepatotoxic.

Rolf Teschke

In reply: Teschke questions the temporal sequence in our reported case1 by raising an ambiguity in dates. We wish to clarify: when the patient first presented on 23 May 2006, lethargy, arthralgia and nausea had been present for only about 3 weeks. This was well after the dose increase in black cohosh in March 2006. As such, the dose escalation definitely preceded the patient’s symptoms and liver failure. To further explore causality would require rechallenge with black cohosh, which we consider dangerous and unethical. Other unlikely causes of liver failure raised by Teschke, although theoretically possible, were not evident. The clinical course and histological findings in the pretransplant biopsy and explanted liver categorically excluded alcoholic cirrhosis and non-alcoholic steatohepatitis as causes of the liver failure. We also reiterate that there was no previous history of liver disease or other medication use. Increasing numbers of case reports are being published showing evidence of hepatotoxicity in patients taking black cohosh. Two well documented cases of seriously deranged liver function in patients taking black cohosh, which resolved on ceasing its use, have just been reported.2 Teschke concedes that four other cases have been reported where some causality between black cohosh and hepatotoxicity was evident.3 Neither Teschke nor Naser and Liske offer any reassurance on the long-term safety or lack of toxicity of black cohosh by referencing any properly conducted safety study. Certainly, there is recent in-vitro and in-vivo evidence in a rat model that black cohosh is toxic to hepatocyte mitochondria and impairs oxidative phosphorylation, resulting in apoptotic hepatocyte death.4 It is notable that, based on available evidence, the Australian Therapeutic Goods Administration requires preparations containing black cohosh to carry a warning of potential liver toxicity, stating that “there appears to be an association between the use of black cohosh and liver damage, but that it is very rare”.5 Furthermore, in the United Kingdom, the Medicines and Healthcare Products Regulatory Agency stated, “Warnings regarding rare adverse reactions in the liver should be added to the product information for black cohosh for both licensed and unlicensed products”.6 Government authorities in Europe3 and Canada7 have raised similar concerns. Long-term studies as well as further animal studies would be welcome in this area.

Elizabeth C-Y Chow · Marcus Teo · John A Ring · John W Chen

An otherwise healthy 28-year-old man had a cardiac arrest after a day of motocross racing. He had consumed excessive amounts of a caffeinated “energy drink” throughout the day. We postulate that a combination of excessive ingestion of caffeine- and taurine-containing energy drinks and strenuous physical activity can produce myocardial ischaemia by inducing coronary vasospasm. Clinical recordA 28-year-old male amateur motocross rider was admitted to Port Macquarie Base Hospital in August 2007 after having an out-of-hospital cardiac arrest. He had collapsed shortly after participating in a motocross race. An off-duty paramedic and nurse had been on hand, and effective cardiopulmonary resuscitation was commenced promptly. Paramedics arrived after about 20 minutes of resuscitation. The patient’s initial cardiac rhythm was recorded as ventricular fibrillation (Box 1). He was restored to sinus rhythm after receiving two 150 J biphasic direct-current shocks. Adrenaline 1 mg and atropine 1 mg were both given as adjuvants. He was intubated by paramedics and transported to hospital. Later, the patient recalled feeling well earlier in the day, until after his second race, when he developed dull constant retrosternal chest pain. He described this as being mild in intensity, with no radiation or associated symptoms. It settled within 30 minutes of sitting down to rest. He went on to participate in (and win) one more race that afternoon. He collapsed at about 3 pm, approximately 20 minutes after the last race. There had been no symptoms immediately preceding the collapse that he could recall. The patient had been well in the week preceding these events. He denied having any previous episodes of chest pain or syncope. He had a large breakfast on the morning of the motocross race and had remained adequately hydrated throughout the day. Further, he had consumed 7–8 cans of a caffeinated “energy drink” between 8 am and his collapse 7 hours later. He was otherwise fit and well and taking no regular medication. There was no family history of premature coronary disease, sudden cardiac death or unexplained syncope. He was a smoker with a six pack-year history of smoking. He denied alcohol misuse or illicit drug use. On arrival at hospital, the patient was intubated and sedated. He was haemodynamically stable, and physical examination was unremarkable. An initial electrocardiograph (ECG) showed sinus rhythm and elevated anteroseptal ST segments with reciprocal inferior ST depression. Chest x-ray showed a normal cardiac silhouette and no signs of pulmonary venous congestion. Computed tomography scans of the chest and brain were unremarkable, specifically excluding aortic dissection. Abnormal findings from laboratory tests included an elevated level of troponin I (0.24 mmol/L; reference range [RR], < 0.05 mmol/L) and a lowered potassium level (3.0 mmol/L; RR, 3.6–5.4 mmol/L). Results of a urinary screen for drugs of misuse, including amphetamines and cocaine, were negative. Screening for anabolic steroids was not performed. The provisional diagnosis was of anteroseptal ST elevation myocardial infarction. The patient was given thrombolysis with 50 mg of tenecteplase and commenced on an infusion of intravenous heparin. He was given loading doses of 300 mg of both aspirin and clopidogrel, and 25 mg of metoprolol, all by nasogastric tube. Hypokalaemia was corrected via intravenous infusion. The patient was transferred to a tertiary referral centre for cardiac catheterisation. On arrival there, an ECG showed evolving ischaemic changes across the anterolateral leads (Box 2). A troponin I peak level of 12.2 mmol/L was measured; his potassium level had normalised at 4.0 mmol/L. Echocardiography showed mild left ventricular enlargement and low-normal systolic function with a hypokinetic anteroseptal segment. Coronary angiography, performed on the same day, gave normal results. No attempts were made during angiography to induce vasospasm. The patient was cooled for 24 hours and extubated without difficulty. He was discharged after 6 days. At discharge, he was taking atenolol 50 mg, aspirin 100 mg, spironolactone 25 mg and perindopril 2.5 mg. On follow-up 2 months later, the patient reported that he had remained well and symptom-free. Echocardiography showed preserved global left ventricular function with a limited residual area of akinesis of the anteroseptal wall. He continued taking aspirin, perindopril and atenolol (reduced to 25 mg). He was advised not to compete in motocross races for 6 months, after which a stress echocardiogram was performed; this was negative for exercise-induced ischaemia. DiscussionWe postulate a possible role of excessive consumption of caffeinated energy drinks in triggering the life-threatening cardiac events described in this case. Although sudden cardiac death is an uncommon occurrence in people under the age of 40 years, when it does happen it is most often associated with the presence of structural heart disease, most frequently premature coronary atherosclerosis. Other common associations are hypertrophic obstructive cardiomyopathy and myocarditis.1,2 However, autopsy review studies have found that some 10%–12% of subjects in this age group have no obvious cardiac abnormalities on postmortem examination.1,2 Of identified causes in this group, many are familial sudden cardiac deaths or disorders of conduction, such as Wolff–Parkinson–White syndrome.3 Our patient had electrocardiographic and echocardiographic features indicative of transmural ischaemia localised to the anterior territory. This is suggestive of a regional rather than a global process, and suggests an ischaemic event rather than a primary arrhythmia. However, the angiogram did not show any significant coronary lesions. Although non-stenotic atherosclerotic plaques may rupture or denude and cause infarction through the formation of superimposed thrombi, which may have then been dissolved by the administration of thrombolytics, we believe that — considering this man’s relative youth — there is a distinct possibility that the underlying abnormality was coronary vasospasm. An arrhythmia, possibly triggered by the ingestion of stimulants in the presence of hypokalaemia and physical exertion, was a differential diagnosis. However, this would not account for the regional abnormality seen. The cause of this patient’s hypokalaemia is unclear, but may have been related to electrolyte losses from excessive sweating during exertion. This effect may have been exacerbated by the diuretic effect of caffeine. The role of illicit stimulants, especially cocaine, in causing coronary vasospasm in young people is well established.4 However, this patient denied cocaine use and returned a negative result on his drug test, making this an unlikely cause. The energy drink consumed by our patient contains 80 mg of caffeine (equivalent to one cup of espresso) per can. He drank seven or eight cans within 7 hours — up to 640 mg of caffeine in total. The drink also contains high doses of taurine (an amino acid) and glucuronolactone (a glucose metabolite), neither of which are considered to have significant toxicity, although there is a paucity of data.5,6 Caffeine is a naturally occurring xanthine derivative related to theophylline; it has a number of potential pharmacological actions on the cardiovascular system. Its primary mechanism of action is thought to be through competitive inhibition of adenosine receptors.7 It also induces catecholamine release, and causes a rise in intracellular calcium in myocytes through release of calcium from the sarcoplasmic reticulum, leading variably to smooth muscle contraction and relaxation.8-10 The role of caffeine in triggering arrhythmia is well established.8 There have been a number of case reports on hospitalisations or deaths due to caffeine toxicity, although the mechanism usually seems to be tachyarrhythmia and involves far higher doses than in this case.11,12 The median lethal dose in rats is 200–400 mg/kg.13 A 1997 case report described a young woman who suffered a myocardial infarction due to caffeine toxicity; however, this involved an oral dose of 20 g.14 In-vitro studies have shown that taurine has an inotropic effect on cardiac muscle similar to that of caffeine, and potentiates caffeine-induced muscle contracture. Few taurine toxicity studies have been performed, and there are insufficient data to suggest what an unsafe level of taurine consumption might be, if any.9,14 Both taurine and caffeine have been shown in vitro to have physiological effects on intracellular calcium concentration within vascular smooth muscle, and they could conceivably induce coronary vasospasm. In-vivo studies have demonstrated a capacity for caffeine to decrease myocardial blood flow during exercise.15 We postulate that, in physiologically predisposed individuals, a combination of excessive ingestion of caffeine- and taurine-containing energy drinks and strenuous physical activity can induce myocardial ischaemia by coronary vasospasm, with potentially fatal results. Caffeine has been removed from the list of prohibited substances in sport but remains on a monitoring program run by the World Anti-Doping Agency.16 Anecdotal reports suggest that the many caffeinated energy drinks now on the market are widely used by amateur and professional athletes to enhance their performance. We are concerned that a combination of exercise and the caffeine contained in these drinks may have the potential to trigger serious cardiovascular events. We accept that this is a single case, which does not and cannot establish causality. However, in the context of concerns reported in the media in recent years relating to similar events overseas, and in the presence of a plausible pharmacological mechanism, we believe that the potential dangers of these caffeinated energy drinks should be highlighted, and monitoring for future adverse events should be conducted. 1 Patient’s initial cardiac rhythm, showing ventricular fibrillation 2 Patient’s electrocardiograph on arrival at tertiary referral centre, showing evolving ischaemic changes across the anterolateral leads

