Original Research
5 February 2019

Compounded Topical Pain Creams to Treat Localized Chronic Pain: A Randomized Controlled Trial

Publication: Annals of Internal Medicine
Volume 170, Number 5

Abstract

Background:

The use of compounded topical pain creams has increased dramatically, yet their effectiveness has not been well evaluated.

Objective:

To determine the efficacy of compounded creams for chronic pain.

Design:

Randomized controlled trials of 3 interventions. (ClinicalTrials.gov: NCT02497066)

Setting:

Military treatment facility.

Participants:

399 patients with localized pain classified by each patient's treating physician as neuropathic (n = 133), nociceptive (n = 133), or mixed (n = 133).

Intervention:

Pain creams compounded for neuropathic pain (ketamine, gabapentin, clonidine, and lidocaine), nociceptive pain (ketoprofen, baclofen, cyclobenzaprine, and lidocaine), or mixed pain (ketamine, gabapentin, diclofenac, baclofen, cyclobenzaprine, and lidocaine), or placebo.

Measurements:

The primary outcome measure was average pain score 1 month after treatment. A positive categorical response was a reduction in pain score of 2 or more points coupled with a score above 3 on a 5-point satisfaction scale. Secondary outcomes included Short Form-36 Health Survey scores, satisfaction, and categorical response. Participants with a positive outcome were followed through 3 months.

Results:

For the primary outcome, no differences were found in the mean reduction in average pain scores between the treatment and control groups for patients with neuropathic pain (−0.1 points [95% CI, −0.8 to 0.5 points]), nociceptive pain (−0.3 points [CI, −0.9 to 0.2 points]), or mixed pain (−0.3 points [CI, −0.9 to 0.2 points]), or for all patients (−0.3 points [CI, −0.6 to 0.1 points]). At 1 month, 72 participants (36%) in the treatment groups and 54 (28%) in the control group had a positive outcome (risk difference, 8% [CI, −1% to 17%]).

Limitations:

Generalizability is limited by heterogeneity among pain conditions and formulations of the study interventions. Randomized follow-up was only 1 month.

Conclusion:

Compounded pain creams were not better than placebo creams, and their higher costs compared with approved compounds should curtail routine use.

Primary Funding Source:

Centers for Rehabilitation Sciences Research, Defense Health Agency, U.S. Department of Defense.

