Evidence Check 2: Homeopathy - Science and Technology Committee Contents


Supplementary memorandum submitted by Professor Edzard Ernst (HO 16a)

  In the document submitted on 5 November 2009, I stated that "systematic reviews or meta-analyses of the totality of the clinical trial data fail to show that homeopathic remedies generate clinical effects beyond those of placebo". This is an appendix substantiating this claim which I ask to be attached to my previously submitted evidence.

1.  SYSTEMATIC REVIEWS OF HOMEOPATHY

  In 2002, I published a summary1 of all systematic reviews that emerged after Linde's positive Lancet meta-analysis (first row in Table 1). Six re-analyses of Linde's data—including two by Linde himself [never cited by homeopaths!]—arrived at a less than positive conclusion (Table 1). Furthermore, 11 new and independent systematic reviews published after Linde's article also fail to conclude that homeopathy is effective (Table 2). Since the publication of my article1, further negative systematic reviews have appeared, eg the well-known one by Shang et al in the Lancet2 and our review of homeopathy for childhood conditions.3

2.  SHANG ET AL

  Probably, the review by Shang et al2 has been criticised by homeopaths. While no review can ever be without limitations, these criticisms have been refuted. If needed, I can provide further written evidence on this issue.

3.  THE EVIDENCE IS GETTING WEAKER

  We published a further analysis testing whether the evidence for or against homeopathy is getting stronger.4 It compares the old5 with the new edition6 of one of our books. Both are based on systematic reviews employing virtually the same methodology.5, 6 The indications included in our books are those which are common in primary care, frequently treated with CAM and for which clinical trials are available. The literature was searched up to March 2000 for the first5 and up to May 2005 for the second edition.6 To evaluate the data, we created a parameter which we called the "weight of the evidence". This was a compound variable consisting of the level of evidence (eg whether there was a single trial or a meta-analysis), the quality of the primary studies and the volume (ie total number of trials and their total sample size).7 The weight was graded in three categories: low, moderate and high. We graded the direction of the evidence in five categories: clearly positive, tentatively positive, uncertain, tentatively negative and clearly negative. In Table 3, we compared the weight and direction of the evidence of homeopathy for treating those conditions which were included in our book: AIDS, anxiety, asthma, cancer, chronic fatigue syndrome, fibromyalgia, hay fever, headache, hypertension, labour induction, migraine, osteoarthritis, overweight, premenstrual syndrome, rheumatoid arthritis, stroke, tinnitus and upper respiratory tract infection. Our comparison suggests that, as more clinical trials of homeopathy become available, the overall evidence gets not stronger but weaker. For four conditions for which no trial evidence had been available in 2000, new evidence had emerged in 2005. In three cases, this was clearly negative, and in one it was rated as uncertain. Changes in either the weight or the direction of the evidence were observed in four of the 18 homeopathy-related indications (Table 3). By definition, the weight could only grow between 2000 and 2005. For one condition, namely chronic fatigue syndrome, the direction of evidence changed in a "positive" sense. For three indications, the evidence had altered in the opposite sense: anxiety, asthma, rheumatoid arthritis. (Table 3)

4.  OTHER EVIDENCE

  Homeopaths often argue that there are further systematic reviews which allegedly do show that homeopathy works. Examples are a recent Swiss Health Technology Assessment or the review by Mathie.8 The problem is that these articles do not fulfil the formal criteria for a systematic review, originate from homeopaths, are open to bias and can be criticised on important methodological grounds.9

5.  CONCLUSION

  Systematic reviews of rigorous trials of homeopathy fail to demonstrate that homeopathic remedies have effects beyond those of placebo. Monitoring the development of the evidence over time we find that the overall evidence-base of homeopathy is becoming more and more negative. Confronted with such data, homeopaths tend to counter that the method of testing homeopathy in clinical trials is flawed and the hierarchy of evidence is of disputed value. Nowadays they frequently cite Sir Michael Rawlins (NICE) in support of this view who recently gave a lecture discussing that the evidence from randomised clinical trials should not be seen in isolation. Homeopaths fail to mention, however, that Sir Michael also made the following statement about homeopathy: "As far as homeopathy is concerned it breaks every rule in the evidential base! It is biologically implausible; it is almost always used to treat conditions where the natural history is unpredictable; and the signal to noise ratio is close to one!".10