Adam J Berger MB BS, BSc(Med) · Kevin Alford MB BS, FRACP, DDU

The 2008 National Medicines Symposium examined the science, policy and practice of quality use of medicines The concept of quality use of medicines (QUM)1 was developed in Australia in the early 1990s to promote and support judicious, appropriate, safe and effective use of medicines, including prescription, non-prescription and complementary medicines. The QUM strategy is based on a partnership between consumers, health professionals, the medicines industry and government. Many practitioners, individuals and organisations have been working for over a decade to embed the principles of QUM into the Australian health system. These include the National Prescribing Service (NPS; an independent, non-profit organisation funded by the Australian Government Department of Health and Ageing) and the Pharmaceutical Health and Rational Use of Medicines (PHARM) Committee (which promotes, reviews and oversees the implementation of QUM strategy in Australia, and provides expert advice to the Minister for Health and Ageing and the Department of Health and Ageing). The biennial National Medicines Symposium, hosted by NPS and the PHARM Committee, provides an opportunity for all partners to meet together to share insight and experiences. The 2008 Symposium, held in Canberra from 14 to 16 May, brought together 500 delegates representing practitioners in the field, consumers, health professionals, the medicines industry, government and academics. Delegates heard from local and international speakers and saw QUM in action showcased in 118 poster presentations and 14 workshops developed around the theme QUM — the science, policy and practice. This report summarises several of the key plenary addresses that highlighted the challenges facing QUM in the 21st century. Full proceedings are available on request from infoATnps.org.au. Global challenges to quality use of medicinesTwo international speakers identified global challenges for QUM in the 21st century: confronting commoditisation of health, bridging the access gap to medicines, dealing with diversity in people, and meeting the needs of an ageing population. In her presentation, Medicines, consumers and society: trends and challenges, Professor Anita Hardon (Medical Anthropologist, Amsterdam School for Social Science Research, University of Amsterdam, the Netherlands) identified the issues faced in developing and industrialised countries. She said there is a worldwide trend towards people believing that they need both traditional and modern medicines to stay healthy and treat disease. In many developing countries, modern pharmaceuticals and traditional medicines are aggressively promoted, while all over the world regulatory processes fail to control the circulation of alternative or traditional medicines, which consumers are increasingly using to complement pharmaceutical treatment — at relatively high cost. At the same time, access to medicines is stratified: in industrialised countries, vocal patient collectives call for research on and marketing approval of better and newer medicines, with ever-increasing demands on public health resources, while in resource-poor settings, health systems fail to provide people access to essential life-saving drugs. After more than 20 years of conducting empirical research into medicines use in Africa, Asia and Europe, Professor Hardon has concluded that it is critical for science to radically reorient towards consumer needs and experiences with medicines. The colour, taste and shape of medicines, past experiences, perceptions related to the “newness” or cost of medicines, and social and economic factors all need to be taken into account. QUM, she said, must be seen in the social context of people’s lives. An ageing world: implications for quality use of medicines was the theme of Ms Jean Slutsky’s (Director, Center for Outcomes and Evidence, Agency for Healthcare Research and Quality, United States Department of Health and Human Services, Rockville, Md, USA) presentation. The challenge, she said, is to find integrated treatment strategies that meet the needs of an ageing population, especially the needs of patients with multiple comorbidities. The effects of treatment on older people are not always investigated, and current clinical guidelines often do not include recommendations for modifying treatments for older patients with and without multiple comorbidities. Understanding which medicines exacerbate a comorbidity and which treatment objectives are the most important to meet are at the core of designing a pharmaceutical treatment program that is safe, rational and beneficial, said Ms Slutsky. Innovations in drug therapies need to be evaluated to determine which represent added value, offer minimal enhancements over existing choices, fail to reach their potential, or work for some patients but not others. Consumers need to be involved to ensure that their values and preferences guide decisions about drug therapy and enable them to manage their own care. Both speakers emphasised the importance of communicating the risks and benefits of medicines to consumers. Quality use of complementary medicinesHerbal and natural remedies are our new first preference was the topic of the presentation given by Ms Margaret Williamson (Manager of Research and Development, NPS, Sydney, NSW), who is leading research to explore the use of herbal and natural medicines in Australia. In 2006, around 65% of Australians reported using herbal and natural medicines in the previous 12 months,2 an increase of 23% since 2004.3 Australians spent around $1.31 billion on these medicines in 2004.3 Herbal and natural medicines are more likely to be used by women and people who are middle-aged, have post-secondary education, are employed, or have a higher income. People most commonly report using herbal and natural remedies for promoting health and preventing illness. People with chronic or recurrent illnesses also use them to complement conventional therapy or alleviate the adverse effects of conventional treatment, or as an alternative to conventional therapy. Personal beliefs on life and health are strongly connected to people’s use of herbal and natural remedies. These beliefs include the desire to take a holistic approach to maintaining or improving health and wellbeing, wanting to exercise control over one’s own health, and perceptions that these remedies are natural, risk-free and inherently safe. Critical to the quality use of complementary medicines, Williamson said, is: building the evidence base for their safety, efficacy and quality; providing independent, accurate and accessible information for consumers and health professionals; improving “pharmacovigilance”, ensuring that these products are documented in all health records; and improving their regulation to ensure products meet appropriate quality standards. Active communities for quality use of medicinesActive community engagement was the theme of several presentations and posters. In his presentation, Revolution or evolution: how do we activate communities for QUM?, Mr Bill Bowtell (Director, HIV/AIDS Project, Lowy Institute for International Policy, Sydney, NSW) highlighted the lessons learned from the successful Australian approach to preventing HIV/AIDS that could be applied to other health issues, including QUM. This approach, he said, was based on acceptance that: evidence-based science is the basis for action; HIV/AIDS education could bring about sustained change in at-risk behaviours; high-risk groups would educate peers effectively and sustainably; government would not resort to punitive measures, sanction, isolation and quarantine; and government would tell the truth about HIV/AIDS. Communities active in QUM were honoured in the biennial QUM Awards, with two awards made in the “Community” category. Through the Good Medicines Better Health Pilot Project run by the Aboriginal Health Council of South Australia, the National Aboriginal Community Controlled Health Organisation and NPS, Aboriginal health workers are being educated and empowered to speak confidently within their own communities about medicines. The Seniors Quality Use of Medicines National Peer Education Program, developed and delivered in partnership with NPS, the Council on the Ageing (COTA) Partnership and the COTA Alliance, provides seniors with the opportunity to become better informed about medicines and improve their skills in discussing health and medicines issues with health professionals. In conclusionIs QUM an efficient use of health care resources? was the question asked by Professor Rachel Elliott (Lord Trent Professor of Medicines and Health, School of Pharmacy, University of Nottingham, UK). Economic evaluation of QUM initiatives is necessary to ensure appropriate use of health care resources, she said, and must also include the opportunity cost and the cost of inadvertent effects of QUM initiatives, remembering that even evidence-based, well thought-out policy can have unintended consequences. She also reminded delegates of the importance of understanding that, despite assumptions to the contrary, patients do not always take their medicines. Non-adherence to medicines needs to be understood and addressed if QUM initiatives are to be efficient, she said. In her closing address, Ms Barb Shea (Vice-President, Canadian Optimal Medication Prescribing and Utilization Service, Canadian Agency for Drugs and Technologies in Health, Ottawa, Ontario, Canada) congratulated Australia on its leading role on the world QUM stage. The symposium showcased the breadth of QUM projects in Australia and the diversity in the groups involved. Speakers explored the QUM challenges being faced in hospital settings, pharmacy, general practice, residential aged-care facilities and oncology, along with specific medicines issues related to veterans, children, pregnant and breastfeeding women, and people with asthma, diabetes and other chronic conditions. The broad range of delegates in attendance reflected how QUM is integrating across all health sectors and the community, nationally and worldwide.

Sharene A Jackson

Routine thromboprophylaxis in hospitalised medical patients is based on trials that predominantly use asymptomatic deep vein thrombosis (DVT) as the endpoint. As asymptomatic DVT is 10–30-fold more common than symptomatic DVT, this exaggerates estimates of benefit and cost-effectiveness. Based on symptomatic disease, the number needed to treat per venous thromboembolism (VTE) prevented is high (150–1600), and the true cost-effectiveness of thromboprophylaxis for symptomatic event reduction is uncertain. The incidence of major bleeding among patients receiving prophylaxis is at least equal to the reduction in clinical VTE. Routine thromboprophylaxis in hospitalised medical patients is not warranted, and better patient selection is needed.

