Pharmacology

The essential guide to herbal safety. Simon Mills, Kerry Bone. Missouri: Elsevier Churchill Livingstone, 2005 (xvi + 684 pp). ISBN 0 443 07171 3. With the dramatic growth in the use of herbal medicines, consumers and practitioners alike need to access reliable information on the safety and efficacy of herbal medicine. The essential guide to herbal safety is extremely topical and fills a considerable gap in the literature. This is an outstanding reference text on herbal safety that deals not only with a range of critical issues (safety monitoring of herbal medicines, herb–drug interactions, quality control), but also provides a series of exemplary monographs on herb safety. The text brings together contributions by acknowledged experts in the field. The safety monographs contain useful information on the current regulatory status of each herb in selected jurisdictions. The LD50 data for various extracts of the herb serve to highlight the relative risk represented by different extract forms (water, ethanol, etc) and the role of individual phytochemical constituents. Categories descriptive of known toxicity in pregnancy and lactation are provided for each herb. I would have liked the authors to provide similar toxicological categories or grades for general consumers, however this would have required substantial input by clinical toxicologists. Overall, the text is extremely well researched, integrating various data sources. It is an excellent book to have in hand and will undoubtedly become an important resource. At just over $100, The essential guide to herbal safety represents outstanding value. Alan BensoussanDirector, Centre for Complementary Medicine Research University of Western Sydney, NSW

Alan Bensoussan

Objective: To estimate the risk of death from healthcare-associated (nosocomial) bacteraemia caused by methicillin-resistant Staphylococcus aureus (MRSA), and compare it with that of nosocomial bacteraemia caused by methicillin-sensitive S. aureus (MSSA), by meta-analysis of selected studies. Data sources: Medline, EMBASE, Current Contents and Cochrane Library were searched for the period January 1978 (or earliest date of the database, if later than 1978) to December 2000. Study selection: Studies which compared mortality of nosocomial MRSA and MSSA bateraemia. Data synthesis: Nine studies were analysed. All but one found an increased relative risk (RR) of death from MRSA bacteraemia, with RR ranging from 0.89 to 4.94. Meta-analysis showed that patients with MRSA bacteraemia have an RR of death, compared with patients with MSSA bacteraemia, of 2.21 (95% CI, 1.76–2.57) using the fixed-effect method, and 2.03 (95% CI, 1.55–2.65) using the random-effect method. Conclusion: MRSA bacteraemia is associated with a real increase in risk of death, further justifying ongoing MRSA surveillance and control in healthcare facilities.

Michael Whitby · Mary-Louise McLaws · Geoffrey Berry

Soft-tissue injuries are injuries to skin, fascia, ligament, muscle, and tendon. Currently, many therapeutic medications are commonly used in the management of soft-tissue injuries, including: analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, prolotherapy sclerosant agents, aprotinin, glyceryl trinitrate, botulinum toxin, and glucosamine. Despite their regular use for soft-tissue injury, few medications have strong evidence of a consistent therapeutic effect. In this article, we review the proposed mechanisms of action, side effects, and the evidence base (based on National Health and Medical Research Council levels of evidence1) for common soft-tissue injury treatments. We also suggest appropriate circumstances for using therapeutic medications, with emphasis on the Hippocratic principle of primum non nocere (first do no harm). Non-steroidal anti-inflammatory drugs for ligament and muscle injuryNSAIDs are among the most widely used medications for common soft-tissue injuries such as muscle contusions, muscle tears, and ligament tears. The mechanism of action of NSAIDs is through non-specific cyclo-oxygenase inhibition, thereby blocking the production of prostaglandins from arachidonic acid. Prostaglandin inhibition by NSAIDs decreases the inflammatory response, which can have both positive and negative effects. For example, the arachidonic acid “overflow” pathway may lead to increased leukotriene production and potential tissue damage. Other known negative NSAID class side effects include hypertension, altered renal function, gastrointestinal disturbance (including peptic ulceration), and the recently discovered increased rates of myocardial infarction with non-selective NSAIDs, such as diclofenac and ibuprofen (evidence level III-2 [E32]).2 Potentially desirable class effects of NSAIDs include reduced risk of bowel cancer and increased blood clotting times. Side effects, whether positive or negative, are generally far more relevant for long-term use (such as in patients with rheumatoid arthritis) than with short-term use for sports injury. Many NSAIDs are available as topical preparations. Although the results of tissue penetration studies are variable, for injured body structures which are close to the surface (eg, limbs), topical NSAIDs may offer the advantages of higher local tissue concentrations with reduced risk of systemic side effects. The balance of evidence suggests that NSAID use is associated with a short-term mild to moderate decrease in pain in “minor sports injury” (E2),3 ankle sprains and knee pain (E2),4 and shoulder pain (E1).5 The number needed to treat (NNT) for a positive effect greater than placebo for most conditions is 3–4 patients. There is no evidence that NSAIDs improve muscle function after injury. NSAIDs (and corticosteroids) are catabolic in nature, particularly having their effect on tissues such as the soft-tissue structures of muscles, ligaments, tendon, and fascia, with very little effect on neural tissue. Therefore, in conditions where the pathological disorder is entrapment or impingement of nerves because of soft-tissue proliferation, such as carpal tunnel syndrome, Morton’s neuroma, thoracic outlet syndrome, and intervertebral disc prolapse, there is a strong theoretical basis to support the use of anti-inflammatory medications like NSAIDs (and corticosteroids). There is level II evidence of efficacy of NSAIDs on the inflammatory components of disorders such as bursitis in rotator cuff disease or iliotibial band friction syndrome,6 and synovitis in Morton’s neuroma7 or carpal tunnel syndrome.8 Case study — a torn tendon and bursitis in the shoulder A 46-year-old left-handed woman with a 6-month history of left shoulder pain initially injured the shoulder while playing tennis. She felt a dull ache in the lateral arm immediately after the game, and now has night pain, and pain with activities of daily living. Examination showed restricted range of shoulder motion, muscle weakness, and positive impingement signs. Her x-rays were unremarkable. Ultrasound showed a supraspinatus tendon tear with bursal thickening, and supraspinatus tendon tear with supraspinatus bursitis was diagnosed. Therapy is dictated by the patient’s activity level. If she requires strong overhead function then the goal of treatment should be healing of the tendon tear. However, if she generally only requires use of the arm for activities below shoulder height, then relief of impingement is the primary goal of treatment. Anti-inflammatory treatment for 6 weeks and/or subacromial corticosteroid and local anaesthetic injections (Figure A) are among the best therapeutic options for giving pain relief. These will generally provide analgesia, but may have potentially deleterious effects on tendon healing. Regular use of ice and paracetamol may be used for analgesia as alternatives if healing is considered important. Topical glyceryl trinitrate patches (1.25 mg/24 h) are an appropriate option to help relieve symptoms and increase function with chronic injury (Figure B). Exercise rehabilitation is the cornerstone of managing tendinopathies to regain function — in this situation, concentrating on scapula stabilisation and rotator cuff strengthening. This may be managed by the general practitioner confident in exercise prescription for this shoulder injury, or with the assistance of a sports physician or physiotherapist with experience in rehabilitating such injuries. Surgery may have a role if other treatments are not successful. If the patient requires high levels of shoulder function, direct repair of a tendon tear has a good rate of success, but requires prolonged rehabilitation. Arthroscopic acromioplasty is a procedure with quicker recovery which, like anti-inflammatory agents, is directed at providing pain relief rather than maximising shoulder function. A: Corticosteroid injections for tendon injuries, such as this subacromial injection, provide a short term reduction in pain of 6–8 weeks duration in most soft-tissue conditions. B: Quartered 5 mg/24 h glyceryl trinitrate patch, used for treatment of shoulder tendinopathy. Thus, current evidence does not support NSAID use as solo therapy or long-term therapy for soft-tissue injury, except when the primary disorder is soft-tissue impingement, or predominantly inflammatory (such as bursitis or synovitis). NSAIDs should not be used routinely in soft-tissue injury, as they are, at best, an adjunct to treatment through symptom relief, most notably analgesia (see Case study), and these benefits must be weighed against the risks of gastrointestinal side effects, especially with prolonged use. Non-steroidal anti-inflammatory drugs for tendinopathyThe abnormality in chronic tendinopathy in most cases is degeneration, with no evidence of inflammation (Box 1). Despite this, there is level II evidence that NSAIDs provide short-term mild to moderate decreases in pain in lateral epicondylosis,9 increased abduction in rotator cuff disease,10 but have no efficacy in treating Achilles tendinopathy.11 The mechanism of action of NSAIDs in tendinopathy is unclear. NSAID use decreases fibroblast proliferation and increases “overflow” leukotriene production in tendon both at rest and during exercise, which is additive to the normal effect of increased leukotriene production with cyclic tendon loading. So, there is potential for NSAIDs to cause tendon damage through increased leukotriene formation. Further, as tendinopathies have a tendency to chronicity, the side effects of NSAIDs with prolonged use are an even greater limitation than with other soft-tissue injuries. Thus, the evidence does not support the use of NSAIDs in pure tendinopathy, given their small effect on relieving symptoms and potential adverse effects. Short-term use of ice and paracetamol should provide an equivalent analgesic effect without serious side effects. Non-steroidal anti-inflammatory drugs compared with paracetamol for soft-tissue injuryParacetamol is an analgesic with a centrally mediated mechanism of action. With comparable efficacy to NSAIDs for pain in soft-tissue injury (E2),12 and being both opioid-sparing and NSAID-sparing, it can be used in combination analgesia. It also has a low cost, low side-effect profile, and no risk of local soft-tissue injury. It is often the analgesic of choice for soft-tissue injury. Cyclo-oxygenase-2 (COX-2) inhibitors for soft-tissue injuryCOX-2 inhibitors were developed to selectively block the COX-2 enzyme and the inflammatory process without inhibiting the effects of prostaglandins on gastroprotection or the effects of thromboxane on bleeding time and platelet aggregation. The use of these agents is currently under review because of increased rates of myocardial infarction, with rofecoxib withdrawn from the market and celecoxib only recommended for use in rheumatoid arthritis and osteoarthritis at low dosages. Given the lack of evidence of efficacy for these agents in soft-tissue injury, and significant cardiovascular safety concerns that are yet to be adequately researched, COX-2 inhibitors should generally not be used for treating soft-tissue injuries. They would only be recommended for patients in whom nerve or mechanical impingement is predominant, and non-specific NSAIDs are contraindicated because of a coexisting gastric disorder. They should not be used in patients at high risk of cardiovascular disease. Corticosteroid injections for tendinopathyCorticosteroids are injectable anti-inflammatory medications that inhibit the accumulation of neutrophils and the synthesis of inflammatory mediators, and prevent phagocytosis and lysosomal enzyme release. They have short-term efficacy in symptom relief for degenerative tendinopathies, bringing decreased pain in lateral epicondylosis (E1),13 decreased pain and increased abduction in rotator cuff tendinopathy (E1),14 and decreased pain and increased function in trigger finger (E2).15 However, there does not appear to be a positive effect of peritendinous injections in Achilles tendinopathy (E2).16 Positive results noted in studies occur in, at most, 80% of patients, and are generally limited to 6–8 weeks after injection (Box 1). Longer-term studies (12 months’ follow-up) of the effects of corticosteroid injections in lateral epicondylitis show inferior results to physiotherapy (E2).17 Studies have not shown clinically significant improvements in function with corticosteroid injections (E1) or greater efficacy than NSAIDs for shoulder pain. The demonstrated effect of corticosteroids in decreasing pain of tendinopathies may be the result of improvements in the inflammatory components of tendon injuries such as bursitis in shoulder tendinopathy, and tenosynovitis in trigger finger. The mechanism of any effect of corticosteroid injections in reducing symptoms in purely degenerative tendinopathies is unknown. There is Level IV evidence of tendon rupture with both local corticosteroid injection and oral corticosteroid treatment. This risk may be overstated in view of the frequent use of corticosteroid injections, a lack of evidence of increased rates of tendon rupture with corticosteroid use, and the endstage tendon degeneration noted in tendon ruptures.18 Animal studies indicate that cortico-steroids weaken tendon whether injected into or proximal to the tendon, and it is possible that corticosteroid injections do lead to partial rupture of tendon substance. In non-weight-bearing tendons or patients who place little demand on the affected tendon through heavy loading at work or playing sport, this may lead to symptom abatement through a “medical tenotomy”, with surprisingly little functional loss. Partial tendon rupture in weight-bearing tendons or patients who place higher demand on the tendon is much more significant, and frequently necessitates surgery. Thus, the evidence suggests that a single corticosteroid injection for symptomatic tendon injuries may achieve a mild, short-term reduction in pain for up to 6 weeks, particularly for “non-critical” tendons where rupture may not be a deleterious outcome. This injection should be coupled with a tendon-specific rehabilitation program. Where actual tendon healing is critical to a good outcome, such as overuse injuries to major weight-bearing tendons like the Achilles, corticosteroid injections are probably contraindicated. Prolotherapy and aprotinin injectionsProlotherapy generally refers to the injection of a sclerosant such as phenol, or hypertonic glucose. Theoretically, sclerosants may be useful for soft-tissue conditions, such as ligament injuries, in which joint laxity is an issue. There are no controlled studies examining prolotherapy as a treatment for soft-tissue injury, although there is some low-level evidence supporting prolotherapy for back pack pain and osteoarthritis.19 Given the lack of evidence of efficacy, prolotherapy cannot yet be recommended for treating soft-tissue injury. Its major advantage is that side effects of treatment are likely to be minimal. Aprotinin is a broad-spectrum metalloprotease (MMP) inhibitor used to treat many conditions, but particularly in preventing blood loss during cardiac surgery. Its use in chronic tendinopathy is attractive, as aprotinin may act as a collagenase inhibitor. Certain MMPs have been shown to be present in excessive proportions in patellar tendinopathy and rotator cuff tendinopathy, and aprotinin could potentially normalise the concentration of MMPs in chronic tendinopathy, which may help healing. In treatment for tendino-pathy as a series of two to four injections into the peritendinous space, aprotinin provides superior analgesia when compared with corticosteroid injections and placebo in patella tendinopathy (E2),20 and in Achilles tendinopathy (E3).21 Potential side effects include allergy and anaphylaxis, although death has only been reported when used intravenously for cardiac surgery; the “test dose” of 3–5 mL for major procedures is similar to the therapeutic dose for tendinopathy.22 The use of aprotinin injections for tendon injuries is currently an “off-label” indication. Botulinum toxin for tendinopathyBotulinum toxin type A is a neurotoxin which inhibits the release of the neurotransmitter acetylcholine at the neuromuscular junction, and inhibits skeletal muscle contraction. It results in reduced muscular spasticity, reduces pain and increased function in “whiplash-associated disorder” (E2).23 The use of multiple botulinum injections around the musculotendinous junction as a “last option” in the treatment of lateral epicondylosis has comparable results to extensor release surgery (E2);24 however, placebo injections demonstrate equal efficacy.25 These treatments may all induce local tissue healing responses. Side effects of botulinum injections include allergic reactions, and permanent muscle and tendon injury. Current evidence does not support the use of botulinum toxin injections for tendon injuries. An exception may be in chronic recalcitrant cases of lateral epicondylosis where surgery is considered. Glyceryl trinitrate treatment for tendinopathyGlyceryl trinitrate is a donor of nitric oxide (the endothelium-derived relaxing factor), but the mechanism of action of topical glyceryl trinitrate therapy on tendon is unknown. Nitric oxide inhibition decreases collagen content and collagen synthesis by fibroblasts,26 and nitric oxide donation may stimulate collagen synthesis by fibroblasts. In acute shoulder pain, there is evidence of an analgesic effect of 3 days duration (E2),27 which is of lesser efficacy than corticosteroid injections (E2).28 In chronic tendinopathies, topical glyceryl trinitrate therapy with 1.25 mg per 24 hours has level II clinical evidence of decreased pain, increased tendon force, improved functional measures, and improved symptom resolution in Achilles tendinopathy,29 lateral epicondylosis,30 and supraspinatus tendinopathy.31 Glyceryl trinitrate has a long history of therapeutic use in humans, and the common side effects of rash and headache are rapidly reversible on discontinuation of topical treatment. It should not be used concomitantly in patients taking phosphodiesterase inhibitors such as sildenafil (Viagra; Pfizer), as the additive effect may cause life-threatening hypotension. The use of topical glyceryl trinitrate for tendon injuries is currently an “off-label” indication, although medical practitioners may legally exercise discretion in prescribing this treatment for tendon conditions, provided likely effects, and side effects, such as rash and headache, are explained to the patient. Topical glyceryl trinitrate therapy has robust evidence of efficacy in treating common chronic tendinopathies, the side-effect profile is known and reversible, and this therapy should be used as an adjunct to tendon rehabilitation in chronic tendinopathies (Box 1). Glucosamine and soft-tissue injuriesGlucosamine has a significant analgesic effect in treating osteoarthritis, and it has been suggested that it may aid wound healing through enhanced fibroblastic production of hyaluronate (E5).32 There are no studies on glucosamine in treating soft-tissue injury. ConclusionBox 2 provides a flowchart summarising the evidence-based options for medical treatment of soft-tissue injuries. The widespread use of NSAIDs and corticosteroid injections in the treatment of most soft-tissue injuries requires reassessment based on current evidence, while new drugs such as aprotinin and glyceryl trinitrate hold promise as effective adjunctive treatment for chronic tendinopathies. Evidence-based guidelines on newer therapies There is evidence for the efficacy of topical glyceryl trinitrate therapy in treating common chronic tendinopathies (Achilles tendinopathy, lateral epicondylosis, and supraspinatus tendinopathy) (E2),27-29 and it can be used as an adjunct to tendon rehabilitation. Aprotinin provides superior analgesia compared with corticosteroid injections and placebo in patella tendinopathy (E2).18 This therapy may be particularly useful for chronic tendinopathy of the major weightbearing tendons, where the use of cortisone is contraindicated. Given the lack of controlled efficacy studies, prolotherapy cannot yet be recommended for treating soft-tissue injuries. Current evidence does not support the use of botulinum toxin injections for tendon injuries.23 There are no studies on the use of glucosamine in treating soft-tissue injuries. 1 Tendinopathies Tendon injuries, such as in lateral epicondylosis (tennis elbow, top) and tibialis posterior tenosynovitis (bottom), can be recalcitrant to treatment; conventional treatments such as non-steroidal anti-inflammatory drugs and corticosteroid injections may have a short term analgesic effect, while there is some evidence of efficacy with newer treatments such as topical glyceryl trinitrate therapy. 2 Evidence-based medical management of soft–tissue injuries NSAIDs = non-steroidal anti-inflammatory drugs.

