Compounded Topical Pain Creams Review of Select Ingredients for Safety, Effectiveness, and Use (2020) / Chapter Skim
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6 A Review of the Safety and Effectiveness of Select Ingredients in Compounded Topical Pain Creams
6 A Review of the Safety and Effectiveness of Select Ingredients in Compounded Topical Pain Creams
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From page 121... ...
First, the API should have a mechanism of action to treat pain, and second, the topical formulation must deliver the API to the site of action in an amount that is sufficient to achieve an effect but is also appropriate to be safe. In theory, topical APIs intended to treat local or regional pain act on nerves in the skin or in underlying muscles or joints by blocking nerve signals, reducing inflammation, relaxing muscle spasms, or increasing the effects of other substances (Cline and Turrentine, 2016; Leppert et al., 2018)
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Currently, little is known about the safety and effectiveness of compounded topical pain creams. In the context of the somewhat recent rise in the supply and demand of compounded preparations, this gap in knowledge creates a substantial public health concern.
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In addition, evidence on oral administration is occasionally discussed to highlight otential side effects if the data show evidence of systemic absorption.3 p RESEARCH APPROACH Selection of Active Pharmaceutical Ingredients for Review APIs evaluated by the committee are listed in Box 6-1; these APIs were chosen using a process described in Chapter 1. FDA introduced a list of 37 APIs that have been identified in common formulations of compounded topical pain creams, 10 of which were determined to be of high-priority interest and were selected for evaluation by the committee.
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. Given the committee's research questions, the scope of the literature search was limited to the topical application of any of the 20 ingredients to skin with the intent to treat pain.
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5 In recognition of the limited peer-reviewed evidence to describe the safety and effective ness of compounded topical pain creams, the committee also reviewed submitted resources from national stakeholders, such as the Professional Compounding Centers of America, to support its research efforts. These are available in the study's Public Access Folder; see https://www8.nationalacademies.org/pa/managerequest.aspx?
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that suggest a potential for effectiveness to treat pain in humans. • Based on the available evidence, the 20 ingredients reviewed dem onstrated wide variability in their potential for skin absorption, which was found to be dependent on the drug characteristics, skin condition, and excipient(s)
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A more detailed review of the committee's findings on the safety and effectiveness of multiple-ingredient compounded topical pain creams can be found in the later sections of this chapter.
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studies) Cannabidiol Insufficient Yes, based Insufficient Adult; pediatric data on limited data preclinical data Carbamazepine Insufficient Insufficient Insufficient Adults only data (no data data studies)
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No data • Preclinical studies suggest • Single case report of overdose from • antinociception activity when given excessive use of compounded cream systemically with multiple APIs (baclofen 900 mg) • a combination cream containing In baclofen, amitriptyline, and ketamine, serum concentrations of baclofen have been detected at low therapeutic levels in the blood Not described Evidence of effectiveness and safety • as a liquid in open wounds Via other routes of administration, • there is potential for cardiac and central nervous system collapse if absorbed at ≥ 4µg/mL Not described Potential effectiveness indicated in • a few clinical studies with dermal lesions and limited preclinical studies Evidence of systemic absorption in • preclinical studies Via other routes of administration, • there is potential for depressive effects, liver dysfunction, rash, insomnia, infections, suicidal thoughts or actions Only with systemic doses • Poor-quality data for all topical uses; • relevant data on oral use including pain efficacy and side effects were found
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Clonidine Insufficient Yes, based Yes Adults; geriatric, data on limited pediatric, data non-Hispanic White, Native American, Black, Hispanic/ Latino, Asian Cyclobenzaprine Insufficient Yes, based Insufficient Adults; data on limited data Romanian men data and women Dexamethasone Insufficient Insufficient Insufficient n/a data (no data (no data (no studies) studies)
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• Evidence of serious complications • Two adverse events in children who • with systemic absorption developed toxicity from inappropriate exposure to compounded cream containing clonidine Minimal effects (e.g., rash) • Clinical studies of effectiveness have • significant limitations Central mode of action indicates • topical application would need considerable systemic absorption to be effective n/a No data available on dexamethasone • as a single ingredient in compounded topical pain creams • imited data insufficient to describe L Effectiveness: randomized controlled • rates trial comparing active arms (capsaicin cream)
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Orphenadrine Insufficient Insufficient Insufficient n/a data (no data data studies) Pentoxifylline No, based on Insufficient No, based on Adult, limited data data limited data predominantly (one study)
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n/a • o studies of nifedipine for use on N the skin; all data on effectiveness and safety are from studies on application to anal fissures n/a -- • oncern about lowering blood C • ell-done animal and human W pressure but not significant problem experimental data from a single lab; in healthy subject in an experimental randomized controlled trial in patients randomized controlled trial with pain pending n/a -- n/a Insufficient data available on tramadol as a single ingredient in topical pain creams
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Data are inadequate to quantify the extent to which APIs reviewed in this report are absorbed and present at local, regional, or systemic levels. As reflected in adverse event reports, high levels of systemic absorption of certain APIs in topical pain creams have occurred, potentially enabled by excipient selection.