J Alasdair Millar PhD, FRACP, FRCP

Tumour necrosis factor inhibitors have revolutionised the management of Crohn’s disease, but reports of a possible association between concomitant infliximab and immunomodulator therapy and hepatosplenic T-cell lymphoma (a rare form of aggressive non-Hodgkin’s lymphoma) have emerged. We describe the first case in Australia of hepatosplenic T-cell lymphoma in a patient who had been treated with infliximab and immunomodulators for Crohn’s disease. Clinical recordIn January 2006, a 39-year-old man of European background presented with severe sepsis of unidentified source. This was complicated by hypotension and multiorgan failure, including renal impairment, abnormal liver function and myocardial injury, and he required intensive care. He had a 13-year history of active perianal and ileal Crohn’s disease, which had been treated with prednisolone (varying doses) continuously from 1993, and with azathioprine (2–2.5 mg/kg) from 1993 to 1994 and then continuously from August 1999 (after drainage of a perianal abscess). He had also received three doses of infliximab (5 mg/kg) between November 1999 and January 2000, which achieved a partial response. Azathioprine and prednisolone therapy were continued after infliximab therapy, with relatively good control of symptoms. Results of full blood examinations during azathioprine therapy were within normal ranges. On admission, azathioprine therapy was discontinued, but corticosteroids were continued. Blood cultures grew methicillin-sensitive Staphylococcus aureus. Full blood examination revealed mild anaemia (haemoglobin level, 91 g/L; reference range [RR], 130–170 g/L) and mild lymphocytopenia (white blood cell count, 0.6 × 109/L; RR, 4.0–11.0 × 109/L), but other parameters were initially normal. Biochemical analysis revealed acute renal failure (potassium, 6.5 mmol/L [RR, 3.5–5.0 mmol/L]; bicarbonate, 21 mmol/L [RR, 22–31 mmol/L]; creatinine, 580 μmol/L [RR, 60–110 μmol/L]; and urea, 19.9 mmol/L [RR, 2.5–8.3 mmol/L]). Liver function tests revealed transaminitis (alanine aminotransferase, 432 U/L [RR, < 55 U/L]; aspartate aminotransferase, 2246 U/L [RR, < 50 U/L]; and bilirubin, 53 μmol/L [RR, < 19 μmol/L]). There was also evidence of coagulopathy (international normalised ratio [INR], 2.8 [RR, 0.8–1.3]), grossly abnormal levels of inflammatory markers (C-reactive protein, 218 mg/L [RR, < 8 mg/L]; erythrocyte sedimentation rate, 140 mm/h [RR, 2–14 mm/h]), and elevated troponin I levels (5.24 μg/L; RR, < 0.10 μg/L). Nine days after admission, the patient developed pancytopenia (haemoglobin level, 78 g/L; white blood cell count, 0.9 × 109/L; and neutrophil count, 0.3 × 109/L [RR, 2.0–8.0 × 109/L]). This was attributed to drug-induced suppression of bone marrow, and granulocyte-colony stimulating factor (G-CSF) was administered. On discharge, leukocyte and neutrophil levels were normal, G-CSF therapy was discontinued, and follow-up was arranged. Ten days after the patient was discharged, he re-presented with a 2-day history of fever, malaise and non-specific abdominal pain. Physical examination revealed a temperature of 38.5°C, tachycardia (heart rate, 110 beats/min), and hypotension (blood pressure, 100/60 mmHg); cardiovascular and respiratory systems were otherwise unremarkable. Abdominal examination revealed new hepatosplenomegaly, with no stigmata of chronic liver disease. There was no clinical evidence of lymphadenopathy. Repeat haematological testing revealed pancytopenia: haemoglobin level, 100 g/L; white blood cell count, 0.7 × 109/L; platelet count, 48 × 109/L (RR, 140–400 × 109/L); neutrophil count, 0.0 × 109/L; and lymphocyte count, 0.5 × 109/L (RR, 1.2–4.0 × 109/L). A blood film showed atypical lymphocytes and blast cells. Serum lactate dehydrogenase level was grossly elevated at 5351 U/L (RR, 210–420 U/L), and liver function tests showed abnormal results. Abdominal computed tomography confirmed gross splenomegaly, with the spleen being 24 cm long on its major axis, but no lymphadenopathy. Microscopic examination of a liver core biopsy specimen revealed an atypical lymphoid infiltrate in the sinusoids, especially around central veins (Box), with immunophenotype bcl-2+, CD3+, CD43+, Ki67+, ALK1 −, bcl-6 − , CD5 −, CD10 −, CD20 −, CD30 −, CD79 − and cyclin D1 − . Subsequent genetic studies of a bone marrow biopsy specimen revealed rearrangement of the T-cell receptor γ-chain gene, consistent with hepatosplenic T-cell lymphoma (HSTCL). The lymphoma was treated with one cycle of cyclophosphamide, mesna, dexamethasone, doxorubicin and vincristine, which achieved a partial response, but subsequent salvage chemotherapy with ifosfamide, carboplatin and etoposide did not arrest disease progression. In June 2006, the patient received a sibling allogeneic bone marrow transplant, after conditioning with etoposide and total body irradiation.1 The patient remained largely free of disease after transplantation, with monitoring on an outpatient basis and adjustment of immunosuppression as clinically indicated. However, in April 2007, he was hospitalised for investigation of diarrhoea and worsening liver function. He underwent colonoscopy and biopsy of a caecal polypoid mass; results of histological examination were consistent with recrudescence of HSTCL. Positron emission tomography showed multiple sites of relapse. A palliative approach was adopted, and the patient died in June 2007. DiscussionWe describe the first case, to our knowledge, in Australia of HSTCL in a patient with Crohn’s disease who had been treated with infliximab and immunomodulators. Inhibitors of tumour necrosis factor (TNF) such as infliximab have shown great efficacy in the treatment of luminal and fistulising Crohn’s disease, as well as ulcerative colitis.2 Infliximab is a chimeric (human/murine) monoclonal antibody that binds to human TNF-α. It was approved by the United States Food and Drug Administration (FDA) in 1998 for the treatment of moderate-to-severe Crohn’s disease when response to immunomodulator therapy is inadequate. More recently, the FDA has expanded the indication to include ulcerative colitis refractory to conventional treatment. In Australia, the Pharmaceutical Benefits Advisory Committee recently approved TNF inhibitors for the treatment of Crohn’s disease. However, the safety of such biological therapy is a concern: a recent meta-analysis reported a threefold increase in the risk of malignancy (solid and haematological) with the use of anti-TNF therapy in rheumatoid arthritis patients.3 This increase may be partly due to severity of disease or to other aspects of disease management. Interestingly, to date there have been no reports of HSTCL in rheumatoid arthritis patients. The TREAT (Crohn’s Therapy Resource, Evaluation and Assessment Tool) registry, which monitors over 3000 patients with Crohn’s disease who have been treated with infliximab, has not reported an increased incidence of lymphoma.4 However, it is estimated that a substantially larger number of patients would need to be monitored to detect a significant increase in a rare adverse event, such as lymphoma.5 Between 2000 and 2006, the Adverse Drug Reactions Advisory Committee received 319 reports involving anti-TNF therapy, including five cases of lymphoma.6 HSTCL is a rare form of aggressive non-Hodgkin’s lymphoma that comprises 5% of peripheral T-cell lymphomas. Reports of approximately 120 cases have been published worldwide. Eight cases of HSTCL have been identified from the post-marketing infliximab safety database run by the FDA, which seems more than expected, all in young men with a history of Crohn’s disease and concomitant use of azathioprine or mercaptopurine.7 In addition, there have been 15 reports of ‘‘T-cell lymphoma’’ in patients treated with infliximab, but data from the Adverse Event Reporting System were limited.7 Furthermore, there have been no reports of HSTCL associated with other anti-TNF therapies (eg, etanercept and adalimumab) used for any indication.7 Of note, there have been four reports of HSTCL in patients who received azathioprine or mercaptopurine alone for 4–6 years.8 The case we describe differs substantially from previously reported cases of HSTCL associated with concomitant infliximab and immunomodulator treatment in Crohn’s disease. To our knowledge, it involves the oldest patient and longest lead time (72 months) reported to date. Patients in most other cases have been younger than 22 years, with a lead time of less than 58 months7 (unpublished data, Centocor, Horsham, Pa, USA). Recent data suggest an association between lymphoma — especially HSTCL — and concomitant use of infliximab and immunomodulators in Crohn’s disease. However, the mechanism of this possible association remains unclear. The use of biological therapy as a “bridge” to stabilise the disease, while waiting for immunomodulators to become clinically effective, may need to be considered with increased caution. Immunomodulators might need to be avoided after infliximab therapy, and alternative treatments considered. These may include maintenance with ongoing biological therapy alone, use of newer anti-TNF therapy, or earlier surgery (especially in young men). Until further evidence emerges, long-term surveillance of patients who have used biological therapy is warranted. In particular, biological therapy should be used cautiously in the management of refractory inflammatory bowel disease. The decision to use infliximab should be tempered by observations of an association with HSTCL, and strategies for long-term maintenance therapy need to be developed. Liver core biopsy specimen of a patient with Crohn’s disease, following infliximab and immunomodulator therapy Low magnification (A: haematoxylin and eosin stain; original magnification, × 10) and high magnification (B: CD3 stain; original magnification, × 40) views of a liver core biopsy specimen, showing prominent atypical lymphoid infiltrate in the sinusoids and around central veins, and occasional red cell extravasation. The high magnification shows strong CD3 staining (arrows), findings consistent with hepatosplenic T-cell lymphoma.

Musa Drini MB BS · Peter J Prichard MD, FRACP · Gregor J E Brown PhD, FRACP · Finlay A Macrae MD, FRACP, FRCP

