Systemic Adverse Events Associated with Compounded Topical Pain Products

Dear Editor,

In the United States, local compounding pharmacies may customize medications for an individual patient whose medical needs cannot be met by a Food and Drug Administration (FDA)-approved product [1]. Compounded topical pain products (CTPPs) often contain a combination of pharmacologically active ingredients (e.g., baclofen, ketamine, lidocaine), many of which are not intended to be administered topically or are not FDA-approved for acute or chronic pain. The rationale for the combination of active ingredients used in CTPPs may not always be clear, and there is limited evidence to support efficacy. CTPPs are made by local compounding pharmacies following a clinician’s prescription. Given the heterogeneity of CTPP formulations and that little is known about their safety or efficacy, we posit these drugs may place patients at unnecessary risk of harm.

We searched the FDA Adverse Event Reporting System (FAERS) database and medical literature via Embase and PubMed through April 26, 2019 for cases of clinically significant adverse events following exposure to CTPPs.

Twenty-four cases, including 13 literature cases [2–12], contained sufficient information to identify CTPPs as a potential cause of a systemic adverse event such as agitation, coma, hypotension, and seizures (Table 1). Of the 24 cases, 16 were reported by a health care professional. Systemic absorption in ten cases was confirmed by serum, cerebrospinal fluid, or urine drug levels. Ten cases described application of a CTPP to the face or genitalia, which are readily permeable sites. Two cases had known hepatic impairment that may have affected the metabolism of drugs such as lidocaine, cyclobenzaprine, and amitriptyline. No cases reported renal impairment.

Table 1.

Summary of systemic adverse event cases related to compounded topical pain products (n = 24)

