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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Compounded 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 PREPUBLICATION COPY—Uncorrected Proofs

THE NATIONAL ACADEMIES PRESS  500 Fifth Street, NW  Washington, DC 20001 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-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: https://doi.org/10.17226/25689 Library of Congress Control Number: 2020937383 Additional copies of this publication are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2020 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2020. ­ ompounded topical pain creams: Review of select ingredients for safety, effectiveness, and C use. Washington, DC: The National Academies Press. https://doi.org/10.17226/25689. PREPUBLICATION COPY—Uncorrected Proofs

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org. PREPUBLICATION COPY—Uncorrected Proofs

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo. PREPUBLICATION COPY—Uncorrected Proofs

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) STEVEN 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 SHAH, Expert Consultant, NDA Partners JOYCE S. TSUJI, Principle 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 Study Staff 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 v PREPUBLICATION COPY—Uncorrected Proofs

Consultants S. NARASIMHA MURTHY, Manager, Phoretek Pharma LLC, Professor, University of Mississippi ANNA NICHOLSON, Science Writer, Doxastic LLC vi PREPUBLICATION COPY—Uncorrected Proofs

Reviewers 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 manu- script remain confidential to protect the integrity of the deliberative process. We thank the following individuals for their review of this report: KLAUS EJNER ANDERSEN, University of Southern Denmark GEORGE J. ANNAS, Boston University JANE A. AXELRAD, Axelrad Solutions LLC JAYACHANDRA BABU RAMAPURAM, Auburn University DONNIE RAY CALHOUN, Calhoun Wellness Pharmacy ROGER CHOU, Oregon Health & Science University KAY DICKERSIN, Johns Hopkins University, Emeritus HOWARD MAIBACH, University of California, San Francisco ASHLEE MATTINGLY, University of Maryland School of Pharmacy ROBERT TWILLMAN, Saint Luke’s Health System CHRISTIN VEASLEY, Chronic Pain Research Alliance GARY A. WALCO, University of Washington School of Medicine DIANA J. WILKIE, University of Florida vii PREPUBLICATION COPY—Uncorrected Proofs

viii REVIEWERS Although the reviewers listed above provided many constructive com- ments 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. Respon- sibility for the final content rests entirely with the authoring committee and the National Academies. PREPUBLICATION COPY—Uncorrected Proofs

Preface 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 v ­ ital sign,” clinicians, patients, hospitals, and health systems began to more vigorously treat all types of pain in order to meet a “no pain” patient sat- isfaction standard, often with increasing use of medications (e.g., opioid analgesics, nonsteroidal anti-inflammatories, adjuvants) and other modali- ties. 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 ix PREPUBLICATION COPY—Uncorrected Proofs

x PREFACE 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 chemi- cals 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 sub- dermal 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 pro- viding 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 cen- tered on small independent compounding pharmacies, the U.S. Congress has permitted most compounded preparations to be made with minimal FDA oversight, as compared to commercially available FDA-approved products. However, over the past two decades, there has been a substantial increase in both supply and demand for compounded medications. Consequently, an 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. PREPUBLICATION COPY—Uncorrected Proofs

PREFACE xi 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 chemi- cal production and distribution today, sources and quality of many prod- ucts 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 contain- ing 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 com- pounded 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 avail- able data to distinguish one from another. To facilitate ease of pharmacists compounding topical pain creams, several cream bases are now commer- cially 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 PREPUBLICATION COPY—Uncorrected Proofs

xii PREFACE 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 effective- ness 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 vari- ous ingredients given their likelihood of being absorbed through the skin. Based on this information, the committee was ultimately tasked with mak- ing recommendations for how the available scientific data on safety and effi- cacy 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, compound- ing 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, spe- cifically 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 PREPUBLICATION COPY—Uncorrected Proofs

Acknowledgments The committee takes this opportunity to recognize the many indi­ viduals 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 ­ ackson, J study director; Claire Giammaria, associate program officer; ­ ndrew March, A r ­ esearch associate; and Justin Jones, senior program assistant. We appreciate Victor Stewart for his financial assistance on this project, and gratefully ac- knowledge 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 D ­ orothy 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. xiii PREPUBLICATION COPY—Uncorrected Proofs

xiv ACKNOWLEDGMENTS 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 (Phoretek Pharma LLC) for his invested time and support of this study. We thank American Association of Poison ­ C ­ ontrol 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. PREPUBLICATION COPY—Uncorrected Proofs

