Recent research in Clinical Homeopathy

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1 Recent research in Clinical Homeopathy pvtpeeckwm/june%2024%20onc ology%20symposium%20jean%2 0Claude%20Karp%2C%20MD%2 Peter Fisher FRCP, FFHom 0and%20Christelle%20Charvet% Director of 2C%20MD.pdf?dl=0 Research Royal London Hospital for Integrated Medicine

2 Dr Peter Fisher Director of Research and Consultant Physician Royal London Hospital for Integrated Medicine (University College London Hospitals) FRCP, Accredited in rheumatology and homeopathy Member, WHO expert panel on Traditional & Complementary Medicine Member, Advisory and Editorial Board, Cochrane Collaboration Complementary and Alternative Medicine Field Editor-in-Chief, Homeopathy Physician to HM The Queen

3 Contents What is homeopathy? Who uses homeopathy? Real world clinical effectiveness studies Randomized controlled clinical trials Biological models

4 What is Homeopathy? key features Treatment of like with like Similia similbus curentur Minimum dose including ultramolecular dilutions Holism constitution, terrain Sensitivity idiosyncracy, individualization

5 Related concepts: Hormesis in animals hormesis = stimulatory or beneficial effect of low dose of toxin v linear threshold/non-threshold model Stebbing ARD Hormesis - the stimulation of growth by low levels of inhibitors. Sci Tot Environ 1982;22:

6 Samuel Hahnemann Essay on a new curative principle Hufeland s Journal 1796 Described his self pathogenesis of China (Cinchona rubra) source of quinine Same year as vaccination introduced by Jenner This seems to be the reason for this beneficial remarkable fact namely that since the general distribution of Jenner s Cow-pox vaccination, human small-pox never again appeared as epidemically or virulently as years before when one city visited lost at least one-half and often three-quarters of its children by death of this miserable pestilence. Footnote to para 46 Organon 6 th edition

7 Preparation of homeopathic dilutions 1 part mother tincture 1 part 99 parts water/ethanol 99 parts Succussion c/cH Succussion c/cH Succussion c/cH Lactose or sucrose pills

8 Avogadro s Law (Loschmidt s constant) The number of particles in one gram mole of a pure substance is x It is extremely unlikely that dilutions beyond 12c/cH or 23x/dH contain any molecule of the starting substance

9 Who uses homeopathy? How do the results of family physicians who use homeopathy compare with those who do not?

10 Homeopathy use in USA: National Health Interview Survey 2012 Harvard Division of General Medicine and Primary Care 2.1% of US population used homeopathy in past 12 months 15% increase since 2007 More likely to be female, healthier lifestyle, highly educated Respiratory, ORL most common (18.5%) Homeopathy users more likely to use multiple complementary and integrative therapies and to perceive it as helpful than supplement users. Uncommon, users perceive it as helpful Dossett M et al. Homeopathy Use by US Adults: Results of a National Survey. AJPH 2016 doi: /AJPH

