Complementary therapies

To the Editor: I read with interest the contrasting perspectives by Pirotta1 and Dwyer2 on the ethics of prescribing complementary and alternative medicine (CAM) interventions, and the subsequent letters on this subject published in the 17 October 2011 issue of the Journal. Individual CAM interventions should be assessed with the same evidence-based approach we would use for any other intervention. Furthermore, any evidence should be interpreted with the same caution as we do for conventional medicines. The efficacy of an intervention should be judged by the quality of the clinical evidence in the context of its scientific plausibility. Whether an intervention should be recommended depends on the context of the other known evidence-based management strategies and the patient’s individual clinical scenario. It is concerning that the supporters of the use of CAM in general practice appear to be willing to make recommendations for treatment in the absence of quality empirical evidence. Both Pirotta and Kotsirilos make the often-used argument that absence of evidence is not evidence of ineffectiveness.1,3 Pirotta suggests that we can turn to tradition1 and Kotsirilos implies that consumer demand indicates effectiveness.3 It should be acknowledged that both tradition and popularity are unreliable forms of evidence. The absence of quality evidence for an intervention should be a major barrier to recommending it, especially when known, effective alternatives exist. This is regardless of the philosophical tradition of the intervention. Even when there is evidence for efficacy, care must be taken in avoiding overreaching conclusions. For example, Kotsirilos interprets the relevant Cochrane review4 as supporting the use of cranberry for prevention of recurrent urinary tract infections in young women.3 That therapeutic recommendation is unjustified. Although the systematic review did find some evidence for cranberry, it noted problems with its quality and the lack of clarity of dosage and administration. The conclusion of the review in 2008 was that “further properly designed studies with relevant outcomes are needed”.4 A well designed randomised controlled trial was published earlier this year; it does not support the use of cranberry for this indication.5

Chun Wah M Tam

Objectives: To identify patterns of khat use among Somali-Australians in Australia and to explore their views about the links between khat use and personal health.Design, setting and participants: Qualitative study using semistructured focus groups among adult members of Somali communities in Brisbane, Sydney, Melbourne and Perth who volunteered to attend focus groups in January and December 2010.Main outcome measures: Emergent themes related to Somali-Australians’ understanding of the links between khat use and personal health.Results: Nineteen focus groups included 114 participants. Khat use was reported to be common among the Somali community, and more common among men than women. Khat was usually chewed in prolonged sessions, producing mild psychostimulant effects such as increased energy, enhanced mood, reduced appetite and reduced sleep. Khat was widely perceived to be a food, not a drug, and as harmless, or even beneficial, to the user’s health. Many users reported discontinuation effects such as lethargy, sleep disturbances and mood problems after sessions of heavy khat use, and some reported self-medicating with alcohol to cope with such problems. Problems of addiction to khat were identified by some participants, but not all believed it is addictive. Many khat users reported visiting their health professionals for treatment of adverse effects and failing to disclose their khat use.Conclusions: Health professionals require greater awareness of khat use and related health problems. Health promotion activities targeting communities with high levels of khat use are required to increase understanding of the potential risks of regular khat use, to promote harm-reduction strategies, and to increase awareness of services available for those experiencing harm. Health professionals should consider targeted screening for khat use among individuals from Horn of Africa communities who present to health services.

Heather Douglas LLB, LLM, PhD · Merali Boyle LLB(Hons), BSc · Nicholas Lintzeris MB BS, PhD, FAChAM

Pharmacists have an important role in protecting the public from regulatory loopholes If the 2011 Readers Digest survey can itself be trusted, pharmacists are the sixth most trusted profession in Australia, coming in marginally behind nurses (fifth) and before medical specialists (eighth) and general practitioners (ninth), and well ahead of car salesmen (43rd) and politicians (44th).1 What qualities inspire trust? The Concise Oxford dictionary defines trust as “firm belief in reliability, honesty, veracity ...”, so presumably these are the characteristics recognised in pharmacists and applauded by the survey respondents. The advice of community pharmacists in response to customers’ enquiries is widely relied upon, but events in the past few months raise serious questions about the trustworthiness of some in the profession. The first episode involved the marketing of SensaSlim (SensaSlim Australia, Sydney, NSW) a complementary medicine promoted as a new approach to achieving weight loss2 and sold largely through community pharmacies. In September 2010, the Therapeutic Goods Administration (TGA) included the medicine in the Australian Register of Therapeutic Goods (ARTG) as a listed product (labelled with an AUST L number). This means it had been evaluated for quality and safety but not efficacy. The product’s website claimed that a clinical trial involving more than 10 000 patients demonstrated its effectiveness, but requests from many health professionals to SensaSlim Australia failed to produce this evidence. Following complaints from doctors and pharmacists over the ensuing months, SensaSlim was discredited, although the associated legal battles are still unresolved.3 Despite widespread adverse publicity in the media, some community pharmacists continue to promote and sell the product, galvanised perhaps by the 65% profit margin on sales4 rather than the strength of the evidence for efficacy. The second event was the much publicised intention of the Pharmacy Guild of Australia (“the leading advocate for community pharmacy and a vital contributor to improving health outcomes for all Australians”5) to add its “Gold Cross” endorsement to complementary medicines marketed by Blackmores (Sydney, NSW) as “companion products” to prescription medicines for common medical disorders. Justifications for this concept included that some antihypertensive medicines are associated with reduced plasma concentrations of zinc; coenzyme Q10 concentrations are lowered in patients taking statins; hypomagnesaemia has been reported in patients taking long-term proton pump inhibitors; and probiotics might prevent some cases of antibiotic-associated diarrhoea.6 It is a short jump from these observations to the idea that supplements of zinc, coenzyme Q10, magnesium or probiotics should be given routinely when using these medicines. If implemented, this would be a remarkable marketing coup for Blackmores and the community pharmacy. But is there any evidence of possible benefit? A team at the National Prescribing Service published an excellent summary of the available evidence on its website on 30 September.7 They found nothing to support the routine use of these companion products. Under pressure from many pharmacists (including the Pharmacist Coalition for Health Reform) and other health professionals, the Pharmacy Guild announced on 5 October that the plan to endorse the Blackmores products had been dropped. These two disturbing events are symptoms of two underlying problems. First, community pharmacies still rely significantly on product sales for income, rather than a fee-for-service model. This results in a tension between being a health care professional and being a retailer. While recent agreements between the Pharmacy Guild and the Australian Government are trying to address this issue by providing payments to pharmacists for cognitive services such as medication reviews, the uptake of this program has been variable.8 Second, there are regulatory issues around complementary medicines that are yet to be acted upon by the Australian Government and its regulators. For many years, Australia led the world in regulation of complementary medicines. However, the regulations have not kept pace with trends, especially in the case of listed products. In particular, the loophole that allows sponsors to have products such as SensaSlim included on the ARTG without any review of evidence to support their claims is an affront to any regulatory body. When regulation of complementary medicines began in the 1990s, it was agreed that “low-risk” (AUST L) medicines would be allowed onto the market without independent review of efficacy, provided they were safe and of good quality. In 1999, it became a requirement that sponsors of listed products must “hold” the evidence to substantiate their claims. In 2003, a report on complementary medicines in the health system recommended that, as part of the listing process, sponsors should submit a summary of the evidence for efficacy to the TGA.9 The government accepted this recommendation,10 but no implementation has resulted. Enacting this recommendation may protect us from future SensaSlims, and would give a proper basis for the provision of sorely needed evidence-based consumer information about complementary medicines. A positive aspect of the Pharmacy Guild’s forced U-turn is that it demonstrates there are sufficient numbers of alert and concerned people in this country, including many pharmacists, who are prepared to put pressure on the peddlers of untrustworthy proposals. It is presumably these pharmacists who have earned the accolades of trustworthiness for the profession as a whole.

