Homeopathic Treatment of Mild Traumatic Brain Injury: A ... · Homeopathic Treatment of Persistent...

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Aspen Pub./JHTR CHAP-01 November 1, 1999 12:7 Char Count= 0

Homeopathic Treatment of MildTraumatic Brain Injury: A

Randomized, Double-Blind,Placebo-Controlled Clinical Trial

Background: Mild traumatic brain injury (MTBI) affects 750,000 persons in the United States annually.Five to fifteen percent have persistent dysfunction and disability. No effective, standard pharmacologicaltreatment exists specifically for this problem. We designed a pilot research project to study the clinicaleffectiveness of homeopathic medicine in the treatment of persistent MTBI. Method: A randomized,double-blind, placebo-controlled trial of 60 patients, with a four-month follow-up (N= 50), was conductedat Spaulding Rehabilitation Hospital (SRH). Patients with persistent MTBI (mean 2.93 years since injury,SD 3.1) were randomly assigned to receive a homeopathic medicine or placebo. The primary outcomemeasure was the subject-rated SRH-MBTI Functional Assessment, composed of three subtests: a Difficultywith Situations Scale (DSS), a Symptom Rating Scale (SRS), and a Participation in Daily Activities Scale(PDAS). The SRH Cognitive-Linguistic Test Battery was used as the secondary measure. Results: Analysisof covariance demonstrated that the homeopathic treatment was the only significant or near-significantpredictor of improvement on DSS subtests (P = .009; 95% CI−.895 to−.15), SRS (P = .058; 95% CI−.548to .01) and the Ten Most Common Symptoms of MTBI (P = .027; 95% CI −.766 to −.048). These resultsindicate a significant improvement from the homeopathic treatment versus the control and translate intoclinically significant outcomes. Conclusions: This study suggests that homeopathy may have a role intreating persistent MTBI. Our findings require large-scale, independent replication.

Edward H. Chapman, MD, DHtClinical InstructorHarvard University School of Medicine

Richard J. Weintraub, MDAssistant Clinical Professor of PsychiatryTufts University School of Medicine

Michael A. Milburn, PhDProfessorDepartment of PsychologyUniversity of MassachusettsBoston, Massachusetts

Therese O’Neil Pirozzi, ScD, CCC/SPAssistant ProfessorDepartment of Speech-Language

Pathology and AudiologyNortheastern UniversityBoston, Massachusetts

Elaine Woo, MDInstructor in MedicineHarvard University School of MedicineBoston, Massachusetts

INTRODUCTION

This pilot study was undertaken to assessthe effect of homeopathic treatment on thepersistent symptoms and disability resultingfrom mild traumatic brain injury (MTBI). Eachyear, three-quarters of a million Americanssustain an MTBI, defined by the AmericanCongress of Rehabilitation Medicine and theNational Brain Injury Association1 as:

We are indebted to the National Institutes of Health, Of-fice of Alternative Medicine, for its support and fund-ing; to the staff of the Spaulding Rehabilitation Hospi-tal for its openness in pursuing research in a therapythat is controversial; to Diane Gilbert, CRA, RosemarieLee, RNC, Ellen Bassuk, MD, Carol Faulkner, BA, andPatricia Casimira, BA, for their invaluable assistance;to Laboratoires Boiron for providing the medicines usedin this trial; to the Boiron Research Foundation for sup-plemental funding; and to the men and women whovolunteered themselves as subjects in this project, hop-ing to help find a therapy for the injury that has so pro-foundly affected their lives.

Address correspondence to Edward H. Chapman, MD,91 Cornell St, Newton, MA 02462–1320.

J Head Trauma Rehabil 1999;14(6):521–542c© 1999 Aspen Publishers, Inc.

521

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522 JOURNAL OF HEAD TRAUMA REHABILITATION/DECEMBER 1999

a traumatically induced physiologicaldisruption of brain function, manifestedby at least one of the following:

1. any period of loss of consciousness up to30 minutes

2. any loss of memory for events immedi-ately before or after the accident up to24 hours

3. any alteration in mental state at the timeof the accident (feeling dazed, disori-ented or confused)

4. focal neurological deficits which may ormay not be transient but result in a Glas-gow Coma Scale score of no less than13–15 within 30 minutes of the accident.

The natural course of recovery from MTBIis difficult to predict. Recovery falls intotwo patterns—full recovery or persistence ofsymptoms. Most recover from the injury with-out sequelae; however, 5–15% experiencepersistent deficits beyond three months.2,3

Complete recovery is rare among those withsymptoms persisting beyond six months post-injury.4,5 Some of the more common and dis-abling sequelae include: mood disorders, painand fatigue, deficits of attention, and diffi-culties with information processing and newlearning.3,6–8 Effects of subtle injury to thebrain overlap with structural injury in thehead and neck that may contribute to symp-toms such as headache and dizziness. Persis-tence of deficits in physical, cognitive, andaffective functioning result in considerablemorbidity, both social and economic, the costof which is estimated at $3.8 billion peryear.9

Patients with persistent MTBI are difficultto evaluate by current radiological or neu-ropsychological assessment tools for severalreasons:

1. patients are heterogeneous vocationally,educationally, and socially10,11

2. current imaging techniques are insensi-tive to the diffuse microscopic type ofinjury that characterizes MTBI12–14

3. although there are many common symp-toms in a group of MTBI patients, theindividual symptom complexes can bequite variable2

4. current neuropsychological evaluationtools place cognitive performance inbroad categories of age-related popula-tion norms, but, without testing pre-injury for comparison, they fail to iden-tify loss of function in an individual whohad functioned at a “superior” level andis performing at the “average” level post-injury.15–17

These complexities have limited the scopeof research and the availability of validatedmeasures for dysfunction seen in MTBI pa-tients.

Persistent MTBI patients are also very dif-ficult to treat. Current treatment employsa combination of rehabilitation therapiesaimed at helping patients to develop com-pensatory strategies for persistent deficitsand using medications12,18,19 that address thevariety of MTBI-related complaints. Becausepatients rarely present with a single symp-tom, polypharmacy is often required, andmedications used include nonsteroidal anti-inflammatory agents, narcotics, muscle re-laxants, antivertigo agents, psychostimulants,and antidepressants. Pharmacological treat-ment of one symptom may exacerbate otherdeficits, disrupting the fragile balance of post-trauma skills.11,19 Clinicians must weigh ben-efits against the risk of adverse effects. Thelimitations of current pharmacological ap-proaches in MTBI are reflected in the absenceof any published studies of pharmacologicaltreatment since 1993.