11 No CIM Use (n=23009)* Other CIM Use (n=5298)* Supplements Without Homeopathy (n=5500)* Homeopathy Use (n=718)* Homeopathy use in USA: Estimated U.S. Population (66.4) (15.6) (15.8) (2.1) Size^ Sex Female (48.6) demographics 3341 (60.6) 3136 (54.5) 521 (69.9) Male (51.4) 1957 (39.4) 2364 (45.5) 197 (30.1) Age (22.9) 1111 (22.3) 793 (16.3) 115 (18.2) (24.9) Supplementary 1572 Table (29.8) A: Population 1325 Demographics (24.0) 220 (31.1) (33.3) 1779 (34.9) 2174 (41.1) 289 (39.4) (18.9) 836 (13.0) 1208 (18.7) 94 (11.3) Race White (78.1) 4184 (83.6) 4432 (84.5) 597 (87.0) Black 4233 (14.3) 515 (7.5) 518 (7.1) 53 (4.9) American Indian/ 246 (0.9) 58 (0.8) 41 (0.6) -- Alaskan Native Asian 1389 (5.3) 407 (6.1) 354 (5.1) 33 (3.9) Other 415 (1.5) 134 (2.0) 155 (2.7) 31 (3.3) Hispanic 4520 (17.3) 666 (10.3) 599 (9.8) 74 (8.9) Education Region Northeast 3910 (18.9) 972 (19.5) 773 (14.1) 119 (17.6) Midwest 4536 (21.2) 1274 (25.3) 1249 (26.7) 134 (20.3) South 9275 (40.1) 1574 (30.2) 1501 (28.1) 186 (28.3) West High School or 5288 (19.7) 1478 (24.9) 1977 (31.2) 279 (33.8) Marital Status Married/Living Equivalent (58.5) 2713 (62.7) 2869 (64.3) 377 (66.2) with Partner Widowed 2408 (6.6) 372 (4.3) 470 (5.5) 35 (2.4) Divorced > High School (11.3) 901 (10.8) 977 (11.7) 140 (12.8) Never Married 5630 (23.4) 1302 (22.2) 1174 (18.4) 164 (18.3) (52.3) Education < High School 4609 (17.6) 411 (6.7) 443 (6.9) 24 (4.6) High School or 6703 (29.5) 1051 (20.3) 1099 (20.1) 85 (10.7) Equivalent > High School (52.3) 3826 (72.8) 3947 (72.8) 609 (84.7) Family Income < $34, (35.4) 1764 (24.3) 1762 (23.8) 216 (23.1) $35,000 - $74, (30.0) 1573 (28.8) 1742 (31.4) 229 (29.7) $75,000 - $99, (10.6) 602 (12.9) 669 (13.5) 92 (15.8) $100, (17.4) 1102 (28.8) 1097 (27.0) 143 (25.4) < High School 4609 (17.6) 411 (6.7) 443 (6.9) 24 (4.6) 6703 (29.5) 1051 (20.3) 1099 (20.1) 85 (10.7) 3826 (72.8) 3947 (72.8) 609 (84.7)

12 Homeopathy use in USA: perceived helpfulness of therapies

13 Comparative effectiveness of homeopathy in French family practice: EPI-3 EPI3 largest cohort study of homeopathic care ever Compares conventional (CM) mixed (MX) homeopathic (Ho) family physicians Cohorts musculoskeletal disease (MSD) upper respiratory tract infections (URTI) sleep disorders (SD) anxiety and depression (ADD) 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):

14 Diagnoses of patients attending primary care physicians: EPI-3 Conventional, mixed, homeopathy n=6379

15 Demographics & patient attitudes: EPI-3 Patients of homeopathic v conventional primary care physicians slightly more female higher education no big difference in comorbidities or quality of life Large differences healthier lifestyle belief in holistic and natural treatments attitude to participating in own care Lert F et al. Characteristics of patients consulting their regular primary care physician according to their prescribing preferences for homeopathy and complementary medicine. Homp 2014:103, 51-57

16 EPI-3 Musculoskeletal Disease N=1153 CM=conventional medicine, MP= Mixed practice, Ho=homeopathy

17 EPI-3 MSD: results Patients did not differ except for chronicity Higher for homeopathy Similar clinical progression Functional scores same after controlling for baseline NSAID use over 12 months almost half in homeopathy group Homeopathic 4%, Mixed GPs 20% in France Considerable impact on population health and healthcare costs

18 EPI-3 anxiety and depression (ADD) 710 patients, adjusted multivariate analysis Ho and Mx patients less psychotropic drugs than CM Ho odds ratio 0.29; 95 % CI Mx OR = 0.62; 95 % CI: Clinical improvement (Hospital Anxiety and Depression Scale, HADS <9) Ho > CM OR = 1.70; 95 % CI: 1.00 to 2.87 not v Mx