Anthony J Smith BM BCh, DM, FRCP · David A Newby BPharm, PhD

To the Editor: The commissioned article by Pirotta, dealing with the ethics of prescribing alternative complementary treatments that may lack an evidence base,1 contains a number of statements which, if the article had been subjected to peer review, might well have finished up on the cutting-room floor. For example, the statement “it is estimated that as little as a quarter of conventional medicine is based on level-1 evidence” is not backed up by the only monograph cited in support of it.2 Whatever relevance a lack of level-1 evidence may have to the practice of dermatology (for which it is claimed), it plays little part in either modern medicine or the revolutionary advances in surgery, few being the result of a systematic review of multiple well controlled randomised trials. Having said that, the reference to complementary or alternative treatments that lack any evidence base as “medicine” gives a misleading legitimacy to practices that may be — and frequently are — based on cultural, historical or spiritual beliefs, or even just plain wacky approaches to healing. Regrettably, Pirotta adds nothing new to the (uncited) definitive 2004 article by Kerridge and McPhee.3 How times have changed. Not only are doctors now expected to have sufficient knowledge of complementary and alternative medicine to be able to advise their patients of therapeutic alternatives, but we may well have reached the stage where a failure to alert patients of such alternative treatment options may constitute negligence at common law. The New South Wales case of McGroder v Maguire4 is instructive. In that case, the plaintiff, a truck driver, had suffered a neck injury in the course of his employment. Despite a lengthy period of treatment, he continued to suffer from tingling in his arm. The defendant, a general practitioner retained by the plaintiff’s employer, although not having examined the patient, nevertheless referred him to a chiropractor. This referral was held to have been negligent, not because of the referral per se, but because of the patient’s condition. This came to light in the evidence given by a neurosurgeon and orthopaedic surgeon at the trial of the action, both of whom agreed that this case was not one for chiropractic manipulation of the plaintiff’s neck and back. Despite subsequent neurosurgery, the plaintiff became totally incapacitated for work. In the result, both the referring GP and the chiropractor were held to be liable in negligence.

Paul Gerber

To the Editor: We read with interest the commentaries by Pirotta and Dwyer on complementary and alternative medicines (CAMs).1,2 This debate has a long history, spanning more than two decades,3 and the pessimism continues to ignore good science.2 Firstly, integrative medicine (IM), which combines alternative and conventional medical practices, is not and never has been synonymous with CAMs. IM is a global paradigm shift that expands the conventional model of medical care with evidence-based laboratory and clinical research. IM embraces the foundations of medicine, such as (i) the critical role of the doctor–patient relationship, (ii) the importance of lifestyle, and (iii) improving the wellbeing and promoting the natural healing potential of people afflicted with disease.4 Secondly, a thinly disguised commentary on the ineffectiveness of CAMs,2 while dismissing a large body of scientific clinical evidence, is broadly misleading. This is significantly remiss, failing to cite the value of prebiotics and probiotics in digestive diseases,5 the effect of omega-3 essential fatty acids on endothelial function,6 the efficacy of acupuncture for some forms of pain,4 mindfulness-based stress reduction and mindfulness-based cognitive therapy for mental health,7 and emerging modalities such as yoga for menopausal symptoms4 and tai chi for fibromyalgia,4 and many more.4 Moreover, such deliberate carelessness serves only to confuse researchers and clinicians, as well as the public. Evidence-based medicine is critical in expanding the medical model of care; of this there can be no doubt. Adhering to biologically plausible mechanisms of action is the key foundation that will always guide scientific evidence, including that for CAMs. As an example, we have recently scientifically challenged the validity of the antioxidant effect to abrogate free radicals that are purported to contribute to the development of chronic diseases.8 Therapies that deviate from the conventional medical model still elicit an unhealthy cynical response2 that hinders the progress of scientific and medical investigations. If Florey and Fleming had adopted such cynicism and dismissed the biologically far-fetched notion of an antimicrobial mould in a Petri dish (Penicillium notatum), they most probably would not have pursued and contributed to the discovery of the antibiotic penicillin. Thus there is no place in science and medicine for the imprimatur of distrust and scepticism that is levelled without respite at novel concepts, even those with scientific plausibility.

Luis Vitetta · Shoshannah L Beck · Samantha Coulson · Avni Sali

To the Editor: I am concerned that the viewpoints by Dwyer1 and Pirotta2 were published without establishing a clear definition of “complementary and alternative medicine” (CAM). The term CAM is not ideal as it groups many non-evidence-based therapies that have little in common, such as iridology and homoeopathy, with more evidence-based complementary therapies such as acupuncture, nutritional medicine, meditation and some herbal medicines that have demonstrated efficacy. To date there is a growing body of research, including Cochrane reviews, to support the use of some complementary therapies (Box). The fact that many complementary therapies have not been tested and subjected to high-quality research does not necessarily mean they do not work.3 For other complementary therapies, there are mixed findings (negative trials balanced by positive trials, as seen in Cochrane reviews), so one needs to ask why the differences in results? Were there differences in dosage, the quality of the substance or method of the therapy tested? Would you argue with patients who find symptomatic relief for troublesome symptoms of menopause from herbs when they are intolerant to hormone replacement therapy, or relief from osteoarthritic pain from complementary medicines and acupuncture if non-steroidal anti-inflammatory medications are contraindicated because of a peptic ulcer? Demand for complementary therapies in Australia is actually coming from consumers. If they found the therapies unhelpful, why would they continue with them? A better term for complementary and alternative medicine is integrative medicine (IM), defined as: the practice of medicine that reaffirms the importance of the relationship between practitioner and patient, focuses on the whole person, is informed by evidence, and makes use of all appropriate therapeutic approaches, healthcare professionals and disciplines to achieve optimal health and healing.4 The aim of IM is to find common ground and respect for the patients who choose to use complementary therapies and to understand their use. General practitioners have been shown to be very interested in learning about complementary therapies, with one study finding that about 30% of Australian GPs identified themselves as practising IM and most (more than 80%) requesting more education and research in complementary therapies.5 It is important that doctors balance clinical decisions between the risks associated with any therapy, the evidence and the therapeutic clinical outcome (effectiveness) to inform patients appropriately.

Vicki Kotsirilos

Readers who may contemplate referring patients to practitioners of complementary medicine may be interested in the fate of Dr Frederick Axham. He was an English anaesthetist, who was struck off the medical register for medical malpractice in 1911 at the urging of the General Medical Council, having been found guilty of “covering” (ie, professionally assisting a person not on the medical register). Axham had — despite dire warnings — anaesthetised eight patients of Herbert Barker, a renowned bone setter (now a lost art), who had successfully set and stabilised the complex fractures of seven of these eight patients whose fractures had been found to be inoperable by a number of eminent surgeons. Axham, who died in 1926 aged 86 years, still deregistered, was posthumously rehabilitated when the medical faculty of the University of Edinburgh made him a Licentiate of the Royal College of Physicians some weeks after his death.1 The whole affair caused a huge outcry throughout England, leading to a petition to Lambeth Palace, the residence of the Most Reverend Lord Randall Davidson, Archbishop of Canterbury, to make Barker a Doctor of Medicine, in reliance on the Ecclesiastical Licences Act 1533 (25 Henry VIII, c 21). The petition included not only leading members of the aristocracy, but, more importantly, Sir Henry Morris Bt, former President of the Royal College of Surgeons, Sir Alfred Downing Fripp, “Surgeon in Ordinary” to King George V, Sir William Arbuthnot Lane Bt, consulting surgeon to Guy’s Hospital, and physician Sir Bruce Bruce-Porter, all testifying to Barker’s coampetence. It also led George Bernard Shaw to write: Until the General Medical Council, which at present exhibits every constitutional vice that a trade union or professional association can have, is completely reformed by its legal constitution, we shall continue to hasten more and more precipitously to the not far distant day when the vogue of the unregistered practitioners, already very great (Mr. Barker is only a specially famous example of a large and growing body), will become so irresistible that the registered will be shunned by the public and driven to earning a scanty wage by signing death certificates for their unregistered employers.2 Alas, the Archbishop declined to award the degree. A press cuttings file at Lambeth Palace (Davidson’s Papers Vol 404, page 110) shows that he stated on 21 June 1920: The legislation which limits registration to men qualified by the ordinary professional training expressly, and I think rightly, provides that the status acquired by registration is not given by the Degree which the petitioners invite me to confer on Mr Barker.2 In frustration, King George V did the only thing he could do, which was to make Herbert Barker a knight of the realm. Sir Herbert continued bone setting till he died in 1946. Medicine. An Illustrated History