Benefit from homeopathic medicine hasbeen reported in published cases of patientssuffering from the chronic effects of concus-sion and head injury.20–22 Although home-opathy has only limited recognition in theUnited States, it is popular throughout East-ern and Western Europe, many countries

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Homeopathic Treatment of Persistent MTBI 523

in South America, South Africa, Australia,New Zealand, and the Indian subcontinent.Eisenberg estimated that 700,000 Americansused homeopathic medicines in 1990,23 anumber that increased to 3.4 million in1997.24 Four metaanalyses25–28 have reviewedthe status of homeopathic research, includ-ing 189 clinical trials. Although single studieshave demonstrated the efficacy of homeopa-thy in various clinical conditions, includingasthma,29 allergy,30 diarrhea,31 influenza,32

fibrositis,33 and depression,34 issues of quality,reproducibility, and a mechanism of action forhomeopathic medicines limit the conclusionsthat can be drawn from this research.27 In1992, Congress created the Office of Alterna-tive Medicine (OAM) at the National Institutesof Health to fund research exploring the po-tential efficacy of complementary/alternativemedicine (CAM). This pilot study, supportedby one of the 30 initial grants awarded bythe OAM, is the only federally funded studyof homeopathy in the treatment of any clini-cal condition, and it is the first randomized,double-blind clinical trial testing the efficacyof homeopathy in MTBI.

Homeopathy is based on the premise thatspecific “homeopathic” substances act totreat disease or injury by facilitating the body’snatural healing processes. The homeopathictherapeutic system was articulated 200 yearsago by Samuel Hahnemann.35,36 Homeopa-thy’s two fundamental principles, the “lawof similars” and the “minimum dose,” chal-lenge conventional medical understanding.The law of similars states that a substancecan cure the same symptoms that it pro-duces, when given to healthy human subjectsin “homeopathic drug provings” (HDPs).37–39

The homeopathic prescription is individual-ized to the patient, rather than to a specificdiagnosis. Consequently, a different medicinemay be prescribed for each patient witha single diagnosis; or, conversely, the samemedicine to patients with widely varying diag-

noses. For instance, the well-known constel-lation of symptoms produced by Belladonna(atropine)—red, hot, dry, dilated pupils, ag-itation, delirium—could be used to treat afebrile child, no matter what the microbio-logical etiology, or an adult presenting withcluster headaches. Homeopathy differs fromthe conventional models of pharmacologi-cal disease treatment: replacement therapy(insulin, thyroid), isopathy (immunization orallergy desensitization), or allopathy (treat-ments that remove or oppose the manifesta-tions of disease).40

Homeopathy uses medicines in “infinites-imal doses.” The medicines are producedby serially agitated dilution (SAD). One partof the original material, derived from plant,mineral, or animal sources, is serially dilutedand agitated in distilled water or pharmaceu-tical alcohol at a ratio of 1:99 (C or cen-tesimal potency) or 1:9 (X or decimal po-tency) to dilutions of 3X (10−3 molar) to100,000C (10−200,000 molar).41 The final solu-tion is sprayed on sucrose pellets that are ad-ministered sublingually. The dilution used inthis study was 200C (10−400 molar).

A specific mechanism of action for home-opathic medicines has not been identified.Because the probability that the numberof molecules of the original substance ap-proaches zero in dilutions beyond 10−23 mo-lar, homeopaths postulate that changes in thestructure of the diluent water42,43 carry infor-mation that can affect biological systems.44,45

Homeopathic potencies appear to act like cat-alysts, or pheromones, stimulating autoreg-ulatory pathways and generating multisys-tem therapeutic effects.40 The United StatesHomeopathic Pharmacopoeia was part of theoriginal act of 1938, under the authority of theUnited States Food and Drug Administration(USFDA), and is referenced in the legal defi-nition of a drug in every state and by Medi-care. The USFDA regulates the productionof homeopathic medicines, using guidelines

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developed by the Homeopathic Pharma-copoeia Convention of the United States(HPCUS).46 Most are classified in the over-the-counter (OTC) category47 and regulated sep-arately from herbal and dietary supplements.

The decision to investigate homeopathy asa treatment of MTBI is justified for a num-ber of reasons. First, published clinical casereports20–22 suggest efficacy of homeopathicmedicines in MTBI. Second, a single home-opathic medicine can simultaneously affectthe full range of physical, emotional, and cog-nitive functions affected by the brain injury.Third, homeopathic medicines have a rela-tively low incidence of side effects.40 Finally,the individualized nature of the homeopathicprescription, based on a patient’s subjectivesymptoms, makes this approach sensitive toand adaptable to the variable presentations ofMTBI patients.

METHODS

Subjects and enrollment

Subjects were recruited by a letter sent toall patients previously evaluated and treated atthe Adult Head Injury Clinic at Spaulding Re-habilitation Hospital (SRH). Letters were alsosent to rehabilitationists and neurologists inthe Boston area who treat patients with MTBI.We received approximately 100 responses.Sixty-one subjects were enrolled (57 fromSRH and 4 referred from other sources). Thepreestablished inclusion criteria were:

a) symptoms consistent with the diagnosisof MTBI, confirmed by review of medicalrecords

b) time since the original injury of at leastthree months

c) age 18 or olderd) competence to give informed consente) ability to transport self to the study site.

Exclusion criteria included:a) current use of medications for condi-

tions or symptoms not associated with

MTBI—including conventional, homeo-pathic, herbal, etc. (exceptions wereNSAIDs, insulin, thyroid hormone, andvitamins)

b) current use of “energy therapies” knownto interfere with the action of homeo-pathic remedies, including acupuncture,ultrasound, and therapeutic radiation

c) current pregnancy or pregnancy plan-ned for the coming year

d) current use of hormonal contraceptione) inability to discontinue substances (oral

or topical) known to antidote homeo-pathic remedies, such as coffee and aro-matic substances (eg, camphor, mentholand eucalyptus)

f) current acute phase of a major psychi-atric disorder

g) current alcohol or substance abuse.All subjects had a diagnosis of MTBI, con-

sistent with the ACRM definition, confirmedby history taken by the director of the SRHoutpatient head injury clinic (EW); the meanduration since injury for the sample studiedwas 2.93 years (SD 3.1, range 4 months to16 years). The patients’ symptoms resultedfrom traumatic brain injuries incurred in avariety of settings, mostly automobile acci-dents and falls. Of the 61 subjects who metthe eligibility criteria, most had been treatedpreviously, using the range of conventionalmodalities, including physical, occupational,speech/language, and pharmacological thera-pies. Four subjects had not received any pre-vious rehabilitation or pharmacological treat-ment. Thirteen patients (21%) had previouslyused some form of alternative therapy for anyreason, including MTBI, a proportion that islower than the 42.1% reported in the generalpopulation in the United States.23,24 None hadreceived homeopathic treatment for MTBIsymptoms. Twenty-nine subjects (48%) werecurrently taking prescription medications fortheir MTBI symptoms; these were continuedduring the study. As evidenced by the initialmean scores on the Symptom Rating Scale

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(SRS, 3.02) and Difficulty with Situations Scale(DSS, 2.97), the average patient in the studyhad persistent symptoms that significantlylimited their functioning, at least some of thetime, despite having received the range of re-habilitation therapies.

