the effectiveness of homeopathy peter fisher frcp, ffhom clinical director and director of research...

The Effectiveness of Homeopathy

Peter Fisher FRCP, FFHomClinical Director andDirector of ResearchRoyal London Homoeopathic Hospital

Royal London Homoeopathic Hospital

Recent Lancet publication

110 clinical trials of homeopathy, 110 of allopathy said to be matched

21 of homeopathy, 9 of conventional medicine were ‘higher quality’

quality assessed by internal validity only

8 homeopathy, 6 conventional were ‘larger, high-quality’

Recent Lancet publication: conclusions

• ‘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’.

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

Recent Lancet publication: criticisms

• 8 anonymous clinical trials. • Not cited, no information (diagnoses, number of patients etc)• 93% excluded.

• No sensitivity analysis • what is result for all 110 or 21 homeopathy trials of ‘higher quality’?

• Only internal validity• The extent to which a study measures what it purports to measure

• External validity, the extent to which a study measures something meaningful in the ‘real world’

Recent Lancet publication:

quality •

Recent Lancet publication

• ‘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

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.

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

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

‘Classical’ homeopathy for asthma: outcome measures

Main outcome measure active QoL scale of the Childhood Asthma Questionnaire (CAQ)

White et al

n=93 (mean) validation study n=535 (median)i

Asthmatic Non-asthmatic CAQA (4-7 years) range 10-40

35.2 34 34

CAQB (8-11) range 7-35

28.1 28 29

CAQC (12-16) range 8-36

29.4 No data No data

Higher values indicate better quality of life French DJ, Christie MJ, Sowden AJ. The reproducibility of the childhood asthma questionnaires: measures of quality of life for children with asthma aged 4–16 years. Qual Life Res 1994;3:215–24.

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

High quality research?self treatment for prevention of

URTIs 251 children <10y treated with Calc carb,

Pulsatilla or Sulphur 30c, selected by parents Recruited after attending A&E department in

winter By mail, no contact with researchers Constitutional medicine selected by parents

from brief written description, most frequently prescribed medicines by homeopaths

Trondheim, Norway

Quality research?self treatment for prevention of

URTIs No difference in symptom scores over 12

weeks But was there anything to treat? Were

these children really ill? NO! They had symptoms 9% of days

• Normal 0-4 year olds have symptoms 20% of days, 5-9 year olds 11.4% of days

• De Lange 49% of days

Steinsbekk A et al Self-treatment with one of 3 self-selected ultramolecular homeopathic medicines for the prevention of upper respiratory tract infections in children. A double blind-randomized controlled trial. Br J Clin Pharm 2005 59:447-55

Clinical trials of homeopathy:metanalysis 1

89 RCTs

Clinical trials of homeopathy:metanalysis 2

Combined odds ratio 2.45

(CI 2.05-2.93)

Clinical trials of homeopathy:subgroupanalysis

Odds ratios 1.66-5.04

Metanalysis of clinical trials of homeopathy: publication bias

Funnel plot for publication bias

Some bias present

923 unreported trials required to makeconclusions insignificant!

Metanalysis of clinical trials of homeopathy: 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

European Commission Homeopathic Medicine Research Advisory Group

17 randomised, placebo-controlled clinical trials predefined primary outcome in patients total 2617 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

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

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

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

Homeopathy in children with recurrent URTIs

2.612.21

0

1

2

3

Mean daily symptom score

Placebo Homeopathy

5977

0

25

50

75

No of courses of antibiotics

21

16

0

5

10

15

20

25

No of adenoidectomies

49 53

0

10

20

30

40

50

60

Mean % days symptom free

de Lange de Klerk ES. Et LEffect of homoeopathic medicines on daily burden of symptoms

in children with recurrent upper respiratory tract infections. BMJ. 1994: 309;1329-32.

