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.
COMPLEXITY OF PAIN MANAGEMENT
While pain is encountered in all medical specialties, chronic pain management has become a distinct medical subspecialty. With the increasing recognition that pain care is dynamic and complex, interdisciplinary approaches have been encouraged to improve care. In spite of this, the percentage of clinician training time devoted to pain diagnosis and treatment is relatively small; furthermore, that training generally does not encompass today’s full range of treatment modalities for pain. In addition, the large number of patients with chronic pain vastly exceeds the number that can be seen by pain specialists, leaving the difficult task of designing and maintaining pain management plans to other types of clinicians.
Pain management goals set forth by accrediting bodies call for achieving significant reduction in pain severity and, when feasible, elimination of pain. However, the complete elimination of pain is an unrealistic goal
in most situations. A more feasible aim is achieving a level of pain that is tolerable, that leads to improved function, enables return to productive living, and does not otherwise interfere with quality of life. Despite these more pragmatic treatment goals, attempts to eliminate pain have driven increasingly vigorous clinical treatment of all types of pain—through medications or other modalities—across U.S. health systems.
Effective pain therapy hinges on targeting specific mechanisms underlying an individual’s pain. Today, many commercially manufactured pharmacological therapies (analgesics) approved by the U.S. Food and Drug Administration (FDA) are available to treat acute and chronic pain conditions via targeting various systemic pain mechanisms. Commonly prescribed pain medications include opioid agonists, nonsteroidal anti-inflammatory drugs (NSAIDs), and other types of analgesics, such as muscle relaxants, antidepressants, and glucocorticoids. To personalize pain treatment, guidelines suggest that clinicians identify the likely mechanism of an individual’s pain while also remaining cognizant of variability in response to pain treatment across individuals and groups. The complexity of pain management is further intensified in special populations for whom FDA-approved oral pain medications may be unsuitable, intolerable, or inadequate for a variety of reasons.1 These groups include children, the elderly, women who are pregnant, those requiring palliative care, and individuals with coexisting conditions (e.g., spinal cord injury, kidney disease, renal failure). Furthermore, currently available oral medications cannot be used to treat all pain scenarios.
In recent years, these issues 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 report focuses on these topical medications, which are designed to deliver active pharmaceutical ingredients (APIs) to a localized area of the body. This nonoral route of administration for pain medication has the potential benefit, in theory, of local activity and fewer systemic side effects. Ideally, topical analgesics applied to the skin in the form of creams, gels, ointments, or lotions can provide local analgesia near the skin while also minimizing systemic absorption—meaning, uptake of APIs into the blood, which would then circulate to the entire body to have systemic effects. Transdermal medication delivery systems have been developed to move compounds through the skin to achieve systemic levels by an alternative route, such as a fentanyl
1 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).”
patch. However, this report does not focus on the design, effectiveness, or safety of systems designed intentionally to achieve systemic levels of analgesic medications. Instead it focuses on topical pain creams that are thought to act more locally as adjuvant pain medicine therapy.
FDA has approved several topical pain products with formulations that include lidocaine, hydrocortisone, dibucaine, capsaicin, and NSAIDs as APIs. All FDA-approved topical pain products have gone through rigorous safety and efficacy evaluations as part of their approval process. Other APIs determined to be effective in the treatment of pain can be found in FDA-approved oral or injectable formulations for systemic use, but they are not currently available as FDA-approved topical products. The limited number of FDA-approved topical analgesics, coupled with the growing interest in the field of personalized medicine, has led to increasing numbers of customized compounded formulations being prescribed by health care providers in an attempt to individualize and optimize pain management. Certain compounded topical pain creams include APIs that are approved by FDA for oral or systemic use to treat pain, others contain APIs that are used off-label to treat pain, and still others include APIs that have no demonstrated potential to treat pain at all.
Compounded Topical Pain Creams in Pain Management
Overview of Compounding
Compounding has a long history in the field of pharmacy, serving as the primary form of the practice until the advent of the commercial pharmaceutical industry in the mid-twentieth century. Today, compounding is primarily the process of altering or combining ingredients to create medications that are tailored to meet the specific clinical needs of an individual patient. These compounded drugs represent therapeutic alternatives for people with clinical needs that are not met by FDA-approved drug products. Custom formulations can be compounded to create alternate dosage forms, or strengths, or to omit inactive components included in an FDA-approved formulation to which a patient may have an allergy or otherwise cannot tolerate (e.g., lactose, dyes).