Paul Gerber LLB, DJur

Academic GP Marie Pirotta says some alternative therapies are worthy of consideration Yes The use of complementary and alternative medicine (CAM) is hugely popular — each year, over half of the Australian population uses some form of CAM, at a total cost of $A1.8 billion.1 Importantly, most of this use of CAM is not a substitute for conventional therapy. Indeed, CAM is often used together with conventional therapies to treat particular conditions. CAM is usually considered a homogenous static entity, or a creed, to be either believed in or not. However, the “CAM” label incorporates a disparate range of therapeutic approaches, from the esoteric and bizarre through to therapies with accumulating evidence of effectiveness, such as St John’s wort for mild to moderate depression. If the first principle of medicine is to do no harm, is it ethical for general practitioners to actively recommend CAM? Indeed, how should the profession respond ethically to the challenge of CAM generally? One apparent hurdle is that much CAM currently lacks high-quality evidence. However, this should not be taken as proof that a given CAM is ineffective or harmful. To place this in context, it is estimated that as little as a quarter of conventional medicine is based on level-1 evidence.2 CAM research is slowly gaining momentum. It is hampered by factors including lack of financial reward for research investment for products already in widespread use, and few trained independent researchers. With increasing interest and research capacity, no doubt, evidence will accumulate for some CAM, which may be adopted into our armamentarium and become “mainstream”. Yet we cannot ignore CAM while awaiting the results of these trials. A framework for responsible engagement with CAM is needed now: its use is already widespread, even among GPs, and patients want to get their information about CAM from GPs.3 Encouragingly, CAM is largely safe. In Australia, CAM is regulated to pharmaceutical standards by the Therapeutic Goods Administration, so the risk of poor-quality, contaminated or adulterated products is low. While side-effects and interactions do occur, CAM is generally safer than pharmaceuticals.4 So in the context of widespread use, a slowly developing evidence-base, patients’ wish for their GP to provide CAM advice and its relative safety, is it ethical for GPs to recommend CAM? Ethical recommending of any treatment takes place within the framework of a careful history, examination and diagnosis. GPs contribute their clinical experience and scientific knowledge, while maintaining respect for patients’ preferences and values. Patients may value different aspects of treatment than their GP, such as “naturalness”. Together, patients and their GPs explore the risks and benefits of the proposed treatment, relative to other available treatments. Any treatment decision must be monitored for harm and benefit. Discussion of CAM options (including recommending or discouraging use, as appropriate) can be ethically incorporated into this framework. Where evidence is lacking, GPs can turn to the accumulated knowledge over time (sometimes millennia) of the historical use and safety of the CAM. In fact, it is important for GPs to discuss CAM options with patients to ethically fulfil their role as trusted primary care providers. Doctors who do not engage in discussion about CAM may harm the doctor–patient relationship in the longer term — use of potentially harmful CAM may remain undetected, and patients may seek information from less reliable sources. Further, it may be unethical not to inform patients in situations where evidence-based CAM options exist.5 Is it ethical to bill these consultations to Medicare? Of all CAM treatments, only medical provision of acupuncture has its own Medicare item number. Using the framework I describe for ethical, responsible discussion of CAM, I believe it is appropriate to bill Medicare. There are certain circumstances in which recommending CAM would be unethical. These include: if the GP has inadequate knowledge to avoid harm;6 if the use of CAM causes delays in treating serious illness where evidence-based conventional therapies exist; if there is evidence that a CAM is not effective; or if (and this is unusual) unproven or ineffective practices are recommended to vulnerable patients for exploitative financial gain. Further, potential for conflict of interest exists for GPs who recommend and sell CAM. The Australian Medical Council Code of Conduct provides clear guidelines, including declaring to patients one’s professional and financial interest in any product endorsed or sold from one’s practice, and not making an unjustifiable profit from the sale or endorsement.7 Ethical prescribing of CAM is possible within good general practice if GPs have an adequate knowledge of CAM and have their patients’ best interests at heart. Generally, GPs need to keep up-to-date as evidence grows about CAM, and maintain a respectful relationship with patients so they feel able to ask questions about CAM and thus maintain their enviable position as trusted primary care providers.

Marie V Pirotta MB BS, MMed, PhD

Emeritus Professor John Dwyer says doctors should not give alternative therapies their sanction No While the answer to the question in most situations is a definite “no”, the issues associated with the need to ask the question are important and troublesome. In this most scientific of ages, when orthodox medicine is committed to embracing an ever more evidence-based approach to clinical practice (and still has a long way to go), consumers of health care are increasingly exposed to a plethora of nonsense (non-science) claims that waste their money, distance them from effective care strategies and, not infrequently, cause harm. More than half the population will partake of some form of alternative or complementary therapy each year, spending more than two billion dollars to do so!1 Of course it is important to understand why this is so. A reporter from The New Yorker magazine contacted me a few years ago after I had discussed health care fraud in an article for Reader’s Digest. “You don’t seem to understand”, she told me, “that in this postmodern age, people are yearning for simplicity, panaceas and a little bit of magic in their lives”. This is surely a dangerous romanticism given that it is people’s health, and therefore happiness and productivity, we are discussing. Many patients have told me that “alternative practitioners” are likely to give you an hour of their time, a bit of a massage, and send you away with a cocktail of therapies from their shelves. In orthodox medicine, we rightly regard prescribing and dispensing medicines for financial gain an unacceptable conflict of interest. However, we know that enough time with a general practitioner to allow patients to vent their concerns satisfactorily is very often unavailable. Consumers, of course, are bombarded with fraudulent advertising telling them vitamins cure stress and provide energy,2 weight loss is guaranteed with this herbal preparation, glucosamine will take you from your wheelchair to the golf course,3 foot vibrators will cure your ankle oedema, and detoxification will cleanse your body of all those accumulated poisons compromising your health.4 The list is virtually endless. How often do we hear consumers being assured that “natural is best” when exactly the opposite is true. Significant numbers of doctors are advertising their practice of “integrative medicine”, a mixture of the best treatments available from the orthodox and alternative medical universes! I know of no scientific study exploring the motivation for such an approach, so some may believe they are offering superior care while others are, no doubt, responding to commercial opportunities to capitalise on the popularity of complementary approaches. To do so, however, is to abandon scientific medicine — which strives for evidence, rejects the “therapeutic” use of the placebo effect and addresses the psychological nature of many symptoms — for an approach that does not believe in testing, is happy to exploit the placebo effect and rejects a psychological influence on health. Pick up any copy of an alternative health care magazine and you will see doctors and nurses advertising intravenous vitamin therapies for a range of problems, and “chelation” therapy for everything from cancer to heart disease. Our profession should be worried by these trends, which see many doctors practising a form of medicine that would be rejected by most of their peers. To see how professional standards can be consumed by the attractions of less scientifically rigid approaches, one has only to look at what has happened to the scientifically trained men and woman of pharmacy, whose shelves are stacked with useless products they knowingly promote to trusting customers. The scientific study of many of alternative medicine’s claims is taking place in many universities. This is important because, of course, there is really only “good” medicine and “bad” medicine. Scientific studies that determine that an approach, supported previously only by anecdote, has evidence-based merit, should be embraced by orthodox medicine if it fills a therapeutic gap. Claims about therapies that turn out to be inaccurate when studied, would, if they are still propagated, represent bad medicine, and prescribing such therapies would be unethical. Science is the key to converging the approaches we have been discussing.5 However, we don’t need to wait to warn the public in the strongest terms that many alternative strategies are already known to be useless. Homoeopathy, iridology, reflexology, healing touch, and many of the claims made for acupuncture6 are some examples. Private insurance funds that “cover” a number of these totally unacceptable practices give them a totally undeserved imprimatur, and so do doctors who prescribe alternative and complementary procedures. In our national health scheme, Medicare dollars are precious, and it is surely unethical to ask the taxpayer to foot the bill for unproven, highly suspect or useless treatments. In this era of the endless information highway, the community should be able to depend on their doctors for education on just how people should seek out for themselves the evidence supporting proposed care plans. Doctors also need to impress on their patients the importance of divulging what alternative preparations they may be using, as severe complications from chemical interactions may occur. Finally, doctors need to avoid supporting the alternative “last-resort” approach that may be suggested by desperate patients, because the extraordinary expense, false hope and removal from skilled end-of-life care can add so much to suffering.

