The Clinical Evidence Base of Homeopathy

1. The Clinical Evidence Base of Homeopathy Peter Fisher FRCP, FFHom Clinical Director and Director of Research Royal London Homoeopathic Hospital

2. Comprehensive Systematic Reviews & Meta-analyses of homeopathy • Kleijnen BMJ 1991 • 81/105 interpretable studies positive • ‘Would accept that homoeopathy can be efficacious, if mechanism of action were more plausible” and “would probably be sufficient for establishing homoeopathy as a regular treatment for certain indications’. • Linde Lancet 1997 • 89/186 trials had interpretable results • Not compatible with hypothesis that effects of homeopathy are all placebo effects • Not clearly efficacious for any single condition

3. Comprehensive Systematic Reviews & Meta-analyses of homeopathy 2 • Cucherat Br J Clin Pharm 2000 • 17/184 trials predefined primary outcome in patients • total 2001 patients • p = 0.000036 • evidence that homeopathic treatments are more effective than placebo; problems with methodological quality • Shang Lancet 2005 • 8/110 homeopathy, 6/110 conventional ‘larger higher quality’ • ‘weak evidence for a specific effect of homoeopathic remedies, but strong evidence for specific effects of conventional interventions. Compatible with the notion that the clinical effects of homoeopathy are placebo effects’.

4. 8 anonymous clinical trials. • Not cited, no information (diagnoses, number of patients etc) • 93% excluded. • Data ‘dredged’ • Why 8/21? ‘larger’ added post-hoc • Gives the least positive result • No sensitivity analysis • What is result for all 110 or 21 trials of ‘higher quality’? • Or 1-7, 12-20 • Positive! • Did not comply with QUOROM guidelines • No descriptive data for trials, no summary results, • no consideration of external validity etc Shang et al: criticisms Shang A et al Are the clinical effects of homeopathy placebo effects? Comparative study of placebo-controlled trials of homeopathy and allopathy. Lancet 2005;366:726-32

5. ‘8 trials of homoeopathic remedies in acute infections of the upper respiratory tract…indicated a substantial beneficial effect…no evidence that the effect differed between the trial…of higher quality and the remaining trials. Such sensitivity analyses might suggest that there is robust evidence that the treatment under investigation works. However, the biases that are prevalent in these publications…might promote the conclusion that the results cannot be trusted.’ • In fact homeopathic trials are generally of higher quality than matched trials of conventional medicine and show less heterogeneity Shang et al meta-analysis

6. High quality research?‘Classical’ homeopathy for asthma • 93 children 5-15 years with ‘mild to moderate’ asthma • randomised to individualised homeopathy or placebo • double-blind, placebo controlled • treated up to 6 times in one year, 3 NMQPs • 76 children follow up data.

7. High quality research?results • No significant difference between verum and placebo in QoL • Statistically significant difference in severity scores • severity treatment effect –8.0 (95% CI –13.7 to –2.2 , p=0.01, ANCOVA) • Other subscales differences, consistently favouring homeopathy • post-hoc analysis of time lost from school, favoured homeopathy, not clear whether statistically significant

8. High quality research?Authors’ conclusions ‘No evidence that homeopathic remedies were superior to placebo in improving the quality of life of children with mild to moderate asthma as an adjunct to normal treatment in primary care.’ White A et al. Individualised homeopathy as an adjunct in the treatment of childhood asthma: a randomised placebo controlled trial. Thorax 2003;58:317-321

9. ‘Classical’ homeopathy for asthma: outcome measures • Main outcome measure active QoL scale of the Childhood Asthma Questionnaire (CAQ)

10. High quality research? • This study could not possibly have had a positive result because of a ‘ceiling’ effect in the main outcome measure.The (secondary) outcome measures which could improve, did. • patients had normal QoL at entry • the scale cannot discriminate between normal and asthmatic children • in order to achieve ‘clinically significant’ improvement they would have had to finish with QoL scores > 100%! • also had normal PEFR at entry • High internal validity, no external validity

11. Linde et al: Meta-analysis 1 • 89 RCTs

12. Linde et al: Meta-analysis 2 • Combined odds ratio 2.45 • (CI 2.05-2.93)

13. Linde et al: subgroup analysis • Odds ratios 1.66-5.04

14. Linde et al: publication bias • Funnel plot for publication bias • Some bias present • 923 unreported trials required to makeconclusions insignificant!

