8
Recommendations Regarding the Treatment of Patients with Compounded Topical Pain Creams
Compounded topical pain creams may have a potential 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 active pharmaceutical ingredients (APIs) commonly used in these preparations (Chapter 6)
- Inadequate training, procedural protocols, and evidence-based guidance for pharmacists who formulate and dispense these preparations, as well as for prescribing clinicians (Chapter 7)
- Significant gaps in federal and state-level regulation, oversight, and surveillance of non-U.S. Food and Drug Administration (FDA)approved medications (Chapter 4)
In its review of available scientific evidence within the study scope, the committee concluded 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 the treatment of various pain conditions when applied to intact skin. Furthermore, potential for systemic absorption and toxicity of many of APIs reviewed remains largely unknown. These findings give rise to substantial concerns related to excessive application of compounded topical preparations, as well as 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 the 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 their research findings, the committee puts forth three overarching conclusions:
Conclusion 8-1: 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.1
Conclusion 8-2: 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.
Conclusion 8-3: 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.
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1 This text has changed since the prepublication release of this report to clarify the available FDA-approved topical NSAID products.
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 transdermally
- 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 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 the 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 United States Pharmacopeia (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.
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