Justin A Paoloni PhD, MSpMed, FACSP · John W Orchard MB BS, PhD, FACSP

Objective: To determine the extent of self-reported use of prescription medications in an Australian community sample.Design, setting and participants: Face-to-face interviews with a random, representative sample of the South Australian population (aged ≥ 15 years) living in metropolitan and rural areas. The study, a Health Omnibus Survey, was conducted between March and June 2004.Main outcome measures: Reported number of prescribed medications used per person, most common categories of medication, and use by individuals of multiple medications for the same body system.Results: From 4700 households selected, 3015 participants were interviewed (65.9% response rate). Of respondents, 46.8% were using prescribed medications; 171 respondents (5.7%) were taking six or more medications, and four were taking 16 or more; 23.2% were using medications for the cardiovascular system, with 11.9% using agents acting on the renin–angiotensin system. Prescription medication use increased with age, with over 10% of respondents aged ≥ 55 years using six or more medications.Conclusions: Use of multiple prescribed medications was common, with the potential for significant drug interactions. Assuming a similar pattern of medication use Australia-wide, reducing the number of prescribed medications by one for people taking six or more medications would save the federal government about $380 million a year.

Robert D Goldney MD, FRANZCP, FRCPsych · Laura J Fisher BA(Hons)

Robert D Goldney Professor of Psychiatry, University of Adelaide, The Adelaide Clinic, 33 Park Terrace, Gilberton, SA 5081. Robert.goldneyATadelaide.edu.au To the Editor: Two recent items in the Journal might potentially lead to misinterpretation of the evidence on managing depression in young people. The first was the book review entitled Darker side of “wonder drugs” by Jureidini1 in which there was no disclosure that the author of the review is president of Healthy Skepticism, a body which has been quite strident in its opposition to antidepressant therapy. The second was the unattributed comment in the editorial by Rey and Dudley describing “parents who believe their children killed themselves because they were taking SSRIs [selective serotonin reuptake inhibitors] . . .”,2 which may imply subtly that this has occurred frequently. In a review of the United Kingdom General Practice Research Database of more than three million people,3 there were no suicides among the 6976 aged 10–19 years who had been prescribed one of two SSRIs or two tricyclic antidepressants; however, 15 people in that age group who had not received an antidepressant drug died by suicide. Furthermore, in a review of 14 857 suicides in Sweden, of the 52 involving people under 15 years, no SSRIs were detected, and in the 15–19-years age group, those taking SSRIs had a lower relative risk of commiting suicide than those taking other antidepressants.4 Clinicians with responsibility for children and adolescents can be reassured by these data, and also by the fact that the American Food and Drug Administration “black box” warning (their most potent warning) about antidepressants has recently been modified.5 Furthermore, the American Academy of Child and Adolescent Psychiatry and the American Psychiatric Association have provided a new resource about the use of medication in treating childhood and adolescent depression,6 which has been endorsed by over a dozen United States organisations comprising a “national coalition of concerned parents, providers, and professional associations”. This should allay questions that have rightly been raised, but that have been answered in favour of the judicious use of antidepressants, along with other therapeutic measures for children and adolescents with severe depression. In view of the strong association between child and adolescent mood disorders and suicide,7 the above research findings and the recommendations of respected professional bodies raise the issue of potential legal action for not at least trialling antidepressant medication in young people with severe depression if non-pharmacological measures are ineffective.