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

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

Homeopathy in the ‘real world’:averting antibiotics for acute otitis media

Frei H, Thurneysen A. Homeopathy in acute otitis media in children: treatment effect or spontaneous resolution? Br Hom J 2001;90:180-182

• ‘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 GPs268 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

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)(p<0.001)parental time off work (p<0.001)

• Equivalent direct medical costs

• Confounders include smoking & day care

Homeopathy in the ‘real world’:cost-effectiveness 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

• Homeopathy v conventional medicine for respiratory & ear complaints in primary care

500 consecutive cases of upper, lower respiratory tract and ear complaints

6 primary care sites, 4 countries Results

281 homeopathic, 175 conventional treatments Equivalent severity (HCQ-5) Treatment response 83% homeopathy, 68% conventional Homeopathy fewer adverse effects, greater satisfaction

Homeopathy in the ‘real world’:multinational study in upper & lower

respiratory tract complaints

Riley D. Open label trial of homeopathy vs conventional medicine for respiratory and ear complaints seen in primary carte settings. J Altern Complement Med 2001;7:149-159

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)

PatientDoctor

Quality of life (SF-36) Cost

Consultations, medication, physiotherapy, hospitalisation, sick pay, medical devices/appliancesConventional and homeopathic medication

Homeopathy in the ‘real world’:Effectiveness of homeopathy in routine care

Results 101 homeopathic, 59 conventional GPs493 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 monthEconomic data from Krankenkasse (38%)Homeopathic v conventional GPs in Germany



Patient assessment of severity (0-10, 10 = worst possible) adjusted for gender, age, educational level, symptom duration and gender/age interaction

Adults:Conv 5.9 → 4.4 Homp 5.7 → 3.2

P=0.002


Physician assessment of severity (0-10, 10 = worst possible) adjusted for gender, age, educational level, symptom

duration and gender/age interaction

Children:Conv 3.9 → 2.7 Homp 4.6 → 2.0

p<0.001


Quality of Life scores SF-36 adjusted for gender, age, educational level, symptom duration and

gender/age interaction

MCSp=0.273

PCS1st 6m

p=0.0.0162nd 6m

P=0.649

Health economicsTotal adjusted costs

Adults homeopathic €2155, conventional €2013, (p=0.856)

Children homeopathic €1471, conventional €786 (p=0.137)

MedicationAdults homeopathic €270, conventional €639 (p=0.117)

Children homeopathic €334 conventional €424 (p=0.637)


ConclusionPatients seeking homeopathic treatment had better outcomes overall, compared to patients on conventional treatment, for similar costs


Witt C et al. Outcome and costs of homeopathic and conventional treatment startegies: a comparartive cohort study in patients with chronic disorders. Comp Ther Med 2005:13;79-86

• 1998 - 2005 Switzerland• Efficacy, appropriateness, cost-effectiveness: homeopathy, anthroposophy, neural

therapy, phytotherapy, Traditional Chinese Medicine• During evaluation covered by compulsory health insurance • Literature analysis & empirical research

• Literature analysis. • Meta-analysis (Shang)• Review of 22 systematic reviews

• 10 homeopathy as system • 7 single condition• 3 specific homeopathic remedy (Arnica) • 2 specific homeopathic remedy in defined condition

• 20/22 at least trend in favour of homeopathy, 5 clear efficacy• On 3-point scale (probable – questionable – improbable), efficacy probable

Homeopathy in the ‘real world’: PEK Programm Evaluation Komplementärmedizin(Complementary medicine evaluation programme)

• Empirical• Prospective practice evaluation, cost-effectiveness evaluation, population survey, clinical survey

Homeopathy in the ‘real world’: PEK

Patient profile conventionalhomeopathy (CAM)

number of patients 3,078 2,934

serious 10.1% 16.2%

moderately serious 52.7% 60.5%

chronic 41.9% 41.9%

comorbidity 59.4% 64.1%

Homeopathy in the ‘real world’: PEK

Results conventionalhomeopathy (CAM)

number of patients 3,078 2,934

satisfied with treatment 43.3% 52.3%

side-effects 15% 9.1%

referrals 9.7% 5.7%

costs of treatment 931 SFR 708 SFR (CAM)

costs after correction 709 SFR 661 SFR (CAM)

