penetran arthritis pain relief

Alternative Medicine Review ◆ Volume 3, Number 5 ◆ 1998 Page 361

A Topically Applied Quaternary AmmoniumCompound Exhibits Analgesic Effects for

Orthopedic Pain

Holley W. Hadley, M.D., Lee A. Fischer, M.D., Julian Whitaker, M.D.

AbstractOBJECTIVE: To investigate the effectiveness of a topically applied emulsion of

an analgesic ammonium solution for the temporary treatment of pain associated witharthritis, tendinitis, and bursitis. DESIGN: 100 subjects in a single center, presentingwith chronic pain associated with arthritis, tendinitis, or bursitis trialed against placeboin a double-blind cross-over protocol. MAIN OUTCOME MEASURES: Measures oftreatment success include reduction in pain, improvement in clinical and/or mechanicalevaluations, and evaluation of local and systemic adverse effects. Analysis wasconducted at two weeks, after one week’s clearance, and again after two weeks.RESULTS: For chronic neuralgia associated with arthritis, tendinitis, and bursitis, thetest material had a positive effect at temporary pain reduction. Several subjects alsorecorded improvements in mechanical evaluations from baseline. Withdrawals due tosystemic or local adverse reactions were minimal. CONCLUSION: A topical emulsionof a strong ammonium solution utilizing quaternary ammonium, enhanced with certainpenetration enhancers, is effective for temporary relief of pain associated with arthritis,tendinitis, and bursitis.Altern Med Rev 1998;3(5):361-366.

IntroductionTopically applied non-steroidal anti-inflammatory drugs (NSAIDS) are widely adver-

tised and used for acute and chronic painful conditions. Relief from pain is a major impetus forseeking clinical intervention. There are millions of NSAID prescriptions written each year inthe United States for the treatment of chronic pain and approximately $300 million per yearspent on over-the-counter topical remedies.1 Marketing research indicates consumers are skep-tical of the efficacy of topical products. There has been growing interest around the world intopically applied NSAIDS in over-the-counter preparations.

Holly Hadley, MD, is a practicing family physician in West Palm Beach, Florida. She has financial interests in TransDermal Technologies.Correspondence address: 2669 Forest Hill Blvd., Ste 100, West Palm Beach, FL 33406; e-mail: [email protected]

Lee Fischer, MD, is a practicing family physician and medical director of Palm Beach Center for Clinical Investigation.

Julian Whitaker, MD, is medical director of Whitaker Wellness Institute; editor of Health and Healing, a monthly health newsletter.

Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprints Without Written Permission

Alternative Medicine Review ◆ Volume 3, Number 5 ◆ 1998

The history of the use of ammoniumcompounds as pain relievers is probably as oldas civilization itself. Urea, a natural by-prod-uct of metabolism, containing quaternary-likeammoniums, has been used as a topical anal-gesic and healing adjuvant for burns and cuts,and poultices containing urea compounds havebeen used to reduce swelling and inflamma-tion.

MethodsCriteria for Inclusion: Subjects were

recruited from advertisement to patients of afamily practice in Palm Beach County, Florida,and by advertisement in the local daily news-paper.

Subjects included were otherwisehealthy individuals presenting with chronicpain (defined as longer than six weeks) sec-ondary to arthritis, or chronic or acute pain oftendinitis or bursitis in at least one joint. Sub-jects may or may not have been receivingNSAID medications to treat their pain, butwere required by the protocol to discontinueall pain medication two weeks prior to begin-ning the study. Subjects ranged from 24 to 90years of age. Demographics of age, sex, diag-nosis and site of involvement are shown inFigures 1-4, respectively.

Subjects were evaluated for ability torecord their responses to daily scheduled dos-ing of the test materials and for their willing-ness to complete the entire five weeks of theprotocol.

Subjects were screened by the contractresearch organization, Palm Beach Center forClinical Investigation, and when selected, weregiven a physical examination, includingbaseline mechanical measurements, beforebeing admitted to the study.

Test Materials: TransDermalTechnologies, Inc., the sponsor of the trial,provided both the active and placebo testmaterials. These test materials weremanufactured under U.S.F.D.A. Good

Female 74.8% 77

Male 25.2% 26

103 Subjects

Figure 2. Sex distribution.

37-50 18.4% 19

18-36 5.8% 6

65-79 36.9% 38

80+ 11.7% 12

51-64 27.2% 28

103 Subjects

Figure 1. Age distribution

Figure 1. Age distribution.

Other 5.8% 6

Arthritis 59.2% 61

103 Subjects

Tendinitis 30.1% 31

Bursitis 4.9% 5

Figure 3. Diagnosis.