Traditional compounding, which primarily involves altering an FDA-approved drug into different dosage forms or strengths in response to a prescription written for an individual patient, has historically occurred in individual small-scale pharmacies, hospitals, or even physicians’ offices. For example, a liquid form of a drug could be compounded for a person with cancer who cannot swallow tablets or capsules; a concentrated drug could be diluted for safer clinical use by a hospital pharmacy; or a specialized preparation or concentration of a drug could be compounded for a person
in hospice. However, recent years have seen an emergence of large-scale compounding pharmacies that produce and sell greater volumes of compounded preparations in preset formulations, sometimes across state lines. This change in the compounding landscape prompted Congress to create a separate category of compounding facility—called an “outsourcing facility”—that is subject to an increased level of federal oversight, although not as strict as FDA oversight for commercial products. (See below for an additional discussion of compounding pharmacies and outsourcing facilities.)
Benefits and Risks of Compounded Topical Pain Creams
Topical pain creams have a range of potential advantages, the most compelling being their nonsystemic route for administering pain medication. Furthermore, when not systemically absorbed, topical application of pain medications is thought to potentially avoid certain adverse side effects linked to oral analgesics. A few specific topical agents have presented sufficient evidence to FDA to be formally approved; however, no comprehensive reviews or evidence-based clinical guidelines have empirically demonstrated advantages of compounded topical pain creams in specific patient populations.
Among patients and clinicians, common misperceptions are that medications applied topically are safer or that local application may be more effective compared to oral or other systemic routes of delivery. Despite the many theoretical advantages of using topical approaches to treating pain, a drug is not inherently (or necessarily) safer or more effective simply because it is delivered through the skin. In principle, compounded pain creams can be formulated with enhancers, which are chemicals distinct from APIs, in order to (1) deliver APIs into cutaneous tissues (e.g., skin and dermal tissues) to produce local effects, or (2) drive APIs into subcutaneous tissue to produce regional effects, such as in muscles or joints. However, certain delivery enhancers combined with specific APIs can lead to systemic absorption and produce unintended systemic effects (e.g., in the central nervous system) and side effects that occur with other systemic delivery systems.
There is little to no publicly available information on the various formulations and compounding protocols used by different compounding pharmacists or compounding physicians across the country. Compounded topical pain creams frequently combine more than one API—and sometimes up to four to six APIs—which creates potential for combined toxicity and drug–drug interactions. In addition, owing to inadequate labeling requirements for compounded preparations, health care providers and patients may not be aware of all potential interactions or side effects of the components in a given topical pain cream. Furthermore, patients may not know that compounded preparations are not subject to the same level of
extensive testing and stringent regulatory oversight as FDA-approved products. Therefore, this is potential cause for concern regarding the safety and effectiveness of the preparations prescribed and dispensed for patient use.
A specific concern is that the safety of topical drug formulations depends on the rate and extent of the drug’s absorption into the skin and beyond. This is determined by the drug’s physiochemical properties, dose, and mechanism(s) of action, as well as activity of the vehicle used to support drug delivery. Formulating a compounded topical pain cream requires selecting an appropriate vehicle for the API from the wide range of available excipients.2 Although excipients are frequently called “inactive” ingredients, they ultimately affect the quality, safety, and potential effectiveness of a compounded preparation by affecting solubility, stability, release of the active ingredient, and skin penetration. Excipients also have the potential to interact with other ingredients or with APIs in ways that are difficult to predict.
Several cream bases are now commercially available, some of which contain proprietary ingredients including skin penetration enhancers and other chemicals. In this context, even the compounding pharmacist may not know all of the ingredients present in the proprietary compound and how they may affect API effectiveness. Furthermore, there is currently little publicly available evidence regarding the quality and safety of the range of excipients used in compounded preparations, particularly with respect to how they influence absorption of a specific API, meaning how they facilitate the travel of the API from topical (local) to transdermal (regional and systemic) action. Thus, lack of transparency about ingredients in the cream base is an important safety issue.
Reports of patients who have experienced adverse events related to topical pain cream drug toxicity from systemic absorption underscore the importance of better understanding the safety of these preparations. The skin is a formidable barrier to active ingredients in topical pain therapies and, consequently, compounded pain creams may contain much higher concentrations of APIs than oral formulations. This is not generally a concern when topical pain therapies are used on a restricted local area by adults with healthy intact skin, and the excipient included in the formulation does not result in toxic levels of systemic absorption. However, it is a major concern that can create life-threatening situations in cases where those therapies are topically applied to large areas relative to body size, to skin that is unhealthy or injured (e.g., diaper rash, other skin rashes, burns), or to skin that is thin or otherwise delicate, as in young children or older adults.
