Scientific studies in homeopathy

1. Scientific studies in homeopathy An overview IV Congreso Nacional de Homeopatía, 11 June 2010 Dr Ton Nicolai, President European Committee for Homeopathy

2. What is evidence based medicine? • It is “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients” (Sackett) • It is not "cookbook" medicine. It requires a bottom up approach that integrates the best external evidence with individual clinical expertise and patients' choice. • Three pillars: external evidence, clinical expertise, patients’ choice.

3. What is evidence based medicine? Traditional hierarchy of evidence:

4. Clinical results Hundreds of thousands of case histories, recording successful cases

5. Clinical results • Observational studies in thousands of patients (D, CH, GB): consistent positive results in 40-70% of them as regards • presenting disease symptoms • overall wellbeing • reducing the use of conventional medication • The majority of patients have chronic conditions, many have multiple pathologies and many have not responded to previous conventional treatment.

6. Cost-effectiveness studies • Several studies (D, F, CH) show: GPs practising homeopathy have better results at comparable costs in comparison with conventionally practising GPs. • Homeopathic medicines are less expensive but consultations last longer and are therefore more expensive than conventional consultations.

7. Cost-effectiveness studies • From a long-term and large-scale perspective homeopathy is cost-effective because• improvement of general health, • lower frequency of future consultations, • less absenteeism, • fewer visits to medical specialists,• shorter stay in hospitalin comparison with patients who receive conventional treatment only.

8. Clinical experimental research • The concept of evidence is multi-faceted, but in recent years it has become progressively reduced to accepting randomised controlled trials (RCTs) as the gold standard. • While RCTs can be useful in assessing the effects of a single intervention on a single symptom or outcome, they are far less suitable when studying the overall effects of a holistic therapy in a complex organism with multiple problems. • Notwithstanding this there have been a considerable number of RCTs in homeopathy with far more positive than negative outcomes.

9. Clinical experimental research • 142 RCTs have been published in peer-reviewed scientific journals. • From them 120 (85%) RCTs were placebo controlled, 22 RCTs (15%) were controlled by other than placebo. • Summary finding in 44% of the RCTs was positive for homeopathy, negative in 8% and statistically non-conclusive in 48%.

10. Clinical experimental research • Conclusion of 4 out of 5 systematic reviews of all RCTs in homeopathy: • “Homeopathy has an effect greater than placebo”.

11. Clinical experimental research • The 5th, the well-known 2005 Lancet meta-analysis: “There was weak evidence for a specific effect of homoeopathic remedies, but strong evidence for specific effects of conventional interventions. This finding is compatible with the notion that the clinical effects of homoeopathy are placebo effects” • It was heavily criticised for being biased and not meeting basic (QUOROM) scientific standards.[Shang A et al. (2005) Are the clinical effects of homoeopathy placebo effects? Comparative study of placebo-controlled trials of homoeopathy and allopathy. Lancet, 366:726-32]

12. 2005 Lancet review/meta-analysis • This review/meta-analysis, originally a part of the Swiss CAM Evaluation project PEK, was performed by a team led by a very competent opponent of homeopathy, professor Matthias Egger.

13. 2005 Lancet review/meta-analysis • This team started with 110 clinical trials of homeopathy, which were matched with 110 clinical trials of conventional medicine. • They reduced these to 21‘higher-quality trials’ and then to 8 ‘larger higher-quality trials’. • The final conclusion was based on these 8 studies.

14. 2005 Lancet review/meta-analysis • Interestingly, the authors found that “trials of homeopathy tended to be of higher methodological quality than conventional-medicine trials, although most trials of either type of medicine were of low or uncertain quality”. • 21 high-quality trials in homeopathy • 9 high-quality trials in conventional medicine

15. 2005 Lancet review/meta-analysis • The definition of ‘higher quality’ was based on opaque, unpublished criteria. • The trials on which the conclusion was based, were not mentioned in the publication.

16. 2005 Lancet review/meta-analysis • The Evaluation Committee of the Swiss PEK Study criticised the authors for that in April 2005; in the Lancet publication (August 2005) these data were still missing. • After publication the authors still refused to disclose these data. • After more pressure the data were disclosed in December 2005, but no Odds Ratios, no Confidence Intervals, no Standard Errors were given.

