Pharmacology

To the Editor: I would like to comment on two articles that appeared recently in the MJA. “Doctors behaving badly?”1 was an anticlimax. It was not, as would be expected, an exposure of misconduct by doctors, but dealt with the potential conflict of interest that occurs when they interact with the pharmaceutical industry. No evidence of doctors “behaving badly” was provided, yet a solution to this potential problem was proposed — “disclosure” (ie, yet more paperwork), accompanied by a disclaimer that this was unlikely to work. This is an important issue, but the content of the article cannot justify such a misleading title. I can only assume it was the result of editorial intervention, in which case there is some hypocrisy at work, given that the inside front cover and the outside back cover of the same issue of the Journal are taken up with full-page drug advertisements, and within, a $10 000 prize was offered for the best original research article published in the Journal (sponsored by a drug company). The second article, From the Editor’s Desk “Tilting at titles”,2 which cited the dreaded Australian values, suggested that titles such as “doctor” should be trashed altogether and replaced by an introduction such as “Hello. I’m Jean Smith. I am a urologist and together we will confront your prostate problem” — a statement that is unlikely to give great confidence to the average digger. Doctor Samuel Johnson put this argument to rest in 1775:3 What is implied by the term Doctor is well known. It distinguishes him to whom it was granted, as a man who has attained such knowledge of his profession as qualifies him to instruct others. A Doctor of Law is a man who can form lawyers by his precepts. A Doctor of Medicine is a man who can teach the art of curing diseases. My concern is that there appears to be an editorial assumption that doctors are preoccupied with titles and are willing to treat patients unethically for a few glasses of Kooyong Pinot Noir and a good feed. This might be good press, but not in the MJA. Perhaps some disclosure is required. To return to Johnson: There are but two reasons for which a physician can decline the title of Doctor of Medicine, because he supposes himself disgraced by the doctorship, or supposes the doctorship disgraced by himself.

Padraic J Grattan-Smith

In reply: We agree with Dietz that unbiased sources of information about new therapeutic options are increasing, and many are available electronically. Virtual Mentor, the American Medical Association’s ethics journal, has suggested reducing drug company influence on doctors’ prescribing by stopping companies paying for continuing medical education,1 and the Australian Competition and Consumer Commission is exposing this issue. Fisher recommends full and frank disclosure of links with industry, but he does not state to whom these disclosures should be made. The revised Royal Australasian College of Physicians guidelines recommend that employing hospitals create a Conflict of Interest Committee to receive employees’ declarations, and to advise when a duality of interest may be construed as a conflict of interest.2 The Box shows the disclosure statement that one of us displays in his consulting room, copies of which are sent to referring doctors when letters are written about patients. Grattan-Smith felt the title of our article was misleading. However, the title is stated as a question precisely because the assessment of professional behaviour, and particularly the assessment of possible conflicts of interest, is a matter of considerable dispute. It is clear that the relationships that doctors have with industry may constitute bad behaviour in the eyes of some, including the editorial writer in the Sydney Morning Herald.3 We do not, as Fisher suggests, contend that interaction with the pharmaceutical industry inevitably compromises prescribing decisions, but agree with him that full and frank disclosure, rather than the simple notification that a relationship exists, offers at least some reassurance that the possibility of influence is being acknowledged and managed. Collins asserts both that we hinted that doctors who attend educational symposia organised by pharmaceutical companies and subsequently order the product are acting improperly, and that doctors attend such meetings for the free food and wine. We do not believe that either statement is correct, and accept that the choices that doctors make to attend such events are generally motivated not by gluttony, but by a range of complex factors, including a desire for education, clinical feedback and professional collegiality. Nothing in the interaction between doctors and the pharmaceutical industry is simple. Although the editorial from the Sydney Morning Herald suggests that avoidance is the simplest response to this dilemma, we would argue that such a complex issue requires a complex response and that support for adequate disclosure should be a necessary (but insufficient) component of the medical profession’s response, if it hopes to maintain the high regard in which it is held by the Australian public. Example of a disclosure statement displayed in the consulting room and enclosed with letters about patients Disclosure of interests that might influence my prescribing and treatment of cancer patients Pharmaceutical companies I have received no honoraria or financial support for more than 10 years from pharmaceutical companies for: serving on advisory boards consultancies providing patients' data relating to drug use enrolling patients in a clinical trial speaking at a company-sponsored event During the past 10 years I have not: received financial or other support from pharmaceutical companies for my research activities or staff received travel, registration, accommodation or other support from pharmaceutical companies for me or my staff to attend regional, national, or international conferences or meetings received research support from pharmaceutical companies received personal gifts from pharmaceutical companies attended company-sponsored meetings, launches of new drugs I am not a principal investigator on trials supported by pharmaceutical companies. I do invite eligible patients to consider entry on some pharmaceutical company sponsored trials, but I derive no personal financial benefit. I do not accept free samples of drugs from pharmaceutical companies. I do not welcome visits from representatives of pharmaceutical companies. Martin Tattersall

Martin H N Tattersall · Ian H Kerridge

Objective: To study drug prescribing by brand name versus generic name in an Australian teaching hospital.Results: Overall, 53% of drugs were prescribed by brand name. Brand names were preferred when they were shorter and easier to remember and spell, when there was only one brand on the market, and when the brand name ended in an x.Conclusion: Doctors might be encouraged to prescribe generically if generic names were devised using the same principles marketers use for devising brand names.

Jonathan Bromley MB ChB · Nicholas A Buckley MD, FRACP

Off-label prescribing is the prescription of a registered medicine for a use that is not included in the product information. The practice is common, with rates up to 40% in adults and up to 90% in paediatric patients. Off-label prescribing is not illegal and may sometimes be clinically appropriate, but is associated with a number of clinical, safety and ethical issues. To date, no explicit guidance has been available to help clinicians assess appropriateness in off-label prescribing. We describe the development of a guide for clinicians, policymakers and funders of health care in evaluating the appropriateness of medicines proposed for off-label use. Three broad categories of appropriate off-label use are identified:off-label use justified by high-quality evidence; use within the context of a formal research proposal; and exceptional use, justified by individual clinical circumstances. An appropriate process for informed consent is proposed for each category. If there is no high-quality evidence supporting off-label use, and the medicine is not suitable for exceptional or research indications, its use is generally not recommended. This will reduce inappropriate use, enhance patient safety by reducing exposure to unnecessary risk, and may stimulate more clinically relevant medicines research.

Madlen Gazarian MB BS(Hons I), MSc(ClinEpi), FRACP · Maria Kelly BPharm, DipEd · John R McPhee BCom(Hons)(LegStud) · Linda V Graudins BPharm, DipHospPharm, FSHP · Robyn L Ward MB BS(Hons I), PhD, FRACP · Terence J Campbell MD, PhD, FRACP

To the Editor: Since my article on medical abortion was published in the Journal,1 I have received some information from colleagues, and from women who have undergone abortions, about the current practice of medical abortion in Australia. I believe this may be of interest to readers of the MJA. More than a dozen practitioners have informed me that they have used misoprostol or methotrexate/misoprostol combinations to induce early abortion (before 9 weeks’ gestation) outside of hospitals, and a number of women have reported undergoing such abortions. The number of cases involved in this anecdotal sample is at least several hundred annually. Induced abortion using methotrexate/misoprostol was practised in the United States up until the introduction there of mifepristone/misoprostol regimens in 2000.2,3 There is wide experience of this drug combination reported in the medical literature, and the consensus is that, in the short term at least, it is safe and effective, although less effective than the mifepristone/misoprostol combination.2-4 Both drugs are licensed for purposes other than abortion in Australia, as elsewhere (misoprostol for treatment of gastric ulceration; methotrexate as a cytotoxic agent, and for psoriasis and rheumatoid arthritis), but the use of drugs “off-label” is an acknowledged medical practice.5 Misoprostol in particular is widely used in obstetrics for cervical ripening and treatment of postpartum haemorrhage.5 These early abortions take place “under the radar” in the sense that there is no specific Medicare item number; the administration of the drugs occurs in the course of a standard consultation. There is nothing irregular about this, but it does mean that the inaccurate data we currently have on the number of abortions performed in Australia are even more inaccurate than initially thought. It should be noted also that misoprostol alone or in combination with other prostaglandins is being used in Australian hospitals, as overseas, in a more evident manner for the induction of late abortion in cases of severe fetal abnormality detected after 13 weeks’ gestation.5 As well, methotrexate is commonly used in the treatment of early, unruptured ectopic pregnancy, in doses well below those used in oncology. The communications I have received on the subject lead me to believe that medical abortion is currently extensively practised in Australia.

