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Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use (2020)

Chapter: Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams

« Previous: Appendix F: Adverse Events Table
Suggested Citation:"Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams." National Academies of Sciences, Engineering, and Medicine. 2020. Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25689.
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Appendix G

Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams

As discussed in Chapter 6, evidence is inadequate to quantify the extent to which the active pharmaceutical ingredients (APIs) reviewed in this report are absorbed and present at local, regional, or systemic levels. Given the limited data, little is known regarding the relative risk for adverse effects caused by systemic absorption. To consider the potential safety concerns for the systemic absorption of APIs in this report, below is a summarized list of the known adverse events derived from the U.S. Food and Drug Administration (FDA)-approved product labels and data derived from Micromedex, a pharmaceutical database resource.

Suggested Citation:"Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams." National Academies of Sciences, Engineering, and Medicine. 2020. Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25689.
×

TABLE G-1
Adverse Events Associated with Systemic Absorption of Active Pharmaceutical Ingredients Used in Compounded Topical Pain Creams

Drug Product Formulation(s) Drug Class FDA-Approved Pain Indications Off-Label/Non-FDA Uses for Pain
Amitriptyline Oral Tricyclic antidepressants None Fibromyalgia, postherpertic neuralgia
Baclofen Oral, intrathecal Skeletal muscle relaxant Muscle spasms Trigeminal neuralgia, peripheral neuropathy
Bupivacaine Injection Local anesthetic None Pain
Cannabidiol Oral Cannabinoid None None
Carbamezapine Oral Anticonvulsants Trigeminal neuralgia None
Clonidine Transdermal Alpha2 adrenergic agonist None None
Clonidine HCl Epidural, oral Alpha2 adrenergic agonist None Muscle spasms
Cyclobenzaprine Oral Skeletal muscle relaxant Skeletal muscle spasm Fibromyalgia
Dexamethasone Oral, ophthalmic, injection Adrenal corticosteroid None None
Doxepin Oral, topical Tricyclic antidepressants None Chronic pain
Gabapentin Oral, topical Anticonvulsants Postherpetic neuralgia Fibromyalgia, diabetic peripheral neuropathy
Suggested Citation:"Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams." National Academies of Sciences, Engineering, and Medicine. 2020. Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25689.
×
Example Adverse Effects from FDA-Approved Label Example Adverse Effects from Micromedex (2019)
Cardiovascular, the CNS and neuromuscular, anticholinergic, allergic, hematologic, gastrointestinal, and endocrine adverse reactions (Sandoz, 2014) Black box warning for increased suicidal thoughts; cardiac arrhythmias
Drowsiness, dizziness, and weakness (Metacel Pharmaceuticals, 2019) Gastrointestinal bleeding
Excitation and/or depression of the CNS system as well as cardiovascular adverse reactions (Pfizer, 2012) Cardiac arrest, respiratory depression
Somnolence, decreased appetite, diarrhea, transaminase elevations, fatigue, malaise, asthenia, rash, sleep disorders, and infections (GW Pharmaceuticals, 2018) Increased suicidal thoughts; increased liver enzymes
Dizziness, drowsiness, unsteadiness, nausea, and vomiting adverse reactions. The most severe reactions observed have been in the hemopoietic system, skin, liver, and cardiovascular system (Novartis, 2009) StevensJohnson syndrome, toxic epidermal necrolysis, atrioventricular block, syncope, liver failure
Dry mouth, drowsiness, fatigue, headache, lethargy, and sedation (Boehringer Ingelheim Pharmaceuticals, 2011) Atrioventricular block
Dry mouth, drowsiness, dizziness, constipation, and sedation (Boehringer Ingelheim Pharmaceuticals, 2009) Atrioventricular block
Drowsiness, dry mouth, fatigue, and headache (McNeil Consumer Healthcare, 2013) Cardiac dysrhythmia, heart block, myocardial infarction, syncope
Allergic reactions, cardiovascular, dermatologic, endocrine, fluid and electrolyte disturbances, gastrointestinal, metabolic, musculoskeletal, neurological/psychiatric, and ophthalmic adverse reactions (Fera Pharmaceuticals, 2004) Cardiomyopathy, hyperglycemia, pancreatitis
Burning/stinging at the site of application, drowsiness, dry mouth, pruritus, and fatigue (Bioglan Pharma, 2002) Ventricular arrhythmia, thrombocytopenia, suicidal thoughts, kidney damage
Dizziness, somnolence, and peripheral edema (Pfizer, 2010a) StevensJohnson syndrome
Suggested Citation:"Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams." National Academies of Sciences, Engineering, and Medicine. 2020. Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25689.
×
Drug Product Formulation(s) Drug Class FDA-Approved Pain Indications Off-Label/Non-FDA Uses for Pain
Ketamine IV, IM Local anesthesia None Acute pain
Lidocaine Rectal, topical Local anesthetic Postherpetic neuralgia Diabetic neuropathy, acute pain
Meloxicam Oral NSAID Osteoarthritis, rheumatoid arthritis None
Memantine Oral NMDA receptor antagonist None None
Naproxen Oral NSAID Rheumatoid arthritis, osteoarthritis None
Nifedipine Oral Calcium channel blocker None None
Orphenadrine Injection, oral Skeletal muscle relaxant Musculoskeletal pain None
Pentoxyifyline Oral Vasoactive phosphodiesterase inhibitor None None
Topiramate Oral Anticonvulsants Migraine prophylaxis None
Tramadol Oral Opioid agonist Chronic pain Cancer pain