John M Dwyer AO, MB BS, FRACP, PhD

Clinical record A 75-year-old man presented with a 2-month history of lethargy, nausea and poor appetite. His medical history included widespread plaque psoriasis. He had used Chinese herbal products for 3 years to treat the psoriasis, with significant improvement. The products included long dan xie gan wan, lei gong teng and ke yin wan, which he had obtained from outside Australia by mail order. He was not taking any other medications. On physical examination, he was hypertensive (blood pressure, 200/100 mmHg) and exhibited “metabolic flap”. The rest of the physical examination showed no abnormalities. Laboratory investigations revealed renal failure with a serum creatinine level of 965 μmol/L (reference range [RR], 60–120 μmol/L), serum urea level of 43.1 mmol/L (RR, 3.0–8.0 mmol/L) and a normocytic, normochromic anaemia with a haemoglobin level of 70 g/L (RR, 130–170 g/L). Results of a serum electrophoresis and tests for antinuclear antibody, antineutrophil cytoplasmic antibody, antiglomerular basement membrane antibody, complement C3 and C4 and serum immunoglobulins were all unremarkable. Urinary microscopy revealed an inactive urine sediment with minimal proteinuria (0.13 g/L [RR, 0.16g/L]). A renal ultrasound revealed unobstructed, small kidneys with cortical thinning bilaterally. A renal biopsy showed severe tubulointerstitial fibrosis and atrophy. There was no evidence of glomerulonephritis, nor of acute tubular necrosis (Box). These findings were consistent with chronic exposure to a nephrotoxin. As the patient’s Chinese herbal products were suspected as the source of the nephrotoxin responsible for his nephropathy, they were sent to the Australian Therapeutic Goods Administration (TGA) to be analysed. High-performance liquid chromatography and mass spectrometry identified aristolochic acid in the Herbal International brand of long dan xie gan wan,1 and the product was subsequently recalled from the Australian market by the TGA. Haemodialysis was initiated and later converted to continuous ambulatory peritoneal dialysis. The patient died 4 years after initial presentation, following withdrawal from dialysis. In Australia, the use of complementary and alternative medicine (CAM), including Chinese herbal products, is increasing. However, scientific evidence on the safety, efficacy and quality of CAM, as well as regulatory controls, does not appear to support such popularity.2 Some herbal products contain aristolochic acid (AA), which is known to be nephrotoxic and carcinogenic.3 Aristolochic acid nephropathy (AAN), first reported in Belgium as “Chinese herbal nephropathy”,4 is characterised by progressive fibrosing interstitial nephritis leading to renal failure and severe anaemia. AAN is a worldwide problem, but its true incidence is unknown and probably underestimated,5 and though many cases of AAN have been reported, to our knowledge this is the first reported case in Australia. Many countries have prohibited the production and sale of herbal products containing AA,6 but despite bans, these products continue to be available through the internet or supplied through mail order. In most of the reported cases, when the patient discontinued use of the drugs their renal disease still progressed rapidly to end stage.3 After exposure to AA, there is also a very high incidence of uroepithelial atypia and transitional cell carcinoma, and AA is now recognised as a potent urological carcinogen.7 Tissue samples from some patients with AAN and urothelial malignancy have revealed AA-related DNA adducts, which may be carcinogenic through a defect of DNA repair.8,9 The pathophysiological mechanisms of AAN are still unknown. In a rat AAN model, AA renal tubule toxicity has been associated with defective activation of antioxidative enzymes and mitochondrial damage. Activation of renal fibroblasts has also been proposed as the main source of collagen deposition leading to renal interstitial fibrosis.10 Therapeutic strategies have consisted mainly of supportive care in patients with AAN and renal failure. One study suggested that corticosteroids may slow the rate of renal deterioration.11 Renal transplantation may be an effective treatment strategy for those who progress to end-stage renal failure, with one report indicating no recurrence of AAN in five such patients after a follow-up period of 1 year.12 The clinical course of AAN has been related to the intensity and duration of AA exposure.13 A mean cumulative dose of 192 g of Aristolochia fangchi was ingested by one group of patients who developed end-stage renal failure related to AA.13 However, in most cases, the accumulated AA dose is difficult to ascertain because the dose is recalled retrospectively by patients; the patient may ingest herbal medicines irregularly and there is no strict recommendation of dosing on labels; the AA levels in the herbal mixtures vary due to different manufacturing processes; and the quantity of AA also varies in different herbs and even in the same herb grown in different areas.14 Also, patient factors such as genetic polymorphism, environmental chemicals and drugs may result in individual differences in susceptibility to AA toxicity.5 Many different brands of long dan xie gan wan are available and are commonly sold as a “liver tonic” containing the herb Caulis aristolochiae manshuriensis. This herb is known to contain AA, and there have been cases of nephropathy with similar clinical presentations reported after its ingestion.15 C. manshuriensis was not labelled as an ingredient in our patient’s brand of long dan xie gan wan. Although AA in long dan xie gan wan is the most likely aetiology for his nephropathy, other potential contributing nephrotoxins such as heavy metals and ochratoxin A, found in other products he was taking concomitantly, cannot be excluded.16,5 In Australia, the sale of CAM is regulated by the TGA.17 In July 2001, alerts to health practitioners were distributed by the TGA,18 and in January 2002, bans on herbal products suspected to contain AA were instituted,19 but this patient was still able to purchase the product by mail order. Chinese herbal medicines containing AA remain available for purchase over the internet and through Chinese herbal retailers.6,20 Internet commerce has revolutionised accessibility to herbal medicines and has made regulation more difficult. A South Australian public survey in 2004 found that about half of CAM users believed that CAM products were independently tested by the TGA, and did not report their use to their general practitioner.2 It is therefore apparent that tighter regulations on CAM are needed. The occurrence of this case in Australia highlights the need to review CAM regulations and for clinicians to be vigilant in their assessment regarding the use of CAM, especially when the aetiology of renal dysfunction cannot be identified. Until more stringent regulations are put in place to ensure quality, safety and efficacy of CAM, public awareness of their dangers should be raised. Renal tissue showing severe, diffuse interstitial fibrosis and tubular atrophy, with no evidence of significant interstitial inflammation Lessons from practice Herbal remedies can be sources of nephrotoxins. Aristolochic acid found in herbal remedies can cause rapidly progressive interstitial nephritis, leading to end-stage kidney disease and urothelial malignancy, therefore requiring regular surveillance for abnormal urine cytology and cystoscopy. In clinical assessments, clinicians need to enquire specifically about use of herbal products. Drug regulatory authorities should maintain more stringent surveillance on herbal products.

Winnie Chau BPharm(Hons) · Richard Ross MB BS, BSc(Hons) · Jordan Y Z Li MB BS, FRACP · Tuck Y Yong MB BS, FRACP · Sonja Klebe MD, PhD, FRCPA · Jeffrey A Barbara MB BS, PhD, FRACP

To the Editor: A 28-year-old man presented to his general practitioner with a history of epigastric pain and constipation over 1 month. In addition, he had a history of chronic low back pain. Findings on physical examination were unremarkable. Laboratory investigations showed normo-chromic, normocytic anaemia with basophilic stippling (Box 1). His whole-blood lead level was subsequently estimated to be 4.12 μmol/L (level recommended by the National Health and Medical Research Centre for all Australians, < 0.48 μmol/L). The patient was referred for toxicological review. Further questioning revealed he had used three Ayurvedic medicines (Vatyog [Arya Aushadhi Pharmaceutical Works, Indore, India], Sahacharadi [Arya Vaidya Nilayam, Madurai, India] and Gandharvahastadi [Arya Vaidya Nilayam, Madurai, India]) for back pain, dispensed to him 3 months earlier during a trip to India. He ceased taking the medications, and a 19-day course of oral chelation with succimer was administered. His blood lead concentration fell rapidly, with a moderate rebound 6 weeks after the completion of chelation therapy. A negative blood lead result for the patient’s pregnant partner excluded environmental exposure in the patient’s home. Vatyog and Sahacharadi were analysed for heavy metals (Gandharvahastadi was not available for analysis). Sahacharadi was lead-free, but the Vatyog tablet tested contained 448 μg of lead. The patient had potentially ingested 896 μg of lead daily for 3 months. World Health Organization guidelines recommend daily lead intake should not exceed 3.5 μg/kg/day.1 Dietary intake of lead in developed nations has been reported to be about 0.1–0.7 μg/kg/day.1 Ayurvedic medicine originated in India more than 2000 years ago and relies heavily on herbal products.2 Many people take Ayurvedic medicine without any problems. In some traditional remedies, salts of heavy metals are included as active ingredients.3 A study in the United States found that one-fifth of Ayurvedic herbal products manufactured in South India and sold in Boston contained potentially harmful concentrations of lead, mercury or arsenic, or combinations of these.2 In Australia, traditional Indian and Chinese medicines authorised for supply are regulated as complementary medicines and must meet manufacturing and quality standards that ensure the absence of contaminants.3 However, there is no quality control of medications imported for personal use or purchased over the internet. Importantly, this case involved tablets prepared by a registered pharmaceutical manufacturer and presented in sophisticated packaging (Box 2). Reports of lead contamination from traditional Indian and Chinese medicines have been intermittently publicised4,5 and include recent warnings from the New South Wales Health Department concerning Ayurvedic medicines. Patients with lead toxicity commonly present with non-specific clinical features, and lead poisoning might only be suspected when a blood film shows anaemia with basophilic stippling. While enquiring about a patient’s environmental, occupational and social history is important for determining possible sources of lead exposure, clinicians should also ask patients if they have used alternative and complementary medicines and whether these were obtained in Australia or from overseas. 1 Blood film from the patient showing coarse basophilic stippling 2 Packaging from the lead-containing Ayurvedic medicine

Nilika G Wijeratne · James C G Doery · Andis Graudins

Professional ethical codes identify the issue of conflict of interest, which can distort doctors’ objective judgements concerning the best interests of patients. Legal fiduciary duties may be owed by doctors to patients in situations of potential conflict of interest. Prescribing and dispensing functions have been largely legally separated to prevent conflicts of interest arising. The advent of integrative medicine has been accompanied by an apparent growth of in-house selling of therapeutic products. Medical merchandising constitutes a prima-facie conflict of interest and may amount to notifiable conduct under the Health Practitioner Regulation National Law provisions. We believe that doctors who sell therapeutic products should adhere to strict conditions to avoid significantly departing from accepted professional standards. Doctors who have a reasonable belief that a colleague is failing to comply with these conditions could consider notifying the Medical Board of Australia.