Robert D Goldney

Peter R Mansfield,* Melissa K Raven,† Jon N Jureidini‡ * Research Fellow, University of Adelaide, SA; † Lecturer, Flinders University, Adelaide, SA; ‡ Head, Department of Psychological Medicine Women's and Children's Hospital, Adelaide, SA. peter.mansfieldATadelaide.edu.au To the Editor: Rey and Dudley cite clinical experience as the basis of their recommendation of selective serotonin reuptake inhibitors (SSRIs) — chiefly fluoxetine — for youth with severe depression plus severe impairment or failure of non-drug therapy.1 They do not discuss the evidence on efficacy because they claim that it is “ambiguous enough for scholars to be divided”. It is true that industry-funded scholars are continuing to suggest that SSRIs (chiefly fluoxetine) provide a worthwhile benefit.2 However, the evidence is unambiguous. The four published comparisons of fluoxetine versus placebo for children and adolescents have all been negative on their pre-specified primary endpoints.3,4 A tiny average benefit is likely, but the magnitude of this benefit is unlikely to exceed the magnitude of less frequent but more severe harms. Furthermore, the common clinical impression of worthwhile benefit is to be expected given the large average improvements seen in placebo groups. Rey and Dudley speculate that psychosocial treatments may be less effective with uncooperative teenagers.1 However, that group may also be at higher risk of the dangers of intermittent use of, and overdosing with, antidepressant drugs. Rey and Dudley cite Timimi’s critique of the concept of childhood depression5 as supporting “treating depression primarily as a moral or social problem”. However, Timimi did not even allude to depression as a moral problem, and advocated a multi-perspective approach that normalises emotional responses to adverse life experiences and includes interventions addressing biological factors, such as diet, exercise, and cognitive abilities. Rey and Dudley use a related straw-man argument in their final sentence when they suggest that the only alternatives to SSRIs are tricyclic antidepressants, victim blaming, and non-treatment. Rey and Dudley deny being influenced by the gifts and funding that they have received from drug companies. There is compelling evidence that gifts and funding are effective, on average, for influencing beliefs, especially among people who have an illusion of invulnerability.6 We are not aware of any way that any individual can know that he or she has not been influenced.

Peter R Mansfield · Melissa K Raven · Jon N Jureidini

Joseph M Rey,* Michael J Dudley† * Professor, Psychological Medicine, University of Sydney, PO Box 142, North Ryde, NSW 1670. † Senior Lecturer in Psychiatry, University of New South Wales, Randwick, NSW. jreyATmail.usyd.edu.au In reply: The data available are inconclusive, but suggest that treatment with selective serotonin reuptake inhibitors (SSRIs) may increase the short-term (less than 14 weeks) risk of suicidal thoughts or self-harm in children and adolescents slightly, by about 2%. However, SSRI treatment may actually decrease the number of completed suicides,1 as Goldney also highlights. To show whether SSRIs influence the risk of completed suicide, a rare event, requires a randomised trial including up to two million individuals.2 This will not happen. Hence, clinicians must rely on accumulated data from experimental, epidemiological, and observational studies. Disagreements about interpretation will doubtless continue. In response to Mansfield and colleagues, we personally know of media reports influencing some practitioners to revert to using tricyclic antidepressants, and child psychiatrists to avoid treating depressed adolescents. We do not shrink from our interpretation of the implications of Timimi’s reconceptualisation of “depression” as “unhappiness”. Regardless of how childhood depression is classified or named, we remain concerned that the impetus for clinicians to diagnose and treat it not be lost. Its social correlates include stigma and racism, which often involve seeing mental health problems as moral failures of character. Our view is that fluoxetine shows a favourable harm–benefit profile in moderate to severe depression. According to the Treatment for Adolescents with Depression study,3 which was not funded by drug companies, four children need to be treated with fluoxetine for one to show much or very much improvement attributable to medication. This compares with having to treat 21 children for one to display a widely defined harm-related event. The numbers improve further when fluoxetine is combined with cognitve behavioural therapy (3 and 50, respectively). Pending new studies, clinicians would be unwise to ignore these data when treating serious depression in young people, a recurring illness that produces much suffering, physical and psychosocial disability, and suicide (odds ratio estimates ranging from 11.0 to 27.0).4 Our opinions are consistent with those of the recently released joint clinical guidance by the colleges of psychiatrists, general practitioners, and physicians.5 Mansfield and colleagues suggest that our editorial’s content might have been influenced by drug company gifts. We provided the educated readers of the Journal with information to judge this for themselves.

Joseph M Rey · Michael J Dudley

Duncan Topliss Chairman, Adverse Drug Reactions Advisory Committee, Therapeutic Goods Administration, Department of Health and Ageing, Canberra, ACT 2601. adracAThealth.gov.au Comment: Three essentially independent reviews of the use of selective serotonin reuptake inhibitor (SSRI) antidepressants in children and adolescents have been undertaken in Australia in the past 9 months.1-3 The review by the Adverse Drug Reactions Advisory Committee1 had input from representatives of the Royal Australian and New Zealand College of Psychiatrists and the Division of Paediatric and Child Health, Royal Australasian College of Physicians (RACP). All three reviews noted the paucity of information to support the efficacy of these and other antidepressants in children and adolescents, and the frequent observation of increased suicidal thoughts and self-harm in clinical trials. The colleges’ review2 and the National Prescribing Service Rational Assessment of Drugs And Research (RADAR) review3 support the ADRAC advice that: Any use of SSRIs in children and adolescents with MDD [major depressive disorder] and other psychiatric conditions should be undertaken only within the context of comprehensive management of the patient. Management should include careful monitoring for the emergence of suicidal ideation and behaviour which may particularly develop early in therapy, or if therapy is interrupted or irregular because of poor compliance. Cognitive behaviour therapy, if it is available, may enhance the outcome in MDD. An SSRI should be chosen for a child or adolescent with MDD or other psychiatric condition only after taking into account the recent evaluations of clinical trial data and the Australian product information. Prescribers should be aware that the marketers of fluvoxamine and sertraline (indicated for obsessive compulsive disorder) advise against their use in children and adolescents with MDD, and the marketers of citalopram, escitalopram, paroxetine, venlafaxine and fluoxetine warn or caution against their use in patients aged less than 18 years for any indication. It is important to note that children and adolescents who are being treated for MDD with an SSRI should not have their medication ceased abruptly.

Duncan Topliss

To the Editor: A 47-year-old woman presented with a 1-week history of spontaneous prominent and painful bruising and haematomata, 5–6 weeks after commencing meloxicam 15 mg daily for osteoarthritis and plantar fasciitis. The bruises varied in size from 2 cm × 2 cm to 3 cm × 4 cm. She had a past history of acne rosacea, for which she was taking clonidine 100 μg daily, and reflux oesophagitis, for which she was taking pantoprazole 40 mg daily. Meloxicam, being the only new drug taken by the patient, was suspected as the causative agent and was therefore discontinued. Activated partial thromboplastin time (APTT) at presentation was 58 s (reference range, 22 s –38 s). A week after stopping meloxicam, it had fallen to 37 s. All other haematological parameters, including platelet count and international normalised ratio, were normal, as were renal and liver function. New bruises and haematomata stopped appearing 2 days after the patient stopped taking meloxicam. She continued taking clonidine and pantoprazole. Meloxicam is a selective nonsteroidal anti-inflammatory drug (NSAID) (a cyclo-oxygenase 2 [COX-2] inhibitor). It was chosen for this patient in view of her reflux oesophagitis and because she had already been unresponsive clinically to one of the other COX-2 inhibitors. Unlike non-selective NSAIDs, meloxicam has been shown to have negligible effect on platelet function as measured by bleeding time.1-3 Rinder et al4 reported no prolongation of APTT or prothrombin time after 8 days of regular administration of meloxicam at 7.5 mg, 15 mg or 30 mg. In spite of these contrary findings, I believe the prolongation of APTT and spontaneous bruising and haematomata in this patient were directly attributable to meloxicam, as the bruises disappeared 2–3 days after stopping the drug (with no other changes in the patient’s existing medication) and a repeat APTT a week after cessation of the drug was normal.

Anil M Kurien

Aim: To evaluate the efficacy and safety of an annual intramuscular injection of cholecalciferol for vitamin D deficiency.Design: Prospective open-label study.Participants: Five men and 45 women (mean age 66.3 years) with vitamin D deficiency who were given a single therapeutic intramuscular injection of 600 000 IU (15 mg) cholecalciferol (vitamin D3).Outcome measures: Serum levels of calcium, creatinine, 25-hydroxyvitamin D3 (25OHD3) and parathyroid hormone, as well as early morning 2-hour urine calcium/creatinine excretion index. Specimens were collected at baseline and after 4 and 12 months of therapy. Data are reported as mean ± 1 SD.Results: Vitamin D deficiency was severe (< 12.5 nmol/L) in one participant, moderate (12.5–24 nmol/L) in 14, and mild (25–49 nmol/L) in 35. Twenty-four participants (48%) had secondary hyperparathyroidism. Following intramuscular cholecalciferol injection, serum 25OHD3 levels normalised in all participants and remained above 50 nmol/L throughout the study. Serum 25OHD3 levels were significantly higher at 4 months (114 ± 35 nmol/L), and 12 months (73 ± 13 nmol/L) compared with baseline (32 ± 8 nmol/L) (P < 0.001), increasing by an average of 128% over the 12 months. There was a corresponding decrease in serum parathyroid hormone levels at 4 months (6 ± 3 pmol/L) and at 12 months (5.2 ± 3 pmol/L), with a 30% decrease at 12 months from baseline (7.4 ± 4 pmol/L) (P < 0.01). Primary hyperparathyroidism was unmasked in one participant at 4 months and mild hypercalcaemia (serum calcium, < 2.70 mmol/L) was noted in two participants (4%) at 12 months. Serum creatinine levels remained normal in all participants throughout the study, while increases in 2-hour urine calcium/creatinine excretion index were seen in 10 participants (20%) at 12 months, three of whom had had elevated values at baseline.Conclusions: Once-yearly intramuscular cholecalciferol injection (600 000 IU) is effective therapy for vitamin D deficiency. While this therapy appears to be safe, the potential for developing hypercalciuria needs to be examined in a large randomised controlled trial.

Terrence H Diamond MB ChB, MRCP, FRACP · Kenneth W Ho MB BS · Peter G Rohl MB BS, FRACP · Matthew Meerkin FRCPA, FAACB, FACB

The aromatase inhibitors deplete oestrogen by inhibiting aromatase, the enzyme that synthesises oestrogen from androgens. They are effective as therapies for breast cancer only in postmenopausal women whose tumours express oestrogen or progesterone receptors. As adjuvant therapy, tamoxifen and the aromatase inhibitors have similar efficacy in the first 5 years of treatment. Aromatase inhibitors can be used as an alternative to tamoxifen in women with symptomatic intolerance or a contraindication to tamoxifen. Early data suggest that switching to an aromatase inhibitor after 2–5 years of tamoxifen therapy is beneficial in women with high-risk disease. Aromatase inhibitors are associated with more hot flushes than placebo, but with fewer hot flushes, less endometrial toxicity and venous thromboembolism, and more arthralgia, myalgia and bone fracture than tamoxifen.