All topical ophthalmic agents should be considered potentially potent systemically Many Australians are prescribed topical ophthalmic medications for chronic conditions such as glaucoma, ocular inflammation, infection and allergy. Despite their overall safety, these agents have the potential to cause significant systemic side effects and to have serious interactions with oral medications. In many cases, these effects may go unreported by the patient or misdiagnosed by the medical community. There is a need for improved prescribing practices in both the ophthalmic and general medical communities, with increased awareness of the full range of therapeutic agents being taken by the patient. With the recent passage of legislation allowing optometrists prescribing rights under the Pharmaceutical Benefits Scheme (PBS) (National Health Amendment [Pharmaceutical Benefits] Act 2007 [Cwlth]), it is timely to remind all health care practitioners of the potential hazards of topical ophthalmic medications. Pharmacokinetics make ocular drug delivery more akin to intravenous than to oral administration.1 Topically administered medications gain access to the highly vascular nasal mucosa and are variably absorbed, avoiding first-pass hepatic metabolism.2,3 One drop of timolol 0.5% solution in each eye approximates a 10 mg oral dose for treating systemic hypertension or angina.2 All topical agents should be considered as potentially potent systemically. A retrospective analysis of de-identified PBS billing data from Medicare Australia revealed that, between 1999 and 2004, 20 000 Australians per year had been exposed to co-supply of topical and systemic β-blockers.4 This combination has been linked with adverse respiratory and cardiovascular events, as well as reduced topical ocular hypotensive efficacy.5 The scale of this as a Quality Use of Medicines issue is larger than was anticipated. Multiple factors may be responsible: an assumption that topical therapy is systemically “homoeopathic”; the fact that many patients may not mention eye drops when asked about their drug history; and the fact that patients may not remember their full list of medications. Topical medications usually constitute first-line therapy for glaucoma. Parasympathomimetics (pilocarpine derivatives) have been in use for 140 years, topical β-blockers for 30 years, and, more recently, carbonic anhydrase inhibitors, α2-agonists and prostaglandin analogues have emerged. While the overall safety of these agents is recognised, there is a potential for serious side effects in a small proportion of people. As well as their own direct effects systemically, topical agents may have significant additive or interactive effects with systemic medications. Topical β-blockers may precipitate or aggravate bronchospasm, congestive heart failure, bradyarrhythmias, sinus arrest, a variety of central nervous system effects and dyslipidaemias.6-8 In this issue of the Journal, Schweitzer and colleagues (page 406)9 describe a case involving two episodes of melancholic depression in a patient who had been prescribed β-blocker antiglaucoma agents. Taking these medications has been rated as the most significant risk factor for falls in glaucoma patients.10 Parasympathomimetics locally provoke brow ache and/or headache, miosis and myopia, and, with systemic absorption, carry the risk of bradycardia, hypotension, bronchospasm,7 gastrointestinal symptoms and urinary frequency. Topical α2-agonists have been associated with central nervous system depression and with profound hypotension in children.11 Topical carbonic anhydrase inhibitors do not seem to produce the metabolic side effects of their oral counterparts, but may be associated with an idiosyncratic bone marrow suppression and sulphonamide allergy.6 To date, topical prostaglandin analogues have not been associated with cardiovascular or respiratory side effects, adding support to their use as first-line antiglaucoma agents.6 However, their use has been associated with headache, flu-like symptoms and myalgias in up to 10% of patients, with case reports of neurological referral and investigation.11,12 Co-prescription of systemic and topical β-blockers can reduce heart rate in patients with glaucoma.5 Simultaneous administration of topical timolol and systemic verapamil has been associated with severe bradycardia.7 Co-administration of topical α2-agonists with oral monoamine oxidase inhibitors carries a risk of hypertensive crisis and is contraindicated.3 Salicylates have been shown to cause accumulation of systemically administered carbonic anhydrase inhibitors; this is also theoretically possible with topical carbonic anhydrase inhibitors.3 Topical steroid drops are key to the management of ocular allergy and inflammatory disease. While they are well tolerated systemically, their ocular side effects are potentially blinding: potentiation of infection, cataract and glaucoma. Commonly perceived as a “safe” alternative, fluorometholone has been associated with all these ocular side effects, albeit less frequently.13 Topical chloramphenicol is commonly prescribed to treat infective conjunctivitis, and is used perioperatively with ocular surgery. Although bacteriostatic rather than bactericidal in action, its broad spectrum of activity and lack of systemic use make it an ideal first-line ocular topical agent. Its potential to induce life-threatening aplastic anaemia remains controversial: the risk has been estimated to be about 1 in 150 000, at worst,14 but it is likely to be much lower.15 Whether the rare occurrence of this condition is by a dose-dependent or a dose-independent (idiosyncratic) mechanism,14,15 prescribers need to be cautious when prescribing for patients with a personal or family history of blood abnormalities. Concern about this risk has been enough to marginalise the use of chloramphenicol in the United States. Additionally, chloramphenicol should only be prescribed when conjunctivitis is likely to be bacterial in origin and for clinically appropriate time periods.16 We believe prescribing practice can be improved with simple steps: (i) take a full drug history, and specifically ask about eye drops; (ii) physicians must remember to ask whether the patient’s optometrist has prescribed any medication, and should be aware of the newer combination preparations (Combigan [Allergan], Cosopt [Merck, Sharp and Dohme], DuoTrav [Alcon], Xalacom [Pfizer]), all of which contain the β-blocker timolol; (iii) ophthalmologists (and now optometrists) should be aware of a patient’s concurrent systemic health and medication status before commencing any topical agents, particularly β-blockers. The eye is not an isolated organ but may be influenced by systemic diseases and therapies. Further, recent publications1,4,8 highlight the converse — topical therapies for the eye may have significant systemic effects and/or interactions with systemic medications. It is important to be alert to possible systemic side effects and interactions between systemic and topical agents and to investigate and modify treatment regimens appropriately. Limit the use of topical steroids, and use them only with adequate supervision. Remind all patients using topical medications to follow the “double DOT” procedure (Don’t Open eyes Technique and Digital Occlusion of the Tear duct), which involves closing the eyes and applying digital pressure over the lacrimal sac for 1–2 minutes after drop administration (Box 1, Box 2). This reduces systemic absorption by two-thirds, thereby significantly widening the safety margin of all agents.17,18 Recent legislative changes across Australia allow practitioners who are not medically trained to prescribe topical medications, although, at present, legislation varies from state to state. These changes underline the importance of general practitioners and physicians recognising the potential systemic effects of these topical ophthalmic medications and being alert to interactions with other medications. Improved communication between all health care practitioners and ophthalmologists will be vital for patient safety. 1 Lacrimal drainage system 2 The “double DOT” procedure* for reducing systemic absorption of topical ophthalmic medications * Don’t Open eyes Technique and Digital Occlusion of the Tear duct.

Ivan Goldberg MB BS, FRANZCO, FRACS · Gregory Moloney MB BS · Peter McCluskey MB BS, FRANZCO

Clinical record A man in his 70s was prescribed DuoTrav eye drops (Alcon Inc; combined prostaglandin analogue [travoprost] and β-blocker [timolol]) for worsening glaucoma. (He had previously been treated with latanoprost.) Within 2–3 days, he felt depressed and described “a black cloud descending over [him]”. His symptoms included tiredness, poor concentration, sleep disturbance, and loss of libido and appetite. Normally fit and active, with a zest for life and a good sense of humour, he struggled to get up in the mornings and lost interest in socialising. His general practitioner prescribed venlafaxine (75 mg, then 150 mg) for the depression. Subsequently, DuoTrav therapy was stopped and a combination of travoprost, brimonidine tartrate and brinzolamide started. A month later, his sleep and appetite were considerably improved and he rated himself as 70% better. Eleven years previously, he had suffered an episode of major depression with melancholic features after his initial diagnosis of glaucoma, for which he was prescribed the β-blocker betaxolol.1 At that time, his symptoms had been worse and of longer standing, requiring hospitalisation and electroconvulsive therapy (ECT). He had recovered slowly, while continuing to experience lethargy and a heavy head. Only several months later, when the episode of depression was linked to the initiation of betaxolol and the β-blocker was stopped, did he fully recover. Within 48 hours of ceasing betaxolol therapy, he felt more energetic, alert and alive. The patient had been treated once before with ECT when he experienced his first depressive episode, at the age of 50 years, associated with severe work-related stress. Both subsequent episodes of depression were seemingly unrelated to stressors or life events. The most common medical treatments for glaucoma in Australia are prostaglandin analogues. However, β-blockers still comprise a substantial proportion of all prescriptions, either alone or in combination. Despite their topical administration, β-blockers are absorbed from the eye through the conjunctival epithelium, lacrimal channels, nasal mucosa and gastrointestinal tract into the systemic circulation. Although only small amounts are absorbed, concentrations may be sufficient to cause systemic β-adrenergic receptor-mediated effects, including slowing of heart rate, lowering of blood pressure and non-response to bronchodilators. Central effects such as depression have also been reported. Lessons from practice Ophthalmic β-blockers are absorbed systemically and may cause central side effects. Depression is an occasional adverse effect of β-blockers, including those used for glaucoma. Ophthalmic β-blockers should be avoided in patients who have a history of clinical depression. When depression evolves soon after commencing β-blocker treatment, serious consideration should be given to changing the medication, as the β-blocker may be the causative agent. The literature investigating a causal relationship between β-blockers and depression is controversial. An evidence-based review concluded that depression was an uncommon side effect of treatment with β-blockers and usually occurred only in the presence of a pre-existing condition.2 Randomised controlled studies of β-blockers in cardiovascular disease found the incidence of depressive symptoms was similar in β-blocker- and placebo-treated groups.3 However, a review of 24 case reports4 showed a temporal relationship between the use of β-blockers and depression in more than half the cases. If there is a close temporal relationship between the commencement of a new treatment and the development of symptoms, the symptoms are considered likely to have been caused by the medication. In the initial case that we reported on this patient,1 depressive symptoms began within days after the diagnosis of glaucoma and commencement of betaxolol treatment. The patient’s symptoms only fully remitted when the drug was stopped, providing further evidence of a causative relationship. The case we report here describes recurrence of depression after the introduction of another β-blocker, timolol, and again cessation of symptoms when treatment was stopped. The recurrence of the syndrome following a re-challenge further strengthens the argument for a causal relationship. (The travoprost component of the medication was unlikely to have been the cause of the depression.) It is possible that the onset of the disorder occurred coincidentally with the introduction of the medication (though such an event is unlikely to have occurred twice) or was caused by the underlying illness for which the new medication was prescribed. In the only study we could find of ophthalmological patients with depression with and without glaucoma, no association was shown between depression and glaucoma.5 Glaucoma is mostly a disease of older people, a group prone to developing depressive illness. Depression is often dismissed in older people as a normal reaction to ageing, loss or chronic illness. However, it is treatable, with a very good prognosis. Older patients are frequently taking multiple medicines and may develop depressive symptoms as a side effect. The purpose of this case presentation is to emphasise that even a drug that is administered topically, such as antiglaucoma eye drops, is absorbed systemically and can potentially cause adverse effects elsewhere, including centrally. There are credible theoretical reasons why β-blockers may cause depression: the number of β1 receptors is increased in the brains of suicide victims and chronically stressed animals, and antidepressants cause down-regulation of β1 receptors. The fact that only a few patients develop depression after taking β-blockers may be due to genetic differences. It is possible that poor metabolisers of the enzyme cytochrome P450 2D6 will be exposed to higher systemic concentrations of β-blockers than those who are normal or fast metabolisers.6,7 To our knowledge, there have been no studies of depression in relation to β-adrenergic receptor gene polymorphisms, although associations have been found between these polymorphisms and haemodynamic effects after administration of betaxolol and timolol.8 Variability between individuals in the time course, affinity and extent of receptor occupation may also be relevant. Vuori and Kaila9 found substantial β1 and β2 blockade in plasma for up to 12 hours after administration of topical timolol. Thus, 12-hour dosage intervals could lead to substantial systemic blockade and could explain the reported systemic side effects. Our report adds to the evidence that depression is an occasional adverse consequence of treatment with β-blockers, including topical antiglaucoma agents. Development of depression is a serious consequence. Discontinuation of a β-blocker may relieve symptoms, but specific antidepressant treatment may also be needed. As there are alternative antiglaucoma medications, it is prudent not to prescribe β-blockers for patients who have a history of depressive illness. If depression develops after commencement of a β-blocker antiglaucoma agent, an alternative medication should be substituted if possible.

