Is Topical Ketamine Ready For Prime Time?
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
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
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 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.