NOTE: CNS = central nervous system; FDA = U.S. Food and Drug Administration; HCl = hydrochloride; IM = intramuscular; IV = intravenous; NMDA = NmethylDaspartate; NSAID = nonsteroidal antiinflammatory drug; REMS = Risk Evaluation and Mitigation Strategy.

Suggested Citation:"Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams." National Academies of Sciences, Engineering, and Medicine. 2020. Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25689.
×
Example Adverse Effects from FDA-Approved Label Example Adverse Effects from Micromedex (2019)
Cardiovascular, respiratory, ocular, genitourinary, psychological, neurological, and gastrointestinal adverse reactions (JHP Pharmaceuticals, 2012) Bradyarrhythmia, cardiac dysrhythmia, respiratory depression
Application site reactions such as irritation, erythema, and pruritus (Scilex Pharmaceuticals, Inc., 2018)
Diarrhea, upper respiratory tract infections, dyspepsia, and influenzalike symptoms (Boehringer Ingelheim Pharmaceuticals, 2012) Black box warning for increased risk of cardiovascular events, gastrointestinal bleeding and ulceration
Dizziness, headaches, confusion, and gastrointestinal adverse effects (Forest Pharmaceuticals, 2013) Cerebrovascular accident, seizures, kidney failure
Gastrointestinal, the CNS, dermatologic, cardiovascular and special senses disturbances (visual and hearing) adverse reactions (Roche, 2007) Black box warning for increased risk of cardiovascular events, gastrointestinal bleeding and ulceration
Peripheral edema, headache, dizziness, fatigue, nausea, and constipation adverse reactions (Bayer Healthcare, 2011; Pfizer, 2010b) Myocardial infarction, ventricular arrhythmia, suicidal thoughts, kidney damage
Dry mouth, tachycardia, palpitation, urinary hesitancy or retention, and blurred vision (3M Pharmaceuticals, 2006) Palpitations, tachyarrhythmia
Cardiovascular, digestive, and nervous system adverse reactions (Validus Pharmaceuticals, LLC, 2016) Thrombocytopenia
Paresthesia, anorexia, and weight loss (Janssen Pharmaceuticals, Inc., 2017) Dermatologic: Erythema multiforme, StevensJohnson syndrome, toxic epidermal necrolysis
Constipation, nausea, dizziness, and headache (Johnson & Johnson, 2009) Black box warning for addiction, abuse, misuse. Required REMS by FDA. Respiratory depression, accidental ingestion, sedation, coma, and death if used with benzodiazepines or alcohol
Suggested Citation:"Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams." National Academies of Sciences, Engineering, and Medicine. 2020. Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25689.
×

TABLE G-2
Potential Drug–Drug Interactions for Select APIs (Oral Administration)