Table 1

THE SYSTEMATIC REVIEW BY LINDE ET AL11 AND ITS SUBSEQUENT RE-ANALYSES
Reference

Included trials (number)

Total patient
number
Assessment of methodological quality

Meta-analysis


Overall conclusion*


Comment

Linde (1997) 11
all double-blind and/or randomized placebo-controlled trials of any clinical condition (n=186) 2,588yesof 89 trials which could be submitted to meta-analysis: OR = 2.45; of 26 "good quality trials": OR = 1.66 (both in favour of homeopathy) clinical effects of homeopathy are not completely due to placebo review was criticised for
1)  including different remedies
2)  including different conditions
3)  including non-randomized trials
Ernst (1998) 12 all studies from Linde et al11 which received 90
(of 100) points in at least 1 of the 2 quality ratings, using highly dilute remedies, following the principles of "classical"* homeopathy
(n=5)
587yesOR=1.0
(no evidence in favour of homeopathy)
homeopathic remedies are associated with the same clinical effects as placebo this analysis specifically tested the efficacy of highly diluted remedies (other remedies could still work via conventional pharmaceutical effects)
Linde (1998) 13 all trials from Linde et al11 which tested "classical"* homeopathic remedies against placebo, no treatment or another treatment
(n=32)
1,778yes19 placebo-controlled trials were submitted to meta-analysis; OR = 1.62; however, when this analysis was restricted to the methodologically best trials the effect was no longer significant individualised homeopathy has an effect over placebo; the evidence, however, is not convincing not all of the included trials were randomized and many had other serious methodological weaknesses
Linde (1999) 14 all trials from Linde et al11 which could be submitted to meta-analysis
(n=89)
n.d.p.yesthe mean OR of the best studies was not in favour of homeopathy there was clear evidence that studies with better methodological quality tended to yield less positive results the authors felt that these results "weaken the findings of [their] original meta-analysis"
Morrison (2000) 15 26 trials classified by Linde et al11 as high quality
(n=26)
n.d.p.yesnone no significant trend was seen when correlating security of randomisation and trial result large multicenter trials were recommended
Ernst (2000) 16 all trials from Linde et al11 that received quality ratings between 1-4 on the Jadad score
(n=77)
n.d.p.yesnone there is a ... strong linear correlation between OR and Jadad score (n=0.97, p<05); homeopathic remedies are, in fact, placebos extrapolation from this correlation implies that the most rigorous studies yield an effect size of zero
Sterne (2000) 17 89 trials of Linde et al11 review compared to 89 trials of allopathic medicines n.d.p.yesstrong evidence for publication bias causing a false positive result in favour of homeopathy when adjusting high quality trials [of homeopathy] for publication bias, the OR changed from 0.52 to 1.19 but remained unchanged for allopathy paper probably not peer-reviewed, adjusting for bias nullified the effect of homeopathy but not for allopathy



RCT = randomized clinical trial, OR = odds ratio, * = verbatim quotes, n.d.p. = no details provided.
* classical homeopathy = approach where remedies are individualised according to patient characteristics deemed important by homeopaths.

Table 2

INDEPENDENT SYSTEMATIC REVIEWS OF HOMEOPATHY


Reference


Included trials (number)