Informed consent from each subject, usinga form approved by the Human Subjects Com-mittee of the SRH in Boston, was obtainedfor participation in the study. Each subjectthen completed the self-rated functional as-sessment and a battery of cognitive-linguistictests administered by a speech and languagepathologist (TO-P) and designed to assess thesubject’s baseline cognitive ability and painsymptoms, as well as a one-hour homeopathicevaluation conducted jointly by the homeo-pathic physician (EC) and staff psychiatrist(RW).

The homeopathic medicine appropriate toeach case was chosen, using a classic homeo-pathic process.39 Characteristic symptoms foreach patient were determined; these symp-toms were then cross-referenced with home-opathic medicines known to elicit or curethese symptoms, a process called repertoriza-tion, performed using a computerized reper-tory program;48 and the single medicine mostsimilar to the patient’s case was determinedby study of relevant materia medica by thehomeopathic physician (EC) and the staffpsychiatrist (RW). While taking the homeo-pathic medications, subjects were asked notto use coffee or aromatic substances (eg, Ben-Gay, Tigerbalm, menthol, eucalyptus) knownto antidote homeopathic medicines. Medica-tions prescribed for MTBI symptoms werecontinued, as were any current occupational,speech, or physical therapies. Subjects re-turned monthly for four months to assessprogress and adjust homeopathic medication.

Measures

At the time that the study was designedand implemented, there was no validatedmeasure in use that was both sensitive to

the range of dysfunction seen in a heteroge-neous population of MTBI patients and able todetect changes resulting from treatment.Therefore, we chose as our predetermined,primary outcome measure a patient-rated,three-part, functional assessment tool devel-oped by the clinical staff at the SRH, Speech-Language Pathology Department (SRH-SLPD).Along with performance on objective stan-dardized tests, this assay is used at SRH to es-tablish therapy goals and was judged by thestaff as a useful and reliable assessment tool,although it had not been validated in pub-lished trials.

The functional assessment is composed ofthree subscales: the SRS assesses 34 physi-cal, cognitive, and affective symptoms of trau-matic brain injury (see Table 1); the DSSassesses the functional disability associatedwith 18 day-to-day situations (see Table 2);and the Participation in Daily Activities Scale(PDAS) evaluates daily function in 13 com-mon activities: watching TV, doing crafts, ex-ercising, reading, playing games, traveling,shopping, volunteering, cooking, attendingmovies/theater, socializing, dancing. All threescales employ a 1–5 Likert scale: 1 (“never”),2 (“rarely”), 3 (“sometimes”), 4 (“most of thetime”), and 5 (“always”). Patients rated eachitem in response to the instruction, “Pleaserate the degree to which the following applyto you now.”

The secondary outcome measure usedwas the SRH Cognitive-Linguistic Test Bat-tery, which includes selected elements ofthe Woodcock-Johnson tests of Cognitive Abi-lities—Revised49 (a. Analysis-Synthesis Sub-test, b. Visual-Auditory Learning Subtest). Ad-ditionally, a measure of social support, theProvision of Social Relations (PSR) scale,50

and questionnaires to determine routine de-mographic information and previous use ofhomeopathy and other alternative therapieswere administered at intake.

All subjects (N= 50 in the analysis sam-ple) were administered the functional assess-

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Table 1. Mean scores on the Symptom Rating Scale

Treatment Control

Symptom Pre Post Pre Post

1. Short term memory problems 3.96 3.41 3.61 3.562. Short attention span 3.81 3.31 3.82 3.413. Slow thinking 3.96 3.23 3.35 3.264. Headache 3.69 3.26 3.61 3.395. Mental fatigue 3.85 3.37 3.35 3.176. Sleep disturbances 3.63 3.19 3.59 3.437. Impatience 3.70 2.74 3.18 3.048. Frustration 3.56 3.96 3.45 3.309. Distractibility 3.26 3.03 3.26 3.36

10. Withdrawal from social activities 3.26 2.67 3.48 3.2611. Anxiety 3.35 2.89 3.32 3.3212. Irritability 3.35 2.89 3.30 3.3013. Confusion 3.35 3.07 3.14 3.1414. Reading problems 3.15 2.59 3.30 3.0415. Lack of motivation 3.19 2.85 3.26 3.1716. Drowsiness 3.00 2.65 3.23 3.0417. Depression 3.96 2.63 3.18 2.9618. Anger 3.07 2.30 2.96 2.9119. Memory loss for the accident 2.68 2.63 3.18 2.6820. Feelings of helplessness 2.81 2.31 3.00 2.7821. Poor judgement 2.85 2.44 2.86 2.5022. Writing problems 2.70 2.59 2.95 2.8723. Fearful 2.67 2.52 2.70 2.5224. Cry easily 2.67 2.30 2.52 2.5225. Explosive temper 2.44 2.22 2.83 2.7326. Blurred vision 2.30 2.30 2.82 2.8727. Ringing in the ears 2.56 2.30 2.45 2.2328. Hearing problems∗ 2.44 2.44 2.52 2.2629. Fear of “going crazy” 2.19 2.11 2.41 2.3930. Guilt 2.43 2.11 2.43 2.0931. Nausea 2.30 2.04 2.04 2.2332. Inconsideration 2.33 1.69 1.96 1.9633. Vomiting 1.44 1.22 1.39 1.5734. Seizures* 1.43 1.31 1.43 1.43

The first ten symptoms (those with a median of 4 = most or all the time) were used in the post-hoc analysis.∗Two symptoms, hearing problems and seizures, were removed from the analysis, due to negative correlations in thereliability analysis.