15. Linde et al: conclusions • Not compatible with hypothesis that effects of homeopathy are all placebo effects • Not clearly efficacious for any single condition • Further research warranted Linde K et al. Are the clinical effects of homeopathy placebo effects? A meta-analysis of placebo controlled trials. Lancet 1997;350:834-43

16. European Commission Homeopathic Medicine Research Advisory Group • 17 randomised, placebo-controlled clinical trials • predefined primary outcome in patients • total 2001 patients • Statistical significance • p = 0.000036 • Conclusion • evidence that homeopathic treatments are more effective than placebo; problems with methodological quality Cucherat M et al. Evidence of clinical efficacy of homeopathy. A meta-analysis of clinical trials. Eur J Clin Pharmacol 2000;56:27-33

17. Reviews of evidence by condition • Mathie 2003 • Clinical trials homeopathy v placebo or other treatment 1975-2002 • 50/93 positive, most others inconclusive • Evidence favours homeopathy: allergic rhinitis, childhood diarrhoea, fibromyalgia, influenza, pain, side effects of radio-/chemotherapy, sprains, upper respiratory tract infection. • Jonas et al 2003 • Review of 12 systematic reviews of clinical trials of homeopathy for specific conditions. • Homeopathy effective for allergies, childhood diarrhoea, influenza, postoperative ileus, • Not for migraine, delayed-onset muscle soreness, influenza prevention. Mathie R. The research evidence base for homeopathy: a fresh assessment of the literature. Homeopathy 2003, 92:84-91. Jonas WB et al. A critical overview of homeopathy. Ann Int Med 2003, 138:393-399.

18. Focussed systematic reviews and meta-analyses: positive • Childhood diarrhoea (Jacobs et al., 2003) • HIV/AIDS (Ullman, 2003) • Influenza treatment with Oscillococcinum®(Anas barbariaehepatis et cordis extractum HPUS) (Vickers & Smith, 2006) • Osteoarthritis (Long & Ernst, 2001) • Post-operative ileus (Barnes, Resch & Ernst, 1997). • Rheumatic diseases (Jonas, Linde & Ramirez, 2000). • Seasonal allergic rhinitis (Lüdtke & Wiesenauer, 1997) • Seasonal allergic rhinitis (Taylor et al., 2000) • Upper respiratory tract infections and allergy (Bornhöft et al, 2006)

19. Focussed systematic reviews and meta-analyses: negative • Arnica (Ernst & Pittler, 1998) • Delayed-onset muscle soreness (Ernst & Barnes, 1998) • Headache and migraine prevention (Ernst, 1999) • Influenza prevention with Oscillococcinum® (Vickers & Smith, 2006)

20. Focussed systematic reviews and meta-analyses: inconclusive • Chronic asthma (McCarney, Linde & Lasserson, 2004) • Dementia (McCarney et al., 2004) • Depression (Pilkington et al., 2005) • Induction of labour (Smith, 2004)

21. ‘Vote count’ clinical research in homeopathy • 119 randomised peer-reviewed clinical trials (RCTs) of homeopathy to end 2005. • v placebo or active comparators • 49% positive for homeopathy • 3% negative • 48% inconclusive

22. Oscillococcinum® in influenza-like syndromes: Cochrane review • Anas barbariae hepar et cordis extractum (HPUS) • Hearts and livers of wild ducks(!) • Birds are vectors of flu • 7 RCTs: 4 treatment, 3 prevention • Reduces duration of disease • Patients more likely to consider active treatment effective • Not effective for prevention • Promising results, more research required Vickers A, Smith C. Homoeopathic Oscillococcinum for preventing and treating influenza and influenza-like syndromes. (Cochrane review). Cochrane Library 2006:1

