Topical Pain Creams
Review of Select Ingredients for Safety, Effectiveness, and Use
Debra A. Schwinn and Leigh Miles Jackson, Editors
Committee on the Assessment of the Available Scientific Data
Regarding the Safety and Effectiveness of Ingredients
Used in Compounded Topical Pain Creams
Board on Health Sciences Policy
Health and Medicine Division
A Consensus Study Report of
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This activity was supported by a contract between the National Academy of Sciences and the U.S. Food and Drug Administration. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.
International Standard Book Number-13: 978-0-309-67215-3
International Standard Book Number-10: 0-309-67215-5
Digital Object Identifier: https://doi.org/10.17226/25689
Library of Congress Control Number: 2020937383
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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2020. Compounded topical pain creams: Review of select ingredients for safety, effectiveness, and use. Washington, DC: The National Academies Press. https://doi.org/10.17226/25689.
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COMMITTEE ON THE ASSESSMENT OF THE AVAILABLE SCIENTIFIC DATA REGARDING THE SAFETY AND EFFECTIVENESS OF INGREDIENTS USED IN COMPOUNDED TOPICAL PAIN CREAMS
DEBRA A. SCHWINN (Chair), President, Palm Beach Atlantic University (from April 2020); Professor, University of Iowa Carver College of Medicine (until April 2020)
STEPHEN BYRN, Professor, Purdue University
DIANA D. CARDENAS, Emeritus Professor and Chair, University of Miami Miller School of Medicine
BARBARA INSLEY CROUCH, Professor and Executive Director, Utah Poison Control Center, College of Pharmacy, University of Utah
EDMUND J. ELDER, Director, Zeeh Pharmaceutical Experiment Station, University of Wisconsin–Madison
JOHN T. FARRAR, Associate Professor of Epidemiology and Neurology, University of Pennsylvania Perelman School of Medicine
CARMEN GREEN, Professor, University of Michigan
FRIEDHELM SANDBRINK, National Program Director for Pain Management, U.S. Department of Veterans Affairs
VINOD P. SHAH, Expert Consultant, NDA Partners
JOYCE S. TSUJI, Principal Scientist, Exponent
CAROL S. WOOD, Research Staff Scientist, Oak Ridge National Laboratory
National Academy of Medicine Fellow
DIMA QATO, Assistant Professor, University of Illinois at Chicago
LEIGH MILES JACKSON, Study Director
CLAIRE GIAMMARIA, Associate Program Officer
ANDREW MARCH, Research Associate
JUSTIN JONES, Senior Program Assistant
DANIEL CESNALIS, Financial Officer (until June 2019)
ANNA ISABEL CAMILO JAVIER, Financial Officer (until January 2020)
VICTOR STEWART, Financial Officer (from February 2020)
MARIAM SHELTON, Program Coordinator (until August 2019)
BRIDGET BOREL, Program Coordinator (from October 2019)
ANDREW M. POPE, Senior Director, Board on Health Sciences Policy
S. NARASIMHA MURTHY, Professor of Pharmaceutics and Drug Delivery, University of Mississippi
ANNA NICHOLSON, Science Writer, Doxastic LLC
This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process.
We thank the following individuals for their review of this report:
Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report nor did they see the final draft before its release. The review of this report was overseen by ELI Y. ADASHI, Brown University, and DAVID L. EATON, University of Washington. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies.
Pain is complex and often hard to treat. Acute and/or chronic pain affects millions of individuals each year and is associated with morbidity and increased health care use. Once pain became regarded as the “fifth vital sign,” clinicians, patients, hospitals, and health systems began to more vigorously treat all types of pain in order to meet a “no pain” patient satisfaction standard, often with increasing use of medications (e.g., opioid analgesics, nonsteroidal anti-inflammatories, adjuvants) and other modalities. In retrospect, return to functional activity is a better goal because zero pain is unrealistic in many medical situations.
Clinicians who treat pain recognize that elucidation of the specific mechanism underlying an individual’s pain is essential for rational pain therapy. As a result, a variety of oral medications have been developed over the years to target various pain mechanisms. However, not everyone can tolerate specific oral medications, given coexisting diseases and age-related changes, and there is a general desire to limit systemic effects of drugs whenever possible. In addition, currently available oral medications do not effectively treat all pain scenarios. In recent years this has led to emergence of a host of alternative approaches to treating pain (providing analgesia). One such approach is topical analgesia.