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Supplemental Material

Supplement. Study Protocol

References

1.
Steingrímsdóttir ÓALandmark TMacfarlane GJNielsen CS. Defining chronic pain in epidemiological studies: a systematic review and meta-analysis. Pain. 2017;158:2092-2107. [PMID: 28767506]  doi: 10.1097/j.pain.00000000000010091
2.
GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1211-1259. [PMID: 28919117]  doi: 10.1016/S0140-6736(17)32154-2
3.
Gaskin DJRichard P. The economic costs of pain in the United States. J Pain. 2012;13:715-24. [PMID: 22607834]  doi: 10.1016/j.jpain.2012.03.009
4.
Swedish Council on Health Technology Assessment. Methods of treating chronic pain: a systematic review [Internet]. Stockholm: Swedish Council on Health Technology Assessment; 2006 Oct. SBU Yellow Report No. 177/1 + 2. [ 28876750]
5.
Brady KTMcCauley JLBack SE. Prescription opioid misuse, abuse, and treatment in the United States: an update. Am J Psychiatry. 2016;173:18-26. [PMID: 26337039]  doi: 10.1176/appi.ajp.2015.15020262
6.
Manchikanti LPampati VHirsch JA. Utilization of interventional techniques in managing chronic pain in medicare population from 2000 to 2014: an analysis of patterns of utilization. Pain Physician. 2016;19:E531-46. [PMID: 27228520]
7.
Cohen SPRaja SN. Pain. In: Goldman L, Schafer AI, eds. Goldman-Cecil Textbook of Medicine. 25th ed. Philadelphia: Elsevier Saunders; 2015:143-152.
8.
Harirforoosh SAsghar WJamali F. Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm Sci. 2013;16:821-47. [PMID: 24393558]
9.
Ness TJJones LSmith H. Use of compounded topical analgesics—results of an Internet survey. Reg Anesth Pain Med. 2002;27:309-12. [PMID: 12016606]
10.
Derry SWiffen PJKalso EABell RFAldington DPhillips Tet al. Topical analgesics for acute and chronic pain in adults—an overview of Cochrane Reviews. Cochrane Database Syst Rev. 2017;5:CD008609. [PMID: 28497473]  doi: 10.1002/14651858.CD008609.pub2
11.
Casale RSymeonidou ZBartolo M. Topical treatments for localized neuropathic pain. Curr Pain Headache Rep. 2017;21:15. [PMID: 28271334]  doi: 10.1007/s11916-017-0615-y
12.
Derry SWiffen PJMoore RAQuinlan J. Topical lidocaine for neuropathic pain in adults. Cochrane Database Syst Rev. 2014:CD010958. [PMID: 25058164]  doi: 10.1002/14651858.CD010958.pub2
13.
Boardman LACooper ASBlais LRRaker CA. Topical gabapentin in the treatment of localized and generalized vulvodynia. Obstet Gynecol. 2008;112:579-85. [PMID: 18757655]  doi: 10.1097/AOG.0b013e3181827c77
14.
Safaeian PMattie RHahn MPlastaras CTMcCormick ZL. Novel treatment of radicular pain with a multi-mechanistic combination topical agent: a case series and literature review. Anesth Pain Med. 2016;6:e33322. [PMID: 27252902]  doi: 10.5812/aapm.33322
15.
Hiom SPatel GKNewcombe RGKhot SMartin C. Severe postherpetic neuralgia and other neuropathic pain syndromes alleviated by topical gabapentin [Letter]. Br J Dermatol. 2015;173:300-2. [PMID: 25524254]  doi: 10.1111/bjd.13624
16.
Thompson DFBrooks KG. Systematic review of topical amitriptyline for the treatment of neuropathic pain. J Clin Pharm Ther. 2015;40:496-503. [PMID: 26059975]  doi: 10.1111/jcpt.12297
17.
