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14 Articles in Volume 15, Issue #6
Antihistamine for G-CSF–Induced Bone Pain
Book Review: Advanced Headache Therapy
Brain Drain: Lymphatic Drainage System Discovered in the Brain
Case History of Chronic Migraine: Update 2015 Part 2
Disturbed Sleep: Causes and Treatments
Is Topical Ketamine Ready For Prime Time?
Letters to the Editor: Central Sensitization, Microglia Modulators, Supplements
New App Helps Interpret Urine Drug Test Results
Osteoarthritis Update: 2015
Pain Catastrophizing: What Clinicians Need to Know
PPM Editorial Board: Tips for Treating Osteoarthritis
Practical Overview of Osteoarthritis
Status Report on Role of Stimulants in Chronic Pain Management
Treatment of Osteoarthritis

Is Topical Ketamine Ready For Prime Time?

A literature review reveals limited evidence of efficacy, but larger studies are needed.

Topical analgesics are appealing to clinicians because their lack of systemic absorption results in limited adverse effects (AEs).1 Other benefits of topical analgesics include direct access to target sites, convenience, ease of use, painless administration, and improved patient acceptance and adherence, all of which may reduce overall treatment costs.2-4 Most topical analgesics are indicated for nociceptive pain, with few indicated for neuropathic pain.

Ketamine is a N-methyl-D-aspartate (NMDA) antagonist used for general anesthesia that has been formulated and studied as a topical agent, mainly for the management of neuropathic pain. Over the past several years, there has been a rise in the number of prescriptions written for topical ketamine, coincident with the increased popularity of compounding pharmacies.5

Ketamine: A History of Pain Control

Ketamine is a dissociative anesthetic that is used to induce anesthesia and can be administered via multiple routes, including oral, intravenous, intramuscular, nasal, epidural, and topical (see Table 1).6 Ketamine was first discovered in 1962 and was used as a battlefield anesthetic during the Vietnam War. One of the first reports of ketamine use for pain management was in children in the emergency department in 1989.7 In the 1990s, it was discovered that peripheral nerve endings in skin contain glutamate receptors that are involved in nociception.8 Given that ketamine is one of the best available NMDA antagonist on the market, it started to be used in the late 1990s topically for analgesia.

Mechanism of Action

There are multiple mechanisms through which ketamine provides analgesia (See Figure 1). Ketamine is a glutamate NMDA antagonist. NMDA receptors are involved in neurotransmission for nociception and are found in peripheral tissues.9-11 NMDA receptors are found on unmyelinated and myelinated axons in the peripheral somatic tissues, giving topical ketamine a target for providing analgesia.12,13 Other mechanisms of action of ketamine are its effects on opioid receptors,14 muscarinic receptors,15,16 ion channels (Na, K),17 monoamine transporters (including dopamine and serotonin),18-23 and neuronal nitric oxide synthase.24 In addition, it behaves as an anti-inflammatory by acting on Toll-like receptor (TLRs), which leads to down regulation of proinflammatory gene expression.25 The TLRs are a recently discovered family of pattern recognition receptors, which show “homology with the human interleukin-1 receptor family. Engagement of different TLRs can induce overlapping yet distinct patterns of gene expression that contribute to an inflammatory response.”26

Pharmacology

Topical ketamine is administered by compounding with a base (vehicle). The 2 bases that are commonly used are Lipoderm and pluronic lecithin organogel (PLO), transdermal bases used by compounding pharmacies to administer medications through the skin. Lipoderm is a smooth textured hypoallergenic gel, whereas PLO is a hypoallergenic emollient cream. Lipoderm manufacturer PCCA conducted a study comparing ketoprofen delivery with Lipoderm versus PLO and found that Lipoderm delivers medication more rapidly and with better absorption.27 As a result, there may be varying results with the type of compounding base that is used with topical ketamine. Other bases that have been used in studies include white petrolatum, cetearyl alcohol, soybean lecithin granules, and isopropyl palmitate.

Topical ketamine strengths range from 0.5% to 10% in published studies, with the majority of studies using from 0.5% to 2.0%. There are very few studies at higher doses. Compounding pharmacies have dispensed ketamine in doses ranging up to 20%. The optimal dose and frequency of application are unknown. The safety of topical ketamine >10% is unknown.

Literature Review of Topical Ketamine

Postherpetic Neuralgia

The studies for postherpetic neuralgia (PHN) have been mixed to positive in terms of efficacy. There have been 3 randomized controlled trials with placebos.28-30

In the first study, 92 patients with diabetic neuropathy, PHN, or postsurgical/post-traumatic neuropathic pain with allodynia, hyperalgesia, or pinprick hypesthesia were randomly assigned to receive 1 of 4 creams (placebo, 2% amitriptyline, 1% ketamine, or 2% amitriptyline-1% ketamine combined). A reduction in pain scores of 1.1-1.5 units was observed in all groups, and there was no difference between groups. Blood concentrations revealed no significant systemic absorption and minimal side effects.28

In the second study, topical ketamine when combined with amitriptyline was shown to be efficacious (ie, reduction in numerical pain scale) when compared with a placebo.29

In the third randomized controlled study, there was a significant effect on pain intensity (less time with intense pain), but topical ketamine did not result in any statistical difference in pain scores among the 12 participants.30

