Peter Fisher FRCP, FFHom Clinical Director, Director of Research Royal London Hospital for Integrated Medicine Member, External Advisory Panel National Institute for Health & Care Excellence (NICE) Editor-in-Chief, Homeopathy Homeopathy and its clinical effectiveness
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Homeopathy and its clinical effectiveness · homeopathy •Do homeopathic medicines have beneficial effects that are not placebo effects? •Does homeopathy as a whole system of medicine
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Peter Fisher FRCP, FFHom Clinical Director, Director of Research Royal London Hospital for Integrated Medicine
Member, External Advisory Panel National Institute for Health & Care Excellence (NICE)
Editor-in-Chief, Homeopathy
Homeopathy and its clinical effectiveness
Samuel Hahnemann Born Meissen 1755 Died Paris 1843
Similia similibus curentur Let like be cured by like
‘All substances are poisons; there is none which is not a poison.
The right dose differentiates a poison and a remedy’
Theophrastus Bombastus von Hohenheim ‘Paracelsus’ (1493-1541)
• Homeopathic clinical uses • bright red sore throat • Acute otitis media • <noise, jarring
Preparation of homeopathic dilutions
1 part mother tincture
Succussion 10-2 1c/cH
Succussion 10-4 2c/cH
Succussion 10-12 6c/cH
99 parts
1 part
Lactose or Sucrose pills
Avogadro’s Law (Loschmidt’s constant)
• The number of particles in one gram mole of a pure substance is 6.023 x 1023
• It is extremely unlikely that dilutions beyond 12c/cH or 23x/dH contain any molecule of the starting substance
Hormesis in animals
Stebbing ARD Hormesis - the stimulation of growth by low levels of inhibitors. Sci Tot Environ 1982;22:213-234
hormesis = stimulatory or beneficial effect of low dose of toxin v linear threshold/non-threshold model
Efficacy and Effectiveness
• Efficacy: ideal circumstances • Does it do what it is supposed to do in ideal
circumstances? • eg randomized controlled in university hospital
• Effectiveness: routine circumstances • Does do what it is supposed to do in routine
circumstances?
Validity
• Internal validity • How much a trial minimises or avoided bias
• External validity • How generalisable are the results
• Model validity • How well it reflects good practice
Scientific questions raised by homeopathy
• Do homeopathic medicines have beneficial effects that are not placebo effects?
• Does homeopathy as a whole system of medicine provide benefit in terms of effectiveness and cost-effectiveness?
• Do substances cure diseases or syndromes similar to those that they cause?
• Can substances diluted beyond the Avogadro limit have effects in living systems?
• How might any such effects be mediated? • Do symptoms reported by healthy volunteers in homeopathic
pathogenetic trials (‘provings’) reflect the therapeutic potential of substances?
• Is homeopathy safe?
Lancet 2005 Meta-analysis (Shang A...Egger M)
• 110 matched trials of homeopathy and conventional medicine
• Reduced to 21 ‘higher quality’ trials of homeopathy, 14 conventional
• Further reduced to 8 homeopathy, 6 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’.
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
Shang et al funnel plots: standard error v log odds ratio
SE 0.12-1.65 SE 0.13-01.52
homeopathy conventional
Small SE (lowest quartile) = larger
Shang et al: criticisms
• 8 anonymous clinical trials. • Not cited, no information (diagnoses, number of patients etc) • 93% excluded.
• Data ‘dredged’ •Why 8/21? ‘larger’ added post-hoc
•No sensitivity analysis •What is result for all 110 or 21 trials of ‘higher quality’? •What if homeopathy works for some indications, not others?
•Did not comply with QUOROM guidelines •No descriptive data for trials, no summary results, no consideration of external validity etc
Shang et al vital details emerge
• Christmas Eve 2005 identity of the 8/6 trials published on website
• Enough detail to enable approximate reconstruction of methods
• ‘conclusions not as definite as reported’
Rutten ALB, Stolper CF. The 2005 meta-analysis of homeopathy: analysis of post-publication data. Homp 2008;97:169–177.
Lüdtke R, Rutten ALB. The conclusion on the effectiveness of homeopathy depend highly on the set of analysed trials. J Clin Epidem 2008:61:1197–1204.
Odds Ratios: Shang’s original set
8 studies Odds Ratio (OR)=0.88, 95% CI 0.66-1.18 21 studies OR=0.76, CI 0.59-0.99 p=0.039
• 519 long-distance runners • mostly London marathon 1997
• Arnica 30x (30dH) v placebo
• randomised double-blind
• No difference between groups • muscle soreness • time
Vickers A, Fisher P et al. Homoeopathic Arnica 30x is ineffective for muscle soreness after long-distance running: a randomized, double-blind, placebo-controlled trial. Clin J Pain 1998;14:227-231
Odds ratios without muscle stiffness but including Linde’s
high quality studies
OR 25 trials 0.74 (95% CI: 0.59–0.94).