Drug Product Potentially Major or Life-Threatening Drug–Drug Interactions
Amitriptilyne Concurrent use of NSAIDS and TRICYCLIC ANTIDEPRESSANTS may result in an increased risk of bleeding. Concurrent use of CYCLOBENZAPRINE and TRYCYCLIC ANTIDEPRESSANTS may result in increased risk of serotonin syndrome.
Baclofen Concurrent use of TRAMADOL and CNS DEPRESSANTS may result in an increased risk of respiratory and CNS depression.
Carbamazepine Concurrent use of TRAMADOL and SEROTONERGIC CYP3A4 INDUCERS may result in increased risk of serotonin syndrome and reduced TRAMADOL plasma concentrations.
Clonidine Concurrent use of DOXEPIN and CLONIDINE may result in decreased antihypersensitive effectiveness.
Clonidine HCI Concurrent use of DOXEPIN and CLONIDINE may result in decreased antihypersensitive effectiveness.
Cyclobenzaprine Concurrent use of CYCLOBENZAPRINE and TRICYCLIC ANTIDEPRESSANTS may result in an increased serotonin syndrome. Concurrent use of CYCLOBENZAPRINE and TRAMADOL may result in an increased risk of respiratory and CNS depression; increased risk of serotonin syndrome; and an increased risk of paralytic ileus.
Dexamethasone Concurrent use of CORTICOSTEROIDS and NSAIDS may result in an increased risk of gastrointesinal ulcer or bleeding.
Doxepin Concurrent use of NSAIDS and TRICYCLIC ANTIDEPRESSANTS may result in an increased risk of bleeding. Concurrent use of TRAMADOL and SEROTONERGIC AGENTS WITH ANTICHOLINGERIC PROPERTIES may result in increased risk of paralytic ileus and increased risk of serotonin syndrome.
Ketamine Concurrent use of TRAMADOL and CNS DEPRESSANTS may result in an increased risk of respiratory and CNS depression.
Meloxicam Concurrent use of MELOXICAM and NSAIDS AND SALICYLATES may result in increased risk of bleeding. Concurrent use of NSAIDS and TRICYCLIC ANTIDEPRESSANTS may result in an increased risk of bleeding.
Memantine Concurrent use of MEMANTINE and SELECTED NMETHYLDASPARATE ANTAGONISTS may result in increased adverse events of NmethylDasperate agonists.
Naproxen Concurrent use of NSAIDS and TRICYCLIC ANTIDEPRESSANTS may result in an increased risk of bleeding. Concurrent use of CORTICOSTEROIDS and NSAIDS may result in increased risk of gastroinstestinal ulcer or bleeding.
Nifedipine Concurrent use of NIFEDIPINE and CYP3A4 INDUCERS may result in decreased NIFEDIPINE exposure.
Orphenadrine Concurrent use of TRAMADOL and CNS DEPRESSANTS may result in an increased risk of paralytic ileus; increased risk of respiratory and CNS depression.
Suggested Citation:"Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams." National Academies of Sciences, Engineering, and Medicine. 2020. Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25689.
×
Drug Product Potentially Major or Life-Threatening Drug–Drug Interactions
Pentoxyfilline Concurrent use of PENTOXYFILLINE and NSAIDS may result in an increased risk of bleeding.
Topiramate Concurrent use of TRAMADOL and CNS DEPRESSANTS may result in an increased risk of respiratory and CNS depression.
Tramadol Concurrent use of TRAMADOL and CNS DEPRESSANTS may result in an increased risk of respiratory and CNS depression.

NOTE: CNS = central nervous system; NSAIDS = nonsteroidal antiinflammatory drugs.

SOURCE: Micromedex, 2019.

REFERENCES

3M Pharmaceuticals. 2006. Norflex (orphenadrine citrate) extended-release tablets and injection label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf (accessed December 17, 2019).

Bayer Healthcare. 2011. Adalat CC (nifedipine) extended release tablets for oral use label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020198s023lbl.pdf (accessed December 17, 2019).

Bioglan Pharma. 2002. Zonalone (doxepin hydrochloride) cream label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20126slr006_Zonalon_lbl.pdf (accessed March 16, 2020).

Boehringer Ingelheim Pharmaceuticals. 2009. Catapres (clonidine hydrochloride, USP) label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017407s034lbl.pdf (accessed December 17, 2019).