Ilona C Nordman MB BS · Andrew J Spillane BM BS, MD, FRACS · Anne L Hamilton MB BS, FRACP

What we need to knowWhat we need to do

J Paul Seale PhD, FRACP

Assessment of real cost effectiveness, with data linked to individual health outcomes while protecting patient privacy, is an essential challenge we need to meet Pharmacogenetics and pharmacogenomics — the use of genetic and genomic information, respectively, to tailor drugs to the treatment of individual patients — make it possible to use information from the human genome in ways that will radically transform the prevention and treatment of human disease.1,2 Over the past several years, Australians have been given access to several drugs which can be prescribed under a taxpayer-funded scheme only if the patient has a specific molecular disease target that predicts a good treatment outcome. The first such drug was trastuzumab for the treatment of breast cancer in women whose tumours over-express the HER2 protein. This drug was supplied by the government from December 2001 through a special program outside the Pharmaceutical Benefits Scheme (PBS). Another drug, imatinib, was also listed on the PBS in December 2001 for use in the accelerated and blast phases of chronic myeloid leukaemia, and in October 2002 for use in the chronic phase of that disease. In December 2004, gefitinib was listed for the treatment of non-small cell carcinoma of the lung in patients with evidence of an activating mutation in the epidermal growth factor receptor gene. These drugs are likely to be harbingers of a stream of drugs in which genetic information about individuals or their tumours (whether they result from DNA or RNA sequence changes, or protein alterations) will be used to maximise the efficacy of treatment. Funding the provision of new biological agents under the PBS will present a major financial outlay. Though the number of eligible patients may be small, the costs per patient are high (eg, more than $45 000 per patient per year for imatinib and more than $50 000 per year for gefitinib and trastuzumab). The high cost of providing these drugs to relatively small numbers of patients will add to the cost of the PBS when annual growth in government expenditure on pharmaceuticals averaged 10.5% between 1992–93 and 2002–03 (increasing from $1.883 billion to $5.121 billion).3 The Australian Pharmaceutical Benefits Advisory Committee (PBAC) makes recommendations to government on which drugs to list on the PBS on the basis of their comparative clinical efficacy, safety and cost-effectiveness.4 Given the high price of many of these new and existing biological agents, it has been argued that alternative models of access are needed, because they may only be cost-effective in a subgroup of patients with a disease.5 The PBAC has used a number of strategies that allow access to new biological agents while respecting the principle of cost-effectiveness. These options depend critically on identifying the subgroup of patients in whom the drug is cost-effective compared with the main available alternative treatment. Patient groups are defined by the presence of particular molecular markers of disease severity, underlying disease mechanism, or treatment prognosis.4 The PBAC has recently developed a collaborative model to enable the listing of the tumour necrosis factor-alpha inhibitor class of biological agents (including etanercept, adalimumab and infliximab) and anakinra, an interleukin-1 receptor antagonist, all of which are used in managing rheumatoid arthritis. Although molecular markers were not part of the restrictions for these drugs, the collaborative model that was developed can be applied more broadly. This model involves working with key stakeholders in the relevant medical specialty, representatives from the pharmaceutical company producing the drug, and consumer organisations to develop restrictions that will ensure that the drugs are used in ways that are the most cost-effective.4,6 These restrictions include detailed rules for initiation and continuation of therapy. The initiation rules may include a specified diagnostic test and/or evidence that the patient has failed to respond to existing treatments for the condition. Continuation of treatment requires evidence of adequate benefit on some appropriate clinical or biological test. Patients who start taking the drug are required to sign an agreement indicating that they understand and accept that PBS-subsidised treatment will cease if the criteria defining a satisfactory response to the drug are not achieved in the follow-up clinical assessment.6 An underlying difficulty (and additional cost) in listings with molecular targets is that the mechanism for identifying the target population is not coordinated with the drug development process. We need to evaluate the effects of genetically or genomically targeted drugs that are listed on the PBS on patient outcomes to improve the existing regulatory arrangements for these new drugs. Ideally, such evaluations should use data that link information on drug use and individual health outcomes. Linked data are currently very difficult to obtain for reasons of patient privacy and confidentiality, but methods should be put in place at the time of drug listing, with appropriate privacy safeguards, that enable the impact of these drugs to be assessed. The policy and economic challenges posed by these drugs also warrant wider public discussion. Increased public appreciation of the challenges that these drugs pose to the PBS is essential if we are to develop a broadly supported policy that will make these very expensive drugs available to patients who have the potential to benefit from them at a price that reflects their therapeutic value and at a cost that the government and the taxpayer are prepared to bear.

Wayne D Hall AM, PhD · Robyn Ward MB BS, FRACP, PhD · Winston S Liauw MB BS, MMedSci, FRACP · Jo-anne E Brien BPharm, BS(Pharm), PharmD · Christine Y Lu BPharm, MSc

Objective: To evaluate the effectiveness of a community-based and GP-based intervention in reducing unnecessary antibiotic prescribing for upper respiratory tract infections (URTIs) including sore throats, sinusitis and otitis media.Design: Analysis of pharmacy dispensing data in June to October before (2000) and after (2001) the intervention, which commenced on 25 June 2001.Setting and participants: Local consumers, health professionals, the Adelaide Southern Division of General Practice, the South Australian Government, and the local media in a rural region of South Australia, covering about 2000 square kilometres, with a population of over 20 000.Intervention: Community dissemination of consumer information on antibiotic use for URTIs (including a local media campaign) and education of health professionals (including sessions with general practitioners at the four practices in the study area) on current Australian therapeutic guidelines for antibiotics, and a validated clinical scoring system for decision making in managing sore throat.Main outcome measures: Total dispensing data from local pharmacies for the months of June to October in 2000 and 2001, covering the six antibiotics considered most likely to be used for URTIs (amoxycillin, amoxycillin/clavulanic acid, cefaclor, doxycycline, erythromycin and roxithromycin).Results: The dispensing of the six antibiotics reduced by 32% overall, from 77.1 to 52.9 defined daily doses per 1000 population per day, with statistically significant reductions in the range of 31%–70% for individual antibiotics; there was no reduction for amoxycillin with or without clavulanic acid.Conclusion: The intervention was associated with reduced dispensing of unnecessary antibiotics for URTIs.

William B Dollman BPharm, MAppSc, FSHP · Vanessa T LeBlanc BA(Psych) · Lynette Stevens · Peter J O’Connor PhD · John D Turnidge MB BS, FRACP, FRCPA

Jim Stockigt Senior Endocrinologist, Alfred Hospital, Melbourne; and Professor of Medicine, Monash University, VIC 3004. jrsATnetspace.net.au To the Editor: In May 2004, Sigma, the sole Australian supplier of l-thyroxine sodium, instructed pharmacists that thyroxine tablets should be stored refrigerated, both in pharmacies and after dispensing. Thyroxine bottles now carry explicit labels: “keep refrigerated” or “refrigerate at all times”. This instruction seems to have been accepted by health professionals, but patient-support groups immediately questioned the refrigeration directive. In response, Sigma conceded that thyroxine tablets can be stored at room temperature (< 25°C) for up to 4 weeks, with refrigeration still the preferred option. There are major unresolved issues about the potency, stability and bioavailability of various thyroxine preparations that are marketed competitively in the United States.1 With a single supplier in Australia, we can avoid between-preparation variations, provided that stability and consistency are maintained. The instruction to refrigerate thyroxine tablets seems to be uniquely Australian. None of my co-authors of the website <www.thyroidmanager.org>2 is aware of a refrigeration directive in any other country. The local instruction seems to have followed interaction between the Therapeutic Goods Administration and the manufacturer, so that unopened bottles could be marketed with a longer shelf life. Is the rest of the world missing out on something important? Is there something peculiar about the Australian formulation that makes it unstable at room temperature? Could this directive be without firm basis, or even dangerous? There is currently no evidence on whether thyroxine in already-opened, unsealed bottles is more or less stable at 4°C than at room temperature, but the need to keep the tablets dry has been widely emphasised.3 Consider the condensation that will occur during 200 daily openings of a refrigerated glass bottle, whatever it contains. If damp tablets lose potency, this would lead to apparent under-treatment. In the months since refrigerated storage was recommended in Australia, preliminary observations suggest that apparent under-dosage (ie, unexpected rises in serum TSH) may indeed occur in previously compliant patients (personal observation). If dosage were increased, the adjustment could result in over-treatment after a change to a fresh preparation. Thyroxine has a narrow therapeutic window, and excessive dosage can have serious effects, especially if there is associated cardiac ischaemia. While refrigeration of sealed bottles of thyroxine might extend the shelf life, the instruction to refrigerate unsealed bottles seems ill-advised. When an existing formulation is modified, it is generally the obligation of a manufacturer to demonstrate safety. The stability of tablets in sealed bottles and those in current use are quite separate issues. To establish how tablets in current use are influenced by refrigeration, it is necessary to measure the thyroxine content of remaining tablets from bottles of 200, opened and used daily for up to 6 months. Without such data, it is preferable to instruct patients not to store currently used bottles of thyroxine at refrigerator temperature.

Jim Stockigt

Ovais Siddiqui Regulatory and Medical Manager, Sigma Pharmaceuticals, Locked Bag 268, South Croydon, VIC 3136. ovais.siddiquiATsignet.com.au In reply: Sigma Australia acquired Oroxine (thyroxine sodium) from the original manufacturer in 1999, and launched Eutroxsig, an identical product, in 2002. During 2002–03, as a result of advances in analytical technology for some pharmaceutical products, product specifications, including shelf life and storage conditions, were updated, so that the product’s quality, safety and efficacy could be maximised or maintained throughout the claimed shelf life. For Oroxine and Eutroxsig, the new stability data showed a loss of up to 10% of thyroxine sodium in the first 6 months when stored below 25°C, with some plateauing thereafter. As an interim measure, Sigma, in agreement with the Therapeutic Goods Administration (TGA), decided to immediately reduce the shelf life from 24 to 12 months (“store below 25°C”) and set the lower release to 98.0% (up from 92.5%), while investigating reasons behind the loss in potency. The manufacturing process was confirmed to consistently yield tablets with very reproducible chemical and physical attributes in accordance with the release criteria. During manufacturing, however, about 2% of the thyroxine sodium is lost, with a corresponding similar increase in degradants. To limit the degradants responsible for the reduction in potency of thyroxine at room temperature, it was agreed with the TGA that thyroxine should be stored at 2°– 8°C (“Refrigerate. Do not freeze”), based on good stability data generated at this temperature. Consumer Medicine Information (CMI) and Product Information (PI) were updated in May/June 2004 to reflect this change. The new stability studies support the storage of Oroxine and Eutroxsig in the refrigerator; however, repeated in-use handling may result in an increase in condensation and microbial contamination. This may lead to changes in the physical characteristics of these products, including the growth of mould. There may be a further increase in condensation if the lid is not tightly closed. One possible solution is for patients to place up to 4 weeks’ supply of tablets in a spare, previously used, Oroxine or Eutroxsig amber-coloured bottle and store out of the fridge (below 25°C) for current use, while keeping the remaining stock in the fridge. Sigma is looking at options to improve the packaging so that the above problems are minimised or eliminated. Oroxine and Eutroxsig, manufactured by Sigma, are sold in Australia only. Sigma does not have access to formulation details, stability results and justification for the storage conditions used in other countries; therefore, we are unable to comment on such issues. As an Australian company, we are obliged to follow the regulatory guidelines of the Therapeutic Goods Act 1989 (Cwlth). Sigma recommends that the label instructions regarding storage conditions after opening be strictly followed to maximise the quality, safety and efficacy of the product.