Comprehensive Systematic Reviews & Meta-analyses of
homeopathy • Linde 1997 • 89/186 trials had interpretable results
Linde et al: Meta-analysis 1
89 RCTs
Linde et al: Meta-analysis 2
Linde et al: subgroup analysis
Combined odds ratio 2.45 (CI 2.05-2.93) Subgroups 1.66-5.04
Linde et al: publication bias • Funnel plot for
publication bias
• Some bias present
• 923 unreported trials required to make conclusions insignificant!
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
But the literature has never been adequately searched…
• 489 records potentially eligible
• 226 minor, repeat, not randomised, not homeopathic
• 41 individualised, 96 non individualised • 80 non peer reviewed
• 30 eligible but not listed by Linde or Shang Mathie RT et al. Randomised controlled trials of homeopathy in humans:
characterising the research journal literature for systematic review. Homeopathy (2013) 102, 3-24
But the literature has never
been adequately searched…
…and what about the quality of the homeopathic prescribing?
‘Model validity’ • Model Validity of Homeopathic Treatment (MVHT).
• The extent to which homeopathic interventions and outcome measures reflect state-of-the-art homeopathic practice
• Developed by International Scientific Committee for Homeopathic Investigations
• 6 domains • Each scored yes (y), no (n), uncertain (u)
Mathie RT et al. Method for appraising model validity of randomised controlled trials of homeopathic treatment: multi-rater concordance study. BMC Medical Research Methodology 2012, 12:49
Model validity: domains
• Is the condition amenable to homeopathic intervention? • Is the intervention consistent with homeopathic principles? • Would the rationale for the intervention be supported by a
significant body of homeopaths? • Does the main outcome measure reflect the key effects
expected? • Is the main outcome measure capable of detecting change? • Is the length of follow-up for the main outcome appropriate?
Focussed systematic reviews and meta-analyses: positive
• Adverse effects of cancer management (Kassab et al 2009) • Fibromyalgia (Perry et al 2010) • Childhood diarrhoea (Jacobs et al., 2003) • HIV/AIDS (Ullman, 2003) • Osteoarthritis (Long & Ernst, 2001) • Post-operative ileus (Barnes, Resch & Ernst, 1997). • Rheumatic diseases (Jonas, Linde & Ramirez, 2000).
Focussed systematic reviews and meta-analyses: positive 2
Focussed systematic reviews and meta-analyses: inconclusive
• Anxiety (Pilkington et al. 2006) • Arnica (Lüdtke & Hacke 2005) • Attention deficit hyperactivity disorder (Coulter & Dean 2007) • Cancer (Milazzo, Russell & Ernst 2006) • Childhood and adolescence ailments (Altunç et al 2007) • Chronic asthma (McCarney, Linde & Lasserson, 2004) • Dementia (McCarney et al 2004) • Depression (Pilkington et al 2005) • Headache and migraine treatment (Owen & Green 2004) • Induction of labour (Smith 2004)
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
Homeopathy for prophylaxis diarrhoea • Biological Farming Systems Group, Wageningen
University, Netherlands • Commercial pig farm • Randomised, observer blind placebo-controlled • 52 sows last month of gestation • Coli 30K (Unda) or placebo sprayed on vulva x2/week • 525 piglets followed for 1 week
- in piglets
Homeopathy for prophylaxis of diarrhoea in piglets: results
• no strong evidence that the effectiveness of Arnica depends on the type of surgery
Brinkhaus B et al, Homeopathic arnica therapy in patients receiving knee surgery: Results of three randomised double-blind trials. Comp Ther Med 2006 14, 237—246
Arnica for knee surgery
Effects on swelling over time (standardised effects and 95% CIs). 0 = no between group difference, positive favours Arnica
ART = Arthroscopy
CLR = Cruciate ligament reconstruction
AKJ = Total arthroplasty
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
Isopathy for respiratory allergy: meta-analysis
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
Isopathy in respiratory allergy: summary of results
Isopathy in perennial rhinitis: change in nasal inspiratory peak flow
P=0.0001 ‘comparable to steroids’
Homeopathy v conventional treatment in acute otitis media (AOM): randomised controlled trial
• Jaipur, India • Regional Research Institute
• 81 entered, 2-6 years • Randomised to homeopathy or conventional
Homeopathy v conventional treatment in AOM: results
• Cure at 21 days • Conventional 100%, Homeopathy 95% • Antibiotics:
• Conventional 97.5%, Homeopathy 0%
Sinha MN et al Randomized controlled pilot study to compare homeopathy to conventional therapy in acute otitis media. Homeopathy 2012
Day 3 7 10 21