Contents ACRONYMS AND ABBREVIATIONS xxiii SUMMARY 1 1 INTRODUCTION 15 Charge to the Committee, 18 Report Scope, 18 Key Definitions, 22 Study Approach, 25 Organization of the Report, 26 References, 27 2 ROLE OF TOPICAL PAIN CREAMS IN PAIN MANAGEMENT 31 Complexity of Pain, 31 Pharmacological Approaches to Treating Pain, 34 Complexity of Pain Management, 36 References, 40 3 FUNDAMENTALS, USE, AND COMMON INGREDIENTS IN COMPOUNDED TOPICAL PAIN CREAMS 45 Fundamentals of Compounding, 45 Overview of the Use and Demand for Compounded Preparations, 47 The Use of Compounded Topical Pain Creams, 49 xv PREPUBLICATION COPY—Uncorrected Proofs

xvi CONTENTS Pain Conditions for Which Compounded Topical Pain Creams Are Commonly Used, 50 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams, 52 References, 58 4 GAPS IN REGULATION, OVERSIGHT, AND SURVEILLANCE 63 Current Regulation and Legislation, 63 Gaps in Federal and State Regulation and Oversight for Compounded Preparations, 75 References, 82 5 SCIENCE OF COMPOUNDED TOPICAL PAIN CREAMS 87 The Art and Science of Compounding, 89 Dermal Absorption, 90 Factors Affecting Dermal Absorption, 93 Critical Factors Affecting Drug Delivery: Active Ingredients and Excipients, 104 References, 115 6  REVIEW OF THE SAFETY AND EFFECTIVENESS OF A SELECT INGREDIENTS IN COMPOUNDED TOPICAL PAIN CREAMS 121 Research Approach, 123 Summary of Research Findings, 126 A Review of the Safety and Effectiveness of Select Active Pharmaceutical Ingredients in Compounded Topical Pain Creams, 135 Multiagent Compounded Topical Pain Creams, 188 References, 200 7 ADDITIONAL CONCERNS RELATED TO THE USE OF COMPOUNDED TOPICAL PAIN CREAMS 213 Inadequate Training and Expertise for Individuals Who Compound, 214 Inadequate Training and Guidance for Clinicians Who Prescribe Compounded Medications, 216 Safety Concerns for Patients, 221 Potential Financial Risks for Patients, 227 References, 229 PREPUBLICATION COPY—Uncorrected Proofs

CONTENTS xvii 8 RECOMMENDATIONS REGARDING THE TREATMENT OF PATIENTS WITH COMPOUNDED TOPICAL PAIN CREAMS 235 Recommendation Regarding Treatment, 236 Recommendations to Address Public Health Concerns, 237 APPENDIXES A Study Approach 241 B Literature Review 247 C Commissioned Paper: Topical Dosage Form Development and Evaluation 257 D Glossary 279 E 503A and 503B Distribution Supplement 285 F Adverse Event Table 287 G Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams 305 H Expanded Discussion on Special Populations to Consider in Pain Management 313 I Biographical Sketches for Committee Members, Fellow, Consultants, and Staff 319 PREPUBLICATION COPY—Uncorrected Proofs

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Boxes, Figures, and Tables BOXES 1-1 Statement of Task, 19 1-2 Classification of Committee-Selected Ingredients of Interest, 21 1-3 Key Definitions for the Report, 24 2-1 National and Global Impact of Pain, 33 2-2 Nonpharmacological Approaches to Treating Pain, 38 4-1 Allowable Compounding Under the FDCA, 70 4-2 United States Pharmacopeia General Chapters Essential to Compounding, 73 4-3 Adverse Event Reporting, 80 4-4 Overview of the U.S. Food and Drug Administration’s (FDA’s) Compounding Priorities, 82 5-1 Key Definitions, 88 5-2 Selected Considerations for Formulation Scientists, 89 5-3 Considerations for the Absorption of Compounded Formulations with Multiple APIs, 102 5-4 Criteria for Determining If a Drug Is Difficult to Compound, 114 6-1 Classification of APIs Chosen for Review of Safety and Effectiveness, 124 xix PREPUBLICATION COPY—Uncorrected Proofs

xx BOXES, FIGURES, AND TABLES 6-2 Summary of Research Findings on Clonidine in Compounded Topical Pain Creams, 136 6-3 Summary of Research Findings on Carbamazepine in Compounded Topical Pain Creams, 140 6-4 Summary of Research Findings on Gabapentin in Compounded Topical Pain Creams, 143 6-5 Summary of Research Findings on Topiramate in Compounded Topical Pain Creams, 147 6-6 Summary of Research Findings on Baclofen in Compounded Topical Pain Creams, 148 6-7 Summary of Research Findings on Cyclobenzaprine in Compounded Topical Pain Creams, 150 6-8 Summary of Research Findings on Orphenadrine in Compounded Topical Pain Creams, 153 6-9 Summary of Research Findings on Nifedipine in Compounded Topical Pain Creams, 155 6-10 Summary of Research Findings on Cannabidiol in Compounded Topical Pain Creams, 157 6-11 Summary of Research Findings on Ketamine in Compounded Topical Pain Creams, 161 6-12 Summary of Research Findings on Bupivacaine in Compounded Topical Pain Creams, 166 6-13 Summary of Research Findings on Lidocaine in Compounded Topical Pain Creams, 169 6-14 Summary of Research Findings on Memantine in Compounded Topical Pain Creams, 172 6-15 Summary of Research Findings on Meloxicam in Compounded Topical Pain Creams, 173 6-16 Summary of Research Findings on Naproxen in Compounded Topical Pain Creams, 175 6-17 Summary of Research Findings on the Use of Tramadol in Compounded Topical Pain Creams, 178 6-18 Summary of Research Findings on Dexamethasone in Compounded Topical Pain Creams, 179 6-19 Summary of Research Findings on Amitriptyline in Compounded Topical Pain Creams, 180 6-20 Summary of Research Findings on Doxepin in Compounded Topical Pain Creams, 184 6-21 Summary of Research Findings on Pentoxifylline in Compounded Topical Pain Creams, 187 PREPUBLICATION COPY—Uncorrected Proofs