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(See the Multi agent Compounded Topical Pain Creams section of this chapter.) Effectiveness Systematic review A systematic review conducted by Wrzosek et al.
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. Randomized controlled trials A double-blind, randomized, placebo- controlled parallel study conducted by BioDelivery Sciences International evaluated the efficacy of topical clonidine 0.1 percent gel in diabetic patients (type 1 or 2)
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A double-blind, randomized, comparator-controlled parallel study evaluated the efficacy of topical clonidine 0.1 percent gel in diabetic patients (type 1 or 2) with painful peripheral neuropathy defined as an NPRS of ≥ 4 during the 24 hours prior to treatment (BioDelivery Sciences International, 2017c)
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describe a 54-year-old woman with neuropathic pain in both feet reported as 8 out of 10 on the N umerical Rating Scale (NRS) following chemotherapy treatment despite b eing prescribed oral gabapentin 2,000 mg daily and oxycodone 20 to 30 mg daily.
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. Some studies, mostly performed prior to gabapentin becoming available, suggest effectiveness in patients with painful diabetic neuropathy and possibly other neuropathic pain conditions.
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BOX 6-3 Summary of Research Findings on Carbamazepine in Compounded Topical Pain Creams Effectiveness: There is no evidence to determine the effectiveness of top ical carbamazepine in the treatment of pain when applied to intact skin. Dermal penetration/bioavailability: There is insufficient evidence on the dermal penetration and bioavailability of topical carbamazepine.
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. From the FDA-approved label, serious adverse effects from oral administration of this API include Stevens-Johnson syndrome, toxic epidermal necrolysis, atrioventricular block, syncope, and liver failure.
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(See the Multi agent Compounded Topical Pain Creams section of this chapter for further discussion of creams with gabapentin in combination with other APIs.) 14 Vulvodynia is outside the scope of this review as the vulva is not representative of normal skin.
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. Effectiveness Randomized controlled trials There are no relevant RCTs that examine the single-drug use of gabapentin in compounded topical creams to treat pain when applied to intact skin.
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Preclinical studies Wang et al.
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The penetration of gabapentin was studied in Franz diffusion cells using porcine skin, with gabapentin compounded as 5 percent in two commonly used commercial bases (Lipobase, Lipoderm) and a standard poloxamer lecithin organogel.
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. From the FDA-approved label, serious adverse effects from oral admin istration of this API include Stevens-Johnson syndrome.
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Safety and adverse effects: There is no evidence on the safety of topical topiramate. However, if systemic absorption to therapeutic levels is achieved through topical application there is potential for side effects similar to other routes of administration (e.g., oral)
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(See the Multiagent Compounded Topical Pain Creams section of this chapter.) Effectiveness Randomized controlled trials There are no relevant RCTs that examine the single-drug use of baclofen in compounded topical creams to treat pain when applied to intact skin.
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Dermal Penetration/Bioavailability No relevant studies with baclofen alone were found in the literature; however, the committee included studies of baclofen used in combination with other APIs. (See the Multiagent Compounded Topical Pain Creams section of this chapter.)
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(See the Multiagent Compounded Topical Pain Creams section of this chapter.) Effectiveness Randomized controlled trials There are no relevant RCTs that examine the single-drug use of cyclobenzaprine in compounded topical creams to treat pain when applied to intact skin.
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Pain creams tested typically contained one or more of 6 percent gabapentin, 2 percent cyclobenzaprine, 5 percent ketamine, or 5 percent amitriptyline by weight, and also frequently contained ketoprofen, baclofen, clonidine, or lidocaine, which were not analyzed. Of the 74 subjects in the topical application group tested for cyclobenzaprine and its major metabolite, norcyclobenzaprine, in urine, only 7 were positive for the former and 6 for the latter.