Malcolm H Parker MB BS, MLitt, MD · Jon L Wardle BHSc(Nat), MPH · Michael Weir BA, LLM, PhD · Cameron L Stewart BEc, LLB(Hons), PhD

Objective: Design, setting and participants: A randomised single-blind controlled trial with a treatment duration of 3 days and a follow-up period of 4 days was conducted at a sauna in Berlin, Germany. Between November 2007 and March 2008 and between September 2008 and April 2009, 157 patients with symptoms of the common cold were randomly assigned to an intervention group (n = 80) and a control group (n = 77).Interventions: Participants in the intervention group inhaled hot dry air within a hot sauna, dressed in a winter coat, whereas participants in the control group inhaled dry air at room temperature within a hot sauna, also dressed in a winter coat.Main outcome measures: Area under the curve (AUC) summarising symptom severity over time (Days 2, 3, 5 and 7), symptom severity scores for individual days, intake of medication for the common cold and general ill feeling.Results: No significant difference between groups was observed for AUC representing symptom severity over time (intervention group mean, 31.2 [SEM, 1.8]; control group mean, 35.1 [SEM, 2.3]; group difference, − 3.9 [95% CI, − 9.7 to 1.9]; P = 0.19). However, significant differences between groups were found for medication use on Day 1 (P = 0.01), symptom severity score on Day 2 (P = 0.04), and participants’ ratings of the effectiveness of the therapy on Day 7 (P = 0.03).Conclusion: Inhaling hot air while in a sauna has no significant impact on overall symptom severity of the common cold.Trial registration: ClinicalTrials.gov identifier NCT00552981.

Daniel Pach MD · Bettina Knöchel CandMed · Rainer Lüdtke MSc · Katja Wruck Documentalist · Stefan N Willich MD, MPH, MBA · Claudia M Witt MD, MBA

Cimicifuga racemosa, better known as black cohosh, has been widely used in Western cultures as a herbal treatment for relieving symptoms of menopause. It has previously been linked to cases of liver toxicity. We report a case of reversible complete heart block in a woman who had recently begun taking a herbal supplement containing black cohosh. We review the known side effect profile of black cohosh and its relationship to our case. Clinical recordIn April 2009, a 59-year-old woman presented to a hospital emergency department after experiencing three episodes of syncope. She had never experienced cardiac ischaemic symptoms and there was no identifiable precipitant for a vasovagal event. She had no history of thyroid disease, hypertension, hyperlipidaemia or diabetes. Her personal and family medical histories were unremarkable, and she was a lifelong non-smoker and non-drinker. She had no recent febrile illness. She took no regular medications, but 2 weeks earlier had commenced taking one tablet daily of Remifemin (Schaper & Brümmer, Salzgitter, Germany; distributed by SciNat Australia, Gold Coast, Qld), a herbal preparation for the alleviation of menopausal symptoms. While undergoing cardiac monitoring in the emergency department, the patient experienced a further episode of syncope. Telemetry (Box 1, A) and an electrocardiogram (ECG) (Box 1, B) demonstrated complete heart block. An atropine bolus was administered and an isoprenaline infusion commenced. The initial ECG performed after commencement of isoprenaline demonstrated 2:1 heart block. The patient’s serum electrolyte levels were normal. Further symptomatic complete heart block occurred while the patient was receiving the isoprenaline infusion (10 μg/min). A temporary pacing wire was placed, with reliable capture at a rate of 60 beats/min, an output of 0.5 V and reliable sensing at greater than 10 mV. Remifemin was ceased. Measures of thyroid function and serial serum cardiac troponin I levels were within normal ranges. Echocardiography demonstrated a structurally and functionally normal heart. The patient required intermittent pacing for heart block throughout the next 2 days, after which pacing was no longer required, and she was successfully discharged on Day 5 with normal sinus rhythm. She underwent 24-hour ECG Holter monitoring 1 week after discharge, which confirmed no further episodes of heart block. She did not recommence Remifemin treatment and, 12 months later, reported no further episodes of syncope. DiscussionThe only listed active ingredient of Remifemin is isopropanolic Cimicifuga racemosa root extract, also known as Actaea racemosa and most commonly known as black cohosh (BC). Remifemin contains the most thoroughly researched formulation of BC.1 BC was traditionally used by Native Americans of Canada and the eastern United States to treat malaria, impaired kidney function, sore throat, rheumatism, menstrual irregularities, and pain during childbirth.2 Recently, there has been interest in its use in the treatment of menopausal symptoms. A recent systematic review identified over 72 studies of BC,3 but only 13 of these were clinical studies involving BC-only preparations published since an earlier review in 2003.4 Findings regarding adverse events were consistent with those of another earlier review, which had found that in more than 2800 patients, the rate of adverse events was about 5.4%, and over 97% of events were minor.3 Most adverse events identified by the more recent review were gastrointestinal symptoms and musculoskeletal and connective tissue disorders.3 Three recently published reviews have examined hepatotoxicity3,5,6 — the most commonly reported serious adverse event associated with BC. They described seven, 42 and 31 cases of hepatotoxicity, respectively, but all three concluded that, in general, data supporting definite causality are lacking. The US Pharmacopeia Dietary Supplements Information Expert Committee, the European Medicines Agency, and the Australian Therapeutic Goods Administration (TGA) recommend that preparations containing BC should carry a warning of possible hepatotoxicity.5-7 Other serious adverse events reported include anaphylaxis, cutaneous vasculitis and myotoxicity.8-10 Studies of BC for mutagenicity, teratogenicity and carcinogenicity have produced negative findings.11 A search of MEDLINE identified no reports of bradycardia due to BC in the literature. However, a Google internet search using the terms “black cohosh” and “heart rate” yielded numerous natural therapy websites describing “slow heart rate” as a side effect of BC. Slow heart rate is also described as a side effect of BC in the Micromedex AltMedDex System database (version 5.1; Thomson Reuters [Healthcare] Inc, Denver, Colo, USA). We notified the TGA of this adverse event. The TGA has received 33 previous reports of suspected adverse events involving BC; none have involved bradycardia or syncope, and one involved hypotension (Rob Crowdy, Adverse Drug Reactions System Database Manager, TGA, personal communication, 3 June 2010). The mechanism by which BC exerts its effects is uncertain. The rhizome of BC contains a number of biologically active constituents, including the triterpene glycosides actein, 27-deoxyactein and cimicifugoside, as well as long-chain fatty acids, resins, caffeic acids, isoferulic acids, phytosterin, fukinolic acid, salicylic acid, sugars and tannins.12 To date, over 50 compounds derived from BC have been described.13 Serotonergic effects not due to serotonin selective reuptake inhibition have been demonstrated with BC preparations.14,15 BC exhibits competitive binding to the 5-HT1A, 5-HT1D and 5-HT7 receptors14-16 and is a partial agonist at serotonin receptors.17 This is noteworthy, as studies show that activation of 5-HT1A receptors in the hypothalamus inhibit hypothalamus-mediated increases in heart rate and blood pressure.18,19 One study investigating the vasoactive effects of BC demonstrated that BC-derived cimicifugic acids inhibit noradrenaline-mediated contraction in rat aortas by inhibition of calcium influx.20 In their 1993 review,4 Borelli and colleagues described a 1935 study in which four glycosidic fractions obtained from the rhizome of BC were administered to dogs; the fraction insoluble in water was found to induce strong arterial hypotension, a decrease in cardiac contraction, and bradycardia to the point of death. Based on the published pharmacology of the components of BC, it is difficult to provide a clear explanation as to how it mediates complete heart block. It is noteworthy that bradycardia is a widely listed side effect of BC in non-academic literature and that profound bradycardia has been documented in animal studies following administration of its extracts.4 Applying the Naranjo algorithm to this case shows that BC was probably responsible for the presentation of our patient (Box 2).21 Given the severity of the adverse reaction and the 2-week delay until its onset, reintroduction of BC while appropriately monitoring the patient to strengthen the argument for causality is not feasible. Although BC is potentially useful in the treatment of menopausal symptoms, it has not been subjected to the extensive postmarketing surveillance that conventional pharmacological agents receive and has potential for numerous adverse effects. It should be considered as a potential cause of unexplained signs or symptoms of cardiac conduction disturbance. 1 Patient’s telemetry and electrocardiogram (ECG) traces Cardiac monitoring telemetry trace (A) and ECG (B) showing complete heart block. 2 Application of the Naranjo algorithm21 to this case Criteria (score applied) Score 1. Are there previous conclusive reports on this reaction? Yes (+1) No (0) Do not know or not done (0) 0 2. Did the adverse event appear after the suspected drug was given? Yes (+2) No (- 1) Do not know or not done (0) 2 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given? Yes (+1) No (0) Do not know or not done (0) 1 4. Did the adverse reaction appear when the drug was readministered? Yes (+2) No (- 2) Do not know or not done (0) 0 5. Are there alternative causes that could have caused the reaction? Yes (- 1) No (+2) Do not know or not done (0) 2 6. Did the reaction reappear when a placebo was given? Yes (- 1) No (+1) Do not know or not done (0) 0 7. Was the drug detected in any body fluid in toxic concentrations? Yes (+1) No (0) Do not know or not done (0) 0 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? Yes (+1) No (0) Do not know or not done (0) 0 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? Yes (+1) No (0) Do not know or not done (0) 0 10. Was the adverse event confirmed by any objective evidence? Yes (+1) No (0) Do not know or not done (0) 1 Total score* 6 * ≥ 9 = definite adverse drug reaction (ADR); 5–8 = probable ADR; 1–4 = possible ADR; 0 = doubtful ADR.