BOXES, FIGURES, AND TABLES xxi FIGURES 2-1 Process of developing an integrative pain treatment plan, 37 4-1 Comparison of select steps within the statutory and regulatory processes for FDA-approved drug products and compounded drug preparations, 66 4-2 Geographic distribution of 503B outsourcing facilities throughout the United States, 71 4-3 Variability in state requirements for 503A compounding pharmacy compliance with USP Chapter <795> and <797> standards, 77 5-1 Anatomy of skin, 91 5-2 Routes of systemic absorption after topical application of a drug, 92 5-3 Structure of stratum corneum, 94 5-4 Transport of drugs through the layers of the skin, 95 7-1 Sample prescription form distributed by a local pharmacy to physician offices in February 2019, 219 7-2 Growth in Medicare Part D spending on compounded drugs by form (2006–2015), 228 TABLES 3-1 Sample of Reported Pain Conditions Treated with Compounded Topical Pain Creams, 51 3-2 FDA-Approved and Off-Label Indications Limited to Pain Indications for Which Topical Pain Creams Are Often Used, 54 5-1 Summary of the Physiochemical Properties Affecting Skin Absorption of Select Active Ingredients Commonly Used in Compounded Topical Pain Creams, 101 5-2 The Amount of Drug Absorbed Across the Human Cadaver Skin from Topical Pain Creams, 103 5-3 The Amount of Drug Absorbed Across the Human Cadaver Skin from Topical Pain Creams with Lipoderm and Lipoderm ActiveMax, 103 5-4 Compendial Excipients from USP-National Formulary 19, 106 5-5 Listed Excipients in Select Compounded Topical Pain Cream Formulations Described on Public Websites, 109 5-6 Listed Components in Lipoderm ActiveMax from Patent US2013/0085171, 110 PREPUBLICATION COPY—Uncorrected Proofs

xxii BOXES, FIGURES, AND TABLES 6-1 Available Clinical Evidence for the Topical Application of Single- Ingredient Compounded Pain Preparations, 128 7-1 Potential Drug–Drug Interactions for Select APIs (Oral Administration), 222 PREPUBLICATION COPY—Uncorrected Proofs

Acronyms and Abbreviations ACCP American College of Clinical Pharmacy API active pharmaceutical ingredient CBD cannabidiol 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 DMSO Dimethyl sulfoxide FAERS FDA’s Adverse Event Reporting System FDA U.S. Food and Drug Administration FDCA Federal Food, Drug, and Cosmetic Act GTN glyceryl trinitrate HCl hydrochloride HHS U.S. Department of Health and Human Services MRI magnetic resonance imaging NABP National Association of Boards of Pharmacy NF National Formulary xxiii PREPUBLICATION COPY—Uncorrected Proofs

xxiv ACRONYMS AND ABBREVIATIONS 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 THC Tetrahydrocannabinol USP United States Pharmacopeia w/w weight per weight PREPUBLICATION COPY—Uncorrected Proofs

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Pain is both a symptom and a disease. It manifests in multiple forms and its treatment is complex. Physical, social, economic, and emotional consequences of pain can impair an individual’s overall health, well-being, productivity, and relationships in myriad ways. The impact of pain at a population level is vast and, while estimates differ, the Centers for Disease Control and Prevention reported that 50 million U.S. adults are living in pain. In terms of pain’s global impact, estimates suggest the problem affects approximately 1 in 5 adults across the world, with nearly 1 in 10 adults newly diagnosed with chronic pain each year.

In recent years, the issues surrounding the complexity of pain management have contributed to increased demand for alternative strategies for treating pain. One such strategy is to expand use of topical pain medications—medications applied to intact skin. This nonoral route of administration for pain medication has the potential benefit, in theory, of local activity and fewer systemic side effects. Compounding is an age-old pharmaceutical practice of combining, mixing, or adjusting ingredients to create a tailored medication to meet the needs of a patient. The aim of compounding, historically, has been to provide patients with access to therapeutic alternatives that are safe and effective, especially for people with clinical needs that cannot otherwise be met by commercially available FDA-approved drugs.

Compounded Topical Pain Creams explores issues regarding the safety and effectiveness of the ingredients in these pain creams. This report analyzes the available scientific data relating to the ingredients used in compounded topical pain creams and offers recommendations regarding the treatment of patients.

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