• Costs include consultations, medication, lab tests and physical therapy • Exclude referral, hospitalisation, side-effects, time lost from work

• Corrected for age, sex, doctor and practice-variables, accidents and home visits • Not corrected for chronicity, severity, co-morbidity

• Descriptive study of effects and benefits of acupuncture and/or homoeopathy,

• Over 900 homeopathy patients in Germany insured by Innungskrankenkasse

• SF-36 quality-of-life questionnaire and absence from work • Medium to large improvements in SF-36 • Evidence of subjective benefit may account for the increase in demand for these treatments

• Especially chronically ill and dissatisfied with previous conventional treatment

Homeopathy in the ‘real world’:homeopathy and acupuncture in

general practice

Güthlin C et al. Measuring the effects of acupuncture and homoeopathy in general practice: An uncontrolled prospective documentation approach. BMC Public Health 2004;4:6

Homeopathy in general practice: SF-36 scores over 30 months

Homeopathy in general practice: SF-36 scores over 6 months

Quality of life Baseline 6 months Effect size (d)

Physical functioning N = 359mean = 84

N = 301mean = 89

d = 0.24

Role physical N = 359mean = 62

N = 301 mean = 83*

d = 0.51

Bodily pain N = 373mean = 57

312 mean = 73*

d = 0.52

General health N = 368mean = 53

N = 305mean = 68*

d = 0.79

Vitality N = 376mean = 48

N = 309 mean = 61*

d = 0.72

Social function N = 378mean = 72

N = 314 mean = 84*

d = 0.48

Role emotional N = 356mean = 73

N = 298 mean = 87*

d = 0.36

Mental health N = 376mean = 59

N = 312 mean = 69*

d = 0.56

* Clinically relevant (>=10 % improvement) d effect size (Cohen), d < 0.3 small, d < 0.8 moderate > 0.8 high

Homeopathy in general practice: absence from work

Start of homeopathic treatment

Anas barbariae hepar et cordis extractum (HPUS) Hearts and livers of wild ducks(!) Wildfowl 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

Oscillococcinum® in influenza-like syndromes: Cochrane review

Vickers A, Smith C. Homoeopathic Oscillococcinum for preventing and treating influenza and influenza-like syndromes. (Cochrane review). Cochrane Library 2001:1

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’

Meta-analysis of homeopathy for childhood diarrhoea

Rhus toxicodendron in primary Fibromyalgia

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 tox in Fibromyalgia

Fisher P et al Effect of homoeopathic treatment on fibrositis (primary fibromyalgia) BMJ 1989 299 365-6

Tender point count

0

5

10

15

initial placeboactive

p=0.007

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 eventsPiroxicam

(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

Motives for attending the Royal London Homoeopathic Hospital (925 responses from 493 patients)

Other6%

Adverse effects from other treatment

14%

Concern about adverse effects

26%

Other treatment ineffective

32%

Personal preference

22%

Sharples F, Van Haselen R, Fisher P. NHS patients’ perspective on complementary medicine. Comp Ther Med 2003;11:243-248.

Safety of homeopathy

• World literature search 1975-1995• Enquiries with regulatory agencies (MCA and

FDA), companies

• Incidence of adverse effects very low• mostly minor and transient • under-reporting • mistaken identity (herbal, not homeopathic)

Safety of homeopathy:conclusions

• Generally very safe

• Main risks are indirect• due to practitioner, not medicine

Dantas F, Rampes H. Do homeopathic medicines provoke adverse effects? A systematic review. Br Hom J 2000;89:S35-38

The 'Benveniste Affair'A slight disagreement...

Davenas E, Beauvais F, Amara J et al. Human basophil degranulation triggered by very dilute antiserum against IgE. Nature 1988; 333: 816-818.