19 EPI-3 ADD: patient characteristics

20 Remission rate (HADS <9) 5th International CEDH Conference - June 24-26, 2016 EPI-3 ADD: remission rate (%)

21 At least 1 psychotrpic drug (%) 5th International CEDH Conference - June 24-26, 2016 EPI-3 ADD: psychotropic drug use (%)

22 EPI-3 ADD: conclusions Patients with ADD who chose Ho v CM had better outcomes: less psychotropic drugs slightly more likely to improve May reflect differences in physicians management patients preferences regression to the mean

23 EPI-3 URTIs 518 adults and children with URTI conventional and homeopathic GPs in France Homeopathic patients less antibiotics OR = 0.43, 95% CI: antipyretic/anti-inflammatory drugs OR = 1.16, 95% CI: Similar evolution Non-significant excess of potentially-associated infections in homeopathy group. Grimaldi-Bensouda L, Bégaud B, Rossignol M et al. Management of upper respiratory tract infections by different medical practices, including homeopathy, and consumption of antibiotics in primary care: the EPI3 cohort study in France PLoS One ;e doi: /journal.pone

24 Comparative effectiveness of homeopathy 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

25 Comparative effectiveness of homeopathy in recurrent URTIs 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

26 Comparative effectiveness of homeopathy in primary care in Germany 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

27 Comparative effectiveness of homeopathy in primary care in Germany 493 patients (315 adults, 178 children) Greater improvement in patients assessments after homeopathic v conventional adults: homeopathy 5.7 to 3.2; conventional 5.9 to 4.4 (p = 0.002) children 5.1 to 2.6 ; 4.5 to 3.2 Physician assessments more favourable for children with homeopathy 4.6 to 2.0 and ; p < 0.001). Costs no significant differences between groups adults: 2155 v 2013 p = children, 1471 versus 786, p = 0.137

28 Comparative effectiveness of homeopathy in primary care in Germany: results SF-36 PCS 1 st 6m p= nd 6m P=0.649 MCS p=0.273 Quality of Life scores SF-36 adjusted for gender, age, educational level, symptom duration and gender/age interaction

29 Comparative effectiveness of homeopathy in primary care in Germany: conclusion Patients seeking homeopathic treatment had a better outcome overall compared to patients on conventional treatment at similar total cost Witt C et al Outcome and costs of homoeopathic and conventional treatment strategies: A comparative cohort study in patients with chronic disorders Complementary Therapies in Medicine (2005) 13:79-86 doi: /j.ctim

30 IIPCOS-I Multinational comparative effectiveness study: homeopathy v conventional in acute respiratory disease 30 doctors, 6 clinical sites, 4 countries 456 patients with acute respiratory problems 281 homeopathy, 175 conventional Response at 14 days 82.6% homeopathy, 68% conventional Adverse events 7.8% homeopathy 22.3% conventional Riley D, Fischer M, Singh B, et al. (2001). Homeopathy and Conventional Medicine: An Outcomes Study Comparing Effectiveness in a Primary Care Setting. Journal of Alternative and Complementary Medicine, 7: Royal London Hospital for Integrated Medicine

31 IIPCOS-II Replication comparative effectiveness study: homeopathy v conventional in acute respiratory disease 1577 patients, 57 primary care sites, 8 countries 10 sites in UK Complete recovery or major improvement at 14d H: 86.9%; C: 86.0% (p = ) no differences children v adults improvement within 7d faster with homeopathy children (p = ) and adults (p = ). Adverse drug reactions more frequent in adults with conventional, not children Haidvogl M Riley D, Heger M et al. Homeopathic and conventional treatment for acute respiratory and ear complaints: A comparative study on outcome in the primary care setting BMC Complement Altern Med. 2007; 7: 7. doi: /