Boehringer Ingelheim Pharmaceuticals. 2011. Catapres-TTS (clonidine) patch label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018891s028lbl.pdf (accessed March 16, 2020).

Boehringer Ingelheim Pharmaceuticals. 2012. Mobic (meloxicam) tablets, oral suspension label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020938s022lbl.pdf (accessed December 17, 2019).

Fera Pharmaceuticals. 2004. Decadron (dexamethasone tablets, USP) label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/11664slr062_decadron_lbl.pdf (accessed December 17, 2019).

Forest Pharmaceuticals. 2013. Namenda (memantine HCl) tablets and solutions for oral use label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021487s010s012s014,021627s008lbl.pdf (accessed December 17, 2019).

GW Pharmaceuticals. 2018. Epidiolex (cannabidiol) oral solution, CX label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf (accessed December 17, 2019).

Janssen Pharmaceuticals. 2017. Topamax (topiramate) tablets, sprinkle capsules for oral use label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020505s057_020844s048lbl.pdf (accessed December 17, 2019).

JHP Pharmaceuticals. 2012. Ketalar–Ketamine hydrochloride injection label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016812s039lbl.pdf (accessed December 17, 2019).

Suggested Citation:"Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams." National Academies of Sciences, Engineering, and Medicine. 2020. Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25689.
×

Johnson & Johnson. 2009. Ultram (tramadol hydrochloride) tablets label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020281s032s033lbl.pdf (accessed December 17, 2019).

McNeil Consumer Healthcare. 2013. Flexeril (cyclobenzaprine HCL) tablets label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017821s051lbl.pdf (accessed December 17, 2019).

Metacel Pharmaceuticals. 2019. Ozobax (baclofen) oral solution. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208193s000lbl.pdf (accessed March 16, 2020).

Micromedex (electronic version). 2019. IBM Watson Health. Greenwood Village, CO. Subscription required to view. https://www.micromedexsolutions.com (accessed October 30, 2019).

Novartis. 2009. Tegretol (carbamazepine USP) chewable tablets, tablets, suspension label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/016608s101,018281s048lbl.pdf (accessed December 17, 2019).

Pfizer. 2010a. Neurontin (gabapentin) capsules/tablets, oral solution label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020235s043lbl.pdf (accessed December 17, 2019).

Pfizer. 2010b. Procardia XL (nifedipine) extended release tablets for oral use label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019684s023lbl.pdf (accessed December 17, 2019).

Pfizer. 2012. Marcaine, bupivacaine hydrochloride injection, USP label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018692s015lbl.pdf (accessed December 17, 2019).

Roche. 2007. Naprosyn (naproxen) tablets, suspension, delayed release tablets label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017581s108,18164s58,18965s16,20067s14lbl.pdf (accessed December 17, 2019).

Sandoz. 2014. Amitriptyline hydrochloride tablets, USP label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/085966s095,085969s084,085968s096,085971s075,085967s076,085970s072lbl.pdf (accessed December 17, 2019).

Scilex Pharmaceuticals, Inc. 2018. ZTlido (lidocaine topical system) label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/207962s001lbl.pdf (accessed March 16, 2020).

Validus Pharmaceuticals, LLC. 2016. Trental (pentoxifylline) extended release tablets label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018631s041lbl.pdf (accessed December 17, 2019).

Suggested Citation:"Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams." National Academies of Sciences, Engineering, and Medicine. 2020. Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25689.
×
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Suggested Citation:"Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams." National Academies of Sciences, Engineering, and Medicine. 2020. Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25689.
×
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Suggested Citation:"Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams." National Academies of Sciences, Engineering, and Medicine. 2020. Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25689.
×
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Suggested Citation:"Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams." National Academies of Sciences, Engineering, and Medicine. 2020. Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25689.
×
Page 308
Suggested Citation:"Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams." National Academies of Sciences, Engineering, and Medicine. 2020. Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25689.
×
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Suggested Citation:"Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams." National Academies of Sciences, Engineering, and Medicine. 2020. Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25689.
×
Page 310
Suggested Citation:"Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams." National Academies of Sciences, Engineering, and Medicine. 2020. Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25689.
×
Page 311
Suggested Citation:"Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams." National Academies of Sciences, Engineering, and Medicine. 2020. Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25689.
×
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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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