Topical application of analgesics has two possible roles. First, skin-based drug application provides an alternative approach to achieve systemic levels of medication, exemplified by the fentanyl patch; however, this first approach is not the focus of this report. A second role involves topical analgesics in the form of gels, patches, or creams applied to the skin to deliver pain medication to a localized area of the body. In theory, topically
applied pain medication provides analgesia near the skin (locally) while minimizing systemic absorption (uptake into the blood with circulation to the entire body). There are many potential advantages of using topical approaches to treating pain, although it would be an error to consider a drug safe simply because it is being delivered through the skin; this was elegantly demonstrated in a recent study showing sunscreen lotion chemicals applied to the skin are absorbed systemically at potentially high enough levels to be of concern,1 as well as in an older study2 that demonstrated how permeable skin can be to organic compounds. Nonetheless, skin does provide a formidable barrier to entry of active ingredients for pain therapy, so these drugs are often applied in much higher concentrations than would be used orally. While this is not a problem for healthy intact skin in most adults, it can create life-threatening situations in cases where pain therapies are topically applied to skin that is not normal (e.g., skin or diaper rash, thin skin at extremes of age, burns) or when applied to large areas relative to body size. Because skin is such a formidable barrier, topical pain creams often contain enhancers, or chemicals specifically designed to help move a drug from the surface through the skin (epidermis and dermis) to regional areas below with a goal of reaching a muscle group or joint for treating pain. Of note, when active drug ingredients move beyond the skin to subdermal regional locations, they are brought in contact with the systemic circulation and some amount of drug will be absorbed into the central circulation.
Because the U.S. Food and Drug Administration (FDA) has only approved a few topical analgesics, pharmacies have filled in the gap by providing compounded topical pain creams. Compounding is a traditional part of pharmacy practice where pharmacists prepare drugs in alternate dosages or vehicles to support the specific clinical need of individual patients; for example, a cancer patient who cannot swallow tablets or capsules might have a pharmacist produce or compound a liquid form of the drug that could be swallowed more easily. Because of the long historical roots centered on small independent compounding pharmacies, the U.S. Congress has permitted most compounded preparations to be made with minimal FDA oversight, as compared to FDA-approved drug products.3
1 Matta, M. K., R. Zusterzeel, N. R. Pilli, V. Patel, D. A. Volpe, J. Florian, L. Oh, E. Bashaw, I. Zineh, C. Sanabria, S. Kemp, A. Godfrey, S. Adah, S. Coelho, J. Want, L. A. Furlong, C. Ganley, T. Michele, and D. G. Srauss. 2019. Effect of sunscreen application under maximal use conditions on plasma concentration of sunscreen active ingredients: A randomized clinical trial. JAMA 321(21):2082–2091.
2 Feldmann, R. J., and H. I. Maibach. 1970. Absorption of some organic compounds through the skin in man. Journal of Investigative Dermatology 54(5):399–404.
3 This text has changed since the prepublication release of this report. Here and in other instances throughout the report, “commercially available product(s)” was replaced with “FDA-approved drug product(s).”
However, over the past two decades, there has been a substantial increase in both supply and demand for compounded medications. Consequently, an increasing fraction of drugs used in the United States are created without FDA oversight for quality, safety, efficacy, labeling, and/or postmarketing surveillance. Moreover, a growing number of reports of patients who have encountered harm using compounded preparations, including topical pain creams, highlights growing concerns.
Adding further complexity, given the global nature of drug and chemical production and distribution today, sources and quality of many products have become significant issues. As such, each individual compounding pharmacy is tasked with checking active ingredients used in compounded products for potency, quality, and lack of contaminants, a process that is impractical for many smaller pharmacies. Current compounded pain creams often contain more than one active ingredient, with many containing four to six drugs, creating the potential for combined toxicity and drug-to-drug interactions. It has been suggested by proponents of topical pain creams that combinations of active ingredients are present in order to target different underlying mechanisms of pain; however, it is interesting to note that some ingredients used today are primarily effective on central nervous system (CNS) pain pathways and not skin or localized regions near skin. Moreover, patients are often charged by the number of active ingredients included in their compounded preparations, which has led to insurance-related concerns regarding cost inflation and possible fraud.
In addition to considering active pharmaceutical ingredients to be compounded into a topical pain cream, the formulation of a topical product requires selection of an appropriate vehicle. There are a growing number of ointments and creams that can be used, with very little publicly available data to distinguish one from another. To facilitate ease of pharmacists compounding topical pain creams, several cream bases are now commercially available, some of which contain proprietary ingredients such as skin penetration enhancers and other chemicals designed to enhance ease of application and attractiveness of the final product to patients. The result is that pharmacists, prescribers, and patients are often not aware of all that is present in the cream and the potential side effects of its components. Because pain drug efficacy depends on relative penetration of active drugs through the skin, in addition to drug concentration, efficacy may vary depending on the cream base used. For best efficacy, each active ingredient concentration should be optimized and tested within a given cream base, an effort that would be costly and time consuming to do for every additional ingredient added to such a preparation.
Finally, given the interprofessional nature of clinical practice today, the pharmacist is often viewed by clinicians as the expert on the team in terms of drug therapy. So, when lists of prefilled prescription forms or
menus for compounded pain creams are faxed to clinicians for marketing purposes, there is a general expectation on the clinician’s part that testing has occurred and that each combination has been shown to be effective. Even when this is not the case, once the clinician signs the form requesting a set of active ingredients and base cream for a patient, his or her signature provides the legal prescription that guides creation of the compounded pain cream; hence, ultimately it is the clinician who bears responsibility for having chosen to include specific or numerous ingredients. In this setting, there have also been cases of fraudulent prescribing.