17. 2005 Lancet review/meta-analysis • After disclosure the data were re-analysed by Luedtke and Rutten. • They found out that Shang et al. discarded four out of six best studies in Linde's meta-analysis (1997) • So, there was selection bias.

18. 2005 Lancet review/meta-analysis • Definition of ‘larger trials’ according to Shang et al.: ‘trials with Standard Error in the lowest quartile’. • Outcome: 8 higher-quality trials, leading to a negative result for homeopathy

19. 2005 Lancet review/meta-analysis Larger higher quality studies, according to Shang et al “Carefully matched homeopathic and conventional trials”

20. 2005 Lancet review/meta-analysis • Definition of ‘larger trials’ normally means ‘larger than median (= middle value)’ • Luedtke/Rutten re-analysed the trials using the ‘larger than median’ criterion. • Outcome: 14 higher-quality trials (n > 65), leading to a significantly positive result for homeopathy (best result )

21. 2005 Lancet review/meta-analysis • Meta-analysis results depend on how the threshold for ‘large’ studies was defined. • Positive for homeopathy if the normal ‘larger than median’ criterion is used. • Negative for homeopathy if the ‘Standard Error in the lowest quartile’ criterion is used.

22. 2005 Lancet review/meta-analysis • 4 of the 21 higher-quality trials in homeopathy dealt with the prevention or treatment of muscle soreness in marathon runners. 3 out of the 4 were negative for homeopathy. • 4 matched conventional trials for the same indication were too small and low quality and were not included. • Highly doubtful if muscle soreness in - very healthy - marathon runners is a medical condition that can be ‘cured’. • When Luedtke/Rutten restricted their analyses to the remaining 17 trials, they found an overall statistically significant positive effect for homeopathy.

23. 2005 Lancet review/meta-analysis • The overall results – and the conclusions drawn from them – change depending on which subset of homeopathic trials is analysed. • The choice of other meaningful subsets could lead to the opposite conclusion.

24. 2005 Lancet review/meta-analysis • Surprisingly, the authors themselves highlight – but dismiss – the fact that 8 trials of homeopathy in upper respiratory tract infections have strongly positive findings overall. • They state that 8 studies is too few to question their conclusion about the whole set of publications. Their conclusion about the whole set, however, was also based on 8 studies. Is eight enough or not? • The authors simply refuse to believe the results of positive clinical trials of homeopathy.

25. 2005 Lancet review/meta-analysis • Shang et al. ‘s valid conclusions: • Quality of homeopathic trials was better than conventional trials, so bias is NOT larger in homeopathy than in conventional medicine • This bias DOES NOT affect small homeopathy studies more than small conventional studies

26. 2005 Lancet review/meta-analysis • RCTs in homeopathy research were performed in 80 different medical conditions So the scientific hypothesis “Are the effects of homeopathy placebo?” does not make sense. • Similarly it does not make sense to ask whether conventional medicine is placebo.

27. Clinical experimental research • The heterogeneity of medical condition has been avoided in systematic reviews focused on RCTs of homeopathy in 15 specific areas. • These condition-specific systematic reviews have indicated effectiveness of homeopathy in childhood diarrhoea, post-operative ileus, hay fever, vertigo, allergies, upper respiratory tract infections and rheumatic conditions. • In addition, there is a balance of positive RCT evidence for fibromyalgia and sinusitis.

28. Clinical experimental research • Critics assert that homeopathy is a sort of super placebo. The long doctor-patient contacts can explain why people experience improvements in their health status. • A recent German study demonstrated that the placebo effect in placebo controlled double blind RCTs in individualised homeopathy is not larger than in conventional treatment.[Nuhn T, Lüdtke R, Geraedts M (2010). Placebo effect sizes in homeopathic compared to conventional drugs – a systematic review of randomised controlled trials]

29. Clinical experimental research A reflection on the scientific behaviour of adherents of conventional medicine toward one form of alternative medicine — homeopathy — teaches us that physicians do reject seemingly solid evidence because it is not compatible with theory.[Vandenbroucke JP, de Craen AJP (2001) Alternative Medicine: A “Mirror Image” for Scientific Reasoning in Conventional Medicine. Annals of Internal Medicine, 135:507-513.] 18

