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Topical amelioration of neuropathic pain and pruritus leading to painful consequences

DII small banner By Warren R. Heymann, MD
Dec. 26, 2016

Increasingly, compounded amitriptyline and ketamine have been utilized for the management of neuropathic pain and pruritus. A review of PubMed reveals its utility in erythomelalgia and diverse neuropathic disorders (peripheral neuropathy, radiation-induced neuropathy, chemotherapy-induced neuropathy, post-herpetic neuralgia, proctodynia, and pain associated with hidradenitis suppurativa). It may also help pruritus, including brachioradial pruritus and post-herpetic pruritus.

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.” (1)

As expected with novel compounded formulas, there appears to be little standardization in dosing. For example, in treating post-herpetic neuralgia, topical amitriptyline 4%/ketamine 2% (2) was prescribed, while topical amitriptyline 2.5%/ketamine 0.5% was utilized for proctodynia (3). In a study of 16 patients with localized pruritus due to a variety of etiologies, including neurodermatitis, 62% had at least some symptomatic relief when amitriptyline 1-2%/ketamine 0.5% was utilized (4).

Cardis and Pasieka reported the case of an 80+ year old man with a history of Parkinson disease and intractable pruritus secondary to atopic dermatitis. He was started on oral mycophenolate mofetil and topical 5% amitriptyline/10% ketamine/ 5% lidocaine (KAL) over the upper body. Four days later, he presented with slurred speech, ataxia, and altered mental status. Toxic blood levels were found. The patient returned to his baseline mental status over the next two weeks. The authors proposed that the patient’s age, atopic dermatitis, and possibly his Parkinson disease predisposed him to systemic absorption of KAL (5).
Unquestionably, the factors that the authors propose for increased systemic absorption may be at play, however,  there appears to be another reason for the increased absorption and toxicity of the combination – the doses appear to be significantly higher that other reports in the literature.

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.

1. Poterucha TJ, et al. Topical amitriptyline-ketamine for the treatment of brachioradial pruritus. JAMA Dermatol 2013; 149: 148-50.
2. Sawynok J, Zinger C. Topical amitriptyline and ketamine for post-herpetic neuralgia and other forms of neuropathic pain. Expert Opin Pharmacother 2016; 17: 601-9.
3. Lehman JS, Sciallis GF. Effective use of topical amitriptyline hydrochloride 2.5% and ketamine hydrochloride 0.5% for analgesia in refractory proctodynia. J Drugs Dermatol 2008; 7: 887-9.
4. Poterucha TJ, et al. Topical amitriptyline combined with topical ketamine for the management of recalcitrant localized pruritus: A retrospective pilot study. J Am Acad Dermatol 2013; 69: 320-1.
5. Cardis MA, Pasieka HB. Safety of topical neuromodulators for the treatment of pruritus. JAMA Dermatol 2016; 152: 1390-1.

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