Isaac Schweitzer DPM, FRANZCP, MD · Kay Maguire BSc(Hons), MSc, PhD · Chee H Ng MMed, FRANZCP, MD

To the Editor: Growing revenue from the sale of products for nicotine-replacement therapy (NRT), such as nicotine patches, has fuelled media interest in the likelihood that “reformed smokers” are “getting hooked on nicotine replacement”.1 While there may be anecdotal evidence of long-term use, there are no current population-based data to indicate whether this is the case in Australia. Overseas data suggest long-term use of NRT is low.2,3 For example, a United States study found the median duration of patch use decreased from 30 days to 21 days following over-the-counter NRT availability.2 Another study found that more than 75% of NRT purchases were for 1 month, while only 5% of smokers purchased NRT for more than 3 consecutive months and less than 1% of purchases continued to 24 months.3 An Australian survey conducted in 2000 suggested that most NRT use (61%) was short-term, lasting less than 2 weeks.4 More recently, our 2004 telephone survey of smoking-related perceptions and practices included an item on length of NRT use. The survey involved households selected at random from the New South Wales electronic white pages, with quotas applied to the sample based on NSW census proportions. The study was approved by the University of Newcastle Human Research Ethics Committee. Of the 3503 participants (response rate, 43%), all 539 current smokers and 1013 former smokers were asked about NRT use. Those who had made their most recent quit attempt in the previous 2 years reported on their NRT use during that quit attempt. Of the 138 who had used NRT on their most recent quit attempt, only three (2%) used an NRT product for 12 weeks (the recommended length of use). Only four NRT users (3%) reported using the product for more than 3 months, and none reported using NRT for more than 6 months. It appears that fears of widespread addiction to NRT products are probably unfounded. In fact, lack of compliance with use recommendations, resulting in inappropriately short episodes of use, is probably a bigger problem, and one that may help explain the disappointing effectiveness of NRT under “real world” over-the-counter conditions.5 Data on frequent repeated short-term use of NRT products would be useful to round out the picture on NRT use in the over-the-counter environment.

Christine L Paul · Flora Tzelepis · Raoul A Walsh · Billie Bonevski

To the Editor: Bethanechol is a parasympathomimetic agent similar to acetylcholine that is known to be a selective stimulant of smooth muscle in the gastrointestinal tract and urinary bladder. It is normally used to treat non-obstructive urinary retention and has not previously been known to have any effect on skeletal muscle. Adults with cerebral palsy usually slowly deteriorate over the years, with gradually increasing muscle tone, worsening speech, mobility difficulties and a loss of independence. There has been no change in their management for decades. While working in a residential facility for adults with cerebral palsy, we serendipitously found that bethanechol significantly reduced the muscle spasticity in a patient for whom it was initially used to treat micturition difficulty. Seven other patients who were wheelchair-bound with cerebral palsy were then progressively given bethanechol in increasing doses. All patients and/or their carers were advised that the medication was being used experimentally, and all consented to participate in a clinical trial. The results are summarised in the Box. In all patients, bethanechol treatment was ceased for a week once the clinical benefits had been established, and all deteriorated during that week. None of the patients suffered any detectable side effects from the use of bethanechol, but many were already taking a proton-pump inhibitor that may have protected them from any gastrointestinal adverse effects. A synergistic interaction between bethanechol and another medication (eg, diazepam) was excluded as an explanation for the results obtained, as no other medication was common to all patients. Bethanechol’s effect seems to be long-lasting, as the first patient has now been using it for 6 months with no deterioration in his improved muscle tone. A Medline search revealed no studies in which bethanechol had been used as a treatment for cerebral palsy. Although our sample was very small, the fact that every patient improved indicates that a larger trial of bethanechol for cerebral palsy is warranted. Clinical outcomes for eight patients with cerebral palsy after treatment with bethanechol Sex (age in years) Diagnosis Final daily dose of bethanechol* Clinical effects M (41) Ataxic and spastic quadriplegia 60 mg Reduced muscle spasm, improved joint movement and speech, improved sense of wellbeing F (53) Ataxic and spastic quadriplegia 60 mg Improved arm movement and speech, looser muscle tone, more relaxed F (47) Spastic quadriplegia, kyphoscoliosis 60 mg Able to abduct legs from previously clamped closed position, loss of leg spasm pain, improved speech, muscle spasm induced by touch eliminated M (68) Spastic quadriplegia, dysphagia 60 mg Less stiffness, speech clearer, easier for carers to move, improved sense of wellbeing M (58) Rigid spastic quadriplegia 60 mg Less limb muscle spasm, improved arm and trunk movement, markedly improved speech F (44) Spastic quadriplegia, epilepsy 60 mg Improved arm and leg movement, easier to roll M (49) Spastic quadriplegia, athetosis 30 mg Chronic spasmodic jerks ceased completely, speech better, able to play carpet bowls better, back extension improved M (68) Spastic quadriplegia, kyphoscoliosis 60 mg Less muscle pain, less back spasm, easier for carers to lift, felt happier and more relaxed * Given orally in three divided doses.

Warwick J Carter

To the Editor: It has been well established that traditional inhalational anaesthetic agents can cause mild and sometimes fulminant liver failure.1 However, while newer inhalational agents are a theoretical cause of hepatotoxicity, such cases have rarely been reported.2,3 We describe desflurane-induced acute liver failure in a 53-year-old woman with achalasia, hypertension, type 2 diabetes mellitus and hyperlipidaemia. She underwent a Heller myotomy for treatment of the achalasia in late 2004. During anaesthesia, desflurane was administered (1.2 minimum alveolar concentration [MAC]) via a Datex–Ohmeda Aestiva/5 anaesthesia delivery system (GE Healthcare, Sydney, NSW). After the operation, her serum alanine aminotransferase (ALT) concentration peaked at 943 U/L (reference range, < 35 U/L). This was attributed to antibiotic toxicity. As the initial myotomy was inadequate, the surgery was repeated 10 days later with desflurane (0.9 MAC) anaesthesia. The patient developed acute liver failure 96 hours after surgery (serum ALT level, 11 600 U/L; pH, 7.06; international normalised ratio, 3.7) and died despite supportive management. A postmortem examination confirmed massive hepatic necrosis and significantly elevated trifluoroacetyl chloride-specific IgG4 antibodies (optical density, 0.585; reference range, < 0.233) — consistent with an inhalational agent being the cause of the necrosis. There are few similar cases of desflurane-induced acute liver failure in the literature to date2,3 and none, to our knowledge, in Australia. Fulminant hepatic necrosis induced by halothane, the original offending agent, occurs in about one in 35 000 adults. This is thought to be immune-mediated and appears to be directly correlated with the metabolism of the anaesthetic, catalysed by cytochrome P450 2E1, to trifluoroacetylated hepatic proteins. The altered protein is seen as “non-self”, generating an immune response that, on re-exposure, leads to inflammation and cellular death.4 Desflurane is metabolised to inorganic fluoride and trifluoroacetyl chloride. However, due to a lower blood : gas partition coefficient and its resistance to degradation (as a result of replacement of chlorine by fluorine at the α-carbon position), desflurane is metabolised by hepatic enzymes to a lesser extent than halothane, enflurane and isoflurane.4 Thus, the degree of hepatic metabolism appears to be related to the potential for hepatic injury, as seen clinically. Evidence for immune-mediated, allergic sensitisation continues to emerge. Identification of IgG4 antibodies, the rarest and most IgE-like immunoglobulins, strongly suggests an allergic component in the pathophysiology of this disease.5 Although hepatotoxicity is a rare complication of the newer inhaled volatile agents, it may have devastating consequences. Anaesthetic agents should be considered in the differential diagnosis of hepatotoxicity, especially in the context of extreme elevation of serum transaminases, suggesting the presence of massive hepatic necrosis. In this case, postoperative ALT elevation was attributed to antibiotic — rather than desflurane — toxicity, with disastrous results following re-exposure, a scenario that might have been prevented if recognised earlier. A full incident report was made at the tertiary hospital involved, and the death was reported to (and examined by) the coroner. The main recommendation made from the case was that inhalational agents should be avoided in the setting of hepatitis.