2 Excipients are vehicles, bases, or solvents that influence the quality attributes, physicochemical characteristics, and/or sensory characteristics of a formulation.
SAFETY AND EFFICACY OF INGREDIENTS IN COMPOUNDED TOPICAL PAIN CREAMS
Given substantial recent growth in the use of compounded topical pain creams, FDA asked the National Academies of Sciences, Engineering, and Medicine to convene a committee to review the safety and effectiveness of ingredients commonly used in these preparations. FDA identified 10 high-priority APIs of interest, and the committee agreed these were appropriate to include for evaluation. Categories considered to be adequately represented from the priority list include 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); NSAIDs (meloxicam); and antidepressants (amitriptyline).
To support comprehensiveness across potential pain mechanisms, the committee expanded the scope of its study by including an additional 10 ingredients that are commonly used in compounded topical pain creams: anesthetics (ketamine, bupivacaine, lidocaine), antiepileptic (carbamezepine), NSAID (naproxen), cannabinoid (cannabidiol), steroid (dexamethasone), calcium channel antagonist (nifedipine), antidepressant (doxepin), and phosphodiesterase inhibitor (pentoxifylline).
These APIs were selected based on (1) mechanism of action or drug class, (2) representation between and within relevant drug classes, (3) widespread use or relevance in clinical pain management, and (4) safety concerns or reported adverse events. The final list of reviewed APIs is not comprehensive for all APIs used in compounded topical pain creams. Therefore, it is important to note that omission of a category or mechanism does not imply safety or efficacy of drugs in that category when used in compounded topical pain creams. For example, certain categories may have been excluded from consideration if the mechanism was not related to FDA-approved treatments for pain indications, such as antihistamines and antibiotics.
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 topical application of any of the 20 ingredients to treat pain when applied to intact skin.
After articles relevant to the committee’s task were identified, systematic reviews and all studies with a comparator group were reviewed for evidence regarding safety and effectiveness of the drug applied topically to treat pain. For ingredients lacking in this level of evidence, case reports, case series, or preclinical studies are discussed where relevant. Additionally,
because study design is not the only measure of quality evidence, the committee’s review also considered evidence of overall methodological rigor detailed in the publications. Using the 2019 Cochrane Risk of Bias Assessment Tool, the committee assessed the risk of bias for all randomized controlled trials identified relevant to the committee’s charge.
From its review of the literature, the committee made several determinations related to the available evidence on the effectiveness and safety risks of the 20 studied ingredients, including (1) out of the 20 APIs reviewed, 3 individual APIs (doxepin, lidocaine, and naproxen) and 1 two-drug combination (pentoxifylline/clonidine) demonstrate potential clinical effectiveness in compounded topical pain creams, and (2) a substantial amount of high-quality research is still needed to identify effectiveness as well as relative risk for adverse effects in response to local (skin-related), regional (muscle, joint, or deep-tissue), or systemic absorption of compounded topical pain creams.
ADDITIONAL AREAS OF CONCERN
Over the course of its research, the committee identified areas of concern and potential opportunities to help mitigate unintended harms related to the use of compounded topical pain creams. These areas include (1) inadequate federal and state-level regulation and oversight, (2) data collection and surveillance, and (3) training and education for health care providers and individuals who compound.
Inadequate Regulation and Oversight
Owing in part to the historical nature of small-scale compounding and to the patient-specific, ad hoc processes it involves, compounding has not traditionally been subject to rigorous oversight at the federal or state level. Recent decades have seen an emergence of a type of compounding that is not patient specific, as well as greater volumes of compounded drugs sold across state lines, thereby widening the potential patient population receiving compounded topical pain creams.3
Of note, within the current regulatory landscape, FDA does not routinely inspect 503A compounding pharmacies nor does FDA assess the quality, safety, or efficacy of the drugs they compound. In addition,
3 U.S. federal law has established two categories of compounding, referred to as “503A pharmacy compounding” and “503B outsourcing facilities.” 503A compounding pharmacies are allowed to produce compounded preparations upon receipt of a valid patient-specific prescription, or in limited quantities in anticipation of future prescriptions. 503B outsourcing facilities are permitted to compound without patient-specific prescriptions and ship prescriptions to clinicians and patients across the United States.
state-level oversight of compounding is limited and widely variable. After the tragic death of 64 chronic pain patients who received compounded injectable steroids contaminated with fungus in 2012, Congress added provisions for FDA oversight of compounding without a patient-specific prescription (503B outsourcing facilities). However, because 503B outsourcing facilities must volunteer to be overseen by FDA, and must adhere to stricter requirements than 503A compounding pharmacies, whether this option to self-identify is commonly used remains unknown. As a potential consequence, an increasing fraction of drugs used in the United States may be created without FDA oversight for quality.