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. The topical pain cream contained 10 percent ketamine, 5 percent diclofenac, 2 percent baclofen, 1 percent bupivacaine, 2 percent cyclobenzaprine, 6 percent gabapentin, 3 percent ibuprofen, and 3 percent pentoxifylline in Lipoderm ActiveMax cream base.
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BOX 6-8 Summary of Research Findings on Orphenadrine in Compounded Topical Pain Creams Effectiveness: There is no evidence on the effectiveness of topical o rphenadrine to treat pain when applied to intact skin. Dermal absorption/bioavailability: Insufficient evidence suggests that topical orphenadrine may penetrate through human skin in in vitro a ssays.
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(See the Multiagent Compounded Topical Pain Creams section of this chapter.) Effectiveness Randomized controlled trials There are no relevant RCTs that examine the single-drug use of nifedipine in compounded topical creams to treat pain when applied to intact skin.
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Dermal Penetration/Bioavailability No data were found on the dermal penetration and bioavailability of nifedipine alone in topical pain creams. Safety and Adverse Effects In Somberg and Molnar (2015b)
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Effectiveness Randomized controlled trials There are no relevant clinical studies that examine the single-drug use of CBD in compounded topical creams to treat pain when applied to intact skin.17 A transdermal gel for regional and systemic delivery of CBD (Zynerba Pharmaceuticals) is in clinical development for treatment of epilepsy, devel opmental and epileptic encephalopathy, fragile-X syndrome, and osteo arthritis (Bruni et al., 2018)
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Safety and adverse effects: There is insufficient evidence on the safety of topical application of cannabidiol. However, if systemic absorption to therapeutic levels is achieved through topical application, there is poten tial for side effects similar to other routes of administration (e.g., oral)
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Dermal Penetration/Bioavailability Preclinical studies Reported advantages of topically administered CBD are the potential for greater systemic absorption of this highly lipophilic drug with poor bioavailability by the oral route, while also avoiding extensive first-pass metabolism of ingested CBD (Bruni et al., 2018) .19 CBD in a polyethylene gel was reported to readily cross the stratum corneum in rats, with some accumulation likely in the skin because this lipophilic compound cannot as readily cross the more aqueous dermis layer (Paudel et al., 2010)
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Addition of a penetration enhancer increased plasma concentrations by 3.7 times. Safety and Adverse Events Preclinical studies Hammell et al.
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. While its systemic effects are well demonstrated, there is no evidence that topical ketamine is superior to placebo for various neuropathic pain conditions in concentrations from 1 to 10 percent, or that it reduces a llodynia or hyperalgesia.
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committee also included studies of ketamine used in combination with other APIs. (See the Multi gent Compounded Topical Pain Creams section a of this chapter.)
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, ketamine 5 percent cream versus placebo (vehicle composed of primarily Aquaphor gel) was studied in 27 patients for the treatment of painful diabetic neuropathy in patients with either type 1 or type 2 diabetes.21 Methods were poorly described.
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To minimize redundancy within the chapter, a review of these studies is described in the Multiagent Compounded Topical Pain Creams section below. Clinical studies In Rabi et al.
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(2002) described the effectiveness of topical ketamine in five patients with complex regional pain syndrome type I (CRPS I)
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, a man in his 80s with Parkinson's disease presented with altered mental status after applying a topical pain cream containing ketamine 10 percent, amitriptyline 5 percent, and lidocaine 5 percent to most of his upper body the day prior to presentation. A stroke was ruled out, and after persistent delirium and altered levels of consciousness, the history of the topical pain cream use was elicited.
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Effectiveness Randomized controlled trials There are no relevant clinical studies that examine the single-drug use of bupivacaine in compounded topical creams to treat pain when applied to intact skin. However, although outside the scope of the current report, there are several randomized clinical trials that demonstrated potential effectiveness of compounded topical bupivacaine in treating pain in patients after receiving skin grafts for a variety of surgical BOX 6-12 Summary of Research Findings on Bupivacaine in Compounded Topical Pain Creams Effectiveness: There is no evidence to suggest the effectiveness of topi cal bupivacaine to treat pain when applied to intact skin.