103 Subjects

Hand / Finger 22.3% 23

No Site 1.9% 2

Legs / Knees 28.2% 29Neck / Spine 19.4% 20

Arm / Shoulder 28.2% 29

Figure 4. Site of involvement.


Alternative Medicine Review ◆ Volume 3, Number 5 ◆ 1998 63

Quaternary A

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series for that subject. The study wasdouble-blind so neither subject nor investigatorknew which test material was being employedduring either phase.

Protocol: Phase I: After the initialphysical exam and baseline measurements,subjects were assigned test materials andinstructed to apply their first dose in thepresence of the investigator. They were givena two-week daily log to be completed for eachapplication of test material, with instructionsfor use four times daily. At the end of the firsttwo weeks, the subjects were evaluated by theinvestigator for pain, mechanicalmeasurements, and general status. They thenwere instructed to return after a wash-outperiod of no less than one week. On the cross-over visit, the subjects were asked if they hadused any medicines for pain, and whether theyhad undergone any significant changes in theircondition during the clearance period. If bothanswers were negative, they were admitted toPhase II of the protocol. If not, they weredischarged.

Phase II: The protocol was identical toPhase I except for the actual content of thetest material. After completing the two-weektrial, subjects returned for evaluation and dis-charge.

All subjects who voluntarily or invol-untarily withdrew from the protocol wereevaluated at discharge for general medicalcondition.

Measurements: Each subject wasevaluated for pain in one joint using a self-marked linear pain intensity scale at baselineand each subsequent visit. The investigatorevaluated each subject on the following:

• Swelling• Tenderness• Pain at rest• Pain on motion

A pain rating system was used with 0 = NoPain, 1 = Mild, 2 = Moderate, 3 = Marked,and 4 = Severe.

Manufacturing Procedures by ABCOLaboratories of Concord, California. Theactive test material was an emulsion ofquaternary ammonium 27 (a quaternaryammonium chloride compound) in water,enhanced with a permeation enhancer,methylsufonylmethane (MSM), lemon oil, andother skin protective agents. All open bondsites on the ammonium compound are filledwith a fatty acid, making it non-irritating. Theplacebo was compounded as sorbitanmonopalmitate and water. Both test materialswere presented as lotions. The active testmaterial was evaluated by the Institute for InVitro Sciences in Gaithersburg, Maryland, forprimary dermal irritation, skin sensitizationand toxicity. Materials tested within non-irritating limits.2

Enough material was prepared for two3-oz. containers of each material to be assignedto each subject. Each container was given aserial number beginning at 98001 and endingwith 98103 and designated as either “A” witha red dot or “B” with a blue dot. “A” contain-ers held one form of test material and the “B”containers the other. A corresponding detach-able label with identical information was at-tached to each container. Assignment of “A”or “B” was randomized and recorded in theMaster Test Material Log. Once numbered andassigned as “A” or “B,” test materials wereplaced in nested, numbered boxes for assign-ment to subjects.

As each subject was entered into theprotocol, they were assigned as subject numberthe next available test material number. Thedetachable label from one of the “A”containers was attached to the subject’s patientrecords retained by the investigator. At the endof Phase I, the test material container wasreturned to the investigator and replaced in itsnest. At the beginning of Phase II the first “B”container was issued. In the event the containerwas exhausted or lost, it was replaced with thesecond container in the appropriate “A” or “B”



Depending on the site of involvement,each subject was further evaluated for gripstrength using a hand dynamometer, pinchforce using a pinch gauge, range of motionmeasured in degrees using small and largegoniometers, degree of swelling of the in-volved joint in centimeters, time to walk 50feet, and duration of morning stiffness. Thesame joint was monitored throughout the trial.

Subjects were instructed to keep a dailylog, including a before-and-after-application-Linear-Pain-Intensity scale and a check boxfor how soon they noticed relief. A weeklysummary was included which asked forgeneral evaluation of overall wellness and

effectiveness of the test material beingevaluated.

Ethics: The protocol for the study wassubmitted to the Institutional Review Boardat Humana-JFK Medical Center in Atlantis,Florida. It was approved for study onMarch 3, 1998, with no substantive correctionsexcept a referral to federal law and an IRBcontact being added to the “Subject InformedConsent Release.”