Given this complicated backdrop, and the increasing use of these products, FDA requested that the Health and Medicine Division of the National Academies of Sciences, Engineering, and Medicine (the National Academies) assess available scientific data regarding safety and effectiveness of ingredients used in compounded topical pain creams. Specifically, this committee was charged with identifying individual ingredients that scientific data support as being safe and effective to treat pain topically, describing concentrations and combinations of ingredients that may raise significant safety issues, and defining the level of expected benefit for various ingredients given their likelihood of being absorbed through the skin. Based on this information, the committee was ultimately tasked with making recommendations for how the available scientific data on safety and efficacy informs use of compounded topical pain creams to treat patients going forward. In making its deliberations, the committee specifically sought information and comments from the general public, as well as various stakeholders (including, but not limited to, patients, clinicians, compounding pharmacists, regulators, pain advocacy organizations, and government payers) as well as examining the scientific literature.
The committee is composed of an outstanding panel of national experts with broad related scientific expertise. In addition to the committee, such a detailed exploration of scientific literature and generation of the final consensus study report would not have been possible without the strong support of outstanding staff members from the National Academies, specifically Leigh Miles Jackson (study director), Claire Giammaria (associate program officer), Andrew March (research associate), Justin Jones (senior program assistant), and Anna Nicholson, our talented editor and writer. Thank you to everyone who participated in this timely and important report.
Debra A. Schwinn, Chair
Committee on the Assessment of the Available
Scientific Data Regarding the Safety and Effectiveness of Ingredients Used in Compounded Topical Pain Creams
The committee takes this opportunity to recognize the many individuals and organizations who so generously gave their time and expertise to inform its work.
To begin, the committee would like to thank the sponsor of this study, the U.S. Food and Drug Administration (FDA), for its guidance and support. The committee also greatly benefited from the discussions with individuals who attended and made their public presentations (see Appendix B). The committee is thankful for the many contributions of these individuals.
The committee could not have done its work without the support and guidance provided by the National Academies of Sciences, Engineering, and Medicine (the National Academies) project staff: Leigh Miles Jackson, study director; Claire Giammaria, associate program officer; Andrew March, research associate; and Justin Jones, senior program assistant. We appreciate Victor Stewart for his financial assistance on this project, and gratefully acknowledge Carolyn Shore and Andrew Pope of the Board on Health Sciences Policy for the guidance he provided throughout this important study.
Many other staff within the National Academies provided support to this project in various ways. The committee would like to thank the executive office staff of the Health and Medicine Division, as well as Dorothy Zolandz, Bettina Seliber, and Taryn Young for the management of the report review and publication process. We would like to thank Jorge Mendoza-Torres, Rebecca Morgan, and the National Academies Research Center staff for their assistance in the committee’s research efforts, as well as the National Academies Press staff.
This committee is grateful to the research and writing consultants that generously contributed to this body of work. We thank the committee’s consultant S. Narasimha Murthy (University of Mississippi) for his invested time and support of this study. We thank American Association of Poison Control Centers, American Chronic Pain Association, American Pharmacists Association, FDA, Institute for Neuropathic Pain, Massachusetts Boards of Pharmacy, National Association of Boards of Pharmacy, and Professional Compounding Centers of America for their generous submission of data and resources, and for the context and perspective they provided.
Finally, the committee is indebted to Anna Nicholson (Doxastic LLC) for her valuable commissioned work, and Mark Goodin for his editorial assistance in preparing this report.
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Boxes, Figures, and Tables
|ACCP||American College of Clinical Pharmacy|
|API||active pharmaceutical ingredient|
|CDC||Centers for Disease Control and Prevention|
|CIPN||chemotherapy-induced peripheral neuropathy|
|CNS||central nervous system|
|CRPS||complex regional pain syndrome|
|DESI||Drug Efficacy Study Implementation|
|FAERS||FDA’s Adverse Event Reporting System|
|FDA||U.S. Food and Drug Administration|
|FDCA||Federal Food, Drug, and Cosmetic Act|
|HHS||U.S. Department of Health and Human Services|
|MRI||magnetic resonance imaging|
|NABP||National Association of Boards of Pharmacy|
|NPDS||National Poison Data System|
|NSAID||nonsteroidal anti-inflammatory drug|
|PCCA||Professional Compounding Centers of America|
|PLC||piroxicam, lidocaine, and cyclobenzaprine hydrochloride|
|PLO||pluronic lecithin organogel|
|PWT||paw withdrawal threshold|
|RCT||randomized controlled trial|
|USP||United States Pharmacopeia|
|VAS||visual analog scale|
|w/w||weight per weight|