23. Isopathy for respiratory allergy: meta-analysis • Isopathy = treatment of ‘same with same’ eg homeopathic dilutions of pollen for hayfever • 4 RCTs • 2 hayfever (mixed pollen 30c) • 1 asthma (individualised allergen, mostly house dust mite 30c) • 1 perennial rhinitis (individualised allergen, mostly house dust mite 30c) • Total n=253 • Highly statistically significant • P=0.0007, 95% CI 4.2-15.4 Reilly D et al Randomised controlled trial of homoeopathy versus placebo in perennial allergic rhinitis with overview of four trial series. BMJ 2000; 321:471-6

24. Isopathy in respiratory allergy:summary of results

25. Isopathy in perennial rhinitis:change in nasal inspiratory peak flow P=0.0001 ‘comparable to steroids’

26. Meta-analysis of homeopathy for childhood diarrhea Jacobs J et al. Homeopathy for childhood diarrhea: combined results and meta-analysis from three randomized, controlled clinical trials. Pediatr Infect Dis J, 2003;22:229–34

27. Homeopathy in the ‘real world’ Averting Ritalin® for ADHD • Homeopathy to avert Methylphenidate (Ritalin®) in ADHD • Attention Deficit Hyperactivity Disorder DSM-IV criteria • 115 children 3-17y, mean 8.3y. 92♂, 23♀. • One withdrawal • Conners Global Index (CGI) ≥14, mean 20.63 at entry • University Paediatric Clinic, Berne • Results • 86 (75%) improved sufficiently not to require Methylphenidate • Mean improvement (parent ratings) 73%, Conners 55% • Mean treatment period 3.5m • 25 (22%) eventually required methylphenidate • Mean treatment period 22m Frei H, Thurneysen A. Treatment for hyperactive children: homeopathy and methylphenidate compared in a family setting. Br Hom J 2001;90:183-188.

28. Homeopathy and ADHD: what happens when treatment is stopped? • 83 children 6-16 years, ADHD (DSM-IV). • Double blind, placebo controlled crossover RCT of individualised homeopathy • 62 responders (50% improvement in CGI), participated in the trial. • 13 non-responders • Responders received verum and placebo for 6 weeks, random sequence • Cognition had improved significantly with open treatment (P<0.0001). • During trial CGI better on verum than placebo (P<0.05). • Long-term CGI improvement 12 points (63%, P <0.0001). • Suggests effectiveness of homeopathy in ADHD particularly behavioural and cognitive. Frei H et al. Homeopathic treatment of children with attention deficit hyperactivity disorder: a randomised, double blind, placebo controlled crossover trial. Eur J Peds 2005; 164:758-67.

29. Homeopathy and ADHD 2: negative result • Double-blind, RCT, private homeopathic clinic, Seattle WA • 43 children 6–12 years DSM-IV criteria for ADHD. • homeopathic consultation and individualized treatment or placebo. Follow up every 6 weeks for 18 weeks. • CGI parent and teacher; Brief performance test; • No statistically significant differences between homeopathy and placebo groups • Statistically and clinically significant improvements in both groups on many outcome measures. • No evidence to support a therapeutic effect of individualised homeopathy. • Future studies should be longer and include a control group not receiving homeopathic consultation. • Comparison to conventional stimulant? Jacobs J et al. Homeopathy for Attention-Deficit/Hyperactivity Disorder: A Pilot Randomized-Controlled Trial. J Alt Comp Med 2005;11:799–806

30. Frei et al Lycopodium Calcarea carbonica Sulphur Belladonna Causticum Phosphorus Total 24 medicines LM3-30, every 1-2 days Jacobs et al Medorrhinum Saccharum officinalis Calcarea carbonica Calcarea phosphorica China officinalis Stramonium Total 41 medicines Dilutions, regime not given Homeopathy and ADHD: treatment comparison But Frei randomised after optimal homeopathic medicine found (mean 3 attempts) Jacobs randomised before 1st prescription Or Dopamine muriaticum and Serotinin?