Caroline M de Costa

To the Editor: The Experimental Drugs Section (EDS) of the Drug Safety and Evaluation Branch of the Therapeutic Goods Administration (TGA) administers the clinical trial notification (CTN) and clinical trial exemption (CTX) arrangements for unapproved medicines used in clinical trials. These arrangements provide an avenue of “exemption”, whereby medicines that have not been approved for marketing in Australia are able to be supplied to patients within the context of a clinical trial approved by a human research ethics committee working under the guidelines of the Australian Health Ethics Committee (a subcommittee of the National Health and Medical Research Council). Although these arrangements cover only clinical trials in which unapproved medicines are used, a substantial number of such trials are carried out in Australia each year. (Clinical trials using unapproved medical devices that also use the CTN/CTX arrangements are administered by the TGA’s Office of Blood, Devices and Tissues and are not included in these statistics.) The EDS often receives queries from stakeholders requesting some form of basic statistical data with respect to clinical trial activity in Australia. The EDS intends to begin use of a new database in 2007 for recording CTNs and CTXs notified to the TGA. It is hoped that this will enable us to publish a basic statistical subset of clinical trial information on an annual basis. As a prelude to this capability, we have manually compiled a few simple statistics on clinical trials notified within the financial year 2004–05. Box 1 breaks down the trials conducted into various body systems or treatment areas. There were 739 separate clinical trials of unapproved medicines commenced over the 1-year period. As many of these are multicentre trials, there are a much greater number of actual trial sites involved. (A good measure of the number of trial sites is simply the raw CTN notification figures, numbering 2776 for the same period.) Box 2 breaks down the trial numbers into the various phases of drug development. Although this is not relevant to all trials, these figures give an indication of the main areas of drug development research currently being conducted in Australia. Given the number of multicentre trials being carried out, we did not think it useful to break down trial numbers by state and territory. We trust that these data convey some idea of current clinical trial activity with respect to unapproved medicines in Australia. 1 Clinical trials of unapproved medicines, by body system and therapeutic area, July 2004 to June 2005* Body system/therapeutic area Number of trials Neoplastic disorders 252 Cardiovascular system 78 Central nervous system 71 Immunology 64 Endocrine and metabolic disorders 60 Infections and infestations 42 Musculoskeletal system 36 Genitourinary system 28 Analgesia 20 Respiratory system 16 Alimentary system 15 Skin 13 Eye 7 Surgical preparations 5 Nutrition 3 Ear 2 Unspecified† 27 Total 739 * Based on clinical trial notification and clinical trial exemption data. † “Unspecified” refers either to trials that were not directed toward a body system or trials in which the system could not be determined from the information on the clinical trial notification form. 2 Clinical trials of unapproved medicines, by trial phase, July 2004 to June 2005* Trial phase Number of trials Phase 1 87 Phase 2 259 Phase 3 277 Phase 4 53 Other† 63 Total 739 * Based on clinical trial notification and clinical trial exemption data. † “Other” denotes trials that were not nominated in a particular phase or to which these designations were not relevant.

Jonathon Rankin · Jenny Mason · Neil Kottege · Natasha Y Andersson

We need to know if and when this organism arrives in Australia There is world-wide concern about a new infectious diseases threat following the recent emergence, in Canada,1 the United States,2 and now Europe,3 of a highly virulent strain of Clostridium difficile (called PCR ribotype 027 in Europe and NAP1 in the US). Rates of detection of C. difficile have risen dramatically: at the Centre Hospitalier Universitaire de Sherbrooke in Quebec Province (population, 7.5 million in 2003) in Canada, the incidence among patients aged ≥ 65 years increased from 102 per 100 000 population in 1991 to 867 per 100 000 in 2003.4 C. difficile disease has been more severe, with the proportion of complicated cases in Sherbrooke increasing from 7.1% (12/169) in 1991–92 to 18.2% (71/390) in 2003,4 suggesting a more virulent strain of the organism is emerging. The Quebec Health Ministry reported a total of 7004 cases of C. difficile infection between 1 April 2003 and 31 March 2004, with 1270 deaths (a crude mortality rate of 18%).5 Loo and colleagues1 reported an attributable mortality of greater than 10% in those aged over 60 years — a remarkably high figure. C. difficile is the most commonly diagnosed cause of infectious hospital-acquired diarrhoea in developed countries. Most patients with C. difficile-associated diarrhoea have been exposed to antimicrobials that reduce “colonisation resistance” of the large intestine, allowing subsequent infection with C. difficile. Acquisition of C. difficile is facilitated by its ability to form spores that are resistant to many disinfectants, so that it remains viable in the hospital environment for long periods of time. Toxigenic isolates of C. difficile usually produce two toxins, toxin A (tcdA, an enterotoxin) and toxin B (tcdB, a cytotoxin), which are considered the major virulence factors.6 Some strains of C. difficile produce an additional toxin called binary toxin (CDT). This was first reported in 1988 but not considered important until now.1,2,7 Binary toxin producers make up the majority of the C. difficile strains isolated in the recent large outbreaks of the disease overseas.1,2 A correlation between binary toxin production and severity of diarrhoea has been demonstrated,7 and more community-acquired C. difficile-associated diarrhoea was found to be caused by binary toxin producers. To determine the effects of binary toxin alone, researchers have characterised C. difficile strains that only produce binary toxin (ie, tcdA– tcdB– CDT+ strains). Although supernatants from tcdA– tcdB– CDT+ strains of C. difficile caused fluid accumulation in a rabbit ileal loop after concentration and trypsinisation, challenge of clindamycin-treated hamsters with these strains resulted in colonisation but not diarrhoea or death, suggesting that binary toxin by itself may not cause disease.8 The significance of binary toxin clearly needs further investigation. A second important feature of this “new” organism is that it produces more toxin A and B than other strains. Production of these toxins in C. difficile is encoded by the tcdA and tcdB genes, respectively. These two genes form part of a highly stable pathogenicity locus (PaLoc), a region of the chromosome that also includes the genes tcdC, tcdR and tcdE. Toxin A variant strains fail to produce toxin A detectable by enzyme immunoassay because of a deletion in the tcdA gene. The tcdC gene is a down-regulator of toxin A and B production. The PCR ribotype 027/NAP1 strain has a deletion in the tcdC gene resulting in it no longer down-regulating, and strains produce toxin throughout the log phase of growth instead of just in the stationary phase.9 Non-toxigenic strains lack the PaLoc. The third important feature of these strains is that they are resistant to fluoroquinolone antibiotics, and excessive fluoroquinolone use appears to be a contributing factor in the recent outbreaks.10 C. difficile develops resistance to quinolones soon after exposure.11 Both the newer fluoroquinolones, such as gatifloxacin and levofloxacin, and, somewhat surprisingly, the older one, ciprofloxacin, have been implicated.10 Ciprofloxacin has always been thought of as a low-risk antimicrobial for inciting C. difficile-associated diarrhoea.12 However, once C. difficile becomes resistant to the later fluoroquinolones, it is also resistant to ciprofloxacin, and the resistance trait may become more important for initiation of disease. Another significant finding from the outbreaks reported overseas is the marked variation in C. difficile-associated diarrhoea rates among different age groups. While older people have always been at increased risk, due primarily to decreased host defences, rates in those ≥ 65 years of age have increased dramatically since 2000.13 One possible novel risk factor is exposure to gastric acid suppressants, such as histamine-2 receptor inhibitors or proton pump inhibitors. These agents have been more commonly prescribed in recent years and may be linked with the increased rates of C. difficile-associated diarrhoea in the community,14 although some case–control studies with hospital patients show no association.1,10 The importance of community onset C. difficile-associated diarrhoea was highlighted recently by a report of severe cases in previously healthy people and peripartum women.15 Is this organism in Australia yet? We do not really know because molecular typing is required to distinguish the outbreak strain from others, and this is rarely done. However, it is probably not here — there have been no reports of more severe C. difficile disease, and Australia uses less of the most incriminated fluoroquinolones than other parts of the world. A major problem is that many laboratories in Australia have moved away from culturing for C. difficile, and to save money and time are using enzyme immunoassay kits. C. difficile toxin A enzyme immunoassay kits will not detect strains that don’t produce toxin A, and toxin A + B kits will not detect binary toxin producers. This diagnostic problem is compounded by the fact that laboratories servicing general practitioners often do not examine faecal samples for C. difficile because of the continuing misconception that C. difficile-associated diarrhoea is a hospital problem only. Given the high mortality rate in recent C. difficile-associated diarrhoea cases overseas, it is important that we know if and when this organism arrives in Australia. How could this be achieved? Should C. difficile-associated diarrhoea become a notifiable disease in Australia, as happened in Canada in response to the outbreak there? This is unlikely to be particularly helpful without molecular typing to distinguish the outbreak strain. Targeted surveillance, with one or two laboratories being funded periodically to type a representative sample of isolates of C. difficile from a variety of Australian hospitals, would seem a more reasonable approach. Finally, the value of sensible policies regarding antibiotic use, and good infection control staff and procedures, cannot be over-emphasised. Antibiotic restriction can be effective in reducing C. difficile-associated diarrhoea.16 In response to the outbreak in Canada, the Quebec government recently provided CA$20 million to hospitals in the province to buy additional equipment and hire infection control staff.17 In the long term, such initiatives are likely to have an impact not only on C. difficile-associated diarrhoea but also on other infection control problem organisms, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp.