U.S. Accountability Office. Compounded drugs: TRICARE's Payment Practices Should Be More Consistent with Regulations. GAO-15-64. Accessed at www.gao.gov/products/GAO-15-64 on 1 November 2018.
19.
Kime P. Agency to act on compound med reimbursements. Accessed at www.militarytimes.com/story/military/benefits/health-care/2015/02/02/tricare-compounded-medications/22523669/ on 1 November 2018.
20.
Bennett MISmith BHTorrance NPotter J. The S-LANSS score for identifying pain of predominantly neuropathic origin: validation for use in clinical and postal research. J Pain. 2005;6:149-58. [PMID: 15772908]
21.
Freynhagen RBaron RGockel UTölle TR. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin. 2006;22:1911-20. [PMID: 17022849]
22.
Tauben D. Nonopioid medications for pain. Phys Med Rehabil Clin N Am. 2015;26:219-48. [PMID: 25952062]  doi: 10.1016/j.pmr.2015.01.005
23.
Cline AETurrentine JE. Compounded topical analgesics for chronic pain. Dermatitis. 2016;27:263-71. [PMID: 27649348]  doi: 10.1097/DER.0000000000000216
24.
Bryson EHartman RArnold JGorman GSweitzer SAsbill S. Skin permeation and antinociception of compounded topical cyclobenzaprine hydrochloride formulations. Int J Pharm Compd. 2015;19:161-6. [PMID: 26685496]
25.
Lawrence Pharmacy. Compounding services. Accessed at https://lawrencepharmacyrx.com/compounding on 1 November 2018.
26.
Ware JE JrSherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30:473-83. [PMID: 1593914]
27.
Rofail DMyers LFroggatt D. Treatment satisfaction and dissatisfaction in chronic low back pain: a systematic review. Journal of Psychology and Psychotherapy. 2016;6:3.  doi: 10.4172/2161-0487.1000260
28.
Cohen SPWilliams KAKurihara CNguyen CShields CKim Pet al. Multicenter, randomized, comparative cost-effectiveness study comparing 0, 1, and 2 diagnostic medial branch (facet joint nerve) block treatment paradigms before lumbar facet radiofrequency denervation. Anesthesiology. 2010;113:395-405. [PMID: 20613471]  doi: 10.1097/ALN.0b013e3181e33ae5
29.
Dworkin RHTurk DCWyrwich KWBeaton DCleeland CSFarrar JTet al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. 2008;9:105-21. [PMID: 18055266]
30.
Derry SConaghan PDaSilva JAWiffen PJMoore RA. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev. 2016;4:CD007400. [PMID: 27103611]  doi: 10.1002/14651858.CD007400.pub3
31.
Davis KDTreede RDRaja SNMeyer RACampbell JN. Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain. Pain. 1991;47:309-17. [PMID: 1664508]
32.
Nguyen VTiemann DPark ESalehi A. Alpha-2 agonists. Anesthesiol Clin. 2017;35:233-245. [PMID: 28526145]  doi: 10.1016/j.anclin.2017.01.009
33.
Chaparro LEWiffen PJMoore RAGilron I. Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst Rev. 2012:CD008943. [PMID: 22786518]  doi: 10.1002/14651858.CD008943.pub2
34.
Eccleston CCooper TEFisher EAnderson BWilkinson NM. Non-steroidal anti-inflammatory drugs (NSAIDs) for chronic non-cancer pain in children and adolescents. Cochrane Database Syst Rev. 2017;8:CD012537. [PMID: 28770976]  doi: 10.1002/14651858.CD012537.pub2
35.
Finnerup NBAttal NHaroutounian SMcNicol EBaron RDworkin RHet al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14:162-73. [PMID: 25575710]  doi: 10.1016/S1474-4422(14)70251-0
36.
Rowbotham MCDavies PSFields HL. Topical lidocaine gel relieves postherpetic neuralgia. Ann Neurol. 1995;37:246-53. [PMID: 7847866]