Marcus W Chin · Dolores B Njoku · Gerard MacQuillan · Wendy S Cheng · Nickolas Kontorinis

To the Editor: We report significant sinus bradycardia in a patient presenting with an acute coronary syndrome shortly after beginning bupropion therapy to assist with smoking cessation. A 53-year-old man was attended by paramedics for typical ischaemic chest pain. He had sinus bradycardia (45 beats/min) and hypotension (blood pressure, 85/60 mmHg), and was found to have a serum troponin I concentration of 1.2 μg/L, but no diagnostic electrocardiographic changes. He was admitted to our hospital with an acute coronary syndrome. He reported his medications at the time of admission as including metoprolol 50 mg twice daily (for hypertension) and paroxetine 20 mg daily (for depression). The patient was given multiple doses of intravenous atropine (total, 1.2 mg) and adrenalin (total, 2 mg). After an adrenalin infusion was begun, he developed ventricular tachycardia (170 beats/min), but his cardiac rhythm spontaneously returned to sinus bradycardia. Two days after admission, two coronary stents were successfully deployed in a critically stenosed right coronary artery. Bradycardia (45–50 beats/min) persisted. The following day, it was discovered that 3 weeks previously, the patient’s general practitioner had prescribed bupropion 150 mg twice daily to assist with smoking cessation, which he had been taking up until the day of admission. Bradycardia continued until hospital discharge. One month after discharge, he was in sinus rhythm (60 beats/min) and was clinically well. Bupropion is a selective noradrenalin, dopamine and serotonin reuptake inhibitor. The mechanism by which it enhances the ability of patients to abstain from smoking is unknown.1 Bupropion inhibits the activity of the cytochrome P450 2D6 isoenzyme, which metabolises metoprolol.2 Concurrent use of bupropion and metoprolol can increase serum metoprolol levels, and clinically significant bradycardia has been reported.3 Further, paroxetine, a selective serotonin reuptake inhibitor (SSRI), is a potent cytochrome P450 2D6 inhibitor, which would have further increased serum metoprolol levels. Bradycardia associated with metoprolol and paroxetine dual therapy has been described.5 Additionally, there is the potential for serotonin syndrome to develop in a patient administered multiple SSRIs. In our patient, the administration of bupropion and paroxetine could have potentially led to serotonin syndrome.6 Our patient’s pharmacological profile was complex, with potential adverse pharmacodynamic effects. The most likely precipitant of the patient’s bradycardia was his acute coronary syndrome, although bupropion may have contributed. The case highlights the potential for significant drug interactions when new drug therapies are initiated. Bupropion and metoprolol (and other drugs metabolised by the cytochrome P450 2D6 isoenzyme pathway) should be co-administered with caution. The importance of common pathways of drug metabolism should be recognised to avoid potential adverse events, particularly when multiple medications are used.

Jacqueline Landau · Andrew E Ajani

Re: “Misleading advertising of PI-based drug information?”, the letter by Jim R Stockigt, in the printed version of the 2 June 2008 issue of the Journal (Med J Aust 2008; 188: 679-680). Professor Stockigt’s affiliations were incorrect and incomplete, and should have read: Further, it should be noted that the question mark in the title was added at the Editor’s discretion.

Jim R Stockigt

To the Editor: Millar and colleagues recently described their comparison of the national inpatient medication chart (NIMC) with 14 other medication charts.1 They concluded that the NIMC contained design features that were adverse and therefore inferior to the medication chart previously used in their hospital. They also stated that the advantages expected by the Western Australian Director-General of Health in introducing the national chart were not experienced at their hospital. Millar et al failed to mention that the NIMC underwent an extensive process of piloting and evaluation in over 30 sites across the country in a structured before-and-after study.2 Failure to recognise (i) the benefits of standardisation as medical, nursing and pharmacy staff move between sites, (ii) the opportunities for structured safe medication practice training,3 and (iii) the value of the collaborative methods used will inhibit the possibility of overcoming problems like those identified by Millar et al in future redesign processes. Millar and colleagues themselves noted that “marked heterogeneity of chart design has been abolished by the NIMC”. The national pilot study considered the entire medication management cycle using a broad definition of medication error (“A prescribing decision or prescription writing process that results in an unintentional, significant reduction in the probability of treatment being timely and effective or increases the risk of harm, when compared with generally accepted practice”4). The NIMC was designed to reduce the risk of errors that prescribers have identified with previous charts.5 The NIMC also reduced the need for all staff to interpret unclear or incomplete prescriptions, thereby further reducing the risk of medication errors.2 We support the comments by Millar and colleagues that the process of implementing clinical practice change must involve significant buy-in and championing by clinicians. The implementation of the NIMC in Queensland recognised the importance of top-down support from senior health officials, combined with the need to increase clinicians’ awareness of risks of current systems and the need for a clear demonstration of the benefits of a revised system to bring about any substantial change in behaviour. We understand that the Australian Commission on Safety and Quality in Health Care has established a quality assurance process which operates at jurisdictional and national levels to adjust the NIMC on the basis of issues raised. This important platform will succeed in addressing the issues raised by Millar et al provided clinicians participate in this collaborative approach to medication safety. We have a rare opportunity, in which Australia is taking a leading role, to address one of the critical safety risks facing patients today. Let us all work together and criticise constructively within a framework of collaboration.

Ian D Coombes · Danielle A Stowasser · Carol M Reid · Charles A Mitchell

In reply: It is understandable that the designers of the national inpatient medication chart (NIMC) should wish to defend it against criticism, especially after 5 or more years of hard work and the major administrative achievement represented by the “top-down” implementation. It is regrettable that the chart at the centre of this otherwise admirable activity turns out to have significant weaknesses compared with the previous medication chart used at Royal Perth Hospital, and that the designers acknowledge this only obliquely by allowing for “future redesign”. Rather, they emphasise secondary outputs such as cross-border familiarity (which we discussed in our article1), “training in structured safe medication practice”, and “collaborative methods”. These supposed advantages are but small crumbs of comfort compared with the imposition of an unsatisfactory chart, loss of local autonomy and increased hazard for patients. There is no evidence that the NIMC has decreased medication errors, defined in relation to patient harm. There was indeed a pilot study, and we referred to it in two different contexts in our paper, but it assessed the chart on the basis of unsatisfactory process-based criteria similar to those employed after the chart was implemented. Perhaps a better indication of the problems of the pilot chart lies in the hundreds of suggested changes made from pilot sites to the NIMC Oversight Committee.2 We note that Coombes and colleagues do not dispute our scientific findings or the design faults we described. Their response repeats unverified claims of benefit that we discussed in our article, and seeks to reassure readers that a process is in place to “adjust the NIMC on the basis of issues raised”, thus acknowledging that “issues” exist. However, readers should be aware that the process referred to is subject to a set of ground-rules which prohibit changes to several design aspects of the chart that we criticised (eg, the block design of the pro re nata [PRN] section).3 Thus, the possibility that the NIMC will be substantially improved is remote. A more likely outcome is that Australia will be left with a chart that satisfies the superficial attraction of national standardisation but contains significant design flaws which represent a hazard to patients. A better approach would be to agree on binding national standard design elements and to restore to individual hospitals or health areas the right to design their own charts within these constraints — “think globally, act locally”.4

J Alasdair Millar · Robyn C Silla · Glenda E Lee · Ann Berwick

* It should be noted that the question mark in the title was added at the Editor's discretion. To the Editor: Why are those who market officially sanctioned information about pharmaceutical products not constrained by the advertising standards imposed on those who sell these products? Medicines Australia, which formulates a code of conduct for the pharmaceutical industry, imposes penalties, both financial and withdrawal of offending material, against misleading advertising of pharmaceutical products1,2 Why are similar standards not applied to advertising of information about these products? There are well documented flaws in Australian drug information sources,2,3 such as MIMS (the Monthly Index of Medical Specialties), that are based on product information (PI) authorised by the Therapeutic Goods Administration (TGA). Some PI is decades out of date;2 bottlenecks in updating TGA-approved PI are apparent.4 In this light, advertising of PI-based information in the bimonthly MIMS summaries seems anomalous. The April–May 2008 bimonthly print edition of MIMS claims to present “100% pure knowledge”, and states that “you can count on MIMS being up-to-the-minute”, and that “MIMS is essential knowledge that Australian health professionals can trust”. Previous bimonthly MIMS summaries make similar assertions. Until PI can be brought to an acceptable professional standard — a task that may be slow4 — it would seem appropriate to rein in misleading claims about PI widely used by health workers. Medicines Australia, or the National Prescribing Service, a government-funded body committed to “quality use of medicines”, could lead this initiative.

Jim R Stockigt

In reply: MIMS is held — and has long been held — in high regard in the Australian health care market. The vast majority of MIMS subscribers recognise that the quality information provided by MIMS is essential in their daily encounters with their patients. However, the product information (PI) produced in MIMS publications is only part of the information provided to health care professionals through various MIMS publications. Furthermore, it must be stated clearly that MIMS is not responsible for producing the PI-based drug information. This responsibility remains with the manufacturer, and the PI is subsequently approved by the Therapeutic Goods Administration (TGA). MIMS collates information from various sources, both locally and overseas, and publishes it in an easy-to-use, well structured and familiar format for its customers. MIMS has long been committed to providing such “essential knowledge that Australian health professionals can trust” since the introduction of the first MIMS publication 45 years ago. However, MIMS does acknowledge that there is an issue with some PI not being reviewed more regularly, and is committed to working closely with any appropriate organisation to address deficiencies in the current process. Nevertheless, it would seem inappropriate to say that PI for all drugs is not a quality information source. PI for the vast majority of drugs published in MIMS is as current as possible, given the constraints of publishing, the updating process by pharmaceutical companies and the delays in approvals through the TGA. The study reported and referenced by Stockigt focused on old, generic-based medicines.1 While there is an issue with manufacturers keeping these current, this is clearly a responsibility of the TGA and the manufacturer, not MIMS. PI for newer products is an important quality information source for the prescribers of medicines; if it were not, then the TGA would not permit manufacturers to make PI available in the first place. With respect to Stockigt’s concerns about the accuracy of MIMS advertising, we stand by our assertion that it is MIMS policy to provide the most up-to-date medicines information available, capably delivered by the MIMS professional editorial team.

