Pain is a diverse, complex medical condition that is often difficult to measure and effectively treat (IASP, 2017; NASEM, 2017). Estimates suggest that millions of Americans suffer from clinical pain conditions (Croft et al., 2010; Dahlhamer et al., 2018; IOM, 2011; Johannes et al., 2010; Nahin, 2015; Portenoy et al., 2004). However, prevalence estimates for pain conditions can vary quite dramatically across pain type (e.g., nociceptive, neuropathic, nociplastic, mixed), pain duration (i.e., acute, chronic), and pain severity. Multiple coexisting conditions and comorbidities are associated with pain—particularly chronic pain—which make it difficult to accurately estimate the overall effect on an individual’s health, function, and quality of life (Dahan et al., 2014; Fine, 2011; IOM, 2011; NASEM, 2017). These complexities of pain contribute to the challenge of determining the true burden of pain in America (IOM, 2011).
To help address the pressing public health issue of pain in the midst of a national opioid epidemic, increasing numbers of health care professionals, patients, and patient advocates are exploring integrative strategies for treating pain, including both pharmaceutical and nonpharmaceutical approaches. Alternate pharmacological pain management options, such as the use of topical pain cream products, have shown some evidence of success (Kopsky and Hesselink, 2012). For many years, topical pain creams have served a role in pain management by providing a level of versatility not available via oral alternatives. Indeed, compared to many oral pain medications, topical dosage forms of medication applied to the skin are often lauded as having fewer side effects, lower likelihood for abuse, and greater convenience (Leppert et al., 2018; Pickering et al., 2017). Given
this background, and to provide alternatives to pain medications approved by the U.S. Food and Drug Administration (FDA), some health care clinicians and patients have begun to turn to compounded topical pain cream preparations.
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 (FDA, 2017). 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 FDA-approved drugs (e.g., liquid formulations when patients cannot swallow pills) (FDA, 2017; Glassgold, 2013; Gudeman et al., 2013; IACP, 2019; USP, 2017). In 2019, the American College of Clinical Pharmacy (AACP) released a report that questions the more current rationales for compounding and provides guidance to assist pharmacists and prescribing clinicians in evaluating the appropriateness of prescribing and dispensing compounded formulations. The authors of the AACP report identify key factors that should be considered in specific situations in which compounding may be needed. These factors include drug cost and availability, dosage and formulation, and allergies and intolerances to excipients (i.e., other active or nonactive ingredients in the medication’s formulation) (McBane et al., 2019).
A key lesson of the report is that any determination of whether the use of a compounded preparation is justified should be made on a patient-by-patient basis. This requires prescribing clinicians and pharmacists to weigh the potential benefits compounding may provide to an individual patient with the risks of using a formulation that does not have rigorous safety and effectiveness data (McBane et al., 2019). See Chapter 3 for an additional discussion on the fundamentals of compounding. Although there may be some advantages to using compounded topical pain creams in pain treatment, it is important to consider key differences that exist between the regulation of compounded preparations and FDA-approved medications. Under current U.S. drug regulatory law, compounded preparations—including topical pain creams that meet certain conditions—are exempt from federal requirements that FDA review and approve their safety, quality, and effectiveness before they are marketed and dispensed to patients.
Although many of the most common ingredients used in compounded pain creams have been FDA approved for pain indications, most have not been FDA approved for topical use. As a result, the drug profiles for many of the ingredients in compounded topical pain creams have not been reviewed or optimized for topical application. This increases the risk of applying too little medication—less than needed to effectively treat pain—or too much medication, which can result in overdose and consequent side effects. In addition, compounded creams may contain
other ingredients that have not been FDA approved to treat pain and, as such, their profiles of safety and effectiveness in compounded preparations are unknown. For example, those ingredients may interact with the active drug to lessen or enhance its action. Furthermore, many compounded pain cream preparations contain multiple active ingredients, many of which are compounded in novel, untested combinations not found in current commercial products.