Case no. (year received by FDA)	Age years (sex)	Compounded topical pain product	Location of application	Description of adverse event	Time to onset	Clinical findings
1 (2003) [2]	35 (M)	AMI 360 mg, BAC 900 mg, LID 900 mg, KETA 900 mg, KETO 1800 mg cream	NR	Seizures and coma	NR	KETA was detected (value NR) in the CSF by gas chromatography and mass spectrometry
2 (2005)	22 (F)	LID 10%, TET 10% cream	Lower extremities (wrapped with saran wrap)	Seizures and cardiac arrest	30 min	Serum LID 7.9 μg/mL (reference > 6 μg/mL potentially toxic); urine positive for THC
3 (2005)	50 (F)	“Jonas Neuropathy” cream contained AMI (% NR)	Lower extremities	Dizziness, nausea, vomiting	Within 7 days	NR
4 (2005)	NR (F)	HYD, KETO, LID cream (% NR)	Lower back, hip	Lower extremity edema and paresthesia in hands	< 24 h	NR
5 (2013) [3]	1.5 (M)	1 pump contained CLO 2 mg, GAB 60 mg, IMI 30 mg, KETA 100 mg, LID 10 mg, and MFA 10 mg ointment (product prescribed to father of patient)	Buttocks (mother intentionally applied for diaper rash)	Hyporeflexia, pinpoint pupils, unresponsiveness	20 min	Serum CLO 9.2 ng/mL (reference 0.5–4.5 ng/mL); serum norketamine 41 ng/mL (reporting limit, > 20 ng/mL)
6 (2014) [4]	23 (M)	CLO 0.2%, GAB 6%, IMI 3%, KETA 10%, LID 2%, MFA 1% cream	Entire body	Hypertensive emergency resulting in subarachnoid hemorrhage	NR	Serum CLO 5200 ng/mL (therapeutic reference 0.5–4.5 ng/mL); IMI 13 ng/mL (therapeutic reference 150–300 ng/mL); desipramine < 10 ng/mL (therapeutic reference 150–300 ng/mL); undetectable LID and monoethylglycinexylidide; urine positive for amphetamines, THC, TCAs; BP 180/87 mmHg; HR 46 BPM
7 (2014)a	58 (M)	BAC 2%, CYC 2%, DIC 3%, LID 2% cream	Left forearm	Atrial fibrillation with rapid ventricular response	“Few minutes” after the third application	HRs 95–175 BPM
8 (2014) [5]	1 (M)	BAC 0.4%, CLO 2%, GAB 5%, KETA (% NR), LID 5% ointment	Hands, mouth (accidental exposure)	Apnea, pinpoint pupils, bradycardia	NR	BP 100/67 mmHg; HR 75 BPM; RR 12/min
9 (2014) [6]	34 (F)	BUP 90 mg, CLO 0.9 mg, CYC 90 mg, FLU 450 mg, KETA 450 mg cream	Intentional ingestion	Obtundation	NR	Urine positive for opiates and methadone
10 (2014) [6]	2 (M)	BAC 2%, BUP 1%, CLO 0.2%, CYC 2%, DIC 5%, GAB 6%, KETA 10%, MEN 1%, NIF 2% lotion	Presumed ingestion (accidental exposure)	Drowsiness, irritability, hypotension	NR	BP 60/30 mmHg; HR 104 BPM; RR 24/min
11 (2014) [7]	29 (F)	BAC 2%, BUP 1%, DIC 3%, GAB 6%, IBU 3%, KETA 10%, PEN 3% cream	Oral mucosa	Altered mental status and seizure-like activity	NR	HR 45 BPM; EEG showed toxic metabolic encephalopathy; urine positive for propofol, caffeine, BAC, DOX, IBU, KETA, LID, TOP
12 (2014)	49 (F)	BAC, BUP, CYC, DIC, IMI, LID, PRI cream (% NR)	Right ankle, shoulder	Agitation, flushing, swollen face, disoriented, difficulty breathing	Immediate	NR
13 (2014)	55 (F)	ALO 0.5%, AMI 2%, BAC 1%, EST 0.1%, GAB 1%, LID 2%, KETA 2% cream	Intravaginal	Sedation	NR	NR
14 (2015)	22 (F)	CYC, KETA cream (% NR)	NR	Death	NR	Per reporter the autopsy described toxic levels of CYC and KETA
15 (2015)	33 (F)	BAC 5%, GAB 5%, KETA 10%, KETO 5% cream	SI joint	Pain, “nerve twitch,” difficulty walking	24 h	NR
16 (2016)	36 (M)	BAC 3%, CLO 0.2%, DIC 2%, GAB 6%, KETA 15%, PRI 7% cream	Calves	Agitation and loss of consciousness	< 24 h	NR
17 (2016)	44 (F)	BEN, LID, TET cream (% NR)	Genital region	Tachycardia, diaphoresis, chest pressure followed by involuntary movements with spasms and teeth chattering	5 min	Per reporter LID level measured the following day was undetectable
18 (2017) [8]	2 (F)	CLO 0.3%, GAB 8%, KETA 10%, PRE 2.5% cream	Face (accidental exposure)	Respiratory and CNS depression	20 min	BP 152/97 mmHg; HR 102 BPM; oxygen saturation 90%
19 (2017)b [9]	58 (F)	AMI 3%, BAC 0.5%, DIC 3%, LID 5%, (unspecified topical formulation)	Neck, oral mucosa	Serotonin syndrome	NR	Serum nortriptyline 288 ng/mL (active metabolite of AMI, reference NR, but described as “elevated”); serum AMI 231 ng/mL (reference NR)
20 (2018) [10]	74 (F)	CLO 0.6%, GAB 6%, KETA 10%, KETO 10%, LID 3% cream	Upper body, perineum, vulva	Delirium and suicidal ideation	14 days	Serum KETA 50 ng/mL and norketamine 33 ng/mL (references NR)
21 (2018) [10]	75 (M)	CLO 0.2%, GAB 6%, IMI 3%, LID 2%, KETA 10%, MFA 1% cream	Back, left lower extremity	Combative, delirium, increasing hostility	Immediate	Diagnostic work-up showed no significant abnormalities
22 (2018)	37 (F)	BEN 2%, LID 6%, TET 4% cream	Left ankle	Chills, cyanotic extremities, dyspnea, hyperventilation	30 min	NR
23 (2018) [11]	1.8 (F)	CAM 3%, CLO 0.2%, GAB 5%, KETO 7%, LID 2.5%, MEN 3%, PRI 2.5% cream	Ingestion, hands (accidental exposure)	AMS, apnea, bradycardia, hypotension, hypothermia	< 10 h	10 h after exposure: serum CLO 2.6 ng/mL (reference at steady state 0.2–2 ng/mL); GAB < 1 μg/mL (reference 2–20 μg/mL); undetectable camphor and ketoprofen
24 (2018) [12]	85 (M)	AMI 5%, KETA 10%, LID 5% (unspecified topical formulation)	Upper body	Encephalopathy	4 days	Urine positive for KETA 2360 ng/mL (reference 0 ng/mL), AMI (value NR), LID (value NR), norketamine (value NR)