A “Study Source Document” wascompleted for each subject in the trial withcomplete medical documentation. Subjectswere given time at initial screening and at eachevaluation to ask questions and were provided

All 103 Subjects

Withdrawals 25.5% 26

No Response 18.6% 19

Positive Response 52.9% 54Placebo Effect 2.9% 3

Figure 5. Types of response.54 Subjects With Positive Responses

Moderate 22.0% 11

Marked 40.0% 20

Significant 12.0% 6

Mild 26.0% 13

0

20

40

60

80

100

54 Subjects with positive responses

Po

siti

ve R

esp

on

se %

Under 18 18-36 37-50 51-64 65-79 80+ Ave. All

Age

0

20

40

60

80

100

54 Subjects with positive responses

Po

siti

ve R

esp

on

se %

Finger/Hand

Arm/Shoulder

Neck/Spine

Leg/Knee

Ave. All

Location

Figure 5. Types of response. Figure 6. Level of positive response.

Figure 7. Positive response by age. Figure 8. Summary response by location.


Alternative Medicine Review ◆ Volume 3, Number 5 ◆ 1998 Page 365

Quaternary A

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onium

is less than 0.01; so the null hypothesis is re-jected.

Figures 7 and 8 are an analysis of the54 subjects with positive responses. The per-centages are based on the number of positiveresponses (54) divided by the number of sub-jects who completed the trial (77), grouped byage and site of involvement.

DiscussionThese results indicate a topically ap-

plied quaternary ammonium compound is sig-nificantly more effective than placebo, with70 percent of the subjects receiving some mea-surable improvement and 40 percent receiv-ing marked relief. The positive response toplacebo was 3 out of 77 subjects (4%). Com-parable response to placebo in other trials oftopically applied NSAID drugs have yieldedplacebo effects as high as 40 percent.3 Lessthan 2 percent of the subjects reported minorside-effects, which were self limiting. A num-ber of subjects in this trial reported dramaticrelief from what had heretofore been intrac-table pain of years’ duration. Subjects whoreported positive results who had used otheroral or topical medications rated the test ma-terial “as good as” or “better than” theirprevious medications.

The only consistent area of poor per-formance was for treatment of acute shouldertendinitis in younger subjects, for which thetest material had virtually no effect. Generally,the test material seemed to work either mark-edly well for younger subjects (less than age51) or not at all.

Subjects reported the mean time toonset of relief was 20 minutes from applica-tion, and the duration of their relief from asingle application ranged from two hours toall day, averaging over four hours.

with contact numbers so the investigator and/or sponsor could be reached at any time.Subjects were informed they could discontinuetreatment at any time and that such a decisionwould not affect their care.

AnalysisThe following statistics were prepared:

• Overall improvement defined as reductionof pain and/or improvement of mechanicalmeasurements within subjects, in active ver-sus placebo test materials.

• Analysis of variance on overall improvement− active versus placebo (99% confidence in-terval).

• Number of subjects with positive responseto placebo and no response to active test ma-terials.

• Comparisons of overall results by age andsite of pain.

• Elapsed time to relief.

Results Of 103 subjects who began the trial,

77 completed the protocol. Of the 77 subjectscompleting the trial, 54 subjects (70%) re-ceived positive results. Of 26 withdrawals, 13(50%) withdrew while on placebo. Of the re-maining 12 withdrawals, 5 indicated in theirlogs the material was working for them.

Subjects’ response was rated on a scaleof 1 = mild response, 2 = moderate response,3 = significant response, and 4 = marked re-sponse. The level of positive responses in vari-ous categories is described in Figs. 5-8.

The mean response was 1.92 ± .002.The confidence interval that the null hypoth-esis (that the active material was no more ef-fective than placebo at relieving pain associ-ated with arthritis, bursitis or tendinitis) is true,



The most interesting results were:• Older subjects experienced the most

relief – increasing with age to over 80 percentpositive response at age 80 and above – weare ignoring the 100 percent response in the18-36 age group because this group was toosmall to constitute a valid sample.

• Fingers / hands / wrists and legs /knees / ankles received more than the average70 percent positive response rate.

AcknowledgementsThe authors wish to thank Berno

Pettersson of Pettersson & Associates; JohnHarbell, PhD., of the Institute for In Vitro Sci-ences; Palm Beach Center for Clinical Inves-tigation; and TransDermal Technologies, Inc.for their invaluable assistance.

References1. Arthritis Foundation Statistics.2. Cytotoxicity and Anti-Inflammatory Assay

Using EpiDerm® Skin Model with MTT andCytokine End Points. Hans A. Raabe, Institutefor In Vitro Sciences, Inc., Study Number97DC08.050031, May 8, 1998.

3. Moore RA, Tramer MR, Carroll D, et al.Quantitative systematic review of topicallyapplied non-steroidal anti-inflammatory drugs.BMJ 1998;316:333-338.


penetran arthritis pain relief

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