Scott C McKenzie MB BS, BSc, FRACP · Atifur Rahman FRACP

To the Editor: I would like to correct some inaccuracies in an article by Jelinek and Gawler in the December 2008 issue of the Journal about a survivor of disseminated osteosarcoma.1 The article describes a 58-year-old man who was diagnosed in 1974, at the age of 24 years, with histologically confirmed high-grade osteosarcoma of the right femur. He underwent a full leg amputation in January 1975, but metastases recurred 11 months later, in December 1975. The authors of the article misreported a sequence of medically significant events, altering the patient’s actual history. (The correct chronology and early clinical history of the case have been published elsewhere.2,3) The errors and omissions in the article by Jelinek and Gawler, together with the correct sequence of events and relevant inclusions, are outlined in Box 1. In summary, the major errors in the article were as follows: Timeline errors. The authors stated that the patient first saw Dr Meares in September 1976, after chemotherapy had failed. In fact, the patient consulted Meares as a first-line treatment approach on 12 December 1975, and did not consider chemotherapeutic options until September 1976. The authors also stated that the patient had palliative radiotherapy in September 1976. In fact, the patient had only one course of palliative radiotherapy treatment, in February 1976. Vegan diet. The patient never followed a vegan diet. Date of photographs. The photographs in Figures B and C of the article by Jelinek and Gawler were taken on 7 July 1977 (Box 2), not at the time of first contact with Meares, as implied in the article. An appraisal of the patient’s symptoms, combined with an accurate clinical history, reveals a more plausible scientific hypothesis for his remission than the effects of diet and meditation. Although diet and meditation may be adjuncts to a patient’s wellbeing, it is unlikely in this case that they were curative, and certainly veganism was not a relevant factor. Immunotherapy with BCG vaccine treatments, the timing of symptoms and the patient’s eventual diagnosis of tuberculosis could be associated with his remission, as postulated by his radiation oncologist in 1978.6 There is extensive scientific literature about remission of cancer, including osteosarcoma, associated with febrile conditions.5,8-15 The patient’s sporadic visits to doctors meant that metastases were not diagnosed histologically and much of the information reported on his case is anecdotal. Clearly, in this and other cases, unbiased investigative scientific research needs to be undertaken before reporting anecdotes and extrapolations as if they were fact. Teasing apart the errors in Jelinek and Gawler’s story, now on the public record and almost medical myth, is an enormous task, but one that must be done, because correctly reporting the patient’s clinical timeline is crucial in any discussion about the causes of his remission and the flow-on effect to cancer patients and their treating doctors.16 1 Corrections to errors in the article by Jelinek and Gawler1 Errors and omissions in the article Facts, corrections and inclusions December 1975: widespread bony and pulmonary metastases were diagnosed. December 1975: an isolated metastasis in an inguinal node was diagnosed. The patient undertook the Gerson dietary regimen,4 immunotherapy with BCG vaccine,5 and the Meares intensive meditation program.6 September 1976: “[the patient] underwent three cycles of palliative chemotherapy with vincristine, adriamycin, cyclophosphamide and darcarbazine, as well as brief palliative radiation therapy”. September–October 1976: growth of tumours on the sternum increased, and metastases were detected in the left lung. Coughing and haemoptysis were present.6 Experimental chemotherapy (with adriamycin, vincristine and methotrexate)2 was ceased at 10 weeks after December 1976. No radiation therapy was given at this time. Palliative radiotherapy was administered in February 1976, not September 1976. September 1976: “He elected to discontinue these therapies as his condition deteriorated further.” “The patient then consulted prominent psychiatrist and hypnotherapist Dr Ainslie Meares ...”. December 1975: the patient first consulted Meares. In February 1976, he abandoned the Meares meditation program. The 10-month discrepancy between December 1975 and Jelinek and Gawler’s stated date of September 1976 (actual date, October 1976) alters the patient’s medical timeline, implying that it was only after other treatments had failed that meditation began and played a key role in his recovery. Dates of photographs shown in the article: “When Meares first saw the patient, he had visible bony tumours protruding from his ribs, sternum (Figure B) and iliac crest, and was coughing up blood containing small spicules of bone (Figure C).” The article by Jelinek and Gawler implies that the photographs in their Figures B and C were taken around the time when the patient first contacted Meares. The photograph in Figure B was actually taken on 7 July 1977, 19 months after his first contact with Meares. Tumours were not protruding from the sternum when Meares first saw the patient to begin meditation in December 1975, and there were no visible metastases. The coughing up of blood containing bone spicules (Figure C) began in mid 1977, not in the period between December 1975 and February 1976. Vegan diet: “[the patient] adhered faithfully to a vegan diet”. The patient never followed a vegan diet. Veganism involves exclusion of all animal products. The Gerson regimen4 includes dairy foods and calf liver juices. For the following 22 years, the patient’s diet included seafood, dairy products and eggs. First appearance of tuberculosis: “Presumably related to immunosuppression from chemotherapy, he developed pulmonary tuberculosis in June 1978, and was treated for this condition for 12 months.” In 1978, an oncologist diagnosed advanced tuberculosis (TB) dating back to early 1976. (Previous x-rays were examined, showing evidence that TB had been present and undiagnosed for at least 2 years. The patient had very advanced TB by June 1978.6) The suspected cause was BCG vaccine treatments administered in December 1975, possibly exacerbated by chemotherapy and associated immunosuppression in late 1976. 2 Original photographs of patient’s chest taken on 7 July 1977 I am in possession of these original photographs (left), which were dated 7 July 1977 (date enlarged in inset). A copy of page 227 from the original edition of You can conquer cancer7 also confirms the accurate date of the photographs as 7 July 1977 (date enlarged in inset)

Grace O Gawler

In reply: In conjunction with the patient’s memory, and teasing out details, where available, from medical records and investigations of over 30 years ago, we sought to piece together our follow-up story of a remarkable recovery from cancer as accurately as possible.1 We did not attempt to reproduce the original case report in the Journal,2 but rather were highlighting the long-term issues that can be associated with such recoveries. We thank Ms Gawler for attempting to clarify the original timelines. However, based on the medical records and published data, as well as checking further with the patient himself, it seems her letter does little more than muddy the waters in this case. Ms Gawler claims the patient abandoned the Meares meditation program in February 1976. This is factually incorrect and misleading. The patient continued to use Meares’ methods to meditate for 3 hours daily until he recovered, and has meditated at least 1 hour daily since then. The timelines quoted around the photographs in Figures B and C in our original article1 were based on information from Meares’ 1978 article.2 He was somewhat inaccurate, as is Ms Gawler, who claims the photos were taken in July 1977. This is incorrect. Figure B was photographed in July 1976 as chemotherapy was commenced. Figure C was photographed in 2008 and documents bony spicules coughed up during the first half of 1977, collected and retained by the patient. Regarding the use of BCG vaccine treatments, the patient reports that none of the three tuberculosis (TB) specialists whom he consulted gave credence to Ms Gawler’s suggestion that the onset of TB was related to the BCG vaccine. Ms Gawler further postulates that the remission could be linked to a febrile condition associated with TB. The patient did have severe night sweats (which may or may not have been accompanied by fever) over a period of 2–3 weeks in February and March 1976, at a time when he almost certainly had not yet contracted TB, and after which the metastases continued to grow rapidly. After this time, the patient never reported fevers that would make sense of this claim. Ms Gawler claims that the patient’s metastases were not diagnosed histologically and that much of the reported evidence is anecdotal. This is misleading and would surely surprise the involved surgeon, oncologist and other physicians, who used the best available medical evidence at the time and cooperated in the preparation of our original article. The case is documented with a thorough medical history, the patient’s surgeon and other specialists were consulted regularly, and accurate records were retained. Full details confirming the report are available in the patient’s biography.3 The metastases were thoroughly investigated and confirmed by the Peter MacCallum Cancer Centre in Melbourne and regularly tracked via x-ray. The original lesion seen on x-ray was diagnostic for osteosarcoma and the diagnosis was confirmed histologically by biopsy, and again after amputation. The case history is certainly complex and compelling. The message is clear: unexpected recovery from disseminated cancer remains a possibility, and is likely to be influenced by lifestyle factors.