Information & Authors

Information

Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 170Number 55 March 2019
Pages: 309 - 318

History

Published online: 5 February 2019
Published in issue: 5 March 2019

Keywords

Authors

Affiliations

Robert E. Brutcher, PharmD, PhD
Walter Reed National Military Medical Center, Bethesda, Maryland (R.E.B., C.K., P.M.)
Connie Kurihara, RN
Walter Reed National Military Medical Center, Bethesda, Maryland (R.E.B., C.K., P.M.)
Mark C. Bicket, MD
Johns Hopkins Medicine and Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (M.C.B.)
Parvaneh Moussavian-Yousefi, PharmD
Walter Reed National Military Medical Center, Bethesda, Maryland (R.E.B., C.K., P.M.)
David E. Reece, MD
Walter Reed National Military Medical Center, Uniformed Services University of the Health Sciences, Bethesda, Maryland (D.E.R., S.R.G., D.E.J.)
Lisa M. Solomon, BS
Walter Reed National Military Medical Center, Johns Hopkins Medicine, Baltimore, Maryland (L.M.S.)
Scott R. Griffith, MD
Walter Reed National Military Medical Center, Uniformed Services University of the Health Sciences, Bethesda, Maryland (D.E.R., S.R.G., D.E.J.)
David E. Jamison, MD
Walter Reed National Military Medical Center, Uniformed Services University of the Health Sciences, Bethesda, Maryland (D.E.R., S.R.G., D.E.J.)
Steven P. Cohen, MD
Johns Hopkins School of Medicine, Baltimore, Maryland, and Walter Reed National Military Medical Center, Uniformed Services University of the Health Sciences, Bethesda, Maryland (S.P.C.)
Disclaimer: The identification of specific products or scientific instrumentation is considered an integral part of the scientific endeavor and does not constitute endorsement or implied endorsement on the part of the authors, Department of Defense, or any component agency. The views expressed in this manuscript are those of the authors and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, or U.S. Government. The views expressed in this manuscript are those of the authors and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, or U.S. Government.
Acknowledgment: The authors thank Zackariya Korme; Aubrey Verdun, MD; and COL Samuel Galvagno, DO, PhD, for their assistance with data entry, recruitment, and statistical planning, respectively.
Disclosures: Dr. Bicket reports grants from Foundation for Anesthesia Education and Research during the conduct of the study and personal fees from Axial Healthcare outside the submitted work. Dr. Cohen reports personal fees from Semnur; grants from SPR Therapeutics; grants and personal fees from Avanos; and advisory board membership at Semnur, Boston Scientific, and Medtronic, outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M18-2736.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer, Johnson & Johnson, and Colgate-Palmolive. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Data Sharing Statement: The following data will be made available upon publication until 5 years after publication: complete deidentified patient data set (contact Steven P. Cohen; e-mail, [email protected]). The following supporting documents will be made available upon publication until 5 years after publication: analytic/statistical code and informed consent forms (contact Steven P. Cohen; e-mail, [email protected]). These data will be made available to anyone requesting it for any purpose with investigator support.
Corresponding Author: Steven P. Cohen, MD, 550 North Broadway, Suite 301, Baltimore, MD 21205; e-mail, [email protected].
Current Author Addresses: Dr. Brutcher: Department of Pharmacy, Walter Reed National Military Medical Center, Building 9, Room 2304, 8901 Wisconsin Avenue, Bethesda, MD 20889.
Ms. Kurihara and Drs. Griffith and Jamison: Pain Management Clinic, Walter Reed National Military Medical Center, Building 9, 3rd Floor, 8901 Wisconsin Avenue, Bethesda, MD 20889.
Dr. Bicket: Johns Hopkins Pain Medicine Division, 600 North Wolfe Street, Phipps Building, 4th Floor, Suite 460, Baltimore, MD 21287.
Dr. Moussavian-Yousefi: 10835 South Glen Road, Potomac, MD 20854.
Dr. Reece: Physical Medicine and Rehabilitation Clinic, Walter Reed National Military Medical Center, Building 19, 1st Floor, 8901 Wisconsin Avenue, Bethesda, MD 20889.
Ms. Solomon: 202 Smarty Jones Terrace, Havre de Grace, MD 21078.
Dr. Cohen: 550 North Broadway, Suite 301, Baltimore, MD 21205.
Author Contributions: Conception and design: R.E. Brutcher, C. Kurihara, D.E. Reece, S.P. Cohen.
Analysis and interpretation of the data: R.E. Brutcher, C. Kurihara, M.C. Bicket, D.E. Reece, S.R. Griffith, S.P. Cohen.
Drafting of the article: R.E. Brutcher, C. Kurihara, M.C. Bicket, S.R. Griffith, S.P. Cohen.
Critical revision for important intellectual content: R.E. Brutcher, M.C. Bicket, L.M. Solomon, S.P. Cohen.
Final approval of the article: R.E. Brutcher, C. Kurihara, M.C. Bicket, P. Moussavian-Yousefi, D.E. Reece, L.M. Solomon, S.R. Griffith, D.E. Jamison, S.P. Cohen.
Provision of study materials or patients: D.E. Reece, L.M. Solomon, S.R. Griffith, D.E. Jamison, S.P. Cohen.
Statistical expertise: M.C. Bicket.
Administrative, technical, or logistic support: C. Kurihara, P. Moussavian-Yousefi, L.M. Solomon.
Collection and assembly of data: R.E. Brutcher, C. Kurihara, P. Moussavian-Yousefi, D.E. Reece, L.M. Solomon, D.E. Jamison, S.P. Cohen.
This article was published at Annals.org on 5 February 2019.

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Robert E. Brutcher, Connie Kurihara, Mark C. Bicket, et al. Compounded Topical Pain Creams to Treat Localized Chronic Pain: A Randomized Controlled Trial. Ann Intern Med.2019;170:309-318. [Epub 5 February 2019]. doi:10.7326/M18-2736

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