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Table 2. Mean pre- and posttreatment scores on the Difficulty in Situations scale

Treatment Control

Situation Pre Post Pre Post

Reading technical or work-related information 3.60 2.85 3.68 3.32Working 3.35 2.96 3.80 3.14Socializing in large groups 3.41 2.85 3.50 3.35Following instructions 3.44 2.78 3.22 3.13Reading novels 2.96 2.27 3.23 3.04Writing letters 2.92 2.60 3.17 3.04Cleaning house 2.92 2.38 3.18 2.96Dealing with finances 2.85 2.44 3.13 3.48Following a schedule 3.00 2.74 2.83 3.04Shopping 2.96 2.52 2.91 3.13Reading newspapers/magazines 2.85 2.19 2.86 2.65Making/keeping appointments 2.78 2.41 2.78 3.00Driving 2.73 2.41 2.78 3.04Socializing in small groups 2.78 2.35 2.52 2.83Meal preparation 2.50 2.30 2.50 2.89Talking on the phone 2.63 2.44 2.30 2.74Listening to radio/watching TV 2.41 2.37 2.35 2.43Eating in restaurants 2.40 2.30 2.22 2.52

ments, cognitive-linguistic tests, PSR scale(n= 49), and alternative medicine question-naire (n= 46) prior to randomization andreceiving the study medication. After initialevaluation (pretest), all subjects were ran-domly assigned to either the treatment (home-opathic) or control (placebo) groups and be-gan taking the prescribed treatment withinone week. Patients were evaluated monthlyby the homeopathic physicians for clinical im-provements in the following patient-reportedcriteria: their overall mental and emotionalstate, their level of energy or well-being, andspecific symptoms or functional complaints.There was no attempt to quantify these pa-tient impressions, nor were measurements ofthe primary or secondary outcome variablesadministered at the interim visits. After thetermination of four-month treatment, the ini-tial functional and cognitive-linguistic assess-

ments were repeated (posttest) on the sub-jects completing the study.

Medications

Eighteen homeopathic medications (seeTable 3) were selected for use in this study,based on the similarity of drugs’ provingsymptoms with the symptoms of people withMTBI,48 the published experience of physi-cians using these remedies in cases of headinjury,20–22 and the author’s (EC) observationof efficacy in cases of head injury. The home-opathic prescription is based on the patient’sindividual pattern of symptoms. For instance,Nux vomica is indicated in patients who areoversensitive to medication, irritable, overlychilly, and who suffer from headaches thatare aggravated by stress; whereas Papaver so-miniferom is prescribed for people whoseMTBI was associated with an experience of

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Table 3. Eighteen homeopathic medications

Homeopathic MedicinesThe 18 study medicines are presented with their common or chemical names, as well as their

“keynote symptoms.”

Argentum nitricum (Silver nitrate, AgNO3). Anticipation, impulsiveness, agoraphobia,claustrophobia, vertigo, and photophobia.

Arnica montana (Leopard’s Bane). Sore, bruised sensations, denial of illness, hopelessindifference, vertigo, head feels hot or enlarged, and diplopia.

Aurum metallicum (Gold, Au). Suicidal depression, feeling of neglecting one’s duty, musicameliorates, violent headaches often with chest oppression, and photophobia.

Baryta carbonica (Barium carbonate, BaCO2). Slow comprehension, irresolution, lack ofconfidence, feels people are ridiculing, and numbness of parts lain on.

Calcarea carbonica (CaCO2) Flabby, fear of insanity and being observed, chilliness, profuseperspiration, worse on exertion, and sleeplessness from cares.

Cicuta virosa (Water hemlock) Convulsions, cramps, strabismus, objects in the vision appearto approach and recede, tinnitus, childish behavior, estrangement, and want of confidencein mankind.

Cocculus indica (Indian cockle) Worse loss of sleep, reaction time slowed, nausea from sightor smell of food, car sickness, weakness, numbness, trembling, empty and hollow sensation.

Helleborus niger (Snow-rose) Stupor, staring/thoughtless, slow, forgetful, feels doomed,what the patient sees, hears or tastes makes no impression on the mind, and worse 4–8 p.m.

Hyoscyamus niger (Henbane) Suspicion, violent outbursts, loquacity or silent disposition,shamelessness, playing with fingers, twitchings, jerks, and cramps.

Hypericum perforatum (St. John’s Wort) Mistakes in writing, omitting letters, injuries tonerves-attended with headache, vertigo, convulsions, neuralgic pains worse with change ofweather.

Lachesis muta (Bushmaster snake venom) Overactivity, loquacity, vivid imagination, passionateand intense, better discharges, especially menses, left-sided complaints, and worse after sleep.

Natrum muriaticum (NaCl) Defensive, closed, cautious, dwells on past, disagreeableoccurrences, silent grief, averse to consolation, headaches, desire for salt, worse with heat, sun,and at the seaside.

Natrum sulphuricum (NaSO4) Objective, realistic, no delusions, sadness and suicidal tendency,headaches, photophobia, vertigo, worse, dampness, aggravated in the morning after rising, andat 4–5 a.m.

Nux moschata (Nutmeg) Dreamy, confused, slowness of response, overpowering sleepiness,sensation of extreme dryness of mouth and throat, yet no thirst.

Nux vomica (Poison-nut) Ineffectual urging [work, stool, micturition], fastidious, ambitious,unrefreshed, irritable, depressed, chilly after over medication, use of stimulants, and cramps.

Papaver somniferum (Opium) Disassociation after fright, flashbacks, unaffected by externalimpressions, or boldness and fearlessness, somnolence, snoring respiration, and constipation.

Silica (SiO2) Obstinate, fixed ideas, lack of confidence, fastidious, occipital headaches, sensitiveto noise, drafts, and slowness.

Sulphur (S) Self-centerd, theorizing, no depth or focus; lazy, messy, warm-blooded, burningpains and sensations, offensive, excoriating discharges, desire for sweets and spicy food, anditching.

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fright and results in a significant degree ofsomnolence or dissociation, often with fre-quent flashbacks of the traumatic event.

The FDA provided investigational new drug(IND) clearance for the medicines used in thisstudy. The medicines were manufactured byLaboratoires Boiron in Norwood, Pennsylva-nia. Two lots (A and B) were generated—thehomeopathic medicine and an identically ap-pearing placebo; both lots contained 70 unit-dose vials of each of the 18 medicines. Eachvial was labeled “Study Remedy 1/X/Y,” withX a number from 1 to 18 and Y the lot designa-tion, A or B. The code designating the alloca-tion of Lot A or B to active or placebo was keptat a locked safe at the manufacturer’s facility.A third lot (C) of unmedicated pellets, labeled“Study Remedy 2” was packaged in multidosevials.

A single medicine was selected by consen-sus of the two physicians, based on the in-dividual characteristics of the patient. Thestudy nurse was informed by phone of thename of the medicine. Assignment to treat-ment arm was made by the study nurse, usinga table of random numbers from a standardmedical text.51 According to the randomiza-tion for each subject, the study nurse pickeda vial of the selected medication from ei-ther Lot A or B and mailed it, along witha vial from Lot C, to the subjects. Receiptand understanding of administration instruc-tions was confirmed by a phone call withinthree days. Study Remedy 1 was administeredsublingually in a single pulsed dose, usingtwo possible protocols, depending on sub-jects’ concurrent use of conventional medica-tions. Patients not currently prescribed con-ventional medications took three individualdoses at twelve-hour intervals; patients tak-ing conventional medicines took one dosedaily for seven days. The longer administrationperiod used for subjects on conventionalmedicines was designed to compensate for

the potential antidoting effect of allopathicmedications.