Ovais Siddiqui

Andrew Firestone Psychiatrist; and Honorary Senior Lecturer, Monash University, Clayton, VIC 3168. afireATtpg.com.au To the Editor: Emerging evidence suggests that the so-called second-generation antipsychotics (SGAs), especially olanzapine and clozapine, can cause abnormal weight gain and increase the risk of diabetes mellitus.1-3 In Australia, there are calls for a prospective multicentre trial to compare the rates of weight gain and diabetes between SGAs.4,5 The Australian data presented here underline the pressing need for such a study. Data were examined for the 10-year period January 1994 to December 2003 for: Total prescriptions dispensed by the Pharmaceutical Benefits Scheme (PBS) and the Repatriation Pharmaceutical Benefits Scheme for 12 antipsychotic drugs; and Reactions reported in the same period to the Adverse Drug Reactions Advisory Committee (ADRAC) for each of these drugs, involving excessive weight gain or obesity, and diabetes mellitus or hyperglycaemic reactions. Reports were included in the survey only when it was considered that no other drug could be responsible. As clozapine is dispensed and recorded differently from other SGAs in Australia, complete data on numbers of prescriptions dispensed were not available. However, total Australian expenditure was available for each tablet strength of clozapine for the full 10-year study period, along with number of prescriptions dispensed and costs for the private hospital sector for the 4 years July 2000 to June 2004. Therefore, I calculated the average script cost for each tablet strength, and extrapolated the script numbers for the 10-year period, as shown in Box 1. Box 2 shows the “report rate” for each SGA for the side effects of weight gain or obesity, and diabetes or hyperglycaemia. The report rate for side effects was greater for clozapine than for any other SGA. Unfortunately, the true situation may be still worse. Clozapine is usually prescribed a month at a time, while the other drugs are prescribed for up to 6 months. Adjusting for this would widen the gap further. Moreover, as ADRAC promotes reporting for new drugs, the report rates for the five drugs introduced during the study period are probably inflated. Clozapine is not one of them. The limitations of ADRAC data are well known.4 Nevertheless, these are currently our best Australian data and strongly suggest that SGAs, of which risperidone has the most favourable profile, cause weight gain and diabetes much more often than the older antipsychotic agents. These data accord with previously published studies1 and support the US advice to avoid olanzapine and clozapine if possible. Recent PBS approval in Australia for use of olanzapine in bipolar disorder further underlines the urgent need for a prospective multicentre study to compare weight gain and glucose metabolism in patients taking antipsychotic drugs. Meanwhile, I suggest that: Patients who have abnormal weight gain with an SGA might be treated with chlorpromazine, trifluoperazine or haloperidol. PBS regulation of clozapine might be amended, to discourage its prescription until after failure of a “first-generation” as well as a second-generation antipsychotic drug. 1 Estimation of the total number of clozapine scripts in Australia Tablet strength (mg) Private hospitals data (Jul 2000–Jun 2004) Total clozapine used (Jul 1994–Jun 2004) Total prescriptions Cost ($) Average cost/ prescription ($) Cost ($) Estimated total prescriptions 25 3 650 230 929 63.27 9 636 814 152 313 50 25 1 443 57.72 85 980 1 490 100 21 057 6 632 499 314.98 153 276 771 486 624 200 69 24 392 353.51 463 131 1 310 Total 24 801 6 889 263 – 163 462 696 641 737 2 Report rates for side effects of antipsychotic drugs No. of years* No. of prescriptions dispensed No. of ADRAC reports Report rate (per million prescriptions dispensed) Weight gain† Diabetes‡ Weight gain† Diabetes‡ Chlorpromazine 10 950 221 0 0 0 0 Fluphenazine 10 327 126 0 0 0 0 Trifluoperazine 10 937 605 1 0 1.07 0 Pericyazine 10 657 514 0 0 0 0 Thioridazine 10 1 983 915 1 3 0.50 1.51 Haloperidol 10 1 499 254 2 0 1.33 0 Flupenthixol 9 121 132 0 0 0 0 Zuclopenthixol 8 93 839 0 1 0 10.66 Olanzapine 6 2 786 334 47 19 16.87 6.82 Quetiapine 4 271 957 1 4 3.68 14.70 Risperidone 9 1 298 156 6 2 4.62 1.53 Clozapine 10 641 737§ 41 61 63.89 95.05 ADRAC = Adverse Drug Reactions Advisory Committee. * Number of years with data available (as some drugs were introduced only after the start of the 10-year period). † Weight gain or obesity. ‡ Diabetes mellitus or hyperglycaemia. § Estimated number (see Box 1).

Andrew Firestone

Ian W Boyd Executive Officer, Adverse Drug Reactions Unit, Therapeutic Goods Administration, Australian Government Department of Health and Ageing, PO Box 100, Woden, ACT 2606. ian.boydAThealth.gov.au To the Editor: Labate and colleagues note that tramadol is the most frequently suspected cause of provoked seizures at their First Seizure Clinic.1 Early in 2003, the Adverse Drug Reactions Advisory Committee (ADRAC) reported to Australian prescribers the results of the first 4 years of experience with tramadol in Australia.2 At the time, ADRAC noted that 26 cases of convulsions had been reported among a total of 354 reports on tramadol. By January 2005, ADRAC had received a total of 921 reports involving tramadol, of which 66 described convulsions. (Labate et al reported that 83 cases of convulsions associated with tramadol had been reported to ADRAC. This is incorrect, but the mistake probably resulted from an error in interpretation of information supplied by the Adverse Drug Reactions Unit.) In 27 cases, tramadol was the only suspected drug, but in the other 39 cases there were various other suspected drugs. This included 20 reports in which there was a suspected drug interaction. Both oral and injected tramadol have been implicated. The product information for tramadol states that convulsions have been reported in patients using tramadol at the recommended dose levels and that the risk may be greater when doses of tramadol exceed the recommended limits.3 In addition, tramadol may increase the seizure risk in patients taking other medications that lower the seizure threshold. Drugs specifically mentioned in this context include the selective serotonin reuptake inhibitors, tricyclic antidepressants and antipsychotic drugs. In the 39 cases reported to ADRAC in which there were one or more suspected drugs in addition to tramadol, tramadol was being used with selective serotonin reuptake inhibitors (10 cases), tricyclic antidepressants (6 cases) and, in 13 cases, other drugs that may also have the potential to lower the seizure threshold, such as pethidine (2 cases), venlafaxine (2), propofol (2) and bupropion (2). In two of the cases in which tramadol was the only suspected cause and two of the cases with multiple suspected causes, the patients were also taking anticonvulsant drugs for seizure control. ADRAC data indicate that, although tramadol alone can induce seizures, these are more likely to occur in the setting of the concomitant use of other drugs that also have the potential to lower the seizure threshold.

Ian W Boyd

Clinical recordsIn 2003, five patients presented to the Oral and Maxillofacial Surgery Unit at Royal Adelaide Hospital, South Australia, with painful exposed bone in the maxilla, or both the maxilla and mandible (Box 1 and Box 2 ). All patients were receiving either pamidronate (Aredia [Novartis]) or alendronate (Fosamax [Merck Sharp & Dohme]). Pamidronate was being given intravenously monthly at a dose of 60mg (one patient) or 90 mg (three patients). The patient taking alendronate received a daily oral dose of 40mg. Duration of bisphosphonate therapy was 6 months to 6 years. Associated risk factors for the development of avascular necrosis included renal impairment in one patient and hypoproteinaemia in another. Initial management of these patients comprised surgical debridement of the exposed bone. Histopathological assessment of surgical specimens showed no histological evidence of myelomatous deposits or Paget's disease from the affected sites in the jaws in any of the patients. None had exposed bone elsewhere in the body. Here we present five cases of osteonecrosis of the jaw associated with bisphosphonate use. In North America, several preliminary reports have been published of unusual cases of avascular necrosis of the jaw in patients using second-and third-generation nitrogen-containing bisphosphonates.1-4 These included pamidronate, alendronate, risedronate and zoledronic acid.2,3 In Australia, bisphosphonates have been available for several years and are commonly prescribed for a range of conditions, including osteoporosis, Paget’s disease, multiple myeloma,5,6 hypercalcaemia of malignancy, and bone metastases of malignancies such as breast and prostate cancer. An estimated 200 000 patients in Australia receive these drugs. Commonly reported adverse reactions involve gastrointestinal symptoms. Bone-marrow depression and thrombocytopenia are also reported rarely. The second- and third-generation bisphosphonates are significantly more potent than their first-generation predecessors, (etidronate, clodronate and tiludronate). They inhibit bone resorption by osteoclastic inhibition, through selective concentration at the interface of the active osteoclast and the bone-resorption surface. The specific mechanism of this inhibition is unknown, but there is evidence for several actions, including inhibition of osteoclast development from precursor cells, increase in osteoclast apoptosis,7 stimulation of osteoclast inhibitory factor, reduction of osteoclast activity, and down-regulation of matrix metalloproteinases. The resulting reduction in osteoclastic activity reduces bone resorption, supporting the use of bisphosphonates for the above indications. However, osteoclastic function is part of the cycle of bone turnover; osteocytes have a life span of about 150 days, after which osteoclasts resorb the mineral matrix of bone and release bone morphogenetic protein and insulin-like growth factors, which in turn induce local stem cells to differentiate into osteoblasts and form new bone. This cycle is critical to maintaining bone stocks and bone viability. If osteoclastic function is too severely impaired, dead and dying osteocytes are not replaced, and the capillary network in the bone is not maintained, resulting in avascular bone necrosis. Dental disease and denture-wearing are ubiquitous. Studies involving larger patient numbers have shown that nearly 80% of cases were initiated by tooth removal.3 Patients who have been using potent bisphosphonates for more than 6 months appear to be at highest risk.2 Other apparent risk factors are residual multiple myeloma or other malignancy, hypoproteinaemia, renal impairment from disease or drugs, and chemotherapy. Although a definite cause-and-effect relationship is yet to be established, the association between bisphosphonate therapy and osteonecrosis of the jaw appears strong.2-4,8-10 The incidence of the potential complication appears low. In South Australia in 2003, about 14 000 patients received prescriptions for the potent second- and third-generation nitrogen-containing bisphosphonates, with about 10% having intravenous administration. Our five patients probably represented all cases of the complication, as our Department is the only oral and maxillofacial surgery service in SA and receives referrals from around the state.8,9 Checking with colleagues and related hospital services has not revealed further cases in SA, but we are aware of other cases in all states of Australia. Indeed, the Adverse Drug Reactions Advisory Committee recently reported another nine cases.10 At present, there is no effective treatment for the condition. Patients are usually referred to oral and maxillofacial surgeons, but surgical intervention is difficult as it often exposes further bone, and, as bisphosphonates affect the whole skeleton, locating viable bone margins may be impossible. Furthermore, removal of painful teeth, while initially alleviating pain, also further exposes bone, causing more pain. Covering exposed bone with tissue flaps has been found ineffective because of the development of fistulae around the flaps and possible complete dehiscence (Box 1). Compounding the problem, some patients must continue with bisphosphonate therapy and/or other chemotherapies to control hypercalcaemia. Hyperbaric oxygen therapy is not useful in bisphosphonate-induced necrosis, and antibiotics are indicated only to treat secondary infection. Because of the lack of effective treatment for the condition, second- and third-generation bisphosphonates should be used only when benefits clearly outweigh risks. When intravenous or high-dose oral bisphosphonates are considered appropriate, referral for full dental assessment and treatment before the start of therapy should be considered. Once bisphosphonate therapy has begun, there should be regular clinical monitoring of oral health. Avoiding tooth removal and dental implants, non-surgical control of periodontal disease, and use of soft liners on dentures also seem prudent. In addition, major debridement surgeries should be avoided if at all possible. In established cases, the primary goals are palliation and control of osteomyelitis. In most cases, progression has been controlled with long-term or intermittent courses of dicloxacillin or cephalexin (to treat any secondary infection), chlorhexidine mouthwash (Savacol), and periodic minor debridement of soft-textured sequestrating bone and wound irrigation. The rapid expansion of indications for bisphosphonates has resulted in their widespread use across many medical disciplines, including endocrinology, rheumatology, medical oncology, haematology and general practice. Most medical practitioners are unaware of this serious and potentially permanent complication. Before prescribing bisphosphonates, medical practitioners should analyse the risks versus benefits for the individual patient, consider alternative drugs, and obtain informed consent after discussing this potential adverse reaction. We also encourage vigilant surveillance of patients who are using a bisphosphonate. Summary Five patients presented to the Royal Adelaide Hospital, South Australia, in 2003 with painful exposed bone in the maxilla, or both the maxilla and mandible. All had been receiving potent second- or third-generation bisphosphonate therapy — monthly intravenous pamidronate in four cases and daily oral alendronate in the other. These cases are among the earliest reported occurrences of this condition in association with bisphosphonate therapy in Australia. The condition presented after tooth extraction in four cases and denture pressure in the other. Osteonecrosis continued for more than a year in three patients despite treatment. 1 Necrosis of the maxilla in a 57-year-old man receiving pamidronate for multiple myeloma The oral cavity showing exposed necrotic maxillary bone and a large oro-antral communication. Computed tomography showing significant bone destruction in the right maxilla (outlined). 2 Clinical details of five patients with avascular necrosis of the jaw in South Australia, 2003 Age, sex Presentation Precipitant Bisphosphonate [indication] Other medications Treatment Outcome 57, M Painful exposed bone in maxilla and mandible Tooth extraction Pamidronate (90 mg IV monthly for 6 years) [multiple myeloma] Dexamethasone, methotrexate, warfarin, folic acid, ranitidine, metformin, hydroxychloroquine, verapamil, sertraline, morphine Hyperbaric oxygen, Le Fort I level maxillectomy, bisphosphonate continued Persistent necrosis of midface and mandible 64, M Ulcer in right hard palate with bone sequestrum Tooth extraction Pamidronate (90 mg IV monthly for 2 years) [multiple myeloma] Prednisolone, cyclosporin, itraconazole, sulfamethoxazole–trimethoprim, ranitidine, penicillin Sequestrectomy, local debridement, bisphosphonate continued Resolution 73, M Pain, swelling of anterior maxillary alveolus Tooth extractions Alendronate (40 mg orally daily for 5 years) [Paget’s disease] Amlodipine, tramadol, perindopril Local debridement, sequestrectomies, primary flap closure, bisphosphonate ceased Resolution 78, F Painful exposed bone in maxilla Denture pressure Pamidronate (90 mg IV monthly for 18 months) [Paget’s disease] None Hyperbaric oxygen, local debridement, denture reline, bisphosphonate ceased Persistent areas of exposed bone 84, F Non-healing extraction site in left maxillary alveolus Tooth extraction Pamidronate (60 mg IV monthly for 6 months) [Paget’s disease] Diltiazem, simvastatin, ferrous sulfate, aspirin, bendrofluazide Wide intraoral resection with primary flap closure, bisphosphonate ceased Persistent fistula IV = intravenous.