Finally, based on current federal law, there is no specific requirements for 503A compounding pharmacies or 503B outsourcing facilities to include safety information or drug warnings on their labels or package inserts. As a result, labeling for compounded topical pain creams is often insufficient to educate patients and clinicians about their use and potential risks. Together, these issues are a cause for public health concern, especially given the more recent evolution toward precision medicine and personalized care and resultant resurgence of compounding in recent years (McPherson et al., 2019).1
Importantly, certain compounding pharmacies have taken advantage of regulatory loopholes in the current environment of limited federal and state regulations, giving rise to questionable practices and procedures for the development and marketing of compounded formulations. In a number of high-profile fraud cases, the U.S. Department of Justice has implicated pharmacies and medical professionals for pushing unnecessary compounded prescriptions on patients. These compounds often included ingredients that would provide maximal reimbursement to prescribing clinicians and pharmacies but provide questionable benefit to the patient (DOJ, 2017, 2018a,b,c). At the other extreme, many compounded pain creams are not reimbursed by insurers, burdening patients with the costs and creating potential disparities in access as a result.
In 2016, the Office of Inspector General for the U.S. Department of Health and Human Services released a report expressing concern over the rapidly rising cost of compounded preparations for Medicare (HHS, 2016). In this report, researchers found that between 2006 and 2015, Part D annual spending for compounded preparations climbed from $70.2 million to $508.7 million—an increase of 625 percent. And although there was growth in spending across all forms of compounding, the largest area of growth was for compounded topical preparations. This growth may have been driven by an increase in the average cost of prescriptions as well as an increase in the number of beneficiaries receiving the medications. For example, the average cost for compounded topical preparations rose from
1 Several private marketing reports predict the global market for compounded medications will continue to see a robust growth over the next few years (e.g., Ugalmugale and Mupid, 2018; Zion Market Research, 2018).
$40 in 2006 to $331 in 2015, an increase of 727 percent. From 2006 to 2015, the number of beneficiaries receiving compounded topical preparations grew 281 percent (from 73,368 to 279,873).2 This substantial increase in the development and dispensing of compounded preparations to patients is both striking and disconcerting, given the lack of regulatory oversight regarding these medications’ quality, safety, and effectiveness.
Although many compounded pharmacies are not required to report adverse events to FDA, a number of adverse events related to compounded preparations—including topical pain creams—have been reported over the past several years. These issues range from accidental exposures to local irritation of skin to unintended overdoses that sometimes resulted in coma and even death.3 These diverse and complex safety and effectiveness issues related to development, marketing, and use of compounded topical pain creams create a public health concern for a multitude of stakeholders including medical practitioners, patients, health advocacy organizations, and federal and state public health agencies.
To explore issues regarding the safety and effectiveness of the ingredients used in compounded topical pain creams, FDA requested that the National Academies of Sciences, Engineering, and Medicine appoint an ad hoc committee to conduct a study of the ingredients used in compounded topical pain creams. The resulting Committee on the Assessment of the Available Scientific Data Regarding the Safety and Effectiveness of Ingredients Used in Compounded Topical Pain Creams was charged with conducting a study adhering to the Statement of Task in Box 1-1.
Given the broad charge to evaluate the safety and effectiveness of ingredients used in compounded topical pain creams, the committee first identified strategies to define and limit the scope of its work. In the committee’s first open-session meeting, the study sponsor, FDA, introduced a list of 37 active pharmaceutical ingredients (APIs) that have been identified
2 As a comparison, a National Academies report (2018) determined that since the early 1980s prescription drug spending had increased at almost 4 percent annually, even after adjusting for inflation and population growth. In addition, Joyce et al. (2018) described that although generic drug prices declined in aggregate between 2007 and 2013, a small but growing fraction of generic drugs doubled in price over the course of 1 year.