31. Homeopathy in life-threatening sepsis in ICU • RCT in University of Vienna, Intensive Care Unit • Individualised homeopathy v placebo, double-blind • 70 patients with severe sepsis • standard criteria, mortality ~ 50% • Outcome survival at 30 & 180 d • Baseline characteristics well matched: • age, sex, BMI, prior conditions, APACHE II score, signs of sepsis, number of organ failures, mechanical ventilation, vasopressors, haemofiltration, laboratory parameters

32. Homeopathy in life-threatening sepsis in ICU • Results • Day 30 survival homeopathy 81.8%, placebo 67.7%, p = 0.19. Day 180 survival homeopathy 75.8%, placebo 50.0%, p = 0.043. • No adverse effects • NNT = 4 • 1 patient saved for every 4 treated • recombinant activated protein C NNT = 16, bleeding event 1:665. Conclusions • Homeopathy may be an useful addition with long-term benefit for severely septic patients. A constraint is limited number of homeopaths. Frass M et al. Adjunctive homeopathic treatment in patients with severe sepsis: a randomized, double-blind, placebo-controlled trial in an intensive care unit. Homeopathy 2005:94;75–80

33. Homeopathy in life-threatening sepsis: medicines prescribed

34. Double-blind, crossover RCT • Rhus tox 6c, identical placebo 4 weeks each • 'Double selection': 30 patients with primary fibromyalgia and Rhus tox indicated • ~25% of Fibromyalgia patients • Precautions • tests for contaminants • after entry no contact between prescriber & patient • assessment and dispensing by blinded metrologist Rhus toxicodendron in primary Fibromyalgia

35. Rhus tox in Fibromyalgia p=0.007 placebo initial active Fisher P et al Effect of homoeopathic treatment on fibrositis (primary fibromyalgia) BMJ 1989 299 365-6

36. Double-blind, parallel group RCT • n=62, 3 month treatment phase • Homeopathy as indicated (41 different medicines) • Rhus tox and Calcarea carbonica most frequently used • Verum significantly compared to placebo for: • Tender point count • Tender point pain • Global health • Quality of life • Trend for depression Individualized homeopathy for primary Fibromyalgia

37. Individualized homeopathy for primary Fibromyalgia: results POMS=Profile of Mood States. Statistical analysis by ANOVA Bell I et al. Improved clinical status in fibromyalgia patients treated with individualized homeopathic remedies versus placebo Rheumatology 2004;43:577–582

38. Homoeopathic v conventional topical treatment in OA knee • 172 patients with OA knee • radiographically confirmed • SRL gel v Piroxicam gel • Change in VAS • SRL mean -16.5mm • Piroxicam mean - 8.1mm • SRL fewer adverse events Piroxicam (n=86) SRL (n=86) Van Haselen R, Fisher P. A randomised controlled trial comparing topical Piroxicam gel with a homeopathic gel in osteoarthritis of the knee. Rheumatology 2000;39:714-719

39. Homeopathy in children with recurrent URTIs • RCT in Free University of Amsterdam paediatric outpatients • March 1987-January 1992 • 175 children with recurrent URTIs • 18 months to 10 years • stratified for age • 90 boys 80 girls

40. Homeopathy in children with recurrent URTIs de Lange de Klerk ES.et al. Effect of homoeopathic medicines on daily burden of symptoms in children with recurrent upper respiratory tract infections. BMJ. 1994: 309;1329-32.