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. Dermal Penetration/Bioavailability Randomized controlled trials No clinical studies were found on the dermal absorption or bioavailability of topical bupivacaine through intact skin.
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See Box 6-13 for a summary of research findings. (See the Multiagent Compounded Topical Pain Creams section of this chapter.)
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. However, with extensive systemic absorption, there is potential for adverse effects, including precipitating CNS distur bances, such as psychosis and seizures.
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The 508 patients in the studies had different types of neuropathic pain, with pain after herpes zoster infection the most common. Six studies enrolled participants with moderate or severe postherpetic neuralgia, and the remaining studies enrolled different, or mixed neuropathic pain conditions, including trigeminal neuralgia and postsurgical or posttraumatic n euralgia.
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See Table G-1 in Appendix G No clinical evidence was found on the effectiveness or safety of memantine use in compounded topical pain creams.
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Effectiveness Randomized controlled trials A review of randomized clinical trials provided insufficient evidence to compare topical NSAID therapies with oral delivery of the same agent, other topical treatments, or other treatments (Glass, 2006)
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Preclinical studies have examined the potential for skin irritation after topical application. However, if systemic absorption to therapeutic levels is achieved through topical application there is p otential for side effects similar to other routes of administration (e.g., oral)
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. From the FDA-approved label, serious adverse effects from oral admin istration of this API include increased risk of cardiovascular events, gastrointestinal bleeding, and ulceration.
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333) examined "the effectiveness and safety of topical non-steroidal anti- inflammatory drugs in acute and chronic pain conditions." In a review of five placebo-controlled trials, the authors determined that topically applied naproxen did not show significant efficacy in acute pain conditions (e.g., soft tissue trauma, strains, and sprains)
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(1990) also did a comparative study between 10 percent naproxen gel and 10 percent ketoprofen gel in 30 patients with moderate to severe pain caused by acute soft tissue lesions.30 There were 15 patients in the naproxen group (8 male, 7 female; mean age: 72.2 years)
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(See the Multiagent Compounded Topical Pain Creams section of this chapter.)
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. Effectiveness Randomized controlled trials There are no relevant clinical studies that examine the single-drug use of tramadol in compounded topical creams to treat pain when applied to intact skin.
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No relevant evidence exists regarding effectiveness, absorption, or safety of dexamethasone alone or in combination with other active ingredients in compounded topical pain creams. From the FDA-approved label, serious adverse effects from oral administration of this API include cardiomyopathy, hyperglycemia, or pancreatitis.
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In addition to reviewing studies where amitriptyline alone was analyzed, the committee also included studies of amitriptyline used in combination with other APIs. (See the Multiagent Compounded Topical Pain Creams section of this chapter.)
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To minimize redundancy within the chapter, a review of these studies is described in the Multiagent Compounded Topical Pain Creams section below. 33 Risk-of-bias assessment by committee: Low (see Appendix B for more details)
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. Dermal Penetration/Bioavailability Clinical studies Five urine samples were collected to evaluate drug levels resulting from topical amitriptyline application (Glinn et al., 2017)
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(Gerner et al., 2003) . Drowsiness was reported in a patient treated with 10 percent cream for neuropathic pain in the feet (Kopsky et al., 2012)
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(See Appendix B for more details.) Effectiveness Randomized controlled trials One randomized, double-blind, placebocontrolled human study was conducted to assess the analgesic efficacy of topical administration of 3.3 percent doxepin HCl cream compared to 0.025 percent capsaicin cream and a combination cream of 3.3 percent doxepin and 0.025 percent capsaicin for treating chronic neuropathic pain BOX 6-20 Summary of Research Findings on Doxepin in Compounded Topical Pain Creams Effectiveness: There is limited evidence to suggest that topical doxepin may be effective to treat chronic human neuropathic pain when admin istered at 3.3 percent concentration as an aqueous cream on intact skin.
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. Dermal Penetration/Bioavailability Preclinical studies Permeation through human cadaver skin was reported as having a flux of 2.74 ± 0.14 µg/h cm2 following application of doxepin formulated in a 3 percent (weight/volume)
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In addition to reviewing studies where pentoxifylline alone was analyzed, the committee also included studies of pentoxifylline used in combination with other APIs. (See the Multiagent Compounded Topical Pain Creams section of this chapter.)