in common formulations of compounded topical pain creams.4 Of these 37 APIs, FDA identified 10 to be of high-priority interest, which the committee elected to include for evaluation. Categories considered to be adequately represented from the priority list include the following:
- Muscle relaxant drugs with different mechanisms of action (baclofen, cyclobenzaprine, orphenadrine)
- Opioid agonists (tramadol)
- NMDA receptor antagonists (memantine)
- Alpha-2-adrenergic receptor agonists (clonidine)
- Antiepileptics (gabapentin, topiramate)
- Nonsteroidal anti-inflammatory drugs (NSAIDs) (meloxicam)
- Antidepressants (amitriptyline)
4 It is the committee’s understanding that the FDA-presented ingredients were identified from examples of commonly compounded topical pain medication formulas and that the list was generated through online research efforts, as well as through personal communications with other government agencies (e.g., Centers for Medicare & Medicaid Services, U.S. Department of Defense, and U.S. Department of Veterans Affairs).
Recognizing that this priority list was not a comprehensive list of ingredients used in compounded topical pain cream preparations, the committee elected to expand the scope of its review in an attempt to produce a more comprehensive report. Upon deliberation, the committee ultimately identified the following 10 additional ingredients to examine in its research efforts:
- Anesthetics (ketamine, bupivacaine, lidocaine)
- Antiepileptic (carbamazepine)
- NSAIDs (naproxen)
- Cannabinoid (cannabidiol)
- Steroid (dexamethasone)
- Calcium channel antagonist (nifedipine)
- Antidepressant (doxepin)
- Phosphodiesterase inhibitor (pentoxifylline)
Each of these additional drugs uses a mechanism relevant to the treatment of pain and is used currently in some compounded pain topical creams, but none of them are represented on the original FDA priority list. A complete list of the 20 ingredients the committee chose to investigate can be found in Box 1-2. Factors considered by the committee for choosing these ingredients included, but were not limited to
- mechanism of action or drug class,
- representation between and within relevant drug classes,
- widespread use or relevance in clinical pain management, and
- safety concerns or reported adverse events.
A local anesthetic was not included in the original FDA priority list because several of these drugs are already FDA-approved for topical use. However, the committee chose to evaluate bupivacaine, because of its known cardiotoxicity, and lidocaine, because it is commonly mixed with other priority ingredients. Uniquely, lidocaine can be considered a positive control for other topical ingredients because there is an FDA-approved lidocaine gel patch.
It is important to note that the omission of a category, or mechanism, does not imply safety or effectiveness, or potential usefulness of drugs in that category used in compounded topical pain creams. For example, certain categories may not have been considered if the mechanism was not related to FDA-approved treatments for pain indications (e.g., antihistamines, antibiotics).
Definition of Topical
The term topical generally encompasses all of the preparations and products that are intended for application on the skin, mucous membranes, or cavities. Topical products are typically developed as semisolid preparations or transdermal patches and are most commonly applied to elicit local effects in or on the skin (e.g., treatment of burns). Importantly, certain topical medications have the capability to also permeate (travel) through the skin to act regionally (e.g., for the treatment of muscle or join pain) or systemically (e.g., for the treatment of migraines) at sites a distance away from the topical application site (Leppert et al., 2018). Such distal responses may be intended or unintended actions of the topical product, but they are critically important features in the consideration of a medication’s safety profile. An illustrative example comes from the recent article by Matta et al. (2019), where systemic absorption levels of topical sunscreens’ active ingredients were found to exceed the threshold established by FDA for potentially waiving certain nonclinical toxicology studies for sunscreens.
For the purpose of this report, the term cream will be used to designate any semisolid preparations (e.g., cream, ointment, gel, lotion) intended for external application to the skin. Creams have relatively soft, spreadable consistency and are rubbed at the site of application. A transdermal patch is a more complex topical delivery system that is designed to deliver drugs intended for systemic absorption; however, for the purpose of this report, such systems are outside of the study’s scope.