Homeopathy v conventional treatment in AOM: results
Homeopathic eardrops v standard care in AOM:
randomised controlled trial • 119 children 6m-11y, 94 (79%) followed up • Symptom scores lower with homeopathic
eardrops than standard treatment • significant at 2nd & 3rd assessments
• rate of improvement faster in ear drop group • p = 0.002
• no significant side effects Taylor JA, Jacobs J. Homeopathic ear drops as an adjunct to standard therapy in children with acute otitis media. Homeopathy (2011) 100, 109-115
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
Homeopathy in the ‘real world’: averting antibiotics for AOM
Frei H, Thurneysen A. Homeopathy in acute otitis media in children: treatment effect or spontaneous resolution? Br Hom J 2001;90:180-182
Homeopathy v Fluoxetine: non-inferiority trial
• Double dummy RCT • Mild to moderate depression • Referred to Homeopathy and Depression clinic Jundiaí
Medical School (São Paulo, Brazil) by public health system professionals
Adler U et al. Homeopathic Individualized Q-potencies versus Fluoxetine for Moderate to Severe Depression: Double-blind, Randomized Non-inferiority Trial eCAM 2009 doi:10.1093/ecam/nep114
homeopathy ‘side effects that interfere markedly with performance’ (p=0.275).
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.
Homeopathy and ADHD 2: negative result
• Double-blind, RCT, private homeopathic clinic, Seattle WA • 43 children 6–12 y 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 homeopathy v placebo • Statistically and clinically significant improvements both groups • No evidence of 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
Homeopathy and ADHD: treatment comparison
• 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
But Frei randomised after optimal homeopathic medicine found (mean 3 attempts)
Jacobs randomised before 1st prescription
• 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
Homeopathy in the ‘real world’ Averting Ritalin® for ADHD
Frei H, Thurneysen A. Treatment for hyperactive children: homeopathy and methylphenidate compared in a family setting. Br Hom J 2001;90:183-188.
•‘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
Cost-effectiveness of homeopathy 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
Cost-effectiveness of homeopathy in recurrent URTIs
Trichard M et al. Pharmacoeconomic comparison between homeopathic and antibiotic treatment strategies in recurrent acute rhinopharyngitis in children. Homeopathy 2005:94:3-9
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preceding year 1st year 2nd year
Specific conventional theapy General conventional therapy
Cost benefit of Homeopathy in chronic respiratory disease
Asthma: change in prescribing costs (%)
Year 1 Year 2
homeopathy specific -71 -54
general -64 -50
control specific +11 +4
general +31 +16
**
**
**
** p<0.01 v baseline
Rossi E et al. Cost–benefit evaluation of homeopathic v conventional therapy in respiratory diseases Homp (2009) 98:2-10
Swiss Health Technology Assessment: homeopathy for upper respiratory tract
infections and allergies
Homeopathy for URTI/A types of homeopathy
Homeopathy for URTI/A: results
• 6/7 trials comparing to standard treatment, showed equivalence • 1 (penicillin vs. homeopathy for streptococcal
tonsillitis) inferior
• 8/16 placebo-controlled significant result in favour of homeopathy • none individualized • 4 trend , 4 no advantage
Swiss HTA Homeopathy for URTI/A:
conclusions • Overall 24/29 trials positive
• significance or trend favouring homeopathy compared with placebo or standard treatment
• ‘. . .the trial results showed probable effectiveness of homeopathy for allergies and infectious diseases of the upper respiratory tract .’
Bergemann SM et al. Clinical studies on the effectiveness of homeopathy for URTI/A . In Bornhöft G, Matthiessen PF. Homeopathy in healthcare – effectiveness, appropriateness, safety, costs. Berlin: Springer 2011
Comparative effectiveness of homeopathy in French family practice: EPI-3
• EPI3-MSD (musculoskeletal disease) largest cohort study of homeopathic care ever • compared conventional, mixed and homeopathic General
Practitioners • representative sample of patients consulting for MSDs
• Also cohorts for • upper respiratory tract infections • sleep disorders, anxiety and depression
• Clinical benefit, medical care and medication, adverse effects, loss of therapeutic opportunity
Rossignol M et al. Impact of physician preferences for homeopathic or conventional medicines on patients with musculoskeletal disorders: results from the EPI3-MSD cohort. Pharmacopepidemiol. Drug Saf. 2012, 21(10):1093-101.