George A Jelinek · Ruth H Gawler

To the Editor: I applaud the Medical Journal of Australia’s recent attempt to increase the evidence base of complementary medicine.1 However, it is disappointing that the Journal’s idea of doing so seems to be to import the same dogmatic and misinformed debate currently occurring in the United Kingdom. Ernst makes little secret of his antihomeopathic agenda and engages in some “cherry picking” of his own, neglecting, for example, to mention the substantial methodological criticisms of some of the references he chooses to use to support his points.2 Further, expert testimony at the British House of Commons Science and Technology Committee’s evidence check on homeopathy identified 24 condition-based systematic reviews and meta-analyses on homeopathy, of which nine were positive, five were negative and 10 were inconclusive.3 As a system of medicine, this compares more closely with the evidence base for conventional medicine than many would care to admit.4 It has also long been observed that the complex and individuated nature of complementary therapies — and many conventional therapies, for that matter (including many surgical and psychological interventions) — makes clinically relevant evaluation with a placebo-controlled trial difficult.5 Cochrane reviews may certainly be “the best” at reviewing the trials, but this means little if those trials were not an appropriate evaluation tool in the first place. Rarely do these trials reflect the real-world settings in which patients, medicines and practitioners exist. The challenge is not simply to be better than placebo, but to produce the largest clinical effect possible in a real-world setting. In his article,1 Ernst himself seems to acknowledge the potential broader real-world benefits that patients receive from homeopathic treatment, as confirmed by observational data,6 yet seems inclined to focus only on reductionist approaches to evaluation that are well known to be ill suited to homeopathic research, or focuses on the implausible nature of the medicine itself. We need to take a different approach and work out why it is that patients who choose to use homeopathy get better (as they quite often do). To do this, we need not just more basic and clinical research, but more health services and public health research on homeopathy — reviewing the reviews adds little if there is simply not enough to review in the first place. Throwing out the baby with the bathwater helps no-one, least of all the patient. And the patient, not ideology, is what it should be all about.

Jon L Wardle

In reply: Wardle’s letter raises several points that deserve comment. Wardle calls me dogmatic, misinformed and antihomeopathic. Such ad hominem attacks hardly promote a rational debate. When I started my job of scrutinising homeopathy 17 years ago, I was pro-homeopathy1 — I once worked in a German homeopathic hospital — and became more sceptical as the evidence base for homeopathy became more clearly negative.2 This, it seems to me, is the opposite of dogmatic. Wardle cites the report by the House of Commons3 in the United Kingdom and claims that it “identified 24 condition-based systematic reviews and meta-analyses on homeopathy, of which nine were positive . . .”. In truth, it was a submission from homeopaths to the House of Commons that made this statement. The report itself found no positive evidence for homeopathy and even criticised how the homeopaths tried to mislead the inquiry.3 Wardle also thinks that clinical trials are “ill suited” to evaluate homeopathy because homeopathy is “complex and individuated” and clinical trials “rarely . . . reflect the real world”. The notion here is that, if the scientific method does not support our belief, it must be the former rather than the latter which is at fault. Adopting this attitude would take us right back into the Dark Ages. After discussing these issues for 17 years, I have the impression that most homeopaths are in favour of rigorous, reductionist science — insofar as it generates the results they want. Whenever this is not the case, they point to observational studies that are wide open to bias and confounding, and therefore show us precious little. Finally, Wardle seems to imply that homeopathy works because patients like it and that this is what truly helps patients. The truth is that medicine has made huge advances only since we buried this attitude. It is time now that proponents of homeopathy do the same — not to conform with a dogma, but because patients would live longer and healthier lives.

Edzard Ernst

To the Editor: In their letter in the 1 February 2010 issue of the Journal, Rashid and Grant reported the first Australian case of hepatotoxicity associated with the weight-loss product Hydroxycut.1 They noted that, in May 2009, the United States Food and Drug Administration (FDA) advised consumers to stop using Hydroxycut products on the basis of 23 reports linking them to serious injury, including one fatal case of liver failure. In response, the Australian sponsor, Export Corporation (Australia) Pty Ltd told the Therapeutic Goods Administration (TGA) that there were differences between the US and Australian formulations of Hydroxycut products. As the TGA had received no reports of adverse reactions similar to those reported in the US, they allowed local marketing to continue. The TGA website advised consumers to exercise caution when using Australian Hydroxycut products;2 however, no such warnings appeared in local promotional material. In contrast, despite also being told that products marketed in the United Kingdom had different formulations, the UK Food Standards Agency (FSA) said: The specific ingredient or dosage which might be causing health problems has not yet been identified. However, as a precautionary measure, the FSA is warning people not to take them. There are no reported illnesses in the UK related to these products. . . . Hydroxycut products have been withdrawn from sale in the USA, Finland and Canada. Ireland has also advised retailers to withdraw the product and consumers to discontinue use of the products.3 Meanwhile, there have been three complaints upheld about the promotion of Australian Hydroxycut products, with another in progress.4 In 2008, the Complaints Resolution Panel (CRP) requested that the sponsor, retailers and website publishers withdraw any representations that the advertised product(s) has benefits in relation to fat-burning, weight loss, or weight management. Regardless, these claims continue to be made by numerous Australian internet pharmacies, and supplement and health food sites. This highlights the impotence of the CRP (which lacks the power to impose sanctions), the ineffectiveness of the TGA (which can impose sanctions, but apparently declines to do so) and the need for regulatory reform.5 A reformulated Hydroxycut is back on the shelves in the US. An FDA spokesperson said: “The only ingredient left in from the original formulation is caffeine. We do not have any evidence that caffeine causes liver toxicity.”6 However, on 14 February 2010, I had no difficulty in purchasing Hydroxycut (AUST L 154243) from a local pharmacy. This product has a similar formulation to products withdrawn overseas. Rashid and Grant called on the TGA to re-examine the continued availability of these products in Australia.1 I reiterate their call. Why is the TGA out of step with other regulators? Why are these products still on the Australian market if their benefits are negligible or absent, if unethical promotion continues despite CRP determinations, and when the risks are clear?

Ken J Harvey

Objective: To evaluate the evidence for and against the effectiveness of homeopathy.Data sources: The Cochrane Database of Systematic Reviews (generally considered to be the most reliable source of evidence) was searched in January 2010.Study selection: Cochrane reviews with the term “homeopathy” in the title, abstract or keywords were considered. Protocols of reviews were excluded. Six articles met the inclusion criteria.Data extraction: Each of the six reviews was examined for specific subject matter; number of clinical trials reviewed; total number of patients involved; and authors’ conclusions. The reviews covered the following conditions: cancer, attention-deficit hyperactivity disorder, asthma, dementia, influenza and induction of labour.Data synthesis: The findings of the reviews were discussed narratively (the reviews’ clinical and statistical heterogeneity precluded meta-analysis).Conclusions: The findings of currently available Cochrane reviews of studies of homeopathy do not show that homeopathic medicines have effects beyond placebo.