Following either of these dosing regimensused for Study Remedy 1, all patients took adaily dose of Study Remedy 2 until the nextfollow-up visit. Study Remedy 2, a separatelypackaged placebo used in both the active andcontrol groups, was included in the protocolto improve compliance by creating conditionsto which patients were accustomed—taking adaily dose of a prescribed medicine.

Subjects were reassessed by the homeo-pathic physician at monthly follow-up visits.If the initial prescription resulted in little orno improvement, as determined by a com-plete review and assessment of change foreach symptom that the subject had reported,the initial medicine was repeated or the pre-scription was changed to a second of the 18medicines, taken from the same Lot—A or B—as the initial prescription. If improvementswere noted, the initial prescription was leftunchanged and the subject was continued onStudy Remedy 2.

Blinding

Concealment was assured because a studynurse (RL) assigned patients to Lot A or B,using a random number list provided by thestudy statistician (MM). The nurse had soleaccess to the medications. Her contact withpatients was limited to phone confirmationof receipt and instructions for administration.Her contact with the clinicians was limitedto communication of the identity of the sub-ject and medicine to be prescribed. The pre-scribing physicians did not see the vials ofprescribed medication and were not awareto which lot subjects had been assigned. Fur-thermore, patients, physicians, study nurse,and statistician were blinded to the designa-tion of Lot A or B as the active or placebocondition. Data entry was done blindly by aresearch assistant (PC) not otherwise involved

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in the study. The code was broken only afterall data analyses were complete. Compliancewith the instruction for medication use wasdetermined by patient self-reporting in follow-up visits.

Statistical analysis

During protocol development, we pre-dicted a moderate to large treatment effect,based on past homeopathic clinical experi-ence with minor head injury. An analysis ofthe statistical power for this experiment52 in-dicated a high probability of detecting a treat-ment effect on at least one of the dependentvariables. Assuming a minimal sample size(n = 25 per group) and only a moderate ef-fect size ( f 2 = .15), the power is equal to.75 to detect a treatment effect in any of thefive outcome variables. With a slightly largersample size (n = 30 per group), the powerincreases to .83. If the treatment effect waslarge ( f 2 = .35), with a sample size of 25 pergroup, the power is .98. We intended to enroll70 patients—35 per group.

According to the protocol, the intentionto treat analysis assumed that dropoutswould be unaffected by treatment and as-signed a posttest score equal to their pretestscore. We planned a regression analysis withgroup (placebo/homeopathic) predictingchange scores on the primary outcome mea-sures. Because there are no published reportsof the reliability of the primary outcomemeasure, an initial analysis was planned todetermine the combination of items on eachsubscale that produced the most reliablemeasurement.

For purpose of analysis, we computed ascale score for each patient on each of thethree subscales by averaging the patient’s rat-ings on all of the items within each subscale.For example, the subjects’ ratings of the 32symptoms on the SRS in the pretest were aver-

aged to create the pretest SRS score. Changescores, generated by subtracting the pretreat-ment score from posttreatment score for eachof the dependent measures, were computedfor each subject. Univariate analyses wereplanned to compare these change scores be-tween homeopathic and placebo groups onthe three patient-rated functional assessmentsand cognitive-linguistic tests using t tests forcontinuous variables and chi-square tests orFisher’s exact tests for discrete variables.

To control for the possibility of increasedType I error resulting from multiple signifi-cance tests, we planned an initial multivariateanalysis of variance (ANOVA). For significantunivariate findings, we planned a series ofanalyses of covariance (ANCOVAs), testing theeffect of the homeopathic treatment on thevarious posttest scores, controlling for the re-spective pretest scores. We planned to assessthe effects of additional covariates, includingage, sex, educational level, years since injury,concurrent use of conventional medications,prior experience with alternative medicine,and social support. To assess the differentialeffect of homeopathic treatment on patientswith different durations of injury, we planneda second ANCOVA, adding to the model an in-teraction term (years since injury multipliedby group [0 = placebo, 1 = homeopathic]).All calculations were performed using SPSS(Statistical Package for the Social Sciences) forWindows.53

RESULTS

Patient characteristics

On the pretest, no significant differencesexisted between the active and placebogroups on demographic variables or on thepresumed effects of head injury, as mea-sured by functional assessments or cognitive-linguistic variables (see Table 4).

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Table 4. Initial demographic and clinical characteristics of patient sample

Treatment PlaceboVariable Group (SD) Group (SD) P

Initial sample size 33 28[n = 61]

Analysis sample size 27 23[n = 50 ]∗

Age (in years) Mean 42.7 (11.3) 43.5 (12.3) .80Range (18–72) (18–75)

Years since injury Mean 3.18 (3.1) 2.73 (3.3) .62Range (0.5–14) (0.5–16)

Gender Males 11 (41%) 13 (56%) .27Females 16 (59%) 10 (44%)

Education Less than H. S. 3 (12%) 4 (17%) .07High school 4 (15%) 1 (4%)Some college 8 (34%) 10 (44%)College graduate 5 (19%) 8 (35%)Graduate degree 6 (23%) 0 (0%)

Concurrent use of 13 (48%) 16 (70%) .13conventional Rx

Prior experience with 4 (17%) 9 (41%) .07alternative medicine [n = 24] [n = 22][n= 46]

Social support mean (SD) 2.19 (.90) 2.08 (.18) .67[n = 49] [n = 26] [n = 23]

Pretreatment measures of Activity 2.34 (.56) 2.16 (.46) .21function mean (SD)

Symptom rating scale 3.02 (.59) 3.00 (.66) .91Ten most frequently 3.69 (.60) 3.46 (.68) .21

reported symptomsDifficulty with situations 2.97 (.93) 2.98 (.79) .96Linguistic 5.97 (3.6) 5.34 (3.1) .51Memory 7.74 (5.5) 7.95 (5.0) .89Cognitive 3.50 (2.1) 3.97 (3.2) .54

∗The “N” for all data is the analysis sample size (50), unless otherwise indicated.

Reliability analyses

Internal consistency

We conducted internal consistency reliabil-ity analyses on the SRS, the DSS Scale, and the

PDAS. All items on the PDAS were used; theCronbach’s alpha was .78. The reliability anal-ysis of the SRS indicated that the responses totwo of the 34 symptoms, hearing problems(r =−.13) and seizures (r =−.01), were not

P1: FDR



consistent with responses to the other items;therefore, these two items were excludedfrom subsequent analyses. The scale com-posed of the remaining 32 items, reported inTable 1, had a Cronbach’s alpha of .93, demon-strating very high reliability. Table 2 showsthe pretreatment and posttreatment averagescores reported on the DSS. One item on thissubscale, listening to radio and watching TV,was excluded, subsequent to reliability analy-sis, which demonstrated it to be uncorrelatedto the other activities in the scale. The DSS,composed of the remaining 17 situations, hada Cronbach’s alpha of .96.