Thomas V Riley PhD, FRCPath, FASM

To the Editor: In an editorial in the 3 April 2006 issue of the Journal,1 Roughead and Lexchin estimated the annual incidence of adverse drug events (ADEs) in patients presenting to general practitioners, based on our data presented in the same issue.2 Calculating the incidence of ADEs from general practice encounter data is fraught with difficulties. Roughead and Lexchin’s calculation depends on all general practice patients having an equal chance of being in the sample. This would only hold true if all patients attended their GP an equal number of times. However, in our study, the age distribution of patients with ADEs shows that they are more likely to belong to older patient groups with a much higher than average general practice attendance rate. They thus represent a smaller proportion of all general practice patients, as their chance of being in the sample is much higher. Adjusting for the age and sex distribution results in an estimated incidence of about 1.6 million people. Further, these 1.6 million would, if asked, have reported an ADE in the previous 6 months. This cannot be extrapolated to an annual incidence of ADEs. The annual incidence figure could in fact be larger than that suggested by Roughead and Lexchin. We believe that recurrent monitoring of ADEs in patients attending general practice is a useful way of measuring the impact of the interventions suggested by Roughead and Lexchin, regardless of the difficulty of extrapolating to population incidence.

Graeme C Miller, Associate Professor and · Helena C Britt · Lisa Valenti · Stephanie Knox

To tackle this problem we need a systems approach involving multiple strategies An article in this issue of the Journal by Miller and colleagues1 provides further evidence of the magnitude and seriousness of the problem of adverse drug events (ADEs) in general practice. Their study highlights our ongoing failure to address the problem of ADEs — medication-related incidents that cause patient harm. “Consumer Medicine Information needs to be routinely used in medical encounters, so that patients can recognise ADEs and know what to report to their GP . . .” Each year in Australia, about 17.5 million people make 95 million visits to their general practitioner.2 Based on Miller et al’s estimate — that 10.4% of patients attending general practice experience an ADE — almost 2 million people have an ADE annually. Moreover, their findings show that these ADEs are not trivial, with about 1 million being moderate or severe and 138 000 requiring hospitalisation, a finding consistent with previous estimates.3 Many of these ADEs are preventable, although the exact proportion of preventable events can be debated. There have now been more than 30 Australian studies estimating the number of ADEs in different settings.3 It is clear that counting is not enough — it is time for action, but what can be done? Every developed country is trying to cope with the problem of ADEs. Australia has many structures and initiatives in place to reduce the occurrence of ADEs, and preventing ADEs necessarily involves them all.3 Regulatory agencies, the medicines industry, quality use of medicines organisations and information providers, safety and quality organisations, professional bodies, health professionals and consumers can all assist. Prevention of ADEs cannot occur without better knowledge. It is noteworthy that the Therapeutic Goods Administration has adopted the European Medicines Agency guideline on pharmacovigilance planning. Increased pharmacovigilance, including observational studies, will require a substantial increase in resources. In Canada, less than 10% of the budget for drug regulation is allocated to issues concerning marketed products, including safety. Yet, in 50% of new drugs, serious adverse drug reactions are detected after market approval.4 We need systems that can deal with the reality that only limited numbers of highly selected patients are studied before a drug is marketed. Regulators may have to consider restricting prescribing of new medications if they have limited safety information, particularly when equally efficacious therapy is available. New systems for detecting early signals of potential adverse drug reactions in expanded populations could complement the current reporting system for adverse drug reactions. An example is the Drug Safety Research Unit in the United Kingdom, which captures information on the first 10 000 patients using a newly marketed drug.5 We need to capitalise on and expand the importance and significance of consumer reporting. Instead of relying on pharmaceutical representatives (as a considerable proportion do), health professionals require easily accessible, balanced information sources that can be used in a timely manner for their clinical decisions.6 Pharmaceutical representatives frequently fail to supply safety information,7 and their promotional techniques may lead to more widespread use of new medications. In Canada, there were almost 50 000 visits by pharmaceutical representatives to doctors for rofecoxib, and over 1 million samples were handed out in its first year on the market. This helped increase rofecoxib prescriptions by 125% in the following year and, in Ontario, led to increased hospital admissions for gastrointestinal bleeds.8 By the time rofecoxib was withdrawn for safety reasons, it accounted for 40% of Australian expenditure on non-steroidal anti-inflammatory agents,9 possibly exposing excessive numbers of people to unnecessary risk. The activities of pharmaceutical representatives are regulated by Medicines Australia’s code of conduct governing pharmaceutical promotion.7 Medicines Australia must find ways to improve the provision of information to health professionals by the medicines industry through active monitoring of the code. If this is not possible, other methods of regulating promotion may need to be considered. Leadership from professional bodies and quality use of medicines agencies is required. Promoting balanced information sources, as a key element of professional standards, may assist in preventing ADEs. Activities sponsored by the National Prescribing Service also should have just as much of a role in preventing ADEs as they do in promoting appropriate management options. Developing a culture of safety in community practice will require leadership from the newly established Australian Commission on Safety and Quality in Health Care. We need a no-blame culture, supporting safer systems in practice, as well as incident monitoring, with timely feedback to practitioners and consumers. Medication safety improvement toolkits, similar to those developed for hospital practice,10 may be suitable for community practice, but their effectiveness in this setting must first be assessed. A study monitoring all incidents of potential or actual harm to general practice patients, including ADEs, found that the most common contributing factor was poor communication between practitioners and patients.11 Professional bodies and medical schools might help by providing educational programs to improve GPs’ communication skills about ADEs. Failure to recognise the signs and symptoms was another contributing factor to incidents.11 Consumer Medicine Information needs to be routinely used in medical encounters, so that patients can recognise ADEs and know what to report to their GP, even if he or she fails to ask. Case-conferencing and reviewing patients’ medication at home have the potential to reduce ADEs.3 These services are funded, but still underutilised. Poor communication between health professionals was another common cause of incidents,11 highlighting the need for better information systems in community practice. It is health professionals, in consultation with patients, who must identify ADEs in practice. Therefore, computerised systems should alert GPs when patients receive new prescriptions and identify all medications they are receiving from any provider.12 This knowledge can trigger GPs to ask about ADEs when patients first return after a new medication has been prescribed, as this is the interval in which most ADEs occur. Knowledge of what their patients are taking can help GPs flag which of their patients are at high risk; ADEs in this group are more likely to be fatal.13 If we do not develop a culture of safety, we will continue to have an extra 140 000 hospitalisations per year caused by ADEs. Although ADEs commonly occur in general practice, preventing them is not solely the responsibility of GPs. We need a systems approach involving multiple strategies to tackle this problem. Otherwise, patients will continue to suffer needlessly from ADEs.

