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DI&I encore: Better than a back scratcher?

DII small banner By Warren R. Heymann, MD
March 30, 2017

The potential toxicity of the combination of topical ketamine/amitriptyline/lidocaine (TKAL) was discussed in a recent entry detailing the encephalopathic findings in an octogenarian Parkinsonian man with atopic dermatitis who was treated with the compound. I concluded: “As our therapeutic options for recalcitrant neuropathic pain and pruritus are relatively limited, perhaps topical amitriptyline/ketamine is a viable option for some patients. It is essential that the optimal minimal effective dose be determined. Following standard precautions of topical therapy (i.e., applying the drug to limited areas of intact skin) should be de rigueur until such time that the precise pharmacology of this combination is elucidated.” (Topical amelioration of neuropathic pain and pruritus leading to painful consequences. December 26th, 2016)

Perhaps it’s worth a look at the bright side.

From the erstwhile Temple Itch Center, Lee et al retrospectively analyzed 96 pruritic patients (68.8% female) with a mean age of 65 ± 14.4 years for whom TKAL was prescribed. Patients reported a mean duration of itch of 76.7 ± 99.2 months with 38% having failed more than 3 previous treatments. TKAL was prescribed at a standardized concentration of 10% ketamine, 5% amitriptyline, and 5% lidocaine compounded in a lipoderm cream, except for 16 patients who were prescribed the combination with 5% ketamine. Patients were instructed to apply sparingly to areas that were the most severe, limiting to less than 30% of total body surface area up to 3 times daily. The most frequent indications were for neuropathic conditions (29%) and prurigo nodularis (19%). The average numeric rating scale was 8.63 ± 1.62 before and 4.19 ± 2.9 after treatment with an average reduction of 4.61 ± 2.77. Although oral systemic medications were concomitantly prescribed, most commonly gabapentin (46%) and mirtazapine (22%), 63% of patients attributed relief directly to the use of TKAL alone with reduction in numeric rating scale seen in all pruritus subtypes. Review of a pharmacy-administered telephone survey that assessed medication tolerability and efficacy of 40 patients revealed that 23 patients (58%) had relief to a great extent and 14 (35%) to a moderate extent, experiencing itch relief within 4.18 ± 3.39 minutes on average. Side effects reported by 16 subjects were primarily a mild localized burning sensation (7%) and redness (6%) at the application site (1).

The mechanism of action of this combination has been described by Poterucha et al: “When given topically, ketamine acts via the same mechanism as it does when given systemically — it blocks N-methyl-D-aspartic acid, kainic acid, and 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)-propanoic acid receptors to prevent synaptic transmission of nerve impulses. Amitriptyline, however, acts very differently topically than it does systemically, where it modulates the effects of serotonin and other neurotransmitters. When administered topically, it blocks voltage-gated sodium channels, preventing the depolarization of axons. It is theorized that the combination of these 2 medications, one acting on the synapse and the other on the axon, can prevent the transmission of pain. It is possible that this same mechanism of action could relieve neuropathic itching via inhibition of irritated C-fibers and centrally sensitized A-fibers.” (2) Per McDonald et al: “To date, there are few reports of lidocaine for the relief of pruritus. Although the mechanism is not well studied, lidocaine was found to reduce itch-evoked c-Fos expression in guanidinonaltrindole-induced scratching models in mice.” They detail the case of woman with advanced stage cutaneous T-cell lymphoma with recalcitrant pruritus whose itch responded to continuous subcutaneous lidocaine infusion (3).

There is more to learn about TKAL. Of course a prospective, blinded study validating its effect on pruritus would be optimal. What is the appropriate formulation regarding the dose for each component? What is the maximal amount that can be used before toxic levels are reached? What is the precise mechanism of action of the combination? It may take a while to get those answers. In the interim, I called the local pharmacy to find out how much TKAL costs — for my most recalcitrant pruritic patients, I think I will encourage them to spend $95 (as confirmed by a local compounding pharmacy) for a 60 gram tube.

1. Lee HG, et al. Topical ketamine-amitriptyline-lidocaine for chronic pruritus: A retrospective study assessing efficacy and tolerability. J Am Acad Dermatol 2017; 76: 760-1.
2. Poterucha TJ, et al. Topical amitriptyline-ketamine for the treatment of brachioradial pruritus. JAMA Dermatol 2013; 149: 148-50.
3. McDonald JC, et al. Control of intractable pruritus in a patient with cutaneous T-cell lymphoma using a continuous infusion of lidocaine. J Pain Symptom Manage 2015; 49: e1-3.

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