32 IIPCOS-II Cumulative recovery rate in first 7 days

33 Swiss Health Technology Assessment: Homeopathy for upper respiratory tract infections and allergies (URTI/A)

34 Homeopathy for URTI/A types of homeopathy

35 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

36 Swiss HTA Homeopathy for URTI/A: conclusions 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

37 Randomized controlled trials and meta-analyses of RCTs

38 No evidence!? randomized controlled trials of homeopathy June 2016: 1118 clinical trials of homeopathy 299 randomized controlled trials 66 individualized v placebo 15 individualized v other treatment 177 non-individualised v placebo 41 non-individualized v other treatment 41% positive, 54% inconclusive 5% negative Similar to RCTs of conventional treatments

39 Comprehensive systematic reviews of homeopathy Topic Positive Tentatively positive inconclusive Tentatively negative Negative All homeopathy Boissel Cucherat Kleijnen Linde Shang Individualized homeopathy Linde Mathie Mathie RT. Controlled clinical studies of homeopathy. Homeopathy 2015;104:

40 Systematic reviews of homeopathy for groups of conditions Positive Tentatively positive inconclusive Tentatively negative Negative Allergy Bellavite 1 Allergy Bellavite 2 URTI & allergy Bornhöft Psychiatry Davidson Arnica Iannniti Rheumatic Jonas Cancer side effects Kassab Arnica Lüdtke Paediatrics Altunç Cancer Milazzo Dermatology Simonart Arnica Ernst

41 Systematic reviews of homeopathy for single conditions Positive Tentatively positive inconclusive Tentatively negative Diarrhea Jacobs Vertigo Schneider Rhinitis Taylor Ileus Barnes Hayfever Ernst Fibromyalgia Boehm Oscillococcinum Mathie Irritable bowel Peckham Fibromyalgia Perry Pollinosis Wiesenauer Osteoarthritis Long Dementia McCarney Asthma McCarney Headache Owen Depression Pilkington Anxiety Pilkington Rheumatoid arthritis Saha Labour Smith Negative Insomnia Cooper ADHD Coulter Headache Ernst Insomnia Ernst Eczema Ernst Muscle stiffness Ernst

42 Recent meta-analysis of best randomized controlled trials of individualized homeopathy 32 RCTs, 24 medical conditions 22 trials analysable 95% confidence interval most reliable trials OR = % CI Mathie RT et al. Randomised placebo-controlled trials of individualised homeopathic treatment: systematic review and meta-analysis. Syst Rev 2014;3:142 Royal London Hospital for Integrated Medicine

43 Recent meta-analysis of best randomized controlled trials: all trials Royal London Hospital for Integrated Medicine

44 Recent meta-analysis of best randomized controlled trials: effect of focussing on best trials Better quality

45 High quality RCT: Individualized homeopathy v placebo for FMS Double-blind, parallel group randomised controlled Trial 62 patients, 3 months treatment homeopathy as indicated (41 different medicines) Rhus tox and Calcarea carbonica most frequently used Homeopathy significantly better than placebo for: tender point count tender point pain global health quality of life Trend for depression

46 Individualized homeopathy for FMS: 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:

47 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, mostly house dust mite 30c) Total n=253 Highly statistically significant P=0.0007, 95% CI 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

48 Isopathy in respiratory allergy: summary of results Subjective Objective

49 Biological models

50 Gelsemium in mouse model of anxiety In Light-Dark test, Gelsemium 5, 9 and 30c were associated with statistically significant increase in number of transitions between compartments Indicates anxiolytic activity comparable to buspirone. non-linear Includes ultramolecular dilutions. Bellavite P et al. Assays of homeopathic remedies in rodent behavioural and psychopathological models. Homp 2009; 98,

51 Gelsemium in mouse model of anxiety Magnani P et al Dose-effect study of Gelsemium sempervirens in high dilutions on anxiety-related responses in mice Psychopharmacology DOI /s