Elizabeth E Roughead BPharm, MAppSci, PhD · Joel Lexchin MSc, MD

Although clinical trials of the antipsychotic amisulpride revealed no cardiac adverse effects, four patients with severe cardiac toxicity after overdose were reported to Australian poisons information centres in 2004–2005. All four had QT prolongation over 500 ms, two had rate-dependent bundle branch block, two developed torsades de pointes, and one died after cardiac arrest. Pending further studies, we recommend electrocardiogram assessment until at least 16 h after amisulpride overdose and, if QT interval is prolonged, cardiac monitoring until the patient is clinically well and conduction intervals are normal. Clinical recordsPatient 1A 39-year-old woman presented to a rural hospital 2 hours after ingesting 24 g of amisulpride (therapeutic dose, 50–1200 mg/day), and unknown quantities of nitrazepam and diazepam. On examination, she was drowsy with a Glasgow Coma Score (GCS) of 14, heart rate of 100 beats per min (bpm), and systolic blood pressure of 70 mmHg. Activated charcoal (50 g) and intravenous normal saline (2 L) were administered, and the hypotension resolved. She was transferred to a tertiary emergency department. On arrival, 7 h after the overdose, her condition remained unchanged. An electrocardiogram (ECG) showed sinus rhythm, heart rate of 67 bpm, QRS interval of 128 ms, prolonged QT interval of 560 ms and bifid T waves (Box 1). Twelve hours after ingestion, her level of consciousness decreased (GCS, 4), and broad complex tachycardia was observed on the electrocardiography monitor and subsequent ECG. No hypotension was recorded. She was intubated, hyperventilated, given NaHCO3, magnesium and calcium gluconate, and transferred to the intensive care unit. The QRS interval narrowed to 112 ms within 4 h, but the QT interval remained prolonged for another 12 h. Patient 2A 40-year-old man presented to a hospital emergency department after ingesting amisulpride (32 g), mirtazapine (300mg), valproate (7 g), amitriptyline (1.25 g) and omeprazole (unknown quantity). On arrival, he had a GCS of 14, heart rate of 90 bpm, and blood pressure of 120/70mmHg. An ECG at presentation showed sinus rhythm with a heart rate of 90 bpm, QT interval of 460ms and bifid T waves. He was admitted to the intensive care unit. About 12.5 h after ingestion, he developed a broad complex tachycardia with rate 120 bpm (left bundle branch pattern), but remained haemodynamically stable. The QRS complex did not significantly narrow when the patient was treated with a bolus of NaHCO3. An NaHCO3 infusion was started, and he was intubated and ventilated. Eighteen hours after ingestion, the QT interval was 560ms, with heart rate of 79 bpm and a normal QRS interval (Box 2A). About 29 h after ingestion, the patient developed pulseless torsades de pointes, but sinus rhythm with a QT interval of 560ms was restored after a single direct current cardioversion shock (Box 2B). He had a second episode of torsades de pointes 32.5 h after ingestion, and an episode of ventricular tachycardia 34 h after ingestion. By 5 days after the overdose, the QT interval had shortened to 360ms (Box 2C). Serum amisulpride level was measured by high performance liquid chromatography using a modified method of Bohbot et al,1 and was 23.2 mg/L at 12.5 h after ingestion. Patient 3A 39-year-old woman presented to hospital about 12 hours after ingesting amisulpride (16–24 g). At presentation, she was drowsy, with a heart rate of 59 bpm and blood pressure of 81/44 mmHg. She was given 1 L of intravenous fluid. An ECG demonstrated sinus rhythm with heart rate of 62 bpm, and QT interval of 600 ms. Two hours after presentation, her condition deteriorated rapidly, with a GCS of 7, heart rate of 99 bpm, and blood pressure of 109/42 mmHg. Multiple intubation attempts were made, and the oxygen saturation fell, but recovered between intubation attempts (91% after 25 minutes). She was successfully intubated 28 minutes after her condition deteriorated. She then developed bradycardia, pulse became undetectable, and cardiac pulmonary resuscitation was begun 30 minutes after the deterioration. Despite resuscitation, she died 17 minutes later. No ECG or telemetry traces were recorded during the resuscitation. Postmortem toxicology analysis performed by the Division of Analytical Laboratories, Sydney, was made available by the coroner: amisulpride (140 mg/L) and fluoxetine (0.2 mg/L) were found in serum, but no tricyclic antidepressants or drugs of abuse. Patient 4A 22-year-old man presented to hospital 2 h 20 min after ingesting amisulpride (4.6 g). There was no family history of sudden death or cardiac arrhythmias. On arrival, he was alert and oriented, had a heart rate of 69 bpm, and blood pressure of 136/61 mmHg. The ECG showed sinus rhythm, heart rate of 63 bpm, and QT interval of 600 ms (Box 3A). Repeat ECGs showed QT intervals between 580 ms and 640 ms. Seven hours after ingestion, he had an episode of pulseless torsades de pointes (Box 3B). Cardioversion was achieved with a 200 J direct current shock. As the QT interval remained prolonged (600 ms), therapy with isoprenaline (60 μg/h) was begun. After an hour, the dose was decreased to 30 μg/h and continued for 20 h. The patient had a second episode of torsades de pointes almost 24 h after ingestion. This was asymptomatic and resolved spontaneously within 30 seconds. He had bradycardia (heart rate, 40 bpm) for 24 h after isoprenaline was ceased. The QT interval gradually decreased to 460 ms at 62 hours after ingestion and was 360 ms 3 weeks later (Box 3C). Box 3D illustrates the time course of serum amisulpride concentration and absolute QT interval over the first 60 h after ingestion. DiscussionAmisulpride is an antipsychotic that has been available on the Pharmaceutical Benefits Scheme in Australia since 2003. A benzamide derivative, it is well tolerated, with relatively few side effects and minimal behavioural toxicity in doses with antipsychotic effect.2 Amisulpride overdoses were first reported to Australian poisons information centres in early 2004, and about 60 telephone calls about amisulpride overdose were made from hospitals to the New South Wales and Western Australian Poisons Information Centres between July 2004 and June 2005, including the four cases reported here. A review of clinical trials of amisulpride reported that it had no effect on the ECG in therapeutic doses and did not produce arrhythmias.3 There are no published data on animal toxicity. It was therefore surprising that such severe effects were seen in overdose. There were a few published reports of overdose in the literature before its introduction in Australia,4,5 and a reference to QT prolongation and torsades de pointes in the manufacturer’s product information, but little indication that overdose could have effects as severe as those reported here, including the first cases of torsades de pointes. During the past decade, there have been sporadic reports of amisulpride poisoning, including two deaths.4-9 Significant QT prolongation was reported in a recent series of eight cases with limited clinical details9 and in another two cases, where it was suggested to be related to hypocalcaemia.7 A patient who suffered multiple cardiac arrests has also been reported. Although torsades de pointes was suspected, it was not confirmed on ECG.6 These cases demonstrate that amisulpride overdose may be associated with clinically significant QT prolongation. The absolute QT interval was over 500ms in all four of our cases and close to 600ms in three. Amisulpride overdose was associated with ECG-confirmed torsades de pointes in two cases and a cardiac arrest resulting in death in another. Unfortunately, no ECG was available to determine if torsades de pointes had occurred in that patient. The magnitude of the effect on the QT interval and the number of cases of torsades de pointes from about 60 cases of overdose reported to the Poisons Information Centres suggests that amisulpride overdose is associated with significant cardiac toxicity. Amisulpride also caused a ratedependent bundle branch block in two cases. Although this coincided with a decreased level of consciousness, it was unlikely to have caused it. Drowsiness occurred in three of the four patients and profound sedation in two, suggesting that amisulpride also causes central nervous system depression. Amisulpride was detected in high concentrations in three of our patients — three to four orders of magnitude above that reported in therapeutic studies.2 In these studies, the peak concentration after a dose of 50mg of amisulpride was 55.7 µg/L (SD, 3.7). Citalopram is another drug that appeared to cause minor or no cardiac effects in clinical trials of therapeutic doses,10 but in overdose has been associated with moderate QT prolongation,11,12 rate-dependent bundle branch block and, rarely, torsades de pointes.13,14 A pharmacokinetic and pharmacodynamic model of citalopram intoxication clearly demonstrated a dose-dependent relationship between drug concentration and QT interval.12 Fortunately, citalopram-associated torsades de pointes appears very rare, with only two published reports. This case series underlies the importance of overdose surveillance by poisons information centres after the introduction of new drugs, or the introduction of new formulations. Clinicians should be aware that amisulpride overdose can cause severe cardiac toxicity, including QT prolongation, bundle branch block and torsades de pointes. Until the risk assessment can be further refined, we recommend assessing the ECG until at least 16 hours after ingestion of an amisulpride overdose. If there is QT prolongation, we recommend cardiac monitoring in a critical care area until the patient is clinically well, and conduction intervals are normal. 1 Electrocardiogram changes in Patient 1 Electrocardiogram 7 hours after ingestion of amisulpride showed sinus rhythm with a prolonged QT interval of 560 ms. 2 Electrocardiogram changes in Patient 2 A: Eighteen hours after ingestion, the electrocardiogram (ECG) showed prolonged QT interval of 560 ms. B: About 29 hours after ingestion, the ECG showed segment of torsades de pointes, before direct current cardioversion and recovery of sinus rhythm. C: Five days after the overdose, ECG showed shortening of QT to 360 ms. 3 Electrocardiogram changes and amisulpride levels in Patient 4 A: Prolonged QT interval on admission (2.3 hours after ingestion). B: Torsades de pointes 7 hours after ingestion. C: A normal QT interval D: Plasma amisulpride concentration (logarithmic scale) and absolute QT interval over the first 60 hours after ingestion.