In addition, compounded drugs are not dispensed with standardized product inserts that describe instructions for use, known side effects, or safety warnings related to use, even if such warnings are required for similar FDA-approved products. In certain cases, compounding facilities may market their compounded drugs—implicitly or explicitly—as safe and effective, incorrectly implying that the drugs meet FDA-approval standards. Many of the adverse events related to compounded topical pain creams reported to FDA can be attributed to patients misusing the cream through overapplication or application on nonintact skin. This points to the need for more specific patient education and labeling of compounded pain creams.
Compounding has become an increasingly lucrative industry over the past two decades, but it is difficult to find verifiable estimates of the number of drugs compounded, types of compounded drugs, number of pharmacists who compound, or true size of the market. Coupled with limited regulatory oversight, this lack of data poses challenges for accurate risk–benefit assessments and for changes to public health policy related to compounded drugs. Additionally, certain stakeholders have taken advantage of the lack of regulations around marketing of compounded formulations. In a number of high-profile fraud cases, the U.S. Department of Justice implicated pharmacies and medical professionals for prescribing unnecessary compounded medications, many of which included ingredients that would provide maximal reimbursement to prescribers and pharmacies. As a result of fraud and kickback controversies, many insurance companies have become reluctant to cover compounded topical pain creams in recent years, placing patients potentially at financial risk as well. Other risks may be faced by patients who are prescribed and dispensed compounded preparations without evidence of their safety or efficacy.
Data Collection and Surveillance
Barriers to surveillance and data collection around the safety and use of compounded medications include the following:
- Fragmented and inconsistent federal and state regulation;
- Lack of centralized data collection;
- Unwillingness on the part of compounding pharmacies and outsourcing facilities to share information on unique formulations or quantity of compounded preparations sold;
- Lack of insurance coverage that would typically provide important data sources; and
- Unstandardized practices and procedures between and within pharmacies.
Potential data on use that could be collected in a standardized format include number, weight, or volume of units prepared; commonly compounded formulations of topical pain cream; number of prescriptions compounded; cost or value of each unit; and number of patients who receive prescriptions. Because reporting of adverse events for compounded preparations dispensed by compounding pharmacies is not legally mandated for 503A pharmacies, there are no standardized surveillance procedures or established protocols for ensuring the appropriate reporting of adverse events related to patient use.
Education, Training, and Procedural Protocols
Pharmacists and other health care providers who perform compounding require theoretical knowledge and practical, hands-on training to ensure the quality, safety, effectiveness, and batch-to-batch reproducibility of compounded formulations. They also require knowledge of the components within the cream base used, because this can be a particularly important driver of drug absorption and drug delivery. A single compounded preparation may require selection of a large number of components, including APIs and excipients. However, these decisions appear to be made without sound scientific evidence for either (1) safety and efficacy of these agents applied topically, or (2) use of the agents in combination with each other and with “inactive” pharmaceutical ingredients, such as excipients or fillers. All of the components in a preparation carry potential risks individually and in each permutation of interaction among them, so it is critical to consider the potential risks associated with polypharmacy and drug–drug interactions. Poor compounding practices, such as inadequate quality control testing, incomplete adherence to standards in United States Pharmacopeia (USP) <795> or <797>, or lack of standardized formulations, can also compromise a drug’s potency and purity.4
4 USP <795> Pharmaceutical Compounding–Nonsterile Preparation contains standards for compounding nonsterile drugs. USP <797> Pharmaceutical Compounding–Sterile Preparations describes requirements for sterile compounding.
As the focus of the practice of pharmacy has shifted over time from compounding to dispensing commercially made FDA-approved medications, education about compounding practices in pharmacy schools has declined. Today, compounding instruction in pharmacy schools is highly variable and often minimal, particularly with respect to training or guidance about which formulations may be most effective to treat specific types of conditions and which populations of patients may benefit most from use of particular formulations. Topical pain creams are a public health risk if they are compounded by personnel lacking requisite knowledge and training to assess potency, purity, quality, and bioavailability.