Compounded Preparations Versus Commercial Products
To ensure consistency with the terminology and guidelines issued by the United States Pharmacopeia and other national compounding and pharmaceutical standard-setting organizations, the committee elected to refer to compounded medications as preparations, rather than products. This decision attempts to reinforce the distinction that compounded preparations are not required to complete the federal-level testing and standards for drug quality, safety, or effectiveness that are required of FDA-approved commercial products. This important distinction will continue to be noted throughout the report.
Focus on Intact Skin
Furthermore, in the committee’s review of the literature on the safety and effectiveness of ingredients in compounded topical pain creams, the
committee maintained an explicit focus on the use of topical creams on intact skin. The committee limited its attention to external skin, excluding mucosal membranes and cavities such as the mouth, eyes, vulva, vagina, anus, and nose. There remains a substantial literature base that reviews the safety, effectiveness, and use of topical pain creams on membrane or mucosal surfaces; however, this evidence was not explicitly reviewed or discussed in this report.
Focus on Human Populations
The committee did not examine the use, safety, or effectiveness of compounded topical pain creams that were explicitly formulated to address health indications relevant to the fields of veterinary science or animal care. Although the animal population is estimated to be one of the largest consumers of compounded medications (Persistence Market Research, 2019), this area of focus was determined to be outside of the scope of the report based on the Statement of Task.
A Focus on Nonsterile Preparations
Compounded products can be sterile or nonsterile. In sterile compounding, medications are prepared in a clean-room environment using aseptic techniques to ensure solutions are free of microorganisms. Sterile compounding is primarily used for injectable, parenteral (i.e., nonoral and nonrectal administration), and ophthalmic preparations. In nonsterile compounding, medications are prepared in a clean environment without sterile techniques required. This type of compounding is mainly used for oral and topical preparations, such as capsules, solutions, suspensions, ointments, creams, and suppositories. Because the focus of this report is on topical applications, not injectable dosage forms, the committee evaluated no sterile preparations. An overview of key definitions is provided in Box 1-3. See Appendix D for a full glossary of terms.
Use of the Terms Effectiveness and Efficacy
The current research study has a charge to evaluate the effectiveness, rather than the efficacy, of compounded topical pain creams. While similar, the terms are not synonymous. Efficacy refers to the therapeutic effect of a treatment under controlled conditions, while effectiveness refers to the therapeutic effect in “real-world” situations in which certain contextual measures (e.g., placebo effect) may not be strictly controlled and broad outcome measures (e.g., health-related quality of life) are considered. Effectiveness data alone may not be sufficient to inform conclusions regarding a treatment’s therapeutic effect (Ernst and Pittler, 2006; Kim, 2013).
For the purposes of this report, the committee evaluated all relevant data produced by randomized controlled trials (RCTs), nonrandomized clinical studies, case reports, and where applicable, preclinical studies to help address the study’s charge. As a result, many of the research findings discussed throughout the report assess outcomes related to the potential effectiveness or efficacy of compounded topical pain creams. Given its broader application to the body of research reviewed, the term effectiveness is used more generally across the report.
The National Academies appointed an 11-member committee of experts to address objectives in the Statement of Task. The committee included experts in a variety of disciplines and fields, including drug research and development, pharmacology, toxicology, pain management and care, drug evaluation, epidemiology, and pharmaceutical compounding and manufacturing. See Appendix I for biographical sketches of the committee members.
The committee met in person for four closed-session meetings and held two half-day virtual meetings to discuss its research, review, and report drafting efforts. In addition to closed-session meetings, three public information-gathering sessions were held to gather additional testimony and data to inform the committee’s charge. See Appendix A for public meeting agendas. Participants in these supplemental information-gathering processes included a range of subject matter experts, including compounding pharmacists, clinicians, researchers, policy experts, and officials representing various stakeholder organizations. Members of the general public were invited to provide comments at all public meetings. The committee used the gathered evidence to formulate findings, conclusions, and actionable recommendations.