Geoffrey K Isbister FACEM, MD · Lindsay Murray MB BS, FACEM · Sally John MB BS · L Peter Hackett MRSC · Tedo Haider MB BS · Phebe O'Mullane MB BS · Sophie Gosselin MD · Frank Daly MB BS, FACEM

Kari A J Jarvinen,* Bradley J McCall,† Clare B Nourse,‡ Joe G McCormack,§ Martyn H Tilse¶ * Senior Public Health Registrar, † Public Health Medical Officer, Communicable Disease Control, Brisbane Southside Public Health Unit, 39 Kessels Road, Coopers Plains, QLD 4108; ‡ Paediatric Infectious Diseases Physician, § Director of Infectious Diseases, ¶ Director of Microbiology, Mater Health Services, South Brisbane, QLD. kari_jarvinenAThealth.qld.gov.au To the Editor: Pertussis continues to be a significant public health problem in Australia. Children aged under 1 year are most at risk from severe, life-threatening complications from the disease.1 Traditionally, erythromycin has been the drug of choice for treatment of cases and prophylaxis in selected contacts. However, its use in neonates is known to carry a risk of infantile hypertrophic pyloric stenosis.1,2 Its propensity to cause QT prolongation and ventricular arrhythmias is also well described.2,3 Both azithromycin and clarithromycin have been recently recommended as suitable alternatives for management of pertussis.2,4 The US Centres for Disease Control now regard azithromycin as the agent of choice for neonates less than 1 month of age.1 There is evidence suggesting azithromycin has less pro-arrhythmic potential than erythromycin or clarithromycin.5,6 Azithromycin does not interact significantly with the hepatic cytochrome P450 system and has less potential for significant drug interactions than other macrolide antibiotics.3,5,6 Azithromycin and clarithromycin also require less frequent administration (1–2 doses per day) and shorter treatment regimens (5–7 days) than erythromycin. In Australia, roxithromycin is the most widely prescribed macrolide antibiotic. However, there are no clinical studies on its effectiveness in pertussis, and in-vitro sensitivity studies suggest it may be inferior to erythromycin. Thus, roxithromycin cannot be recommended in pertussis.4 Updated versions of Australian antibiotic guidelines to be released later this year will recommend azithromycin for pertussis treatment and prophylaxis. However, access to azithromycin for this purpose in Australia is currently limited by the restrictions placed on prescribing through the Pharmaceutical Benefits Scheme (PBS). Azithromycin is currently approved for Chlamydia trachomatis urethritis, cervicitis and trachoma. Pertussis is an approved indication only for the use of 500 mg tablets under the Repatriation PBS. This restriction has important implications for the effective and safe management of pertussis in Australia. Widespread use of newer macrolides in the community is not advisable because of the propensity of macrolides to induce antibiotic resistance, and their greater cost. However, for pertussis infection, Australians need to be able to access agents such as azithromycin. PBS restrictions for this indication need to be revised, for both tablet and liquid formulations.

Kari A J Jarvinen · Bradley J McCall · Clare B Nourse · Joe G McCormack · Martyn H Tilse

The reduction in the incidence of contralateral breast cancer in women treated with adjuvant tamoxifen provided a model for prevention using endocrine agents. Oestrogen-receptor-positive cancer can be prevented with tamoxifen, but side effects limit its clinical utility, and the risk–benefit ratio is not sufficiently high to routinely recommend tamoxifen as a preventive agent. Agents being evaluated in prevention trials include raloxifene and the aromatase inhibitors; these are expected to be at least as effective as tamoxifen and to have fewer side effects. Core needle biopsy (providing histological information) and high-resolution breast ultrasound enhance preoperative assessment of breast cancer. Mammography remains the only screening test shown to reduce breast cancer deaths in randomised trials. Magnetic resonance imaging may have a role in screening women with inherited mutations of the breast cancer genes. Sentinel lymph node biopsy accurately assesses lymph node status and is associated with less morbidity than axillary dissection. Where the biopsy is negative (no histologic evidence of metastases), no further axillary treatment is necessary. Breast reconstruction after mastectomy can produce good cosmetic results, especially where autologous tissue is used. Myocutaneous flaps using latissimus dorsi or transverse rectus abdominus muscles are increasingly popular. Adjuvant trastuzumab therapy in patients whose tumours overexpress HER2 (growth factor receptor) can reduce recurrence rates and improve survival. Neoadjuvant endocrine therapy (as an initial treatment before surgery) is an underutilised treatment in postmenopausal women with oestrogen-receptor-positive large operable or locally advanced cancers. It makes more patients suitable for surgery and offers others the choice of breast conservation.

Nehmat Houssami PhD, FAFPHM, FASBP · Jack Cuzick PhD · J Michael Dixon MD, FRCS, FRCP

Heather E Robinson,* Ellen L Maxwell,† H Miles Prince,‡ Mary A O'Reilly,§ Andrew Jakobovits¶ * Haematology Registrar, ‡ Chair of Haematology Service, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, East Melbourne, VIC 8006; † Haematologist, Melbourne Pathology, Melbourne, VIC; § Infectious Diseases Physician, ¶ Physician, Cabrini Health, Melbourne, VIC. Miles. PrinceATpetermac.org To the Editor: A 32-year-old woman presented with fatigue and jaundice 12 days after an uncomplicated elective caesarean delivery. She had a haemoglobin level of 76 g/L (reference range [RR], 110–160 g/L), reticulocytosis (202 × 109/L, 12.6%; RR, 20–100 × 109/L) and hyperbilirubinaemia (139 μmol/L, 97% unconjugated; RR, < 20 μmol/L). Within 24 hours, her haemoglobin level fell to 37 g/L, and a blood film showed spherocytes and polychromasia consistent with haemolysis (Box). A direct antiglobulin test was strongly positive for IgG and complement. The patient’s obstetric case notes revealed administration of a single intravenous dose of cefotetan at the time of delivery. Donor red cells treated in vitro with this antibiotic reacted dramatically with the patient’s serum, indicating the presence of antibody to the drug–red cell combination. The patient was admitted to the intensive care unit and received 6 units of red cells over 24 hours, until the haemolysis resolved. Cefotetan disodium is a broad-spectrum second-generation cephalosporin commonly used as prophylaxis in abdominal and pelvic surgery. It is given as a single intravenous dose at the start of the operation, and 50%–80% of the dose is excreted within 24 hours.1-3 A positive direct antiglobulin test is seen in one in 250 patients treated with cefotetan, although this in itself does not always imply active haemolysis. The true incidence of symptomatic haemolysis is difficult to determine for several reasons: the severity of haemolysis varies between patients, and, if mild, may go undiagnosed; the process is self-limiting; and, when the drug has been used perinatally, symptoms may not be distinguished from the fatigue and anaemia expected (and therefore accepted) by most new mothers. Furthermore, as in our case of caesarean delivery, the obstetrician is not always aware of drugs administered by the anaesthetist, making the link between the antibiotic and haemolysis easy to miss. The Adverse Drug Reactions Advisory Committee has 15 listings of haemolytic anaemia caused by cefotetan in Australia, which probably represents significant under-reporting. Indeed, the recognition of cefotetan-induced haemolysis prompted a US Food and Drug Administration review of its incidence in 2002, which revealed more than 85 reports worldwide, including 15 fatal cases.4 Cephalosporins are the most common group of drugs to cause haemolytic anaemia (93% of all cases), with cefotetan alone accounting for 83%.5 A patient with haemolytic anaemia induced by one cephalosporin carries a 10% risk of cross-reactivity with other cephalosporins and consequently should avoid further exposure if possible. First-generation cephalosporins are less likely to cause significant haemolysis than second- and third-generation cephalosporins, yet are equally efficacious in surgical prophylaxis.1,3 We therefore recommend the use of cefazolin as an alternative to cefotetan. Blood film in a woman with drug-induced haemolytic anaemia Blood film taken on Day 1 of admission shows features of immune-mediated haemolysis, with polychromasia (vertical arrow) and spherocytosis (horizontal arrow).

Heather E Robinson · Ellen L Maxwell · H Miles Prince · Mary A O'Reilly · Andrew Jakobovits