Glen Carter BDS, MB BS, FRACDS(OMS) · Alastair N Goss DDSc, FRACDS(OMS) · Chris Doecke BPharm, PhD

Clinical records The Adverse Drug Reactions Advisory Committee (ADRAC) has recently received 13 reports of osteonecrosis of the jaw associated with bisphosphonate use — 12 after intravenous bisphosphonate use, and one after oral alendronate use (Box). Ten of the reports implicated zoledronic acid, one pamidronate, and the other implicated both drugs in circumstances where the patient had switched from pamidronate to zoledronic acid. In the nine cases with information on bisphosphonate dose, the monthly doses accorded with those recommended in the product information (90 mg of pamidronate, 4 mg of zoledronic acid). Time to onset varied from 1 month to more than 4 years, although most reports did not specify date of onset, possibly because onset was insidious. Presenting symptoms included localised pain, numbness and altered sensation, exposed bone in the oral cavity, soft tissue infection and, in one case, loosening of several teeth. One report described a dental abscess after radiotherapy. All the reports described the osteonecrosis as occurring in the jaw; four specified the mandible, and two the maxilla. With the exception of the report implicating oral alendronate for treatment of osteoporosis, the reports indicated that the bisphosphonate was being used in the context of malignancy. Four reports documented dental extraction during bisphosphonate therapy in the months before the onset. One patient had had several teeth extracted because they had become loose during bisphosphonate therapy. A further report stated that onset of osteonecrosis occurred before dental extraction. Many of the 13 reports were received soon after diagnosis, but, in at least four cases, the problem had persisted for 2 to 3 months after withdrawal of the bisphosphonate. None of the 13 patients had recovered at the time of reporting. Recently, the United States Food and Drug Administration drew attention to the problem of osteonecrosis (also described as avascular or aseptic necrosis) of the mandible and/or maxilla, occurring in association with intravenously administered bisphosphonates used to control hypercalcaemia in metastatic bone disease.1 In addition, two case series were published recently summarising 99 case reports of osteonecrosis of the jaw associated with bisphosphonates.2,3 Combined with smaller case series, they bring the total reported to 129 cases.4-8 Not all bisphosphonates have been implicated. Most commonly associated with the problem were zoledronic acid and pamidronate, possibly because these are the only intravenous bisphosphonates in widespread use, and because zoledronic acid has been approved for regular use in metastatic disease. However, seven reports implicated oral alendronate or risedronate used to treat osteoporosis.4,6 Osteonecrosis of the jaw closely resembles the occupational disorder “fossy jaw”, which occurred in workers in match factories using white phosphorus in manufacturing.9 The condition was distressingly painful, refractory to treatment and disfiguring to the extent that some sufferers committed suicide. Bisphosphonates are not metabolised and have a strong binding affinity with osteoclasts. They can persist in bone for months and sometimes years after the drug has been discontinued. Accordingly, withdrawal of bisphosphonate therapy does not appear to hasten recovery of the osteonecrosis. Other treatments, including mouth rinses, systemic antibiotics, hyperbaric oxygen and surgical debridement have been tried, but so far none has proven consistently effective. The mechanism underlying the reaction is unknown, but it has been postulated that bisphosphonates inhibit new vessel formation, thereby impairing healing. Although dental extractions and other oral surgery have been identified as precipitants in many cases, there is evidence suggesting that alveolar bone can be involved before, and independently of, such procedures. Indeed, the clinical presentation may closely simulate dental abscesses, “toothaches”, denture sore spots, and osteomyelitis. Documented risk factors include a diagnosis of cancer, concomitant therapies (eg, chemotherapy, radiotherapy and corticosteroids) and comorbid conditions (eg, anaemia, coagulopathies, infection, and pre-existing oral disease).10 Concomitant chemotherapy and corticosteroid treatment, in particular, may result in immunosuppression and thereby predispose to ongoing local sepsis after minor trauma. Because this condition and its complications result in significant chronic pain, dysfunction and disfigurement which are difficult to treat, the focus should be on prevention. It is important that all health professionals, especially dentists, oncologists and oral surgeons, be aware of the possibility that patients being considered for dental extractions or other oral surgery are undergoing intravenous bisphosphonate therapy. Also, it is important for patients to be informed of the risk of this complication of bisphosphonate therapy, so that they have the opportunity to assess the need for dental treatment before starting therapy.11 It is not known at this stage whether discontinuing bisphosphonates before major dental procedures can help prevent the problem, but, given the persistence of bisphosphonates in bone, it is unlikely. Prescribers should also be aware that osteonecrosis of the jaw can occur in association with oral bisphosphonate therapy for osteoporosis. Summary 13 cases of osteonecrosis of the jaw associated with bisphosphonate use have recently been reported to the Adverse Drug Reactions Advisory Committee. Most cases were associated with intravenous bisphosphonate therapy (11 cases with zoledronic acid and one with pamidronate), but one was associated with oral alendronate used to treat osteoporosis. The condition causes chronic pain, dysfunction and disfigurement; no treatment has proven consistently effective, and withdrawing the bisphosphonate does not seem to hasten recovery. The focus should be on prevention through attending to any necessary dental treatment before bisphosphonate therapy begins. Clinical characteristics of 13 patients reported to ADRAC with osteonecrosis associated with bisphosphonate use Age, sex Bisphosponate used, other therapy Indication for bisphosponate Time to onset Symptoms Outcome 42, F Zoledronic acid (4 mg IV every 3–4 weeks), capecitabine, celecoxib, ranitidine, radiotherapy Breast carcinoma 6 months Tooth abscess, osteoradionecrosis (site not specified) Unknown* 46, F Zoledronic acid (4 mg IV monthly), previously pamidronate (90 mg), dexamethasone Breast carcinoma 4–6 months Jaw necrosis (site not specified) Not recovered† 46, F Zoledronic acid (4 mg IV monthly) Breast carcinoma 5 months Maxillofacial pain, exposed bone in oral cavity, dental extractions, gingival swelling, impaired healing Unknown† 57, M Zoledronic acid (4 mg IV, frequency not stated), corticosteroids, chemotherapy Prostate carcinoma > 2 years Exposed, painful bone in mandible, numbness, soft tissue infection Not recovered‡ 67, F Alendronate (oral) prednisolone, leflunomide, celecoxib Osteoporosis ns Maxillary alveolar necrosis, spontaneous loss of teeth, osteomyelitis, oro-antral fistula, condition recurred after surgery Not recovered* 73, M Pamidronate (90 mg IV monthly), thalidomide, corticosteroids Multiple myeloma 1 year Mandibular pain, hypoaesthesia, loosening of teeth, dental extractions, impaired healing, exposed bone Slowly improving§ 75, M Zoledronic acid (4 mg IV, frequency not stated), corticosteroids, chemotherapy Prostate carcinoma > 2 years Exposed, painful bone in mandible, numbness, dysaesthesia Not recovered‡ 79, M Pamidronate (90 mg IV monthly), prednisolone, melphalan Multiple myeloma 1 month Mandibular pain, dysaesthesia, dental extraction, impaired healing, exposed bone, osteomyelitis, recurrent soft tissue infection Not recovered† 80, M Zoledronic acid (4 mg, reduced to 2 mg IV monthly) Prostate carcinoma 8 months Jaw necrosis (site not specified), recent dental surgery Not recovered† 83, M Zoledronic acid (4 mg IV monthly) Prostate carcinoma 4.5 years Jaw necrosis (site not specified) Unknown† ns, F Zoledronic acid (dosage ns) Breast carcinoma ns Jaw necrosis (site not specified) after two dental extractions Unknown* ns, F Zoledronic acid (dosage ns) Breast carcinoma ns Jaw necrosis (site not specified) Unknown* ns, M Zoledronic acid (dosage ns) Multiple myeloma ns Jaw necrosis (site not specified), exposed bone (spontaneous) Unknown* IV = intravenous. ns = not stated. * Not known whether patient continued bisphosphonate therapy after presentation. † Patient stopped bisphosphonate therapy after presentation. ‡Patient continued bisphosphonate therapy after presentation. §Pamidronate was replaced by zoledronic acid, which was ongoing.