In addition to the evidence collected at its public meetings, the committee also conducted reviews of the peer-reviewed literature and gray literature (e.g., research reports, online publications, books for a lay audience) on topic areas relevant to the study’s Statement of Task. In coordination with one of the National Academies’ senior research librarians, the committee constructed a literature search strategy that would identify a broad body of research evidence that could inform its work. Based on the committee’s research questions, the scope of the literature was limited to the topical application of any of the 20 ingredients to intact skin.
For each of the selected ingredients, the committee evaluated all systematic reviews and all studies with control groups for evidence regarding the safety and effectiveness of the drug applied topically to treat pain. For ingredients lacking this level of evidence, case series, case reports, or preclinical studies were discussed when relevant.5 Additionally, because study design is not the only measure of quality evidence, the committee also considered methodological rigor in its review of the evidence. Using the 2019 Cochrane risk of bias assessment tool (Sterne et al., 2019), the committee evaluated the risk of bias in all RCTs identified as relevant to the committee’s charge. See Chapter 6 and Appendix B for additional details on the committee’s literature review.
5 Of note, the committee identified several other published studies with tangential relevance to the committee’s charge (e.g., use of compounded topical pain creams to treat itch); however, only the studies with the most direct relevance were reviewed in this report.
Over the course of the study, the committee’s research efforts uncovered gaps in knowledge about the dermal drug delivery process and the permeability of select ingredients used in topical pain treatment. As a result, the committee commissioned Dr. S. Narasimha Murthy, Professor of Pharmaceutics and Drug Delivery at the University of Mississippi, to develop a review paper on these topics (see Appendix C for the commissioned paper).
Finally, in recognition of the limited peer-reviewed evidence to describe the use, safety, and effectiveness of compounded topical pain creams from a consumer’s perspective, the committee made concerted efforts to collect relevant anecdotal, survey, and (when possible) quantitative data from national stakeholders to supplement its research efforts. The collected data included, but were not limited to:
- Survey data from the American Chronic Pain Association on consumer use of topical pain creams;
- Oral testimony on the clinical need for topical pain creams from a palliative care clinician;
- Submitted literature reviews from the Professional Compounding Centers of America (PCCA) on the safety, effectiveness, and use of compound topical pain creams;
- Additional survey data from PCCA on the quality, safety, and median costs of compounded topical pain creams;
- Data from FDA on reported adverse events related to the use of compounded topical pain creams;
- Data from the National Association of Boards of Pharmacy related to the use of APIs in compounded topical pain creams; and
- Data from the American Association of Poison Control Centers on adverse event cases related to the use of the 20 ingredients in topical pain creams examined by the committee.
The report is organized into eight chapters. Chapter 2 provides a brief overview of the role of compounded topical pain creams in pain management, complexity of pain, and pain treatments. In that chapter, the committee describes the complexity of pain and pain management, reviews standards of care and pharmacological approaches related to pain treatment, and highlights the advantages of using topical pain creams in pain management plans. Chapter 3 explores the fundamentals, use, and common ingredients in compounded topical pain creams. It also provides an overview of the use and demand for compounded preparations as well as pain conditions associated with their use. It concludes with a description of the active pharmaceutical ingredients commonly used in those preparations.
Chapter 4 describes the current federal and state-level regulation and oversight of compounded preparations.
Chapter 5 examines the science behind compounded topical pain creams. This includes reviewing pharmacokinetic properties of the committee’s ingredients of interest and examining the important role of excipients in compounded formulations. Chapter 6 features a review of the key findings from the committee’s literature review efforts for the 20 ingredients of interest commonly used in compounded topical pain creams. The ingredients reviewed are organized by their primary drug class. Chapter 7 describes a selection of concerns associated with the use of compounded topical pain creams that are faced by individuals who compound, clinicians who prescribe compounded preparations, and patients. Chapter 8 is the final chapter of this report and serves as the report’s overall summary chapter. This chapter synthesizes the report’s research conclusions and issues important recommendations to a diverse set of stakeholders, including medical practitioners, patients, health advocacy organizations, and federal and state public health agencies.
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