Elizabeth A Donohoo

To the Editor: We report the case of a 71-year-old woman who presented with a 3-week history of lethargy, subacute confusion and drowsiness. She was known to have a seizure disorder for which she had been taking lamotrigine 100 mg and sodium valproate 500 mg twice a day for 2 years. On examination, the woman was disoriented with regard to person and time, and had constructional apraxia and asterixis. The rest of the physical examination was unremarkable. A full blood count, electrolyte levels, coagulation parameters, arterial blood gas measurements and hepatitis serology were normal. Tests for immunological markers of autoimmune liver disease were negative. Liver function tests showed longstanding raised levels of alkaline phosphatase (158 U/L [reference range (RR), 30–110 U/L]) and γ-glutamyl transferase (434 U/L [RR, < 40 U/L]). Serum drug levels were sodium valproate 51.0 mg/L (therapeutic range, 50–100 mg/L) and lamotrigine 9.5 mg/L (therapeutic range, 3–14 mg/L). The venous blood ammonia level was 109 μmol/L (RR, < 50 μmol/L). A liver ultrasound scan was normal. Computed tomography of the brain showed microvascular changes and an old cortical infarct. An electroencephalogram (EEG) showed diffuse slowing, with a predominance of rhythmical theta activity and some delta activity, suggestive of encephalopathy. As hyperammonaemic encephalopathy secondary to sodium valproate therapy (VHE) was considered a possible diagnosis, sodium valproate treatment was discontinued. The patient’s confusion resolved completely and the asterixis disappeared within a week. At the same time, her blood ammonia level fell to 19 μmol/L and her EEG normalised. Eight months after discontinuing sodium valproate treatment, the woman was still asymptomatic. A subsequent percutaneous liver biopsy, to investigate her persistently abnormal liver function, showed features consistent with primary biliary cirrhosis. Sodium valproate is used not only for management of epileptic disorders but also for migraine prophylaxis and treatment of several psychiatric conditions. Although a generally well tolerated drug, it has a few well known side effects, including hyperammonaemia and, rarely, VHE.1-3 The possible pathophysiology of VHE has been described elsewhere.2 Gerstner et al reported on a series of 19 patients with VHE between 1994 and 2003.4 Review of the literature suggests that VHE is under-recognised, leading to considerable delay in the diagnosis of this potentially reversible condition.3,5 In our patient, it is reasonable to presume that sodium valproate precipitated the encephalopathy on a background of evolving unrecognised liver disease. The marked improvement in her clinical manifestations after discontinuation of valproate further supports this presumption. We have drawn attention to this case to highlight that VHE should be considered in patients presenting with confusion. Prompt measurement of the ammonia level and cessation of valproate treatment should be considered if clinically appropriate. Patients with previously unrecognised liver disease may be at particular risk. Acknowledgement: We thank Professor Peter Roberts-Thomson, Director of the Department of Immunology at Flinders Medical Centre, for his expert opinion and advice.

H S Subhash · Robert J Heddle · David W Schultz · John Ring · Campbell H Thompson

Naltrexone implants have not been subject to the usual rigorous scrutiny required for new devices in Australia, but are widely used through the Special Access Scheme In this issue of the Journal, Lintzeris and colleagues report eight patients with naltrexone implants who developed serious medical complications considered to be related to the implant (→ Unplanned admissions to two Sydney public hospitals after naltrexone implants).1 Intuitively, naltrexone is an attractive treatment for opioid dependence, as it is inexpensive, long-acting and generally well tolerated, and blocks the actions of heroin when taken orally. However, empirical support for naltrexone has been unimpressive,2-4 with research showing that poor adherence to treatment limits its effectiveness. An Australian study found that, while patients who adhered to treatment did well, only 2% were still taking the drug 3 months after conventional inpatient detoxification.5 Naltrexone was registered by the Therapeutic Goods Administration (TGA) in 1998 as “an aid in the maintenance of previously opiate-dependent patients who have ceased the use of opioids”.6 However, the Pharmaceutical Benefits Advisory Committee twice rejected applications for the inclusion of naltrexone in the Pharmaceutical Benefits Scheme as a treatment for opioid dependence on the grounds of lack of evidence of efficacy. Controversy over efficacy was followed by growing doubts about naltrexone’s safety. Intermittent naltrexone consumption lowers opioid tolerance, thereby increasing the risk of heroin overdose. An Australian study found the death rate for those leaving naltrexone treatment was eight times that recorded among participants leaving treatment with agonists such as methadone or buprenorphine.7 As the weakness of the case for oral naltrexone became clearer, a range of interventions were developed to overcome the inherent problems of treatment initiation and poor adherence. The publication in 1997 of an article entitled “I woke up . . . cured of heroin” in a popular Australian magazine8 sparked intense community and political interest in the initiation of naltrexone treatment during general anaesthesia or heavy sedation, followed by oral administration. This was said to be a novel, dramatically effective treatment for heroin dependence. However, subsequent evaluation showed that these approaches increased the cost of oral naltrexone without increasing efficacy.9 More recently, depot injections10 and implants of naltrexone have become the focus of public and political hope. In this historical context, it is concerning that the recent research on naltrexone implants in Australia has not followed usual scientific processes. In particular, naltrexone implants have not been subject to the usual rigorous scrutiny required for new drug products seeking registration in this country. Nevertheless, they are available through the TGA Special Access Scheme; there is no requirement for TGA approval for access to unapproved goods in Australia for Category A patients under this Scheme, and no apparent requirement for collection of efficacy or safety data. Supporters of the naltrexone implant have argued that heroin injectors meet the criteria for Category A patients under the Scheme as “persons who are seriously ill with a condition from which death is reasonably likely to occur within a matter of months, or from which premature death is reasonably likely to occur in the absence of early treatment”.11 Most Category A patients have malignant conditions or rare life-threatening diseases. The annual mortality of heroin injectors is in the order of 1%12 — almost 15 times higher than expected for persons of the same age and sex with no history of heroin use, but hardly in the range generally considered appropriate for the Special Access Scheme. But the inclusion of naltrexone implants in the Scheme and their widespread use (reportedly by more than 1500 individuals) means the product has achieved a substantial market while not undergoing the rigorous evaluation usually applied to drugs before registration. Some of the implants used in Australia are produced locally, while others are manufactured overseas. There are doubts about the quality of manufacture, as well as deficiencies in the safety and efficacy data. As far as we are aware, no major national drug regulatory authority has licensed naltrexone implants for management of opioid misuse. However, a depot injection of naltrexone has been approved by the Food and Drug Administration in the United States, but only for alcohol, not opioid, dependence.10 Although the effectiveness, safety and cost-effectiveness of methadone and buprenorphine treatments for heroin dependence are supported by substantial and compelling evidence, a greater range of pharmacological treatments suited to the broad range of individual patients is required. A recent randomised controlled study of depot naltrexone for the treatment of opioid dependence had encouraging results.13 The strong theoretical rationale for the usefulness of naltrexone in treating heroin dependence justifies further rigorous investigations. However, the uncontrolled use of unregistered products of uncertain quality hampers the development of proper clinical trials. Since the thalidomide disaster in the 1960s, all new medications introduced into Australia have been regarded as ineffective and unsafe until proven otherwise. Constant vigilance is required to ensure that only new medications and devices of proven effectiveness and safety are permitted widespread use. The disturbing suggestions of mortality and morbidity from unregistered naltrexone implants make a strong case for an independent review to determine whether this treatment is sufficiently safe for such widespread use. This review should also assess whether the TGA Special Access Scheme has been used to circumvent the requirement for rigorous assessment of the quality, safety and efficacy of naltrexone implants. This assessment is the cornerstone of a drug regulatory system designed to protect the public from ineffective and unsafe medicines. The TGA has the power under the Therapeutic Goods Act 1989 (Cwlth) (s. 31A(2) and s. 41JD) to seek clarification of the Category A classification of patients, and should do so urgently regarding access to unapproved naltrexone products in Australia.

Alex D Wodak FRACP · Robert Ali FAChAM · David Henry FRCP(Edin) · Lloyd Sansom AO, PhD

Objective: To determine the incidence of lactic acidosis in community-based patients with type 2 diabetes, with special reference to metformin therapy.Design: Substudy within a longitudinal observational study, the Fremantle Diabetes Study (FDS).Participants and setting: 1279 patients from a postcode-defined population of 120 097 people in Western Australia.Main outcome measures: Confirmed hospitalisation with lactic acidosis identified through the WA Data Linkage System during two periods: (1) from study entry, between 1993 and 1996, and study close in November 2001; and (2) from study entry to 30 June 2006.Results: At entry, 33.3% of patients were metformin-treated, and 23.1% of these had one or more contraindications to metformin (55.1% and 38.0%, respectively, after 5 years’ follow-up). Five confirmed cases of lactic acidosis were identified during 12 466 patient-years of observation; all had at least one other potential cause, such as cardiogenic shock or renal failure. From study entry to close, the incidence was 0/100 000 patient-years in both metformin-treated and non-metformin-treated patients. Between study entry and 30 June 2006, incidence was 57/100 000 patient-years (95% CI, 12–168) in metformin-treated patients and 28/100 000 patient-years (95% CI, 3–100) in the non-metformin-treated group, an incidence rate difference of – 30 (– 105 to 46) (P = 0.4).Conclusion: The incidence of lactic acidosis in patients with type 2 diabetes is low but increases with age and duration of diabetes, as cardiovascular and renal causes become more prevalent. Metformin does not increase the risk of lactic acidosis, even when other recognised precipitants are present.

Niklaus Kamber MD · Wendy A Davis MPH, PhD · David G Bruce MD, FRACP · Timothy M E Davis MRCP, DPhil, FRACP

Objective: To study the clinical contexts contributing to harmful medication errors.Design, setting and participants: A qualitative study using semi-structured interviews was conducted between March and August 2005 at Fremantle Hospital, a 450-bed metropolitan teaching hospital. Twenty-six of 46 staff members (57%) identified by pharmacy staff as having contributed to a significant medication error were interviewed. Interviews were recorded and transcribed for thematic analysis.Results: Most errors were due to slips in attention that occurred during routine prescribing, dispensing or drug administration. Knowledge-based mistakes (eg, failure to follow a protocol) also contributed to prescribing errors. Errors were more likely to occur during tasks being carried out after hours by busy, distracted staff, often in relation to unfamiliar patients. Communication problems with senior staff and difficulty accessing appropriate drug dosing information contributed to knowledge-based prescribing errors. Several medical staff were unaware they had committed an error until their involvement with our study.Conclusions: Contextual factors that contributed to slips, lapses and knowledge-based mistakes in our sample are likely to be widespread in hospitals, and their impact on medication error may be substantial. Staff need training in how to recognise and deal with error-prone clinical situations. Safe prescribing practices (eg, the absolute requirement to acquire information before prescribing unfamiliar drugs) must be emphasised. Improved access to drug information at the point of prescribing, attention to communication barriers, and increasing staffing levels in particular areas are other potential strategies for reducing error.