Total patient
number
Assessment of methodological quality

Meta-analysis


Overall conclusion


Comment
Barnes (1997) 18 all placebo-controlled trials of homeopathy for post-operative ileus
(n=6)
776yesweighted mean difference to time until first sign of peristalsis was in favour of homeopathy (-7.4 hours) homeopathic treatment can reduce the duration of post-operative ileus, however, several caveats preclude a definitive judgement the methodologically best trial was convincingly negative
Ernst (1998) 19 all placebo-controlled trials of homeopathy for delayed onset muscle soreness (DOMS)
(n=8)
311yesno meta analysis possible, all randomized trials were negative the evidence does not support he hypothesis that homeopathic remedies are more efficacious than placebo for DOMS DOMS was chosen because it was submitted to clinical trials more often than any other condition
Ernst (1998) 20 all placebo-controlled trials of homeopathic arnica
(n=8)
338yesno meta-analysis possible, no clear trend in favour of homeopathy the claim that homeopathic arnica is efficacious beyond a placebo effect is not supported by rigorous clinical trials this analysis set out to test the remedy that had been most frequently submitted to clinical trials, ie arnica (see also Lüdtke below)
Ernst (1999) 21   all RCTs of homeopathy for migraine prophylaxis
(n=4)
284yesno meta-analysis possible; 3 of 4 trials were negative (including the methodologically best) the trial data ... do not suggest that homeopathy is effective in the prophylaxis of migraine or headache beyond a placebo effect this analysis tested the efficacy for a condition that homeopaths often treat in clinical practice
Ernst (1999) 22 all controlled clinical trials of "classical"* homeopathy versus conventional treatments
(n=6)
605nono meta-analysis possible no clear trend in favour of homeopathy non-randomized studies were also included
Lu­dtke (1999) 23 all controlled clinical trials of homeopathic arnica
(n=37)
n.d.p.yesno meta-analysis possible no clear evidence in favour of homeopathic arnica was found paper probably not peer-reviewed, trials that used arnica in combination with other remedies and those which were not placebo controlled were also included
Cucherat (2000) 24 all RCTs of homeopathy vs placebo with clinical or surrogate endpoints
(n=16)
2,617yescombined 2-tailed p value was highly significant (p=0.000056) in favour of homeopathy there is some evidence that homeopathic treatments are more effective than placebo strength of evidence was estimated to be low by the authors
Vickers (2000) 25 all RCTs of homeopathic oscillococcinum vs placebo for influenza
(n=7)
3,459yesRR=0.64 for influenza prevention; RR=0, 28 for influenza treatment treatment reduced length of illness significantly by 0.28 days the authors stated that "the data are not strong enough to make a general recommendation"
Linde (2000) 26 all RCTs of homeopathy vs placebo for chronic asthma
(n=3)
154yesno meta-analysis possible no clear tread in favour of homeopathy not enough evidence for reliable assessment
Jonas (2000) 27 all controlled clinical trials of homeopathy for rheumatic conditions
(n=6)
392yescombined OR = 2.19 homeopathic remedies work better than placebo not enough trials for any specific condition to allow reliable assessment
Long (2001) 28 all RCTs of homeopathy for osteoarthritis
(n=4)
406yesno meta-analysis possible no clear trend in favour of homeopathy not enough evidence for reliable assessment


RCT = randomized clinical trial, OR = odds ratio, RR = relative risk
* classical homeopathy = approach where remedies are individualised according to patient characteristics deemed important by homeopaths.




REFERENCE LIST  1  Ernst E. A systematic review of systematic reviews of homeopathy. Br J Clin Pharmacol 2002; 54:577-582.

  2 Shang A, Huwiler-Mu­ntener K, Nartey L, Ju­ni P, Sterne J A C, Pewsner D et al. Are the clinical effects of homoeopathy placebo effects? Comparative study of placebo-controlled trials of homoeopathy and allopathy. Lancet 2005; 366:726-732.

  3  Altunc U, Pittler M H, Ernst E. Homeopathy for childhood and adolescence ailments: systematic review of randomized clinical trials. Mayo Clin Proc 2007; 82(1):69-75.

  4  Ernst E, Pittler M H, Wider B, Boddy K. Homeopathy: is the evidence-base changing? Perfusion 2006; 19:1-3.

  5  Ernst E, Pittler M H, Stevinson C, White A R. The Desktop Guide to Complementary and Alternative Medicine. 1st Edition. Edinburgh: Mosby. 2001.