Patrick M Purcell MB BS · Ian W Boyd PhD

Essential psychopharmacology. The prescriber’s guide. Stephen M Stahl. Cambridge: Cambridge University Press, 2005 (xv + 571 pp). ISBN 0 521 01169 8. Psychotropic drugs are heavily marketed and widely prescribed in general practice and Stephen Stahl, an internationally recognised clinician and teacher in psychopharmacology, is tapping into the need for a practical prescriber’s guide to psychotropic drug use. He has skilfully condensed essential information on individual psychotropic drugs and presented it in an attractive, user-friendly format. Information on each drug is broken down into five colour-coded sections: therapeutics; side effects; dosage and use; special populations; and the art of psychopharmacology, including how to get the best use out of a drug. The author also uses a list of icons to alert the reader to the class of drug, mechanism of action and concerns with drug interactions or major side effects. The drugs are listed in alphabetical order by their generic name and are supplemented by an index with generic and trade names allowing quick and easy reference for the busy clinician. For the Australian reader, approved indications for each of the drugs may differ from those in the United States so you may need to access “the yellow book” (Schedule of Pharmaceutical Benefits) to obtain information on PBS listings. Also, some medications are available in the US but are not approved for marketing in Australia. For example, since the book was published, regulatory decisions have led to the withdrawal of nefazodone from the market due to safety issues. There is considerable duplication of information for drugs of a similar class, such as the selective serotonin reuptake inhibitors (SSRIs). However, the advantage is that the prescriber can readily obtain all the information required on a particular drug without needing to access other chapters of the book. While the author clearly states in his introduction that certain drugs and combinations of drugs may be for the expert only, this is not always highlighted in the text, such as combination antidepressants with mirtazapine, venlafaxine or SSRIs, colloquially known as “Californian rocket fuel”. There is much in this book to recommend it to general practitioners, medical students and experts, but it is a glossy production and at $120 for the paperback, the cost is on the high side. Gordon F S JohnsonProfessor of Psychological Medicine University of Sydney, NSW

Gordon F S Johnson

Trikojus: a scientist for interesting times. Ross Humphreys. Melbourne: Miegunyah Press, 2004 (xviii + 154 pp). ISBN 0 522 85095 2. Victor Trikojus (1902–1985) must surely rank among Australia's most controversial men of science. In this extended memoir, Ross Humphreys continues his studies of Australian scientists with an agreeable account of a man who, if not born to controversy, seems to have had controversy thrust upon him. Trikojus is credited with important wartime achievements in the production of drugs, including ascorbic acid (for vitamin C), sulphaguanidine for the treatment of dysentery, mersalyl for the control of wound sepsis, and Merthiosal for the prevention of tropical fungal growths on optical instruments. After the war he had important successes in the study of thyroid metabolism, including the discovery (with Frank Hird) of T3 (triiodothyronine). He was also well known for his dedication to the University of Melbourne where, between 1943 and 1967, he established Australia’s leading Department of Biochemistry, and for his contributions to the promotion of food quality, nutrition, and public health. Among the rare Sydney University graduates to receive an 1851 Exhibition, Trikojus returned from his doctoral years in Oxford and Munich with much to offer his alma mater. Notwithstanding his scientific reputation, he is perhaps best remembered for his wartime detention as an alleged pro-Nazi sympathiser, an image that was in 1999 wildly exaggerated by articles in The Age, The Sydney Morning Herald, and on SBS television. The son of a German-born, naturalised Australian father, Trikojus was caught up in the tide of anti-Nazi (mixed with anti-communist) hysteria that coursed through Australia in 1940, leading to his formal detention in 1941, and to restrictions on his movements until 1944. A less robust character might have given way before what now seems singularly misjudged persecution by ill-informed and ill-advised, if not actually incompetent, security services. During and after the war, Trikojus, whose European manner and conservative mannerisms conjured an image of the “other” in an Australia still deeply British in both form and appearance, attracted misunderstanding. To this image, his outspoken, Russian-born wife of mixed European descent, may have inadvertently contributed. At the same time, his dealings with leading Australian scientists were widely praised, and warmly supported. Humphreys makes good use of the Trikojus archives and, by restoring him to his context, makes fresh sense of his life. If, at times, the account reads like a brief for the defence, the outcome is no worse for that. The book goes well beyond the official biography,1 and recaptures a sense of what life in wartime (and Cold War) Australia could be like for those who differed from the familiar norm. At the same time, it reminds us what a difference a “foreigner” can make to Australian cultural and intellectual life. Trikojus: a Scientist for interesting times was released in time to coincide with the opening of the new Bio21 Institute at the University of Melbourne, and includes a prefatory appreciation by Australia’s most recent medical Nobel Prize winner, Peter Doherty. Roy MacLeodEmeritus Professor of History University of Sydney, NSW 1. Legge JW, Gibson F. Victor Martin Trikojus, 1902-1985. Hist Rec Aust Sci 1987; 6: 519-531.

Roy MacLeod

A major theme of the 2004 World Congress of Clinical Pharmacology and Therapeutics was worldwide equity of access to medicines The 8th World Congress of Clinical Pharmacology and Therapeutics was held in Brisbane in August 2004. There were 940 participants from 60 countries, with Japan, Germany, Korea, South Asia and the United Kingdom well represented. The Congress featured three themes: Medicines and Society; Therapeutic Horizons; and Drug Discovery, Development and Disposition. Our report focuses on the Medicines and Society theme, which was strongly emphasised at the 8th Congress, differentiating it from previous Congresses. The prominence of this theme was to encourage the participation of clinical pharmacologists from South Asia and the Pacific regions, where access to lifesaving medicines and confidence in their quality are matters of everyday importance. The Congress also sought to encourage clinical pharmacologists from the developed world to engage with the serious global inequities in access to medicines for the major infectious diseases in the developing world, such as tuberculosis, malaria and HIV/AIDs, as well as the emerging developed-world lifestyle disorders, notably cardiovascular disease. Equity of access to medicinesSeveral plenary lectures focused on access to medicines in developing countries. Suwit Wibulpolprasert (Senior Advisor on Health Economics, Ministry of Public Health, Thailand) gave an inspirational and challenging presentation Philanthropy for the few — equity of access for the many?, tackling the difficult issue of donated medicines. He exposed the increasing gap between rich and poor in both developed and developing countries, and the many interacting social, political and financial influences that conspire to take resources away from the people who most need medicines. He concluded with practical steps that clinical pharmacologists could take to alleviate problems of access to medicines, such as promoting the use of the World Health Organization (WHO) model list of essential drugs in their own countries.1 This theme was reinforced by Sri Suryawati (Head of the Department of Clinical Pharmacology, Gadjah Mada University, Yogyakarta, Indonesia) who challenged all clinical pharmacologists to become involved in achieving the three “As” of medicine use in their own countries: access, affordability and appropriate use. An important and contentious recent issue has been access to cheap, generic versions of fixed-dose combinations of antiretro-viral drugs to deal with the HIV epidemic in Africa. Lembit Rago (Director of the WHO Division of Quality and Safety of Drugs, Geneva, Switzerland) discussed the difficult progress towards international acceptance of WHO guidance regarding registration of these products. Attention was also given to the rapidly expanding complementary medicines sector. Charlie Xue (Program Leader, Division of Chinese Medicine, RMIT University, Melbourne, Vic) outlined the WHO’s perspective on traditional medicine, and provided examples of the role of complementary medicine as a mainstay of public health systems in South-East Asia and the Pacific regions. Chu Quoc Truong (Director of The National Hospital of Traditional Medicine, Hanoi, Vietnam) related that the Vietnamese government has formally integrated traditional medicine with Western conventional medicine, with apparent good effect, notably wide acceptance of both traditions, allowing selection of cost-effective options from each. Tony Smith (Emeritus Professor of Clinical Pharmacology, University of Newcastle, NSW) summed up the unfinished business for clinical pharmacology and world health. He reminded Congress participants that clinical pharmacology arose as a discipline largely in developed countries and continues to be vital to the stellar advances in drug discovery, providing guidance to early-phase human studies, interpretation of pharmacokinetic, clinical and adverse-effects profiles, and development of product information for virtually every significant new chemical entity entering clinical practice. However, many of the needs of developing countries remain unmet, partly because of the limited numbers of clinical pharmacologists. He highlighted the vital tasks of these “few”: political advocacy for appropriate drug use; elaboration and implementation of national medicines policies; and specific “bread and butter” tasks, such as the collaborative development of standard treatment guidelines and essential medicines lists, and the promotion of rational prescribing, especially through training programs in medical schools. All the plenary speakers uniformly encouraged the international umbrella organisation for clinical pharmacology, the International Union of Basic and Clinical Pharmacology (IUPHAR), to continue to become more proactive in these areas, particularly through strong collaborations with WHO and similar organisations. This paradigm shift was strongly endorsed at the IUPHAR council meeting held during the Congress. Proper use of medicinesAnother theme running strongly through the meeting, and prominent in the Medicines and Society stream, was the concept of QUM (quality use of medicines), which was developed in Australia in the early 1990s. The Congress was an important opportunity for Australia to showcase our progress in QUM, through the gathering of evidence about what actually works, followed by implementation of effective strategies through networks, products and services. The major sponsorship of the Congress by our own National Prescribing Service — itself a prominent outcome of the QUM movement — effectively emphasised the importance of the movement in Australia and its potential for other parts of the world. Tom MacDonald (Professor of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, UK) delivered an entertaining contribution with the important message that large returns in population health outcomes would accrue if we could better implement evidence-based guidelines and improve patients’ adherence to therapy. For the prevalent cardiovascular disorders, lowering blood pressure is the intervention with the best evidence. Despite its proven benefits, blood-pressure control is poor worldwide. There are good arguments to support a more aggressive approach to blood-pressure management and treatment of younger individuals, but long-term compliance is a problem. Drug safetyAn increasing concern echoed in the Congress is the safety of medicines in older people, who are likely to have multiple comorbidities and increasing exposure to multiple, potent medicines. The future conduct of pharmacovigilance for new drugs is being shaped by interesting therapeutic risk management initiatives across the world, some of which were presented in a lively symposium entitled Medication safety and pharmacovigilance. These initiatives seek to better identify, evaluate and minimise the impact of adverse reactions, and to communicate evolving safety risks throughout the life cycle of a drug. Susana Perez-Gutthann (Senior Director, Global Epidemiology, Safety and Risk Management, Pfizer Worldwide Development, Barcelona, Spain) emphasised the need for this process to be proactive. The techniques of pharmacoepidemiology and use of advanced information technology to “mine” large automated health databases have revolutionised pharmacovigilance. The problem of the “therapeutic orphan” status of children was examined in depth by speakers from Europe, the United States and Australia. Incentives to pharmaceutical companies to evaluate already marketed medicines in children, along with mandatory studies for new medicines in this age group (provided they are potentially useful) has been a successful strategy in the US since the mid-1990s and is now having a positive impact in Europe. A paediatric working party has advised Australian Health Ministers via their Advisory Council on steps to improve access to prescription drugs registered for use in children and the quality use of these medicines. However, the Congress heard that political pressure still needs to be maintained to overcome this problem for children in all countries. Advertising medicinesA symposium on the controversial topic of direct-to-consumer advertising of prescription pharmaceuticals drew great interest, as the situations in Canada, the US, Europe, Thailand, New Zealand and Australia were compared. This advertising is legal only in the US and New Zealand. There were two main themes: first, that regulation is difficult; and secondly, as presented most forcibly by Barbara Mintzes (Postdoctoral Fellow, Centre for Health Services and Policy Research, University of British Columbia, Vancouver, Canada), that there are many, and increasing, instances of advertisements that skirt the boundaries of existing laws and regulations in jurisdictions where this advertising is illegal. In developing countries, Krisantha Weerasuriya (Regional Adviser, Essential Drugs and Medicines Policy, WHO Regional Office for South-East Asia, New Delhi, India) pointed out that there is, in reality, often no distinction between supposed prescription and over-the-counter medicines in terms of access. It is very difficult to control direct-to-consumer advertising of so-called prescription drugs when prescription-only status is not upheld at law — the case in most countries in South-East Asia. However, in countries where direct-to-consumer advertising is currently illegal, there appears little appetite for its introduction because of concerns about quality use of advertised medicines, consumer demand leading to distortion beyond the “reasonable” need for medicines, and finally, morbidity and mortality from the adverse effects of medicines whose use was unnecessary. However, it was emphasised that there is continuous and considerable pressure from industry and advertising interests to reverse this attitude. We have concentrated on the theme Medicines and Society, not because the other core themes of the Congress were less important, but because the urgency of addressing inequities in access to essential medicines around the globe is overwhelming. We were delighted that there was strong support to build on this focus at the 9th World Conference of Clinical Pharmacology and Therapeutics, which will be held in Montreal, Canada, in 2008 (http://www.cpt2008.com/).