The process of compounding varies by pharmacist and pharmacy, making compounded formulations more susceptible to modifications in process variables than manufactured drugs. For multi-ingredient topical pain formulations, a sound evidence base is needed to assess
- the degree to which each component contributes (if at all) to effectiveness of the compounded product,
- appropriate dosage and dosing interval for each component, and
- potential interactions among each of the components.
The safety and effectiveness of individual ingredients, ingredient interactions, and absorption by the body should be regulated by setting standardized thresholds or guidelines, while retaining a pharmacist’s ability to customize compounds for patients with specific clinical needs.
Furthermore, there is a lack of clinical guidelines and best practices for clinicians who prescribe compounding preparations or compound themselves. Ultimately, it is the prescribing clinician who bears responsibility for specific types and quantities of ingredients used in a compounded prescription. Providers who prescribe a compounded preparation that causes adverse effects can be exposed to liability, especially if an appropriate FDA-approved alternative is available. State boards of medicine regulate the practice of medicine and all compounding performed by physicians; however, recent national surveys from the U.S. Government Accountability Office and The Pew Charitable Trusts suggest that many state boards of medicine are not actively overseeing the compounding practices of prescribing clinicians. These findings raise significant concerns about best practices when prescribing compounded topical pain creams.
Compounded topical pain creams may have a potential therapeutic role in integrative pain management plans for patients with specific clinical needs. However, three critical areas of concern related to safety and
effectiveness of such compounded topical pain creams need to be addressed by stakeholders:
- Limited evidence to describe safety and effectiveness of APIs commonly used in these preparations;
- Inadequate training, procedural protocols, and evidence-based guidance for pharmacists who formulate and dispense these preparations as well as for prescribing clinicians; and
- Significant gaps in federal and state-level regulation, oversight, and surveillance of medications not approved by FDA.
In its review of available scientific evidence, the committee determined that the vast majority of APIs commonly used in compounded topical pain creams have little to no scientific evidence to support their claims of effectiveness in treatment of various pain conditions. Furthermore, potential for systemic absorption and toxicity of many of the APIs reviewed remains largely unknown. These findings give rise to substantial concerns related to the excessive application of compounded topical preparations, as well as the use of preparations that contain excipients with enhancers that increase absorption of an ingredient beyond the intended site of action.
The committee also determined that selection of active and inactive ingredients used in many compounded topical preparations does not seem to incorporate the full spectrum of complexities related to skin absorption and dose. In many cases, there is no clear clinical rationale for specific combinations of APIs and dosages used. As a result, the committee concluded that lack of publicly disclosed rationales for formulation development, inadequate labeling requirements, and (for 503A compounding pharmacies in particular) the nonstandardized surveillance procedures and protocols for ensuring appropriate reporting of adverse events underpin a substantial public health concern related to the use of these preparations.
From its research findings, the committee drew three overarching conclusions:
There is limited evidence to support the use of compounded topical pain creams to treat pain conditions in the general adult population. The few APIs that show potential effectiveness in compounded topical pain creams (doxepin [tricyclic antidepressant], lidocaine [local anesthetic], and naproxen [nonsteroidal]) are either already available in FDA-approved topical products used to treat pain or in the case of naproxen, other NSAIDs (e.g., diclofenac) are in such FDA-approved products.5
5 This text has changed since the prepublication release of this report to clarify the available FDA-approved topical NSAID products.
In context of the recent rise in supply and demand of compounded preparations, lack of evidence regarding systemic absorption of ingredients used in compounded topical pain creams gives rise to a substantial public health concern. It is important to consider the potential effects of all organic compounds (including APIs and excipients) that may permeate the skin.
There is an opportunity for the U.S. Department of Health and Human Services to provide additional oversight to ensure the safety of compounded pain creams, with prioritized focus on those containing APIs that, when applied topically, cross the skin barrier to enter the bloodstream and act systemically within the body.
RECOMMENDATION REGARDING TREATMENT
Recommendation 1: Caution should be used when prescribing or dispensing compounded topical pain cream preparations.
Prescribing clinicians, compounding pharmacists, and nonpharmacists who compound should exercise caution when considering inclusion of compounded topical pain creams in pain management plans, given the lack of scientific evidence to support their safety or effectiveness beyond a few limited ingredients.