Diabetic Neuropathy

Diabetic neuropathy remains a difficult painful condition to manage. The studies of topical ketamine for diabetic neuropathy have been mixed to poor in terms of efficacy. Mahoney et al conducted a randomized, placebo-controlled study of topical ketamine cream (5%) to see if it was effective in reducing the pain of diabetic neuropathy.31 The study, which included 17 patients with diabetes, found that topical ketamine cream was no more effective than placebo in relieving pain caused by diabetic neuropathy. A second randomized controlled trial also found no statistical difference between topical ketamine and placebo.32 In addition, in an open-label study, ketamine did not result in reduction in pain.28

Complex Regional Pain Syndrome

A randomized double-blind placebo-controlled crossover trial evaluated 10% topical ketamine in 18 patients with complex regional pain syndrome (CRPS) type I, and 2 patients with CRPS type II.33 The outcome measures were sensory tests to light touch, pressure, punctate stimulation, light brushing, and thermal stimuli before and 30 minutes after topical ketamine was applied on the symptomatic and asymptomatic limbs. Ketamine applied to the symptomatic limb decreased allodynia to light brushing and hyperalgesia to punctate stimulation. It did not lead to pain reduction.

Two small open label trials showed reductions in numerical pain scores in pain patients.34,35 In one study, topical ketamine ointment 0.25% to 1.5% was applied to 7 participants, 5 with CRPS type I and 2 with CRPS type II. Four participants with early dystrophic CRPS type I had reduced pain on the visual analog scale. There were no changes in the 3 participants with chronic atrophic CRPS type I and the 2 with CRPS type II.34 In the other open label study, topical ketamine was applied to 5 participants with sympathetically maintained pain; all experienced a decrease in the numerical rating scale (ranging from 65% to 100%).35

Chemotherapy-Induced Peripheral Neuropathy

Two randomized controlled trials evaluated topical ketamine for chemotherapy-induced peripheral neuropathy (CIPN) pain.36,37 In both of these trials, ketamine was combined with other topical analgesics. In one 4-week trial in 208 patients, topical ketamine 1.5% was combined with topical baclofen and amitriptyline and their pain reduction and functional gains were evaluated.36 The study found a statistical difference in sensory and motor subscales based on a questionnaire, as well as improvement in tingling and burning sensation; however, there was no difference between the ketamine and placebo groups on the brief pain inventory.36 In the other trial, ketamine 2% combined with amitriptyline did not result in any statistical difference in reducing pain compared with placebo.37

Topical ketamine below 2% is likely not effective in treatment of CIPN. Further studies are needed to analyze higher concentrations of ketamine. In 2014, the American Society of Clinical Oncology developed CIPN guidelines with a moderate recommendation for duloxetine and a recommendation to consider a topical compounded cream, which include ketamine, amitriptyline, and baclofen.38

Pelvic Pain

One retrospective study evaluated 13 patients with pelvic pain who were given topical ketamine 0.5% combined with amitriptyline 1% to 2%; of these 13 patients, 1 (8%) had complete relief, 6 (46%) had substantial relief, 4 (31%) had some relief, and 2 (15%) had no response.39 One patient reported occasional irritation while using topical amitriptyline-ketamine with lidocaine; no other patients reported local or systemic AEs. The investigators reported that 85% of patients experienced at least some pain relief.

Ketamine’s Safety

Given the data published, topical ketamine appears to have an excellent safety profile, and patients tolerate it well. Based on the studies, the most common AEs were mainly dermatologic—skin irritation, pruritic plaque, and allergic reaction. It is unclear if the AEs were due to the ketamine or the base.

A study conducted by Finch et al found that topical ketamine 10% did not result in any systemic absorption and appeared safe.33 There are no published data on the safety of topical ketamine above 10%. There is only one documented case report of topical ketamine causing systemic effects; in this case the mother of an 18-month-old patient applied ketamine to the baby’s diaper rash, despite it being prescribed for her husband’s neck pain. The compounded ointment consisted of ketamine 10%, clonidine 2%, gabapentin 6%, mefanamic acid 1%, imipramine 3%, and lidocaine 1%.40 The patient had a norketamine level of 41 ng/mL (reporting limit, >20 ng/mL) and a clonidine level of 9.2 ng/mL (reference range, 0.5-4.5 ng/mL). The patient had respiratory failure and altered mental status that resolved in the intensive care unit. In children, compounded pain medication should be avoided or given in smaller doses due to decreased skin to body surface area and the integrity of the epidermis in children. It should be used with caution in patients at increased risk for systemic uptake.

A recently completed pilot trial assessed the safety and blood level of topical ketamine 10% in patients with neuropathic pain.41 In this trial, 9 participants applied 10% ketamine gel compounded with PLO to a 100 cm2 area 3 times daily. There were low serum levels of ketamine at days 0, 3, and 7, with all levels below 10 ng/mL. The only reported AEs were itching, mild burning, and nausea. Overall, topical ketamine is tolerated in adults with local AEs, but further safety studies still need to be performed. It should be used with extreme caution in toddlers and children.

Conclusion

The efficacy of topical ketamine is still inconclusive because studies have been mixed to negative. Topical ketamine’s effectiveness may rely on the dose, pain condition, choice of vehicle, and frequency of application, which may explain the mixed results. Topical ketamine should not be a first-line agent. The majority of the data is from case reports, cases series, pilot trials, and retrospective studies. There are very limited data from randomized control trials of ketamine’s efficacy. Topical ketamine is tolerated well in adults without any systemic AEs. Given the rise in use of compounded ketamine-containing pain medications, it is imperative that physicians become familiar with ketamine’s mechanisms, appropriate uses, and AEs. Further placebo-
controlled studies with larger sample sizes need to be performed to determine ketamine’s safety profile and the appropriate vehicle, dosage, and frequency of application.

 

Last updated on: August 11, 2015
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