Richard O Day MD, FRACP · Donald J Birkett FRACP, DPhil · John Miners PhD · David A Henry FRCP · Gillian M Shenfield PhD, FRACP, FRCP · J Paul Seale PhD, FRACP

Using clinical trials to assess long-term drug safety is problematic; in Australia, simple data linkage based on Medicare numbers may provide useful monitoring information The era of pharmaceutical medicines began with the synthesis of acetylsalicylic acid (ASA) in the late 19th century. The reason for its synthesis was that natural salicylic acid was irritating to gastric mucosa, and the synthesised product less so. Subsequently, more potent non-steroidal anti-inflammatory drugs (NSAIDs) were introduced and, more recently, cyclooxygenase-2 (COX-2) inhibitors, also with a lesser risk of gastric irritation and bleeding. 1 The rapidly widespread and often prolonged use of these agents meant that even a small increase in the risk of a serious adverse event could be very significant in population health terms. This theoretical concern became a reality when rofecoxib (a COX-2 inhibitor) was found to confer an increased risk of cardiovascular disease — a risk uncovered in a trial to determine whether rofecoxib could prevent the recurrence of colorectal polyps. 2 Subsequently, the United States Food and Drug Administration has issued warnings on the cardiovascular safety of celecoxib and naproxen.3,4 More recent information links long-term use of celecoxib and short-term use of parecoxib and valdecoxib (though non-significantly for the latter two) with adverse cardiovascular events. 5,6 This is consistent with a class effect. Although the mechanism underlying the increased cardiovascular risk with COX-2 inhibitors is unknown, there is a biological rationale that might have predicted it and which, in retrospect, should have led to intense postmarketing surveillance of these inhibitors. The non-selective COX inhibitors (ASA and NSAIDs) inhibit platelet aggregation, whereas selective COX-2 inhibitors do not. 7 Selective COX-2 inhibitors may also be prothrombotic through prostacyclin, which has a markedly enhanced action in atherosclerosis.8 The widespread use of COX-2 inhibitors has been part of the historic trend from short-term use of drugs to treat acute conditions to prolonged use of drugs to treat symptoms and prevent disease. This change has brought to light shortcomings in the current methods of drug safety monitoring. In the past, the linchpin of postmarketing surveillance has been the spontaneous reporting system in which doctors, pharmacists and others report recognised adverse reactions to drugs. However, this mode of reporting is useful only for detecting narrow spectrums of adverse events, particularly those occurring soon after drug administration or those that have overt effects (eg, rash, hepatic inflammation or blood dyscrasia). This spontaneous reporting is particularly unsuitable for long-term monitoring of drug safety. These realities are poorly appreciated by healthcare professionals, who often assume that, in comparison with older drugs, a newly registered drug has superior short-term and long-term safety.9 However, the events with the COX-2 inhibitors, which follow on the heels of similar, unsuspected concerns about anti-arrhythmic therapy and hormone replacement therapy, has again highlighted the need for a more systematic approach to long-term safety monitoring of long-term drug therapy.10,11 The accepted gold standard for establishing the balance of long-term drug safety and efficacy is the controlled clinical trial. In 2005, it should not be possible for any long-term medicine to be approved without the security of a large-scale morbidity–mortality trial, or the commitment of the pharmaceutical industry to perform one as soon as practicable. Licensing should be conditional on these requirements being met, and the onus should be on regulators to make these changes in the interests of both the end-users and the pharmaceutical industry. However, even large-scale morbidity–mortality trials have their limitations. They are very costly to establish, and ethical considerations may preclude the use of placebos. Comparisons with other active drugs may be difficult to interpret, as illustrated by the comparison of rofecoxib and naproxen.1 Study inclusion criteria may lead to the exclusion of patients with comorbidity or polypharmacy, and yet these individuals are both more likely to be prescribed drugs and be at higher risk of adverse reactions. In addition, it has proven difficult to continue large-scale trials beyond 5–6 years, so adverse events with prolonged latency, such as malignancy, may not be identified. A solution to long-term drug safety monitoring might include observational epidemiology. Methods must be developed for early identification of users of new drugs and their subsequent disease history determined by data-linkage to various mortality and morbidity databases (such as hospital admissions, cancer and death registries). The inclusion of Medicare numbers on prescriptions in Australia provides a simple means for participation in these studies. An ongoing hurdle is the issue of confidentiality. We do not claim that data-linkage will provide a foolproof answer to drug safety issues. The future mortality and morbidity experiences of any cohort of drug recipients may be influenced by the underlying disease for which the drug has been prescribed. This makes it desirable to have one or more control groups (typically individuals receiving a different drug for the same disease) for comparison. Even if there are control groups, there may still be confounding by differences in indications or contraindications. Therefore, the gathering of linkage data is often relatively low grade, retrospective and useful mainly as a screen for further study if an unexpected finding arises. Such linkages were used in the US to bring into question the cardiovascular safety of rofecoxib before the VIGOR trial.12 Large linked databases are increasingly seen as the only reliable means of gaining the information necessary for monitoring long-term drug safety.13 Our unified healthcare system in Australia, with its standardised Medicare numbers and national databases, has the potential for providing Australia with a strategically important role in this crucial area of drug research.

Mark R Nelson PhD, FAFPHM · Andrew M Tonkin FRACP, MD · Flavia M Cicuttini PhD, FRACP · John J McNeil PhD, FRACP

Identifying these reactions is a good start, now we must focus on managing and preventing them Australia’s voluntary reporting system for adverse drug reactions has one of the highest per capita reporting rates in the world. Reports to the Australian Adverse Drug Reactions Advisory Committee have played a significant international role in identifying previously unrecognised adverse drug reactions (ADRs), such as hepatitis with flucloxacillin and amoxycillin–clavulanic acid. However, in this issue of the Journal (page 267), Burgess and colleagues remind us that, although identifying ADRs is important, managing and preventing them are equally critical. Their study in Western Australia showed that the rate of ADRs associated with hospitalisations in people aged 60 years and over more than doubled between 1991 and 2002. South Australian data for all age groups showed a similar rise and correlated strongly with changes in medication use in the community.3 National data also show increases,3,4 although the correlation with medication use is less clear. As the Australian coding standards allow ADR codes to be applied to any diagnosis, not just the principal diagnosis,5 the WA data may represent all ADRs, not just those linked to admission or length of stay. Efforts to improve coding will have contributed to some of the observed rise as, for example, rates in SA increased in the year casemix funding was introduced. Increases in the number of hospital admissions over time will also have contributed, but the strong correlation with medication use in SA suggests an exposure effect. The rise in ADRs is not inevitable. The Quality in Australian Health Care Study estimated that 43% of adverse drug events were potentially preventable.6 Similarly, an Australian study of ADRs in oncology patients demonstrated that 48% of predictable ADRs were potentially preventable.7 The questions raised by Burgess et al’s study are: why are ADR rates rising and why have we been unable to prevent the rise, given the preventability estimates? Burgess et al suggest the rise represents a failure of the national strategies to improve the quality and safety of medicine use. There are many data available with which to dispute this claim. Over 100 performance indicators are used to routinely monitor the National Strategy for Quality Use of Medicines, with more than 85% of them demonstrating improvements over time and significant development of services and resources.4 The National Prescribing Service (NPS) has driven cultural change about quality prescribing in general practice, with more than 50% of general practitioners now voluntarily participating in initiatives to improve prescribing.8 Improvements in antibiotic, antidiabetic, analgesic and antihypertensive use have been seen, in keeping with NPS messages.8 The Safety and Quality Council are also driving cultural change, supporting the National Medication Safety Breakthrough Collaborative, which has worked with 100 hospitals and over 480 staff. This initiative is now focusing on disseminating knowledge of and sustaining successful practices. What the data on ADRs in hospitals indicate is our failure to focus on management strategies for ADRs as a specific topic within the national initiatives. Quality use of medicines and safety initiatives have generally focused on development of services, appropriate selection of medicines and error reduction. The focus for ADRs has remained predominantly on reporting and identification, with less emphasis on management. To improve ADR management, we must improve our information sources. Product and consumer information list ADRs but usually fail to provide management strategies. Incidence estimates in product information are based on the initial clinical trials and not easily updated when postmarketing surveillance is based on voluntary reporting. Information on the duration of side effects and consumer experience with medicines is also limited. Providing lists of ADRs does little to change behaviour; management strategies are required.9 The data-linkage studies now under way will enable better incidence data to be developed, as well as identify population groups most at risk of ADRs. The newly established consumer reporting service will also facilitate better understanding of consumer perspectives. This must be incorporated into information sources and supported by clear instruction on management. Detection of ADRs in routine clinical practice must also be improved, with more training needed in this area for health professionals. An Australian study of older people considered at high risk of medication misadventure found that 19% had had an ADR which had not been detected in routine clinical care, even though most were using multiple medicines, had comorbidities and were aged over 65 years.10 The other major requirement is to increase participation in services demonstrated to improve use of medicines and to help prevent ADRs. While consumer medicine information is now available for over 2000 products, it is not provided routinely and continues to be regarded negatively among some health professionals, despite consumer calls for information on side effects.11 Home-medication reviews involving general practitioners, pharmacists and patients have been shown to resolve or ameliorate ADRs in 56% of cases.12 However, the 26 000 home-medication reviews undertaken in 2003–200413 represented about 10% of the population likely to benefit from the service. Other multidisciplinary approaches such as clinical pharmacy, hospital discharge planning and case conferencing services have all been shown to reduce adverse drug events,3 but only 13 000 case conferences and 96 000 discharge-planning services were funded under Medicare’s Enhanced Primary Care packages in 2003–2004.14 The latter services account for 3% of hospital admissions involving overnight stays. These services are relatively new, which may contribute to the low uptake. However, their administrative requirements also need to be streamlined, as general practitioners have found them to be bureaucratic and onerous.15 In addition, trying to incorporate new services on top of existing practice may be adding to the burden and low uptake. It may be necessary to redesign general-practice systems to accommodate these new ways of working. Finally, we require a cultural and attitudinal change to the preventability of ADRs and to multidisciplinary practice. ADRs are often considered part of the price to be paid for the therapeutic benefit of medicines. The rise in ADRs despite preventability estimates suggests that we are currently paying too high a price. Preventing ADRs requires active participation by everyone.

Elizabeth E Roughead PhD