Clinical record Patient 1* Histopathology of colonic biopsies from the patients described† A: Biopsy from Patient 1 shows mild diffuse increase of lymphocytes within the crypt and surface epithelium (arrows). Inflammatory cell infiltration of the lamina propria is minimal and there is no collagen deposition.‡ A 78-year-old woman who normally had one to two bowel motions a day presented with a 3-week history of gradual onset of more frequent and looser motions up to six times a day and occasionally at night. She had urgency and episodes of faecal incontinence. Her motions were watery. There was no improvement after she was treated with tinidazole. Her regular medications were alendronate, hydrochlorothiazide, irbesartan, raloxifene, thyroxine, temazepam, aspirin, thiamine, vitamin C, glucosamine, and evening primrose oil. She had also taken lansoprazole (30 mg capsules) daily for 2 months to treat possible reflux. Sigmoidoscopy showed yellowish, watery stool with mucus and a few tiny scattered patches of intramucosal haemorrhage. Biopsy (Figure A) showed mild lymphocytic colitis (defined by the presence of more than one lymphocyte per 20 epithelial cells). Lansoprazole therapy was ceased and the diarrhoea settled within 24 hours. Patient 2* B: Biopsy from Patient 2 shows mild increase in plasma cells in the lamina propria and an obvious subepithelial band of collagen (arrows). There is patchy detachment of the surface epithelium.§ A 53-year-old woman presented to hospital with a 2-month history of diarrhoea and abdominal pain. She was admitted with suspected diverticulitis. Nine months before presentation, she had started taking lansoprazole (30 mg capsules) daily for heartburn. She described having bowel motions seven or eight times per day, and occasionally at night. The diarrhoea had not responded to tinidazole, metronidazole or norfloxacin. Her regular medications were gemfibrozil, tibolone, indapamide and perindopril. Colonoscopy did not detect significant abnormalities. Biopsy showed mild collagenous colitis (Figure B). Lansoprazole therapy was ceased. She was treated with loperamide, then cholestyramine and budesonide. Within 6 months, she was symptom-free without antidiarrhoeal medication. Patient 3* C: Patient 3, there is a mild increase in lymphocytes within the epithelium, and of plasma cells in the lamina propria. The surface epithelium is mildly degenerate, and there is a suggestion of abnormal subepithelial collagen deposition (arrow).‡ A 79-year-old woman had been seen in hospital with a sudden onset of diarrhoea 5 weeks before admission, associated with 10 kg weight loss. She had taken lansoprazole (30 mg capsules) daily for 2 weeks before the diarrhoea began. She had had up to 12 watery motions per day. The diarrhoea had not responded to norfloxacin. Her regular medications were alendronate, perindopril, potassium chloride, chlorthalidone and celecoxib. Appearance on sigmoidoscopy was normal, but biopsies (Figure C) showed mild lymphocytic colitis with occasional subepithelial collagen suggesting transition to collagenous colitis. Lansoprazole therapy was ceased, and she was treated with codeine. Her condition was much improved without antidiarrhoeal medication within a month. When reviewed 6 months later, she was having two loose motions daily, and the celecoxib (200 mg daily) was withdrawn. * All three patients had negative results on serological tests for coeliac disease (transglutaminase and endomysial antibody) and normal serum IgA levels. † Follow-up biopsies were not taken. ‡ Stained with haematoxylin and eosin. § Stained with Masson Trichrome, which shows collagen in green. Microscopic colitis is increasingly recognised as a major cause of persistent diarrhoea.1 It is an idiopathic clinicopathological syndrome of chronic watery non-bloody diarrhoea associated with a normal appearance on colonoscopy and specific histopathological changes of lymphocytic and/or collagenous colitis. There is a high rate of spontaneous resolution and relapse in microscopic colitis, and effective treatment is limited. The pathogenesis of microscopic colitis is poorly understood and is thought to be related to a poorly regulated epithelial immune response to luminal or epithelial antigens including bile acids, toxins, or infectious agents.2 Microscopic colitis has been associated with autoimmune diseases and with exposure to medications, predominantly non-steroidal anti-inflammatory drugs, and, rarely, salicylates, simvastatin, ticlopidine, ranitidine, carbamazepine, Cyclo 3 Fort (a combination of Ruscus aculeatus extract, hesperidin methylchalcone, and ascorbic acid), flutamide, gold salts, and, recently, lansoprazole.2 Lessons from practice Microscopic colitis should be considered as a cause of persistent watery non-bloody diarrhoea; the two major histological forms of microscopic colitis — lymphocytic and collagenous — are probably variations of the same disorder. Even if the bowel appears macroscopically normal on colonoscopy, multiple biopsies should be routinely taken for histopathology, and the pathologist informed of the possibility of microscopic colitis. The possibility of medications as the cause of diarrhoea and microscopic colitis should always be considered; drugs that may cause the symptoms should be investigated, withdrawn, and the effects observed. Not all adverse drug events occur immediately and not all are class effects. Suspected adverse drug reactions should be reported to the Adverse Drug Reaction Advisory Committee for evaluation. Lymphocytic and collagenous colitis are probably aetiologically related, and may be a spectrum of the same disease.3 This is supported by our report of three lansoprazole-associated cases, in which one showed lymphocytic colitis, one showed collagenous colitis and one showed transitional features of both on histopathological examination. The inflammatory infiltrate and collagen deposition in these cases was less severe than that seen in typical cases of lymphocytic and collagenous colitis, probably because of the limited periods of exposure to the inciting agent. Interestingly, Patient 2 had the greatest collagen deposition and the longest exposure to lansoprazole. The rapid resolution of the symptoms on cessation of lanzoprazole therapy in Patient 1 may be related to the very mild lymphocytic infiltrate and lack of collagen deposition, or perhaps lansoprazole caused diarrhoea through another mechanism in this case. Adverse drug reactions can only be recognised if doctors maintain a high index of suspicion. It is not possible to know every possible reaction to the medications that patients are exposed to, and some may not have been recognised before. The absence of an immediate temporal relationship between a drug and the associated disorder (as was seen in the cases presented here) may contribute to failure to diagnose a drug-induced disease. Drugs and their metabolites may affect the colon directly through their pharmacological actions, or through hypersensitivity reactions. Drugs also act indirectly on the colon by altering colonisation by gastrointestinal organisms.4 The association between lansoprazole and microscopic colitis may be related to its action on the colonic proton pump, affecting colonic secretions and pH, which may affect colonic flora and bile salt solubility.5 Alternatively, there may be an idiosyncratic direct hypersensitivity reaction by the colonic mucosa. The association between lansoprazole and microscopic colitis has been reported previously,5-7 and before our patients presented, the Adverse Drug Reaction Advisory Committee had received a single report of a probable association between rabeprazole and unspecified colitis. In a previous report of lansoprazole-associated microscopic colitis,5 substituting omeprazole for lansoprazole did not lead to recurrent diarrhoea. One explanation for the absence of a class effect is that while all proton-pump inhibitors bind the parietal cell proton pump covalently at cysteine 813 or 822, only lansoprazole and rabeprazole bind to cysteine 321.8 Binding of cysteine 321 also inhibits the colonic proton pumps.9 This may affect colonic secretion and pH, predisposing to diarrhoea and microscopic colitis. However, the rarity of the association between lansoprazole and microscopic colitis favours an idiosyncratic immune reaction. Minor variations in the structures of the proton-pump inhibitors may result in different immunological activation, although allergic cross-sensitivity has occasionally been reported among the proton-pump inhibitors.10 Our cases illustrate the importance of considering exposure to medication as a cause of chronic diarrhoea and particularly microscopic colitis, and that adverse drug reactions are not always class effects. Stopping the causative medication may reverse the abnormality in this difficult-to-treat condition. In patients with persistent watery diarrhoea, biopsies should be performed even if colonoscopic appearances are normal, and pathologists should be informed of the clinical possibility of microscopic colitis, as the histological changes may be subtle.

Sarah N Hilmer PhD, FRACP · Timothy R Heap MB BS, FRACP · Robert P Eckstein MB BS, FRCPA · Gillian M Shenfield DM, FRACP · Christopher S Lauer MB BS, FRCPA

C Scott Masters,* Michael J Yelland† * Vice-President, Australian Association of Musculoskeletal Medicine, Caloundra Sports Medicine Centre, 39 Minchinton Street, Caloundra, QLD 4551. † Associate Professor of Primary Health Care, Griffith University, QLD. scotty1ATozemail.com.au To the Editor: Paoloni and Orchard provided a concise summary of the evidence for injections for soft-tissue injuries,1 but omitted some important references on the mechanism of action of corticosteroids and on prolotherapy. An important action of corticosteroids is blocking of transmission in nociceptive C-fibres.2 Given the lack of evidence of inflammation in chronically painful tendinopathies,3 this is a more probable mechanism of action than the suppression of inflammation. Paoloni and Orchard correctly report that steroids have only a temporary effect in suppressing soft tissue pain. However, in low back pain, if their use is preceded by manual therapy and exercises they have the potential to give more prolonged relief of pain and disability.4 A recent Swedish randomised controlled trial (RCT) of polidocanol prolotherapy injections for chronic Achilles tendinopathy showed reduced pain and normalisation of ultrasound abnormalities.5 Similarly, a New Zealand case series of glucose prolotherapy injections showed very positive results for the same condition.6 An Australian RCT into prolotherapy for chronic low back pain (average duration, 14 years) showed sustained reductions in pain and disability with glucose prolotherapy injections, although similar results were obtained with saline injections.7 A pilot study of glucose prolotherapy in 24 elite male kicking-sport athletes with chronic groin pain (mean duration, 15.5 months) who had failed physical therapy reported a pain-free state and return to sports in 82% at an average follow-up of 17.2 months.8 This evidence would suggest there is a role for this glucose prolotherapy in managing soft-tissue pain, especially as musculoskeletal pain is one of the major presentations to primary practice in Australia. Training primary care physicians in prolotherapy injection techniques should be a priority in medical education.