52 Effect of Gelsemium in rat limbic system Effect of Gels on production of the neurosteroid allopregnanolone (3a,5a-THP) production in rat hippocampus and amygdala slices Venard C et al. Comparative Analysis of Gelsemine and Gelsemium sempervirens activity on Neurosteroid Allopregnanolone Formation in the Spinal Cord and Limbic System. ecam 2009 doi: /ecam/nep083

53 Hypericum in nerve injury model Rat sciatic nerve transected sham operation v silicon tube v silicon tube + Hypericum Hypericum 30c twice daily for 1 week. studied 4, 8, 12 weeks after surgery Significantly better function, muscle mass, nerve histology with Hypericum Mohammadi R et al. Homeopathic treatment for peripheral nerve regeneration: an experimental study in a rat sciatic nerve transection model. Homeopathy 2012; 101:

54 Hypericum in nerve transection: mean axon Done at Western College of Veterinary Medicine University of Saskatchewan *P < 0.05 Sil/Hypericum v Sil (ANOVA)

55 Polycrystalline structures in evaporating droplets from wheat seeds treated with Zincum metallicum Polycrystalline structures form in evaporating droplets of biological fluids sensitive to ultra high dilutions (UHDs) Zincum metallicum 30c v lactose 30c and water Stressed and non-stressed wheat seeds Seed-leakage droplets evaporated polycrystalline structures in residues analyzed local connected fractal dimensions (LCFDs) using ImageJ

56 Polycrystalline structures in evaporating droplets from wheat seeds treated with Zincum metallicum Significant differences in LCFD from stressed seeds (p < ) Zincum met 30c reduces complexity v lactose 30c and water. No significant differences in nonstressed Kokornaczyk M et al. Polycrystalline structures formed in evaporating droplets as a parameter to test the action of Zincum metallicum 30c in a wheat seed model. Homeopathy (2016) 105,

57 Polycrystalline structures in evaporating droplets from wheat seeds treated with Zincum metallicum Zincum met Lactose Control Stressed Unstressed

58 Arnica and gene expression in human macrophages: PCR quantitation THP-1 human macrophages, differentiated: mature macrophages IL-4 activated involved in tissue healing Arnica 2, 3, 5, 9, 15c Real-time quantitative Reverse Transcription Polymerase Chain Reaction (PCR) expression of key genes cytokines, receptors and transcription factors

59 Arnica and macrophage phenotypes

60 Arnica and gene expression in human macrophages: PCR quantitation In macrophages differentiated to wound healing phenotype Arnica affected gene expression CXC chemokine ligand 1 (CXCL1) coding for chief chemokine also CXC chemokine ligand 2 (CXCL2), Interleukin8 (IL8) and bone morphogenetic protein (BMP2) MMP1 coding for a metalloproteinase downregulated.

61 Arnica and gene expression in human macrophages: effect of IL-4 treatment

62 Effect of Arnica on CXCL1 gene expression in IL4 treated human macrophages 24h 2h

63 Arnica and gene expression in human macrophages: conclusions Positive influence of Arnica on neutrophil recruitment and on angiogenesis New insights into action as a promoter of healing Some genes it modifies key regulators of tissue remodelling, inflammation and chemotaxis.

64 Summary: Who uses and clinical effectiveness Patients who use homeopathy highly educated, healthy life style Clinical effectiveness studies show Acute: better results in routine practice Chronic: equivalent results with fewer harmful drugs Health technology assessment positive (Switzerland)

65 Summary: Randomized controlled trials, systematic reviews & meta-analyses >1000 clinical trials, ~300 RCTs 44 Systematic reviews Comprehensive, individualized Groups/single conditions Metanalyses positive Including high quality RCTs Particularly allergy and URTI

66 Summary: Biological models Animal models Mouse anxiety Nerve regeneration Arnica in cultured human macrophages High-tech, PCR Droplet crystallization All require stress/presensitzation

67 and if you really want to know what s going on

68 Thank you for your attention