30. Clinical experimental research Most impressive, dear colleague…. But does it also work in theory?

31. Double standards • Critics of complementary medicine often seem to operate a double standard, being far more assiduous in their attempts to outlaw unevaluated complementary medical practices than unevaluated orthodox practices. • These double standards might be acceptable if orthodox medicine was based solely on practices which had been shown to do more good than harm, and if the mechanisms through which their beneficial elements had their effects were understood, but neither of these conditions applies. [Dr Iain Chalmers, director of the UK Cochrane Centre and ardent proponent of systematic reviews (1998)]

32. A sceptic perspective • Sceptics assert: • no scientific explanation for its effectiveness, • similia principle lacks all logic, • ultramolecular homeopathic preparations (concentrations < Avogadro) do not contain any molecules, • molecules are necessary for effectiveness • so all positive clinical evidence for homeopathy is unreliable.

33. A sceptic perspective I cannot understand how it could be possible, so it is not possible.

34. Basic research • Toxicological and pharmacological phenomena such as hormesis, drug rebound effects and paradoxical pharmacology are very widely observed. • They have in common the occurrence of secondary, reverse or paradoxical effects of drugs and toxins in living organisms as a function of dose or time and are closely analogous to the homeopathic concept of secondary drug action.

35. Basic research • Dutch cell biologists Wiegant and Van Wijk examined validity of similia principle on cellular level. • They demonstrated: low stress doses (heat, arsenic or cadmium) can stimulate self-recovery if these cells were exposed to high doses of these stressors beforehand. • Similia principle seems to be a biological phenomenon.

36. Basic research • In homeopathy various potencies (serially agitated dilutions) are used, from low to high. Many homeopathic medicines are not in ultramolecular dilutions. • Relatively low potencies (< Avogadro) can have a usual molecular effect (known: low concentrations down to 10-22 M can be biologically active). • Can ultramolecular preparations have an effect?

37. Basic research • Replicated high-quality basic research in • Biological experiments on intact animals, plants and isolated cells and cell cultures • Physical experiments • Even very high ‘dilutions’ have measurable effects.

38. Basic research • A recent meta-analysis: • 67 in-vitro experiments in 75 publications of research on homeopathic dilutions. • A majority of them reported high-potency effects. • Positive findings were obtained in nearly three-quarters of all replicated studies. • Even experiments with a high methodological standard could demonstrate an effect of high potencies. Witt CM et al (2007). The in vitro evidence for an effect of high homeopathic potencies – A systematic review of the literature. Complementary Therapies in Medicine, 15:128–138

39. Basic research • In biological experiments replicated results, such as • Inhibitory effect of serially agitated high dilutions of histamine on the activation of basophil leucocytes, • effect of serially agitated high dilutions of acetosal on bleeding time, platelet aggregation and coagulation, • effect of serially agitated high dilutions of thyroxine on the rate of amphibian metamorphosis, • protective effect of serially agitated high dilutions of mercury on the mortality of poisoned mice, • effects of serially agitated high dilutions of arsenic on the toxic effect of material doses of arsenic trioxide on wheat shoot growth.

40. Basic research • Physical experiments have demonstrated structural changes of water in ultramolecular homeopathic preparations. • Methods used include: • low temperature thermoluminescence • flux calorimetry • conductometry • Raman and Ultra Violet spectroscopy • NMR (Nuclear Magnetic Resonance)

41. Basic research • GIRI = Groupe International de Recherche sur l'Infinitésimal = International Research Group on High Dilution and Very Low Dose EffectsInternational scientific association of ~ 100 pharmacologists, biologists, physicians, chemists and physicists. • Publications in conventional scientific journals as well as International Journal of High Dilution Research. • Homeopathy Basic Research Experiments (‘HomBRex’) Database contains over 1400 experiments in 1000 publications.

42. Basic research The theory/belief that homeopathy, by its use of ultramolecular preparations, is implausible or impossible, is not correct.

43. How convincing is evidence? Albert Einstein: 

It is harder to crack 
prejudice than an atom

44. Paradigm shift • Thomas Kuhn: The Structure of Scientific Revolutions • A paradigm, or shared view, persists for a while but then becomes obsolete because it becomes disturbed by too many ‘anomalies’, which do not fit into, and cannot be explained by, the existing paradigm. It is then replaced by a new paradigm, which is able to explain the anomalies.

45. Paradigm shift • Possible explanatory models from emerging sciences, such as • systems biology: biological system as a hierarchically organised network of interactions • biosemiotics:“The sign rather than the molecule is the basic unit for studying life”