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Preclinical studies In rats with induced neuropathic pain via (1) chronic postischemia pain, (2)
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, little information was found to inform the effectiveness and safety of topical pain creams containing multiple chemicals. In addition, adverse events were similar to those reported for the individual ingredients.
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(2005b) conducted a randomized placebo-controlled study in 92 subjects to evaluate the efficacy of topical amitriptyline 2 percent versus ketamine 1 percent versus a combination of amitriptyline 2 percent/ ketamine 1 percent for the treatment of neuropathic pain over a 3-week eriod in patients with mixed neuropathic pain.39 The excipient was dep scribed as a moisturizing creamlike base.
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Reason for withdrawal was adverse events in five patients. All groups experienced a reduction in pain over time, but there was no difference between treatment groups with respect to pain measures, sensory measures, or perceived disability.
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in pain score was found for patients with diabetic peripheral neuropathy. Retrospective clinical studies Electronic medical records were reviewed to determine the effectiveness of 1–2 percent amitriptyline/0.5 percent ketamine for treatment of erythromelalgia (n = 36; 89 percent female)
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(2005b) , in a randomized placebo-controlled study of 92 subjects to evaluate the efficacy of topical amitriptyline 2 percent versus ketamine 1 percent versus a combination of amitriptyline 2 percent/ketamine 1 percent for the treatment of neuropathic pain, adverse effects were reported in 30 percent of the subjects and were evenly distributed across treatment groups.43 The most common adverse effects were minor skin irritation at the site of appli ation.
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.44 Three-Drug Combinations: Piroxicam, Lidocaine, and Cyclobenzaprine Hydrochloride (PLC Cream) Effectiveness Randomized controlled trials Popescu et al.
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Although application of the PLC gel before ESWL reduced pain perception and need for opioids, cyclobenzaprine was not evaluated separately and the study did not include a vehicle control/placebo. Safety and Adverse Effects Randomized controlled trials Within the Pricop et al.
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Safety and Adverse Effects Clinical studies Incidences of adverse events were similar between patients on baclofen 10 mg/amitriptyline HCL 40 mg/ketamine 20 mg gel and those on placebo (Barton et al., 2011)
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for neuropathic pain from radiation-induced dermatitis, 3 had irritation at grade 1–2 and 5 reported fatigue at grade 1 (Uzaraga et al., 2012)
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with chronic pain, two topical pain creams were compared to Voltaren (diclofenac sodium) gel before and after treatment using the Visual Numeric Pain Intensity Scale.
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A total of 283 patients with diabetic neuropathy or other chronic pain (no further description) , included 78 receiving the sixdrug cream and 205 receiving the seven-drug cream.
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Safety and Adverse Effects Clinical studies In the clinical study reported by Somberg and Molnar (2015b) described above, adverse events were reported in 5.7 percent of patients using a six-drug cream and in 3.8 percent of patients using a sevendrug cream including skin irritation, burning sensation at application site, rash, and flushing (Somberg and Molnar, 2015b)
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of a compounded topical pain cream to the child's bottom to treat a diaper rash. In the hospital the child was bradycardic and hypo tensive with decreased respiratory effort requiring endotracheal intubation and mechanical ventilation.
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2017c. The efficacy and safety of clonidine hydrochlo ride topical gel, vs clonidine hydrochloride gel comparator to treat painful diabetic neuropathy.
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2019. Compounded topical pain creams to treat localized chronic pain: A randomized controlled trial.
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2014. Topical lidocaine for neuropathic pain in adults.
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2000. Topical ketamine gel: Possible role in treating neuropathic pain.
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2014. Severe postherpetic neuralgia and other neuropathic pain syndromes alleviated by topical gabapentin.
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2012. Central neuropathic pain in a patient with multiple sclerosis treated successfully with topical amitriptyline.
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2005a. Topical amitriptyline and ketamine in neuropathic pain syndromes: An open-label study.
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2013. Neuropathic pain -- Pharmacological management.
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2013. Topical combinations aimed at treating microvascular dysfunction reduce allodynia in rat models of CRPS-I and neuropathic pain.
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2019. Combined tetrahydrocannabinol and cannabidiol to treat pain in epidermolysis bullosa: A report of three cases.
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2012. Topical amitriptyline, k etamine, and lidocaine in neuropathic pain caused by radiation skin reaction: A pilot study.
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International Journal of Molecular Sciences 19(3)
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