Hirst SJ, Hayes MA, Burridge J, Pearce FL, Foreman JC. Human basophil degranulation is not triggered by very diluteantiserum against IgE. Nature 1993; 366: 525-7

Inhibition of basophil activation by ultramolecular dilutions of Histamine

Multi-centre, peer-reviewed full paper on inhibition of

activation of basophils by ultramolecular dilutions of Histamine

Blinded, uses multiple methods to corroborate

Belon P et al. Histamine dilutions modulate basophil activity. Inlamm Res 2004; 53:181-8

Human Basophil Degranulation Test

Human Basophil Degranulation Test (HBDT) is well-established in-vitro model of allergy, described in 1960’s

Basophils are circulating mast cells Contain basophilic granules in cytoplasm Granules stain blue with Alcian Blue Contain histamine and other immune mediators

Human Basophil Degranulation Test

Degranulation is a manifestation of basophil activation

Activation is triggered by cross-linking of IgE on surface, either by specific antigens in sensitive individuals or by anti-IgE (IgG)

Activation is inhibited by Histamine in supernatant (ie negative feedback)

Basophils also express CD63 antigen on their surface when activated

Inhibition of activation of basophils by ultramolecular dilutions of Histamine

4 labs (Paris, Utrecht, Belfast, Florence) Healthy donors

either sex basophils respond to anti-IgE, no medication previous 4 weeks

Independent statistician (Brussels) Histamine 10-30 -10-38M (15-19c), vortexed Main experiment inhibition of degranulation (Alcian

Blue) - all labs

Inhibition of degranulation with histamine 15-19c

Inhibition of degranulation (Alcian blue) with different concentrations of anti-IgE and histamine 15-19c (pooled p<0.0001)

Paris

Utrecht

Belfast

Florence

Effect of H2 antagonists on activation

Ranitidine (10-4M) and Cimetidine (10-5M) partly block effects of dilutions of histamine (Paris & Florence)

Inhibition of activation of basophils by ultramolecular dilutions of Histamine:

discussion

Clearly positive Variations between labs due to sensitivity of donors No theoretical explanation

The Information Medicine hypothesis

Water, and perhaps other polar solvents are, under certain circumstances, capable of storing information relating to substances with which they have previously been in contact, and subsequently transmitting this information to presensitised biosystems.

Fisher 1995

How might water store information? hypotheses

• Geometric models• Formation of clathrates

• Information stored in bond lengths, angles

• Isotopicity• Different isotopes form ordered framework

• Dynamic models• Coherent regions displaying stable laser-like behaviour

• Del Guidice E, Preparata G, Vitiello G. Water as a free electric dipole laser. Phys Rev Letts 1988; 61:1085-1088

Review Schulte J. Effects of potentisation in aqueous solutions. Br Hom J. 1999;88:155-160

Thermoluminescence of ultramolecular dilutions of NaCl and LiCl

• Method• dilutions of LiCl and NaCl in ‘heavy’ water (D2O)• cooled to 770K, bombarded with x- or γ-rays• excites electrons, creates +vely charged ‘holes’• warmed: +ve holes and excited electrons recombine

• generates characteristic thermoluminescence ‘glow’ • Results

• high dilutions (15c = 10-30) of LiCl and NaCl have similar spectrum to dilutions containing molecules of the same substances, and different from D2O

• likely to be due to broken H-bonds

Thermoluminescence signature of ultramolecular dilutions of NaCl and

LiCl

Rey L. Thermoluminesence of ultra-high dilutions of lithium chloride and sodium chloride. Physica A 2003; 323:67-74

Thermoluminescence signature of ultramolecular dilutions of NaCl and LiCl

Rey L. Thermoluminesence of ultra-high dilutions of lithium chloride and sodium chloride. Physica A 2003; 323:67-74

the effectiveness of homeopathy peter fisher frcp, ffhom clinical director and director of research...

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