C Scott Masters · Michael J Yelland

Justin A Paoloni,* John W Orchard† * Conjoint Senior Lecturer, Orthopaedic Research Institute, St George Hospital Campus, University of New South Wales, Sydney, NSW. † Sports Physician, Sports Medicine at Sydney University, Sydney, NSW. pao_26AThotmail.com In reply: We thank Masters and Yelland for their interest in this topic and their notification of additional references, some of which were published after our article was written. We stated in our article that “the mechanism of any effect of corticosteroid injections in reducing symptoms in purely degenerative tendinopathies is unknown”, and that only where bursitis or tenosynovitis is present would the implication of an anti-inflammatory effect be appropriate.1 While blocking nociceptive C-fibres in normal tendon is demonstrated in the study quoted by Masters and Yelland,2 we still believe that corticosteroids should be used with caution for any tendinopathy where tendon weakening would be potentially harmful. We agree that corticosteroids have a much greater potential role in low back pain, which is a broad entity involving both soft-tissue and joint disorder. At the time of writing our article there was a pilot study on polidocanol in painful tendons displaying neovascularisation;3 we thank the authors for advising that a randomised controlled trial has since been published.4 While undoubtedly an exciting new therapy, proponents of polidocanol do not consider its mechanism to be simply a “prolotherapy” effect; they also consider sclerosing the neovessels to be critical, and therefore, that hypertonic glucose (the most commonly recommended prolotherapy agent) may not work as well. We still maintain that prolotherapy currently lacks evidence of efficacy for the treatment of soft-tissue injury in general, although it is relatively cheap and generally free of side effects. Both chronic low back pain, and chronic groin pain, are multifactorial conditions involving joint/bone abnormality which we considered slightly beyond the scope of an article on soft-tissue injuries. We await further publications on the efficacy of prolotherapy with interest.

Justin A Paoloni · John W Orchard

Most people presenting with rheumatoid arthritis today can expect to achieve disease suppression, can avoid or substantially delay joint damage and deformities, and can maintain a good quality of life. Optimal management requires early diagnosis and treatment, usually with combinations of conventional disease modifying antirheumatic drugs (DMARDs). If these do not effect remission, biological DMARDs may be beneficial. Lack of recognition of the early signs of rheumatoid arthritis, ignorance of the benefits of early application of modern treatment regimens, and avoidable delays in securing specialist appointments may hinder achievement of best outcomes for many patients. Triage for recognising possible early rheumatoid arthritis must begin in primary care settings with the following pattern of presentation as a guide: involvement of three or more joints; early-morning joint stiffness of greater than 30 minutes; or bilateral squeeze tenderness at metacarpophalangeal or metatarsophalangeal joints.

Lynden J Roberts MB BS, PhD, FRACP · Leslie G Cleland MD, FRACP · Susanna M Proudman MB BS(Hons), FRACP · Ranjeny Thomas MB BS, MD, FRACP

Antidoping laws generally exist in order to provide a safe and fair environment for participation in sport. These laws should prevent and protect athletes from subjecting themselves to health risks through the use of unsafe, but performance-enhancing drugs. Because of difficulties in proving intent to cheat, the World Anti-Doping Agency enforces a principle of strict liability for positive test results for banned substances. An area of major controversy with respect to liability is the “sports supplement” industry, which is poorly regulated when compared with prescription drugs yet is a potential source of doping violations. Medical practitioners can be found guilty of anti-doping violations if they traffic banned drugs, prescribe these to athletes or otherwise assist athletes in taking banned substances. Medical practitioners are also now required to complete paperwork (therapeutic use exemption forms) to enable athletes to take banned substances which are required on medical grounds for specific illnesses.

John W Orchard PhD, FACSP, FACSM · Deborah J Healey LLM · Peter A Fricker OAM, MB BS, FACSP · Louise M Burke PhD, APD, FACSM · Susan L White MB BS. FACSP

To the Editor: Goldney and Fisher recently reported data on medication use in an Australian community sample and estimated the financial savings that could be made if the number of prescribed medications was reduced.1 However, the assumption that the average number of medications per patient could be reduced ignores the large body of evidence that has accumulated over recent years demonstrating under-use of beneficial medicines. Under-prescribing has been identified in the management of a broad range of chronic conditions, including heart failure, ischaemic heart disease, hypertension, atrial fibrillation, asthma, osteoporosis, pain, and depression.2,3 It has been suggested that under-use of beneficial therapies may be an even bigger problem than over-prescribing, especially in older patients.4,5 As Goldney and Fisher did not collect any clinical information about their study subjects, no conclusions can be drawn about whether medications were more frequently over-prescribed or under-prescribed. Focusing solely on reducing the number of medications prescribed may be misguided and may result in poorer health outcomes. A broader view of prescribing is required, recognising that problems result from both over- and under-prescribing, as well as inappropriate dose selection and monitoring.5

Rohan A Elliott

Robert D Goldney,* Laura J Fisher† * Professor of Psychiatry, † Research Officer, The Adelaide Clinic, Suite 13, 33 Park Terrace, Gilberton, SA 5081. robert.goldneyATadelaide.edu.au In reply: We agree that, because of our research methodology, we could not necessarily assume that any medication prescription was inappropriate, and we noted that on two occasions. However, our economic analysis addressed only those people using six or more prescribed medications (mean, 7.8), and we reported multiple use of same-class medications, and, at times, use of two different preparations of the same medication. Therefore, we believe our estimate of potential cost savings to be conservative. Nevertheless, we accept that our hypothesis needs more formal testing using clinical data.

Robert D Goldney · Laura J Fisher

Artesunate reduces mortality and should now be the treatment of choice in severe malaria in adults: good news for countries in our region, but registration in Australia must wait For nearly 400 years quinine has been the principal drug used to treat severe malaria. Despite its long history of efficacy, quinine has significant limitations. Even with prompt administration, case-fatality rates in severe malaria often exceed 20%.1 Furthermore, quinine requires three-times-daily administration and has a number of adverse effects including hypoglycaemia, vomiting, headache and tinnitus.1 The identification of artemisinin from sweet wormwood (Artemisia annua) in China in the 1970s focused attention on the most rapidly acting of all antimalarial drugs,1 and raised hopes that artemisinin derivatives would reduce the high case-fatality rate in severe malaria. Initial trials using intramuscular artemether demonstrated less toxicity but no clear mortality benefit over quinine,1 most likely due to the erratic absorption of the intramuscularly administered oil-based preparation of artemether.2,3 More recent trials have used intravenous artesunate, a water-soluble derivative with a more favourable pharmacokinetic profile.3,4 The SEAQUAMAT trial, a multicentre randomised trial conducted in Bangladesh, Myanmar, Indonesia and India, recently reported a 34.7% reduction in mortality associated with intravenous artesunate compared with intravenous quinine.5 This is the largest trial ever performed in severe malaria and the first to demonstrate conclusively a mortality reduction over standard quinine therapy. This is good news for malaria-endemic areas in South-East Asia. The burden of malaria in our region is far worse than previously thought, with over 120 million cases each year in south/south-east Asia.6 The World Health Organization now advocates the use of artemisinin combination therapy for uncomplicated malaria,7 a move that is likely to reduce the number of people developing severe disease. Now there is convincing evidence that for those who do develop severe malaria, intravenous artesunate will reduce the risk of death by one-third.5 It is also safer and easier to use than quinine. What about children? In the 202 children in SEAQUAMAT, artesunate was equally safe and effective.5 But the study did not have the statistical power to demonstrate a mortality benefit in the paediatric age group. In the Asian countries that have changed policy, artesunate is first-line treatment for both adults and children. However, because the clinical pattern and rapidity of death is different in paediatric severe malaria in high transmission areas, a randomised trial comparing mortality in African children treated with artesunate and quinine has recently commenced. Several countries in our region recommend parenteral artemisinin derivatives as first-line therapy for severe malaria, including Vietnam, Thailand, Papua New Guinea and Cambodia.8 As a result of SEAQUAMAT, Indonesia has now also changed national policy from quinine to artesunate. However, quinine is still national policy for severe malaria in most other Asia–Pacific countries.8 At US85c–$1 per 60 mg vial when purchased in bulk, artesunate is only modestly more expensive than quinine. And this does not take into account the intravenous infusions and additional nursing required for quinine. The number needed to treat to save one life was between 11 and 20 in the SEAQUAMAT study, making this a very cost-effective policy change. A major issue for many national bodies faced with licensing parenteral artesunate is that neither of the current manufacturers in China and Vietnam produce a formulation approved as compliant with international Good Manufacturing Practice (GMP) speci-fications. Support from the developed country pharmaceutical industry does not appear likely. United States Army plans for independently developing a GMP-compliant formulation have been delayed by the lack of a commercial co-development partner.9 Absence of GMP certification does not necessarily mean poor quality: independent analysis of the lots used in the SEAQUAMAT trial demonstrated satisfactory quality of this drug. However, neither of the current manufacturers has yet received WHO prequalification certification, a requirement for the WHO and several other international agencies to purchase drugs centrally and distribute large quantities at low cost to ministries of health. Nevertheless, forthcoming WHO guidelines will recommend artesunate be made the treatment of choice for severe malaria in adults.10 What about Australia and other developed countries? In settings with well resourced intensive care facilities, the mortality rate from severe malaria is less than that seen in most sites involved in the SEAQUAMAT trial.11 It is possible that the benefit with artesunate (seen after 24–48 hours in the SEAQUAMAT trial) could be attenuated by better treatment of late complications in a developed country setting. However, the magnitude of the mortality reduction was remarkably consistent among the SEAQUAMAT sites, despite varying mortalities and levels of ancillary care. Parenteral artesunate should therefore be the treatment of choice for adult severe malaria in all countries.10 The lack of a GMP-compliant formulation is, however, a major hurdle and means that artesunate cannot be registered in Australia by the Therapeutic Goods Administration12 or in other countries, including the European Union and United States. This creates a paradox. In contrast to the usual situation, a life-saving drug is available and being used in many developing countries, yet cannot be registered in developed countries. Although it is clearly far more important that these drugs are available in malaria-endemic countries, and the number of Australians developing severe malaria each year is small, it is unacceptable that we must continue to use quinine when a drug that reduces mortality by one-third is available elsewhere. Pending the availability of a GMP-compliant product that can be registered, an interim strategy is available in Australia. Hospital pharmacies can import and hold artesunate for category A usage in named patients with severe malaria under the Special Access Scheme, reserved for “very seriously ill patients” with a high short-term likelihood of death in the absence of early treatment.13 This strategy could be coordinated by a consortium of state/territory hospital pharmacies in capital cities and supported by the relevant national professional bodies. Ideally, the quality of an imported lot of non-GMP artesunate should have been confirmed at a Good Laboratory Practice-compliant laboratory. From a global perspective, registration and availability of parenteral artesunate in both malaria-endemic and developed countries would be maximised if current manufacturers were given assistance to become GMP-compliant without delay.