RECOMMENDATIONS TO ADDRESS PUBLIC HEALTH CONCERNS
Given the public health concerns related to the use of compounded topical pain creams, the committee recommends additional research, education, and oversight to support safety, effectiveness, and use of these preparations.
Recommendation 2: Strengthen and expand the evidence base on the safety and effectiveness of active pharmaceutical ingredients and excipients commonly used in compounded topical pain creams.
Pain researchers, public and private funding agencies, and relevant patient advocacy organizations should prioritize research efforts to examine the safety and effectiveness of compounded topical pain creams, including but not limited to:
- Randomized, double-blind, placebo-controlled clinical trials with sufficient numbers of patients to study, both in isolation and in combinations, APIs and inactive ingredients commonly used in compounded topical pain cream formulations
- Clinical research on APIs with demonstrated effectiveness to treat pain in preclinical animal models, which may indicate a potential therapeutic effect in humans (e.g., cannabidiol)
- Obtaining high-quality evidence to inform the safety profile for all APIs that act systemically
- Research on potential new topical or transdermal therapeutic agents to treat pain
Funding agencies that could drive these efforts include the Agency for Healthcare Research and Quality, National Center for Complementary and Integrative Health, other relevant institutes or centers of the National Institutes of Health, and Patient-Centered Outcomes Research Institute.
Patient advocacy organizations that could drive these efforts include the American Academy of Hospice and Palliative Medicine, American Academy of Pain Medicine, American Cancer Society, American Chronic Pain Association, American Society for Pain Management Nursing, Oncology Nursing Society, and U.S. Pain Foundation.
Recommendation 3: Require continued training for clinicians who prescribe compounded pain medication, particularly pain management specialists. Revise current educational requirements for compounding pharmacists and nonpharmacists who compound.
Interprofessional organizations representing pharmacy, nursing, medical sectors, and other professions with prescriber authority to treat pain conditions should advocate for state-level certification of individuals who seek to begin or continue to prescribe compounded topical pain creams. Formal clinical education should be offered in parallel to continuing medical education courses for clinicians who prescribe topical pain creams.
Interprofessional organizations that could drive these efforts include the American Academy of Hospice and Palliative Medicine, American Academy of Physician Assistants, American Association of Nurse Practitioners, American Cancer Society, American Medical Association, American Society of Anesthesiologists, and American Society of Interventional Pain Physicians.
State boards of pharmacy, local and regional schools of pharmacy, and nonprofit professional societies and organizations within the medical and pharmaceutical sectors should support and incentivize more in-depth training on compounding delivered by schools of medicine and pharmacy, as well as relevant nonprofit professional societies and organizations. These courses should:
- Review the compounding process, including the complexities of formulation science, which aim to ensure that all formulations are optimized when multiple APIs are combined.
- Examine current peer-reviewed, evidence-based conclusions on the safety and effectiveness of commonly used APIs and excipients in topical applications.
- Review the potential risks and reported adverse effects associated with the use of compounded topical pain creams.
Additional continuing medical education courses hosted by for-profit organizations should not substitute for this more in-depth training, owing to potential conflicts of interest.
Recommendation 4: Additional state-level oversight of compounded topical pain creams is needed to improve safety and effectiveness.
The National Association of Boards of Pharmacy should convene the state boards of pharmacy to unify and increase their oversight of 503A compounding pharmacies. The charge to increase oversight should also require all 503A compounding pharmacies to do the following:
- Provide a standardized insert for all dispensed compounded pain cream preparations with (1) a detailed description of the formulation, including all APIs and excipient components; (2) clear guidance for use, including how much (cream surface area and volume) and under which conditions to apply; and (3) caution for potential adverse effects.
- Report adverse events to the state boards of pharmacy and FDA through an established mechanism, such as FDA’s Adverse Event Reporting System or MedWatch.
- Monitor, record, and annually report the types, formulations, payers, and dispensing rates of compounded pain cream preparations.
- Uniformly adopt standards in USP <795> to ensure the quality of dispensed nonsterile compounded preparations.
FDA and global standards-setting organizations (e.g., USP) should collaboratively develop standard processes for testing APIs (in solitude and combinations) and excipients commonly used in compounded topical pain creams. These testing standards should include protocols to examine the mechanisms by which APIs are absorbed and released from compounded preparations, with a prioritized focus on APIs in formulations with transdermal properties that allow drugs to travel through the skin to act regionally or systemically.