Descriptive analyses

A summary of the changes in the three pri-mary and three secondary outcome measuresis presented in Table 5. Improvements overtime were not significantly different betweenthe groups’ scores on the PDAS (P = .862)or the Cognitive-Linguistic Screening TestBattery tasks: Linguistic (P = .129), Mem-ory (P = .487), and Cognitive (P = .687).The homeopathic treatment group showedgreater improvement than did the placebo

Table 5. Pretest and posttest scores for primary and secondary outcome measures

Treatment Placebo

Variable Pre Post Change Pre Post Change P

Symptoms (SD)∗ 3.02 (.59) 2.61 (.65) −.40 (.57) 3.0 (.66) 2.87 (.71) −.13 (.39) .058Situations (SD)∗ 2.97 (.93) 2.52 (1.03) −.45 (.63) 2.98 (.79) 3.02 (.97) .04 (.67) .009Activity (SD)∗ 2.34 (.56) 2.60 (.50) .26 (.71) 2.16 (.46) 2.44 (.66) .28 (.42) .862Top 10 Symptoms 3.69 (.60) 3.11 (.70) −.58 (.70) 3.46 (.68) 3.32 (.93) −.14 (.50) .015

(SD)∗

Cognitive (SD)∗∗ 31.3 (16.3) 41.0 (20.4) 9.7 (11.9) 31.0 (18.8) 39.4 (22) 8.3 (11.3) .687Linguistic (SD)∗∗ 46.4 (23.5) 49.3 (23.0) 4.1 (16.5) 43 (21.3) 51.6 (23.9) 10.6 (11.5) .129Memory (SD)∗∗ 43.7 (27.5) 55.3 (28.9) 11.7 (16.5) 41.2 (26.4) 50. (27.8) 8.8 (12.1) .487

Data are reported as mean (standard deviation).∗Data reported as mean score on 1–5 Likert Scale.∗∗Data reported as mean percentile.P values refer to comparison of the change scores, using a t test.

group for the DSS (P = .009) and the SRS(P = .058) (see Table 5).

Our data revealed the limitations of the stan-dardized cognitive, linguistic, and memorytests to assess changes resulting from treat-ment. The average percentile change (posttestminus pretest) in each of these three testsfor each subject was computed. We corre-lated these change scores with the amountof change on the self-reported primary mea-sures. The percentile improvement (or de-cline) in the cognitive, linguistic, and mem-ory scores was unrelated to each other orto the improvement in the self-reported mea-sures. In contrast, improvement in the self-report measures, particularly on the SRS andDSS, showed significant correspondence witheach other.

Our analyses focused on the scales of thethree primary dependent variables—the SRS,the DSS, and the PDAS. Subjects’ posttestscores on these scales were all significantlyintercorrelated, with symptoms and difficultyfunctioning showing the highest relationship(r = .74, P < .01). The PDAS correlated sig-nificantly with these two variables, but at a

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lower level: (r = −.57, P < .01) with theDSS (r = −.52, P < .01) and with the SRS.

Multivariate analyses

To control for the possibility of increasedType I error resulting from multiple signif-icance tests, we conducted a multivariateANOVA, testing the effect of treatment group(homeopathic versus placebo) on changescores (posttest score minus the pretestscore) on the three primary dependent vari-ables: the SRS, the DSS, and the PDAS. TheWilks’ Lambda for the effect of treatmentgroup was .841 (F(3,46)) = 2.89, P = .046).Following this significant multivariate effect,the three primary dependent variables weretested with separate factorial ANCOVAs. Foreach analysis, the posttest score for the vari-able was specified as the dependent variable,with group (homeopathic or placebo) as abetween-subjects variable and with the corre-sponding pretest score as a covariate.

Although the effect of homeopathic treat-ment was not significant for the PDAS(F(1,47) = .195, P = .660), there was a signif-icant effect of homeopathic treatment on theDSS (F(1,47) = 7.34, P = .009; 95% CI −.895to −.15) and an effect close to significanceon the SRS (F(1,47) = 3.77, P = .058; 95%CI −.548 to .01). Although subjects in boththe treatment and the placebo groups im-proved over the course of the study, with theexception of a slight deterioration of functionin the control group (mean 2.98–3.02), thesubjects in the homeopathic treatment groupimproved significantly more.

When additional covariates were includedin the models, including age, sex, education,social support, previous use of alternativemedicine, or years since the accident, nonesignificantly predicted posttest scores on anyof the three primary dependent variables. Forthe SRS, the coefficients for all of these covari-ates were insignificant (P > .25) and wereexcluded from the final model. For the DSS,

in addition to the effect of group, only socialsupport had a coefficient approaching signifi-cance (P = .144).

All but four patients had had previous con-ventional treatment; the lack of variabilityin this factor suggests that previous conven-tional treatment was unrelated to outcomes.Subjects’ current use of conventional medica-tions was significantly correlated with theirpretest scores on the SRS (r = .28, P = .043),the PDAS (r = .36, P = .015), and the DSS(r = .38, P < .001). These findings indicatethat the subjects with a higher level ofinitial symptoms and more difficulty in ac-tivities, such as going to work, were morelikely to be using medication at the start ofthe study. Current use of conventional medi-cations was correlated with change scores onthe three functional scales; use of medicationwas weakly associated with less improvementoverall for the PDAS (r = .18, P = .211), theDSS (r = .04, P = .78), and the SRS (r =−.13, P = .37), although these correlationswere not statistically significant.

Post-hoc analysis of the SymptomRating Scale

Because the SRS included symptoms withvery low incidence (eg, vomiting, seizures), a“basement effect” was suspected. Therefore,we selected all of the symptoms that had amedian pretest score of 4, indicating that atleast half of the subjects reported experienc-ing the symptoms at least “most of the time.”Ten symptoms (see Table 1) fell into this cat-egory. An ANCOVA predicting posttest scoreson a scale composed of these ten items (SRS-10), testing the effect of treatment group andcontrolling for pretest scores on the SRS-10,showed a significant group effect (F(1,47) =5.21, P = .027; 95% CI −.766 to −.048).This result lends support to the conclusionthat the homeopathic treatment produced ameaningful reduction in subjects’ significantsymptoms. When additional covariates were

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entered into the model, including age, sex,education, previous experience with alterna-tive medicine, social support, and years sinceinjury, none of the covariates were significant,(all P > .25), so they were excluded from thefinal model.