  6 Ernst E, Pittler M H, Wider B, Boddy K. The Desktop Guide to Complementary and Alternative Medicine. 2nd edition. Edinburgh: Elsevier Mosby. 2006.

  7 Jadad A R, Moore R A, Carrol D, Jenkinson C, Reynolds D J M, Gavaghan D J et al. Assessing the quality of reports of randomized clinical trials— is blinding necessary? Contr Clin Trials 1996; 17:1-12.

  8 Mathie R T. The research base for homeopathy: a fresh assessment of the literature. Homeopathy 2003; 92:80-87.

  9 Ernst E. Weighing the homeopathic evidence. Homeopathy 2003; 92:67-68.

10 Rawlins M. As cited in Rose L, BMJ Rapid Response. BMJ Rapid Response 2009; 14 July.

11 Linde K, Clausius N, Ramirez G, Melchart D, Eitel F, Hedges LV et al. Are the clinical effects of homoeopathy placebo effects? A meta-analysis of placebo-controlled trials. Lancet 1997; 350:834-843.

12 Ernst E. Are highly dilute homoeopathic remedies placebos? Perfusion 1998; 11:291-292.

13 Linde K, Melchart D. Randomized controlled trials of individualized homeopathy: a state-of-the-art review. J Alt Complementar Med 1998; 4(371):388.

14 Linde K, Scholz M, Ramirez G, Clausius N, Melchart D, Jonas WB. Impact of study quality on outcome in placebo controlled trials of homoeopathy. J Clin Epidemiol 1999; 52:631-636.

15 Morrison B, Lilford R J, Ernst E. Methodological rigour and results of clinical trials of homoeopathic remedies. Perfusion 2000; 13:132-138.

16 Ernst E, Pittler M H. Re-analysis of previous meta-analysis of clinical trials of homeopathy. J Clin Epidemiol 2000; 53:1188.

17 Sterne J, Egger M, Smith G D. Investigating the dealing with publication and other biases. In: Systmeatic reviews in healthcare: meta-analysis in context. In: Egger M, Smith GD, Altman DG, editors. London: 2001. 189-208.

18 Barnes J, Resch K L, Ernst E. Homeopathy for Postoperative Ileus. J Clin Gastroenterol 1997; 25:628-633.

19 Ernst E, Barnes J. Are homoeopathic remedies effective for delayed-onset muscle soreness? A systematic review of placebo-controlled trials. Perfusion 1998; 11:4-8.

20 Ernst E, Pittler M H. Efficacy of homeopathic arnica. A systematic review of placebo-controlled clinical trials. Arch Surg 1998; 133:1187-1190.

21 Ernst E. Homoeopathic prophylaxis of headaches and migraine? A systematic review. J Pain Sympt Managem 1999; 18:353-357.

22 Ernst E. Classical homoeopathy versus conventional treatments: a systematic review. Perfusion 1999; 12:13-15.

23 Lu­dtke R, Wilkens J. Klinische Wirksambeitsstudien zu Arnica in homoeopathischen Zubereitungen. In: Company Report, Carstents Stiftung. Essen, German: 1999.

24 Cucherat M, Haugh M C, Gooch M, Boissel J-P. Evidence of clinical efficacy of homeopathy. A meta-analysis of clinical trials. Eur J Clin Pharmacol 2000; 56:27-33.

25 Vickers A J, Smith C. Homeopathic oscillococcinum for preventing and treating influenza and influenza-like syndromes. The Cochrane Library 2001; 1:1-10.

26 Linde K, Jobst K A. Homeopathy for chronic asthma. The Cochrane Library 1998; 1:1-7.

27 Jonas W B, Linde K, Ramirez G. Homeopathy and rheumatic disease. Rheum Dis Clin North Am 2000; 26:117-123.

28 Long L, Ernst E. Homeopathic remedies for the treatment of osteoarthritis: a systematic review. Br Homeopath J 2001; 90:37-43.

Edzard Ernst MD, PhD, FMedSci, FSB, FRCP, FRCPEd

Complementary Medicine, Peninsula Medical School, Universities of Exeter & Plymouth





 
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