ALO aloe, AMI amitriptyline, AMS altered mental status, BAC baclofen, BEN benzocaine, BP blood pressure, BPM beats per minute, BUP bupivacaine, CAM camphor, CLO clonidine, CNS central nervous system, CSF cerebrospinal fluid, CYC cyclobenzaprine, DIC diclofenac, DOX doxepin, EST estriol, F female, FDA Food and Drug Administration, FLU flurbiprofen, GAB gabapentin, HR heart rate, HYD hydrocodone, IMI imipramine, KETA ketamine, KETO ketoprofen, LID lidocaine, M male, MEN menthol, MFA mefenamic acid, NIF nifedipine, NR not reported, PEN pentoxifylline, PRE pregabalin, PRI prilocaine, RR respiratory rate, TCA tricyclic antidepressant, TET tetracaine, THC tetrahydrocannabinol, TOP topiramate

^aThe case reported hyperbilirubinemia of unknown status; reported medications did not suggest the patient was undergoing treatment. Depending on the severity of hepatic impairment, it is possible that LID and CYC metabolism were decreased, predisposing this patient to cardiac arrhythmias

^bThe case reported cirrhosis that was presumed to be severe due to the presence of esophageal varices. AMI metabolism may have been decreased. Also, the patient was inadvertently administered a higher dose of venlafaxine (300 mg twice daily), which is also hepatically metabolized

The median age was 35 years (range 1.2–85). Eight cases involved young children (n = 5) or elderly adults (n = 3), who are more vulnerable to adverse drug effects. Four children ≤ 2 years old were accidentally exposed to a multi-ingredient CTPP and had systemic toxicity including bradycardia, hypotension, miosis, and respiratory and central nervous system depression. One case involved intentional application of a clonidine-containing ointment to treat an infant’s diaper rash. Within 20 min of that exposure, the infant exhibited miosis and unresponsiveness.

Twenty-three cases reported multi-ingredient CTPPs [mean 4.9 ingredients (± standard deviation 1.8)], with 20 unique combinations. The most common active pharmaceutical ingredients were lidocaine (n = 13), ketamine (n = 13), and baclofen (n = 10). Two adults died, including one with seizure and cardiac arrest leading to anoxic brain injury following misuse of lidocaine/tetracaine cream. The second case was attributed to ketamine and cyclobenzaprine systemic toxicity.

These findings provide case-level evidence of harm associated with CTPPs. We are not surprised to observe these cases because CTPPs do not undergo pre-marketing evaluation for safety and efficacy and often lack adequate manufacturer control. There may be wider variability in product potency, undeclared active ingredients, and variable systemic absorption that contribute to toxicity.

We believe the cases described here are representative of many that likely exist. Underreporting of adverse events for approved drugs and other regulated drug products is a widely known limitation of spontaneous databases such as FAERS, despite regulation that requires manufacturer reporting to the FDA. However, local compounding pharmacies are not compelled by this same mandate. We therefore believe underreporting could be more prevalent for compounded drugs.

There is limited evidence supporting the efficacy of CTPPs, which makes consideration of safety and medical necessity important before prescribing and compounding them. When available and indicated, we advocate for the use of FDA-approved therapies to meet the medical needs of patients. When a clinician determines a need for a CTPP and prescribes one, they should be aware of the potential for systemic toxicities.