Assessment of outlier effects

An examination of the distributions of thepretest and posttest scores for the three pri-mary dependent variables showed only mi-nor deviations from normality. Tests of theassumptions of the multivariate statisticalanalyses that we conducted (Box’s Test ofEquality of Covariance Matrices and Levene’sTest of Equality of Error Variances) showedno significant violation of assumptions. Giventhe relatively small sample size analyzed(N = 50), a small number of outliers in thedata could have biased the results, overesti-mating the actual treatment effect. We usedthe exploratory data analysis procedures pro-vided in SPSS to identify any outliers and far-outliers53 for three dependent variables: theDSS, the SRS, and the SRS-10. The followingoutliers were identified: For DSS, there werethree outliers in the placebo group and twoin the homeopathic; for the SRS-10, therewere two in the homeopathic group and nonein the control; for the SRS, there were twoin the homeopathic group and none in thecontrol. The small number of outliers was re-moved, and the ANCOVAs were recomputed.In each case, the homeopathic treatment in-creased in statistical significance compared tothe analysis with the full scale—for the SRS(P = .03), for the SRS-10 (P = .002), and forthe DSS (P = .0008.)

Effect size/clinical significance

To give meaning to these statistically signifi-cant results of homeopathic treatment, we at-tempted to determine the magnitude of theeffects. Cohen54 suggests the following pa-rameters for interpreting effect size ( f 2):

small effect = 0.02; medium effect = 0.15;and large effect = 0.35. We calculated ef-fect sizes ( f 2) for observed reductions in thethree dependent variables: DSS = .16; SRS =.08; and SRS-10 = .11. These findings indicatethat the observed changes represent medium-range effects of homeopathic treatment.

Because our data are continuous rather thandiscrete, we have reported effect sizes ( f 2)in terms of variance explained, as Cohen54

has recommended. Because odds ratios are of-ten used in the reporting of clinical trials, wecomputed odds ratios by counting the num-ber of subjects who were either improved,unchanged, or worse on the SRS, DSS, andSRS-10 scales, using the following criteria, re-spectively: improved means a median changescore ≤−0.1; unchanged >−0.1 to <0.1;worse ≥0.1. For the PDA positive changescore (see Table 6).

The clinical significance of the homeo-pathic treatment is reflected in the changesthat subjects reported. These ranged frommild subjective changes to larger improve-ments, reflected in several subjects reportingthat they had returned to work or to morenormal functioning. These changes were re-flected in improvements on specific items onthe DSS. The largest improvements (≥−.5)in the homeopathic condition were seen initems measuring reading technical or workrelated information (−.74); following instruc-tions (−.67); reading newspapers (−.65);reading novels (−.60); doing house cleaning(−.54); socializing in small groups (−.50); andsocializing in large groups (−.50).

Effect of duration since injury ontreatment

An interaction term was computed by mul-tiplying the length (in years) since injury bya dummy variable for the group (placebo =0; homeopathic = 1) and was added to theANCOVA model. Analysis of the interaction ef-fect of the duration since injury and whether

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Tab

le6

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utc

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est

atu

so

nSc

ales

Mea

suri

ng

Sym

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ms,

Dif

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s,A

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and

Ten

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equ

ent

Sym

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Sym

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Sym

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meo

pat

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meo

pat

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Bet

ter∗

2214

2312

2017

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59

410

76

611

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341.

511.

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∗ Bet

ter

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−.01

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and

ap

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for

acti

viti

es.

P1: FDR



or not subjects received homeopathic treat-ment suggests that homeopathy can havemeaningful effects on subjects who are manyyears post-injury. In all three ANCOVAs pre-dicting the posttest score, controlling for thepretest score and social support at the timeof the posttest, this interaction term was sig-nificant for reduction in symptoms (F(1,45) =14.8; P < .001) and for reduction in difficultyfunctioning (F(1,45)= 4.17; P = .047), and ap-proached significance for activities (F(1,45) =3.28; P = .077).

To illustrate the meaning of the interac-tion between treatment and years since in-jury, we looked at the change scores for theSRS in three groups defined as one year orless, between one and three years, and threeyears or more since injury (Table 7). Subjectswhose injury occurred one year or less fromthe beginning of the study showed improve-ment in both the homeopathic and placebogroups. Subjects in the placebo group whowere one to three years post-injury at the on-

Table 7. Treatment effect on symptoms bytime since injury

Meanchange

Tx scoreDuration Group N (SD)

≤1 yr Placebo 7 −.386(.181)

Homeopathic 6 −.177(.195)

>1 <3 yrs Placebo 11 −.02(.144)


≥3 yrs Placebo 5 .119(.214)


set of the study showed no further improve-ment; and placebo subjects who were threeyears or more post-injury showed an increasein symptoms. The relative benefit of effect ofhomeopathic treatment appeared to increasewith duration since injury, a finding that holdspromise for patients with persistent MTBIand for whom current treatment options arelimited.

Subjects lost to study

The ten subjects who withdrew were dis-tributed equally between groups: six fromhomeopathic and four from placebo (seeFig 1). Five subjects (three from the activegroup and two from the placebo group)withdrew after the initial visit for per-sonal reasons communicated to the investi-gators. Three subjects (two active and oneplacebo) withdrew after one or two vis-its: One became pregnant and was with-drawn according to the study’s human sub-jects protocol, one became homeless andwas lost to follow-up, and one could notarrange transportation. Two subjects, onefrom each group, did not present for thefinal assessments. One subject, assigned to theplacebo group, was eliminated from the finalanalysis because he inadvertently received adose of active medicine.

We performed an “intent-to-treat” analysisby including these 11 subjects. We did not col-lect data intermediate to the pre- and posttestmeasurements, making it difficult to assesswhether the dropouts were responding differ-ently to the treatment or placebo than werethe remaining subjects. Therefore, given thegeneral trend toward improvement in bothgroups, we conducted the intent-to-treat anal-ysis, assuming that subjects withdrew be-cause they did not improve. The findings ofthis analysis were virtually identical to the re-sults without the dropouts. A regression anal-ysis predicting change scores on the threeprimary functional scales found significant

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Fig 1. Accrual of subjects with mild traumatic brain injury. Approximately 100 patients expressed interestin participating in the study; 61 subjects met all of the eligibility criteria; 50 subjects completed the study.

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effects of homeopathic treatment on the SRS(t = 2.04, P = .046); on the DSS (t = 2.49,P = .017); and for the SRS-10 (t = 2.76, P =.008).

Adverse reactions to medicines

Adverse reactions were rare. One sub-ject from each group reported increased de-pression. One reported nausea and dizzinessafter taking doses of the active medicine; an-other reported ten days of nausea and vomit-ing, with a slight fever after the initial activedose. One active subject reported an initialthree-week intensification of cognitive com-plaints, followed by a significant reduction ofsymptoms. The woman who was withdrawnfrom the study due to pregnancy had no ad-verse outcomes in the pregnancy and deliv-ered a healthy, full-term infant.