41. Homeopathy in children with Acute Otitis Media • RCT: 75 children with confirmed AOM • 18 months to 6 years • Individualised homeopathic treatment • Results • Fewer treatment failures with active at 5d, 2 & 6w • Better diary scores at 24h & 64h with active (p<0.05) Jacobs J et al. Homeopathic treatment of acute otitis media in children: a preliminary randomised placebo-controlled trial. Pediatr Infect Dis J 2001;20:177-183

42. Homeopathy in the ‘real world’: averting antibiotics for acute otitis media • Observational study of homeopathy in primary care • 230 consecutive consultations • Homeopathic treatment, if not pain free in 6 h, 2nd homeopathic medicine, if not pain free at 12h, antibiotic • University Paediatric Clinic, Berne • Results • 39% pain free in 6h, further 33% at 12h • 28% antibiotics • Resolution considerably faster than in reported series • 14% cost savings Frei H, Thurneysen A. Homeopathy in acute otitis media in children: treatment effect or spontaneous resolution? Br Hom J 2001;90:180-182

43. Homeopathy in the ‘real world’: cost-effectiveness in recurrent URTIs • ‘Antibiotic’ v ‘homeopathic’ strategy • Non-randomised, pragmatic cost-effectiveness study • Children 18m-5y, ≥ 5 episodes/year • French GPs, with and without ‘homeopathic orientation’ • 529 recruited, 499 followed at 6m • 231 children treated by 62 non-homeopathic GPs • 268 by 73 homeopathic GPs • Outcomes episodes of URTI, complications, side-effects, quality of life (Par-Ent-Qol), direct and indirect medical costs, parents time off work to care for sick children

44. Homeopathy in the ‘real world’: cost-effectiveness in recurrent URTIs • Results • Homeopathic strategy superior: • medical effectiveness (p<0.001) • complications (p<0.001) • number of consultations (p<0.001) • quality of life (p<0.001) • parental time off work (p<0.001) • Equivalent direct medical costs • Confounders include smoking & day care Trichard M et al. Pharmacoeconomic comparison between homeopathic and antibiotic treatment strategies in recurrent acute rhinopharyngitis in children. Homeopathy 2005:94:3-9

45. Homeopathy in the ‘real world’: Effectiveness of homeopathy in routine care • Comparative cohort study • Selected chronic diagnoses • Adults: headache, low back pain, depression, insomnia, sinusitis • Children: atopic asthma, dermatitis, rhinitis • Homeopathic v conventional GPs in Germany • Outcomes at 6 & 12 months • Severity of symptoms (numerical scale 0-10) • Patient • Doctor • Quality of life (SF-36) • Cost • Consultations, medication, physiotherapy, hospitalisation, sick pay, medical devices/appliances • Conventional and homeopathic medication

46. Homeopathy in the ‘real world’: Effectiveness of homeopathy in routine care • Results • 101 homeopathic, 59 conventional GPs • 493 patients (315 adults, 178 children) • Generally well-matched • Homeopathic adults better educated, • Conventional children heavier use of medical services • 90% returned 6 month data, 80% 12 month • Economic data from Krankenkasse (38%) • Homeopathic v conventional GPs in Germany

47. Homeopathy in the ‘real world’:Effectiveness of homeopathy in routine care Adults: Conv 5.9 → 4.4 Homp 5.7 → 3.2 P=0.002 Patient assessment of severity (0-10, 10 = worst possible) adjusted for gender, age, educational level, symptom duration and gender/age interaction

48. Homeopathy in the ‘real world’:Effectiveness of homeopathy in routine care Children: Conv 3.9 → 2.7 Homp 4.6 → 2.0 p<0.001 Physician assessment of severity (0-10, 10 = worst possible) adjusted for gender, age, educational level, symptom duration and gender/age interaction

49. Homeopathy in the ‘real world’:Effectiveness of homeopathy in routine care MCS p=0.273 PCS 1st 6m p=0.0.016 2nd 6m P=0.649 Quality of Life scores SF-36 adjusted for gender, age, educational level, symptom duration and gender/age interaction

50. Homeopathy in the ‘real world’: Effectiveness of homeopathy in routine care • Health economics • Total adjusted costs • Adults homeopathic €2155, conventional €2013, (p=0.856) • Children homeopathic €1471, conventional €786 (p=0.137) • Medication • Adults homeopathic €270, conventional €639 (p=0.117) • Children homeopathic €334 conventional € 424 (p=0.637)