Edzard Ernst FMedSci, FRCP, FRCPEd

To the Editor: Over-the-counter herbal supplements to promote weight loss have become increasingly popular. Several of these products contain potentially hepatotoxic substances. We present the first reported Australian case of acute hepatotoxicity associated with the weight-loss product Hydroxycut Hardcore (Iovate Health Sciences, Blasdell, NY, USA). Hydroxycut contains various ingredients, including extracts of the herbs Garcinia cambogia and Camelia sinesis (green tea root), and the chromium salt, chromium polynicotinate. A recent review cites these three ingredients as possible causes of Hydroxycut hepatotoxicity.1 A 23-year-old, previously well, construction worker presented to his doctor with a 2-month history of lethargy and jaundice. Test results confirmed serum liver enzyme derangement, and the patient was advised to stop taking the weight-loss supplement. Results of repeat testing a week later showed worsening liver enzyme levels and he was referred to our hospital. On arrival, the patient denied any symptoms except moderate lethargy and icteric sclera. He was usually well with no relevant medical or surgical history. He weighed 83 kg. He denied drinking alcohol, using prescription or non-prescription drugs, or receiving a blood transfusion. He had had unprotected sexual intercourse 2–3 months earlier. A previously obtained tattoo was being extended by a reputable tattoo parlour. He had been using Hydroxycut Hardcore daily for 10 weeks (obtained from his local outlet of a global nutritional products retailer) in an attempt to lose weight and tone muscle. He claimed to have taken the dosage recommended by the manufacturer (six capsules daily); he was taking no other supplements. Physical examination revealed mild jaundice without other features of chronic liver disease or portal hypertension. However, in addition to abnormal blood levels of liver enzymes, bilirubin and iron, results of the patient’s liver biopsy showed severe acute hepatitis (Box). The abnormal test results were consistent with acute drug toxicity. The patient improved without specific treatment and was discharged 8 days after presentation, with near-normal serum liver enzyme levels. He was well on follow-up at 4 weeks. Two reports from the United States link Hydroxycut Hardcore to acute liver injury in otherwise well young males.2,3 The American Food and Drug Administration in May 2009 advised consumers to stop using the product, based on 23 reports linking it to serious injury, including one case of liver failure leading to death.4 In May 2009, Australia’s Therapeutic Goods Administration (TGA) issued a warning to consumers about the product, although noting that no adverse events had so far been reported in Australia.5 In view of this first reported Australian case of Hydroxycut hepatotoxicity, we advise medical practitioners and consumers in this country to be wary of the product, and call on the TGA to re-examine its continued availability. Investigation results for a 23-year-old man with liver dysfunction after using Hydroxycut Hardcore Investigation Result (reference range) Blood tests Aspartate aminotransferase (U/L) 1182 (12–36) Alanine aminotransferase (U/L) 2950 (5–40) Alkaline phosphatase (U/L) 121 (50–140) Bilirubin (µmol/L) 113 (3–18) Prothrombin time (seconds) 13 (11–15) Iron (µmol/L) 68 (11–30) Ferritin (µg/L) 1897 (30–400) Iron saturation (%) 99 (16–50) Paracetamol Not detected Hepatitis A, B, C Negative HIV Negative Autoantibodies Not detected Epstein–Barr virus, cytomegalovirus, toxoplasma, leptospira, coxiella Negative Haemochromatosis genetic testing No abnormality Other tests Abdominal ultrasound No abnormality Percutaneous liver biopsy Severe acute lobular hepatitis with areas of bridging necrosis; no bridging fibrosis or cirrhosis were seen Hepatic iron index 1.1 (< 2.0)

N Nudrat Rashid · Jason Grant

To the Editor: Complementary and alternative medicine (CAM)1 has become increasingly popular, with Australians spending an estimated $1.8 billion on CAM per year.2 We conducted a prospective study to determine the prevalence and patterns of CAM use among Australian patients with osteoporosis and to identify demographic, socioeconomic and disease-specific features that predict its use. A recent Canadian study of 360 patients with osteoporosis showed that 57% used CAM; CAM users tended to be younger than non-users and better educated, but with a lower quality-of-life score for mental health.3 To our knowledge, there have been no similar studies carried out in Australia. We surveyed 202 randomly selected patients of a Sydney tertiary hospital osteoporosis clinic over a 10-month period (March to December 2007). The clinic sees a wide spectrum of people, from healthy postmenopausal women to patients with multiple comorbidities. At their routine clinic visits, participants completed a prospective questionnaire based on previous CAM therapy surveys.3,4 They were asked about use of CAM, reasons for use, cost, perceived benefits, household income, medical insurance status and educational background. Ethics approval for the survey was obtained from the hospital’s ethics review board. The mean age of participants was 68.5 years (SD, 10.9 years); 80% were women; and 56% were born overseas. We analysed responses using firstly a fairly broad “standard” definition of CAM (including all therapies listed in the Box), and then a more stringent definition that excluded hypnosis, multivitamin therapy, tai chi and yoga. CAM use was reported by 104 patients (51%) and 62 patients (31%) based on the standard and stringent definitions, respectively. Comparative popularity of the CAM therapies used by the surveyed patients is shown in the Box. Common reasons for CAM usage were its holistic approach (53%) and the perception that conventional therapy was providing inadequate pain control (29%). Seventy-three per cent of respondents did not consult a physician before starting CAM, and 23% stated that their treating specialists were unaware of their CAM use. Eighty-eight per cent paid for their therapies out of pocket and the mean cost per patient per month was $21. (Given that 2.2 million Australians have an osteoporosis-related condition5 and 51% of these patients use CAM, the estimated annual expenditure on CAM therapies by patients with osteoporosis is $696 million.) CAM users were more likely than non-CAM users to be university-educated (26% v 14%; P = 0.05); to be born in Asia (20% v 13%; P = 0.03); to have a lower lumbar spine bone mineral density T score (mean, − 2.35 SD v − 2.20 SD; P = 0.05); and to make more frequent clinic visits (mean T score, 1.8 v 1.5 visits /12 months; P = 0.03). More than half the respondents (57%) were unable to differentiate between the terms “osteoporosis” and “osteoarthritis”, especially those from a non-English-speaking background (64% compared with 46% of patients from English-speaking backgrounds; P = 0.02) and CAM non-users (57% compared with 41% of CAM users; P = 0.01). The proportion of patients using CAM in our study was comparable to the proportion in a similar Canadian cohort (51% v 57%).3 Patients who resort to CAM for pain relief may be suffering residual fracture pain or coexisting conditions, such as osteoarthritis; patients unable to differentiate between osteoporosis and osteoarthritis may be seeking relief from pain caused by the latter. Given the low rate of patient disclosure of CAM use to physicians in our study and the reasonable chance of interaction between CAM and conventional therapies (17%),3 physicians would be prudent to regularly and clearly discuss concurrent CAM use with patients (using interpreters when necessary) to avoid potentially harmful drug interactions and side effects. At the same time, physicians could recommend appropriate balance-training therapies,6 such as tai chi, which has been shown to improve bone health and prevent falls.7 Proportion of osteoporosis clinic patients who reported using various complementary and alternative medicine (CAM) therapies (n = 104) Therapy No. (%) of patients* Multivitamins 25 (24%) Fish oil 24 (23%) Acupuncture 20 (19%) Tai chi 15 (14%) Glucosamine 14 (13%) Yoga 13 (13%) Chiropractic/osteopathy 12 (12%) Naturopathy 6 (6%) Herbal therapy 5 (5%) Chinese medicine 3 (3%) Aromatherapy 2 (2%) Massage therapy 2 (2%) Homeopathy 1 (1%) Hypnosis 1 (1%) Minerals 1 (1%) Laser therapy 1 (1%) Any CAM (standard definition) † 104 (51%)‡ Any CAM (stringent definition) † 62 (31%)‡ * Percentages total > 100% because patients used multiple therapies. † The standard definition of CAM includes all therapies listed here; the stringent definition excludes hypnosis, multivitamin therapy, tai chi and yoga. ‡ These are percentages of the total sample (N = 202).

Jenson C S Mak · Steven Faux

Objective: To evaluate the evidence for and against the effectiveness of reflexology for treating any medical condition.Data sources: Six electronic databases were searched from their inception to February 2009 to identify all relevant randomised controlled trials (RCTs). No language restrictions were applied.Study selection and data extraction: RCTs of reflexology delivered by trained reflexologists to patients with specific medical conditions. Condition studied, study design and controls, primary outcome measures, follow-up, and main results were extracted.Data synthesis: 18 RCTs met all the inclusion criteria. The studies examined a range of conditions: anovulation, asthma, back pain, dementia, diabetes, cancer, foot oedema in pregnancy, headache, irritable bowel syndrome, menopause, multiple sclerosis, the postoperative state and premenstrual syndrome. There were > 1 studies for asthma, the postoperative state, cancer palliation and multiple sclerosis. Five RCTs yielded positive results. Methodological quality was evaluated using the Jadad scale. The methodological quality was often poor, and sample sizes were generally low. Most higher-quality trials did not generate positive findings.Conclusion: The best evidence available to date does not demonstrate convincingly that reflexology is an effective treatment for any medical condition.

Edzard Ernst MD, PhD, FMedSci

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

Belal Naser · Eckehard Liske

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

Rolf Teschke