DISCUSSION

This study makes a significant contributionto both the assessment and treatment of per-sistent MTBI. This was the first clinical trial toevaluate the efficacy of homeopathy as ther-apy for persistent MTBI. The treatment groupsubjects reported a highly significant reduc-tion on scales measuring difficulty function-ing in situations commonly encountered indaily life and a significant decrease in the re-ported frequency of ten most commonly re-ported symptoms of MTBI.

The study provided initial validation of aninstrument for the assessment of the subjec-tive complaints, which are the hallmark of dis-ability following MTBI. This tool appears to besensitive to changes resulting from treatment.Reported change on these functional scalescorrelated with patient reports of improvedfunction. For instance, the mean change forthe treatment group of −.74 on the DSS (eg,a change on a 1–5 Likert Scale from “most ofthe time” to “some of the time”) for the item“reading technical information” reflected clin-ical improvements sufficient for several sub-

jects who had been unable to work for yearsto return to work. Analysis of the effect ofduration since injury suggested that home-opathy can be effective in reducing symp-toms in even those whose injury is remotein time. It is an exciting possibility that singlehomeopathic agents, prescribed based on in-dividual patient characteristics, can stimulatesignificant improvements in patients with per-sistent MTBI whose symptoms and functionalstatus had been static for years.

The cognitive-linguistic test battery wasemployed in this study in an attempt to finda more objective measure of disability that issensitive to change from treatment. This bat-tery demonstrated baseline deficits and im-proved cognitive functioning in both groups,but the battery did not detect significant dif-ferences in outcome between the treatmentand control groups, consequent to treatment.At least three explanations are possible forthis finding: (a) individuals within a groupof MTBI patients have variable deficits onthe cognitive, linguistic, or memory subtests,as evidenced by the lack of correlation thatwe observed among the change scores onthese three tests—this variability may leadto a loss of sensitivity for the full battery,rendering it unable to detect the changesobserved on the functionally based, patient-rated scales; (b) learning effects of retestingnegated any true effects of treatment; or (c)reported subjective benefit of homeopathictreatment on symptoms and difficulty func-tioning was due to placebo effects. This latterexplanation is unlikely, given the randomized,placebo-controlled design.29 Modifications inthe cognitive-linguistic test battery may yielda more sensitive tool for future studies.

Side effects and possible drug interactionsare concerns that all clinicians have aboutany new therapy. The phenomenon of symp-tom aggravation in the initial phase of homeo-pathic treatment is believed by homeopathsto have positive prognostic significance.55

Homeopathic prescribers hold the belief that

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conventional medicines interfere with or an-tidote the action of homeopathic medicines.Our study was deliberately designed to testthis assumption, assuming that homeopathycan be used as a complementary rather thanan exclusive therapy in MTBI patients. Ourdata indicate the following:• Homeopathic treatment was associated

with minimal side effects in 10% of thesubjects, including an initial symptom ag-gravation in one subject.• Previous use of conventional medicines,

though correlated with a higher initiallevel of symptoms and difficulty function-ing, had no effect on the outcome of sub-sequent homeopathic treatment.• Use of homeopathic medicines concur-

rently with conventional medicines waseffective and safe.• Concurrent use of allopathic medications

may have minimal dampening effect onhomeopathic treatment outcomes. Thiseffect may require adjustments in thehomeopathic prescribing routine.

The observations regarding the interactionsbetween conventional and homeopathic med-ications should be viewed as possible trends,requiring confirmation with a larger samplesize and research protocols specifically de-signed to examine these issues.

Clinical trials with blinding and placebocontrol are typically designed to test a sin-gle medicine or well-defined intervention. Ap-plying this methodology to homeopathy gen-erates challenges for both homeopaths andmethodologists. We had to accommodate theindividualized nature of homeopathic pre-scribing. This meant that, for each subject, wecould theoretically have chosen any one ofthe 1,242 FDA-approved homeopathic medi-cations, each of which is available in a vari-ety of potencies (3X to 100,000C). This needfor flexibility was balanced by the need forconcealment in a blinded, clinical trial—to de-liver preprepared batches (70 vials of eachmedicine in both verum and placebo) to a se-

cure site from which they could be dispensedwithout the awareness of the treatment team.The use of multiple medications makes in-terpretation of treatment effects more diffi-cult for methodologists and clinicians used tosingle-agent trials. This study tested the home-opathic method in patients with MTBI, ratherthan a single medicine. Our compromise touse only 18 medicines in a single potency(200C) may have reduced the effect size of thetreatment. If homeopathic assessment led tothe choice of a medication outside one of thepredesignated 18, as occurred in several in-stances, the treatment outcome would likelybe failure. Future clinical trials of homeopathyshould avoid limiting the number and potencyof homeopathic medicines available.

When we looked at the effect of time sinceinjury on treatment response, our results sug-gest two things—that there continues to besignificant spontaneous recovery from MTBIup to one year and that the relative effect ofhomeopathic treatment appears to increasewith time since injury. On the other hand,the four-month treatment period was proba-bly insufficient to achieve the maximum re-sponse to homeopathy in a population witha mean duration of three years since injury.It is a homeopathic axiom that the longera condition has existed, the longer will bethe period of treatment before achieving max-imal response, estimated at one month oftreatment for every year that a condition hasexisted.55 The four-month duration of treat-ment for a condition with a mean time sinceinjury of three years meant that some subjectswere inadequately treated. The question ofthe time needed to reach the maximal effectof homeopathic treatment can be settled onlyin a study with a longer period duration oftreatment.

In summary, this study was a successfulcollaboration between two groups of special-ists: homeopathic and rehabilitationist. Thispilot study made a significant step in refin-ing an assessment tool sensitive to the full

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range of disturbances resulting from MTBI.We demonstrated a reasonable internal reli-ability and responsiveness of the tool andclarified the need for additional modifica-tions and validation. Our results suggest thathomeopathy—alone or used concurrentlywith conventional pharmacological and reha-bilitation therapies—may be effective in treat-ing patients with persistent MTBI, a clinicalentity for which current treatment has limitedeffectiveness. The limitations imposed by thedesign of this pilot study, including the num-

ber and potency of homeopathic medicinesand duration of treatment, may have led toan underestimate of the actual benefits ofhomeopathic treatment. Further explorationof homeopathy’s role in the treatment of MTBIis needed, including basic science studies todefine the mechanism for the action of home-opathy. The results of this pilot study warranta definitive clinical trial with a larger numberof subjects, a longer duration of treatment,and use of the full complement of homeo-pathic medicines.

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