Nicholas M Anstey PhD, FRACP · Ric N Price MD, FRACP · Nicholas J White FRCP, DSc

Biswadev Mitra,* Peter A Cameron† * Registrar in Emergency Medicine, Emergency and Trauma Centre, The Alfred Hospital, Commercial Road, Melbourne, VIC 3004. † Professor of Emergency Medicine, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC. b.mitraATalfred.org.au To the Editor: We congratulate Kaye and colleagues on their efforts to educate and influence prescribing practice in reducing the use of pethidine.1 The adverse effects of pethidine and its lack of efficacy over other opiates have been known and taught since the early 1990s.2 A decade on, we are still seeing significant use of this drug,3 which has multiple disadvantages when compared with other opioid analgesics. The difficulty lies in doctors’ attitudes to quality improvement and change in health care. It has been noted that doctors’ responses to concern about the quality of health care range widely, from opposition to whole-heartedly embracing legitimate opportunities for improvement.4 While there is such variance, the implementation of evidence-based medicine into practice will lag, sometimes by decades, resulting in unnecessary adverse effects in patients. With clinical guidelines in place, a rigorous education campaign and many hours of research time and resources, Kaye and colleagues have significantly reduced, but not eradicated, pethidine prescribing in New South Wales. In comparison, O’Connor et al report combining a similar educational program with formulary restrictions to effectively eliminate the use of meperidine (pethidine) in their single centre study.5 We can only conclude that clinical evidence, even when combined with quality improvement campaigns, remains less effective than policy changes which restrict doctors’ behaviour. From available evidence, the liberal use of pethidine may cause adverse effects which are preventable by a simple system-oriented approach — in this case, the appropriate risk-management step is restricting pethidine use to very limited situations. We cannot continue to justify use of a drug with poor efficacy, toxicity and serious drug interactions. Pethidine prescribing as a percentage of total narcotics in Launceston General Hospital emergency department, 1992–2004 Note: data not available for some quarters.

Biswadev Mitra · Peter A Cameron

Paul Pielage Director of Emergency Medicine, Launceston General Hospital, Charles Street, Launceston, TAS 7250. paul.pielageATdchs.tas.gov.au To the Editor: I was interested to read the article by Kaye and colleagues about reducing pethidine use in the emergency department by means of evidence-based prescribing.1 In view of published reports describing the disadvantages of pethidine, it was decided in late 1996 to attempt to reduce the amount of pethidine prescribed in the emergency department of Launceston General Hospital. Narcotics were supplied as ampoules of 100 mg pethidine, 10 mg morphine, 15 mg papaveretum (the use of which was trivial) and fentanyl, which was used mainly for anaesthetic induction. Before mid-1996, 50%–72% of all ampoules of narcotics used in the emergency department were of pethidine. Of narcotics used for acute pain management, pethidine would have been much higher as a proportion because it was not used for acute pulmonary oedema, ischaemic myocardial pain, anaesthetic induction and in patients being ventilated. The use of narcotics was monitored by quarterly reports from the pharmacy department of the quantities of the various parenteral narcotics supplied to the emergency department. Papaveretum was removed from the pharmacopoeia in 1999. In 1996, an informal education program was instituted within the emergency department, strongly supported by the nurses, with the aim of convincing junior medical staff on rotation from other areas within the hospital to prescribe morphine rather than pethidine. It had long been observed that such staff prescribed pethidine almost exclusively for acute pain management, and a cultural change was required. As shown in the Box, the percentage of narcotics dispensed as pethidine was steadily reduced over the following years, reaching 5% in 2002. After 2 years at this level it was decided to remove pethidine from the pharmacopoeia. In February of 2005, hydromorphone was introduced and pethidine removed. There have been no complaints or problems as a result, and the whole process was unexpectedly painless and successful.

Paul Pielage

Karen I Kaye,* Susan A Welch,† Linda V Graudins,‡ Andis Graudins,§ Tai Rotem,¶ Sharon R Davis,** Richard O Day†† * Executive Officer, ** Research and Liaison Officer, NSW Therapeutic Advisory Group, PO Box 766, Darlinghurst, NSW 2010. † Senior Pharmacist, †† Director, Clinical Pharmacology and Toxicology, St Vincent's Hospital, Sydney, NSW. ‡ Medication Safety and Quality use of Medicines Pharmacist, Sydney Children's Hospital, Sydney, NSW. § Emergency Physician and Director, Clinical and Experimental Toxicology Unit, Prince of Wales Hospital, Sydney, NSW; and Senior Lecturer (Conjoint), University of New South Wales. ¶ Statistician, School of Public Health and Community Medicine, University of New South Wales, Sydney, NSW. nswtagATstvincents.com.au In reply: As Mitra and Cameron point out, policy change can be effective in influencing prescribing practice. Indeed, use of a restrictive formulary is a strategy used by drug and therapeutics committees in most Australian hospitals. However, where support among clinicians for policy change is lacking, significant time and effort is required by those responsible for policy implementation. Confrontation and lack of interdisciplinary cooperation can be expected. Quality use of medicines (QUM) means selecting management options wisely, choosing suitable medicines if a medicine is considered necessary, and using medicines safely and effectively. Australia is fortunate in having a National Medicines Policy1 and a national strategy for QUM.2 This strategy recognises the importance of active and respectful partnerships, and of consultative, collaborative, multidisciplinary activity to improve the quality use of medicines. To attain QUM, “. . . key partners must be involved at all stages in designing, implementing and evaluating QUM programs . . . Multiple activities and strategies are needed to raise awareness about issues related to QUM. Attitudes, knowledge, skills and behaviours that support QUM need to be developed and maintained”.2 Our approach was based on these principles. Pielage provides another example of the successful use of this approach to limit pethidine prescribing in a large teaching hospital, which should be applauded. Doctors, pharmacists, nurses and consumers are important partners in QUM. An educative, multidisciplinary approach that respects each partner is the most appropriate way to ensure sustained practice change and promote QUM in hospitals and the wider community.

Karen I Kaye · Susan A Welch · Linda V Graudins · Andis Graudins · Tai Rotem · Sharon R Davis · Richard O Day

Jim Siderov Senior Pharmacist, Cancer Services, Austin Health, Studley Road, Heidelberg, VIC 3084. jim.siderovATaustin.org.au To the Editor: Acetylcysteine (Mucomyst [Bristol-Myers Squibb, Melbourne]) is a mucolytic agent commonly used as adjuvant therapy for patients with abnormal, viscid or inspissated mucous secretions in such conditions as chronic bronchopulmonary disease. It is administered as fine nebulae, and its adverse effects in this form are minimal. Patients may observe an initial slight odour, or stickiness on the face after nebulisation. When acetylcysteine is nebulised using a normal nebuliser it produces a dense mist. One of the less well known adverse effects of the medication was recently observed at a major teaching hospital, when an acetylcysteine cloud activated the hospital’s fire alarm! Medical, nursing and pharmacy staff need to be aware of this potentially embarrassing situation. To help alleviate the problem, acetylcysteine can be administered via a jet nebuliser, similar to that used to administer the antimicrobial pentamidine. The jet nebuliser uses an air or gas stream to break liquids up into smaller particles, decreasing the droplet size and thus eliminating the dense mist.

Jim Siderov