Pamela Nichols PhD · Tandy-Sue Copeland DipPharm · Ian A Craib MB ChB, MRCP, FRACP · Paul Hopkins · David G Bruce BSc, MD, FRACP

A woman with acute poisoning from extended-release paracetamol presented at 14.5 hours post-ingestion. The paracetamol’s absorption phase and elimination half-life appeared prolonged, with peak blood concentration occurring at 20 hours post-ingestion, requiring an extended course of intravenous N-acetylcysteine. Current treatment recommendations, based on experience with a different formulation in the United States, may not be appropriate for the Australian formulation. Clinical recordA 25-year-old woman, weighing 54 kg and with no other medical conditions, ingested 96 extended-release paracetamol tablets with suicidal intent (total dose, 64 g [1185 mg/kg]). Onset of nausea and intermittent vomiting occurred after a couple of hours, and about 9 hours later she reported the exposure to relatives. The woman was taken to a regional hospital, from where she was transferred to a tertiary hospital for management, arriving 14.5 hours post-ingestion. She was given antiemetics, and an intravenous N-acetylcysteine infusion was immediately commenced (standard regimen: 150 mg/kg over 60 min, then 50 mg/kg over 4 h, then 100 mg/kg over 16 h). A blood sample collected on admission for laboratory analyses showed a paracetamol concentration of 2235 μmol/L. As this concentration is above the treatment line on the Rumack–Matthew nomogram (Box, A), the N-acetylcysteine infusion was continued. Given the limited available data on the pharmacokinetics of extended-release preparations in overdose, blood samples were obtained about every 6 hours to guide treatment. Changes in the blood paracetamol concentration during the patient’s stay are shown in the Box. The maximum concentration (2487 μmol/L) occurred at about 20 hours post-ingestion, and the apparent elimination phase appeared biphasic on visual inspection (Box, B). The apparent elimination half-life was 9 hours between 20 and 34 hours post-ingestion, decreasing to 5 hours between 34 and 48 hours post-ingestion, suggesting that absorption was ongoing during this time. With the exception of intermittent nausea and vomiting, the patient remained clinically well. After 48 hours, the paracetamol concentration had decreased to a non-toxic (therapeutic) concentration and results of liver function tests were normal. The N-acetylcysteine infusion was ceased, and the patient was transferred to a mental health unit. Despite the large paracetamol ingestion and delayed initiation of N-acetylcysteine, no biochemical evidence of hepatotoxicity or other markers of significant toxicity were observed during admission. Mild coagulopathy was noted at 48 hours post-ingestion (prothrombin time, 19 s [reference range (RR), 9–15 s]; international normalised ratio, 1.7 [RR, 0.8–1.2]; activated partial thromboplastin time, 37 s [RR, 23–34 s]; fibrinogen, 1.3 g/L [RR, 1.5–4.0 g/L]), which is not expected to be significant in this clinical setting.1 A mild increase in total bilirubin level (peak, 28 μmol/L [RR, 2–20 μmol/L]) was also noted, but other liver function test results remained within reference ranges. DiscussionIngestion of paracetamol is one of the most common causes of acute intentional self-poisoning in Australia. Management is well described, and includes consideration of gastrointestinal decontamination and administration of intravenous N-acetylcysteine. The decision to administer N-acetylcysteine is based primarily on the plasma concentration of paracetamol and time of poisoning in relation to the treatment line on the Rumack–Matthew nomogram. Blood paracetamol concen-trations are obtained 4 or more hours after ingestion of immediate-release paracetamol preparations because absorption is largely complete by this time. Patients with a paracetamol concentration above the treatment line should be treated with this antidote, while those with a level below the line do not require treatment.2 N-acetylcysteine is administered as a 20-hour intravenous infusion in the majority of patients. These treatment guidelines reflect clinical experience with the standard immediate-release formulation of paracetamol, with or without coformulants such as codeine or dextropropoxyphene. An extended-release formulation of paracetamol was recently marketed in Australia under three proprietary labels. Each tablet contains 665 mg paracetamol; 31% of the dose is released immediately, while the remaining 69% is released over 6–8 hours at therapeutic doses.3 To determine whether N-acetylcysteine is required in an acute overdose of an extended-release formulation, the manufacturer recommends obtaining an initial paracetamol concentration either on admission or at 4 hours post-ingestion. If this concentration is below the treatment line on the nomogram, a repeat concentration should be determined 4–6 hours later. A 20-hour infusion of N-acetylcysteine is recommended if either concentration is above the treatment line.3 This approach to risk assessment is similar to that recommended for a different extended-release preparation marketed in the United States (650 mg paracetamol; 50% released immediately).4 In volunteer studies of simulated overdose with this US formulation (75 mg/kg orally), the time of peak concentration was similar to the immediate-release formulation, occurring within 4 hours.5,6 However, a study of simulated acute overdose in volunteers using the Australian product (mean dose, 73 mg/kg) found that the absorption phase is prolonged — compared with the standard immediate-release formulation, the time until the maximum concentration occurred was delayed for the extended-release formulation (0.94 v 2.83 hours).7 These differences in absorption kinetics between the Australian and US formulations might influence treatment guidelines. Reported cases of acute overdose with the US formulation have noted that the peak concentration may actually occur up to 12 hours post-ingestion, suggesting that the pharmacokinetics of extended-release paracetamol change substantially in acute overdose.8-12 To our knowledge, no cases of acute poisoning with the Australian formulation of extended-release paracetamol have previously been reported. It is therefore not known whether the current recommendations for treatment are appropriate. Absorption may be sufficiently prolonged in acute overdose of extended-release paracetamol that the peak plasma concentration occurs around 20 hours post-ingestion. In this patient’s case, the only data point earlier than this was at 14.5 hours, when the concentration was already extremely high (Box). Given the amount ingested, it seems likely that at least one of the blood samples that the manufacturer recommends obtaining within 8–10 hours of ingestion would have prompted treatment with N-acetylcysteine. However, due to the lack of data during this period for our patient, this cannot be confirmed. Of importance in this case is the prolonged apparent elimination half-life of paracetamol, such that the concentration remained elevated for 48 hours post-ingestion. This required the N-acetylcysteine infusion to be administered beyond the usual 20-hour protocol that is recommended by the manufacturer and used for immediate-release preparations. The duration of N-acetylcysteine infusion in this patient was guided by the serial blood samples taken about every 6 hours. In the absence of more informative pharmacokinetic data, it seems reasonable that serial blood samples (every 6–12 hours) should be obtained from patients presenting with ingestion of the extended-release formulation, to guide duration of treatment. The absorption kinetics observed in this patient suggest that the ingested tablets formed an aggregate (a pharmacobezoar) in the gut from which absorption is very slow. Therefore, administration of activated charcoal and, potentially, whole bowel irrigation might be considered, even in cases of delayed presentation.13 On the basis of this case, the treatment of acute poisoning with the extended-release formulation of paracetamol differs from recommendations developed for the immediate-release formulation. While it appears reasonable to continue to use the Rumack–Matthew nomogram for determining which patients require N-acetylcysteine, more than one blood sample may be required to confirm that an exposure is non-toxic. Intravenous N-acetylcysteine infusion can be initiated according to the standard regimen, and should be continued until the paracetamol concentration has decreased to a therapeutic level (less than 120 μmol/L or 20 mg/L) if the transaminase concentrations remain normal. If the transaminase levels are rising, N-acetylcysteine should be continued. This can be determined by blood samples taken every 6–12 hours, depending on the time of day, location of the patient, laboratory services available, and compliance of the patient. If the infusion is required for longer than 20 hours, this should be done by continuing the final phase of the regimen (ie, N-acetylcysteine 100 mg/kg bodyweight in 1000 mL of 5% dextrose over 16 hours) until a therapeutic paracetamol concentration is achieved. More experience in the management of acute poisoning with the extended-release formulation of paracetamol is required to better determine the optimal treatment. Linear (A) and logarithmic (B) paracetamol concentration–time profiles after ingestion of extended-release paracetamol, with reference to the treatment line on the Rumack–Matthew nomogram t1/2 = apparent elimination half-life (determined using non-linear regression with a monophasic decay, with GraphPad Prism, version 4.03 for Windows [GraphPad Software, San Diego, Calif, USA]).

Darren M Roberts MB BS · Nicholas A Buckley MD, FRACP

Objective: To study persistence and adherence with the use of common antihypertensive (AHT) medications.Design, setting and participants: Longitudinal assessment of Pharmaceutical Benefit Scheme claim records covering the period January 2004 to December 2006. We analysed a 10% random sample of all Australian long-term health concession card holders who had been commenced on an angiotensin II receptor antagonist (A2RA), an angiotensin-converting enzyme inhibitor (ACEI) and/or a calcium channel blocker (CCB), but for whom no AHT medication had been dispensed in the previous 6 months.Main outcome measures: Proportion of patients failing to fill a second prescription; median persistence time with medication (ie, non-cessation of therapy); persistence with medication over 33 months; median medication possession ratio (MPR, defined as the proportion of prescribed medication actually consumed by patients persisting with treatment).Results: The database yielded information relating to 48 690 patients prescribed AHT medication. Nineteen per cent of patients failed to collect a second prescription. The median persistence time was 20 months. The data were little different from the population average with respect to A2RAs or ACEIs, but persistence was 57% poorer with respect to CCBs (log-rank P < 0.001) (28% of patients prescribed CCBs failed to collect a second prescription; median persistence time, 7 months). There were differences in persistence between individual drugs in the respective classes, the best outcomes being with candesartan and telmisartan (A2RAs; 10%–20% better), perindopril (ACEI; 25% better) and lercanidipine (CCB; 25% better). Median MPRs were generally around 100%, indicating that most patients who collected prescriptions also showed good adherence to treatment regimens.Conclusion: There is an ongoing problem of poor persistence with commonly used AHT medications. This may represent a diminished opportunity for cardiovascular disease prevention.

Leon A Simons MD, FRACP · Michael Ortiz BPharm, PhD · Gordon Calcino BA, GradDipMedStats