Systemiskt upptag av topikalt administrerat amitriptylin och ketamin

Fråga: Vi är intresserade av att veta hur det ser ut med systemiskt upptag av topikalt administrerat amitriptylin och ketamin (motsvarande APL-varor amitriptylin-ketamin i Decubal kräm och amitriptylin i Decubal kräm).

Sammanfattning: Results from a few controlled trials and open-label reports for different peripheral neuropathic pain conditions showed no significant systemic absorption of topical amitriptyline/ketamine and minimal adverse events were reported for both combinations (2% amitriptyline in combination with 1% ketamine, as well 4% amitriptyline in combination with 2% ketamine).

There is some evidence of systemic absorption with higher concentrations or high doses of topically administered amitriptyline. Risk for systemic absorption may increase especially in the setting of pre-existing illness and impaired skin barrier function.

Svar: In Sweden, both combinations (2% amitriptyline in combination with 1% ketamine, as well 4% amitriptyline in combination with 2% ketamine) are available as follows (1):

Amitriptylin-ketamin i Decubal kräm APL Kräm 4 % + 2 %
Amitriptylin-ketamin i Decubal kräm APL Kräm 2 % + 1 %

A few controlled trials and open-label reports have described the results of the topical application of combination of amitriptyline and ketamine for different peripheral neuropathic pain conditions. The secondary study objectives included determination of whether systemic absorption of amitriptyline and ketamine occurred. In these trials, the combination of amitriptyline and ketamine in a 2:1 ratio was evaluated.

In a pilot study (2), twenty volunteers with chronic neuropathic pain were randomly assigned to 5 ml/day for two days with either topical treatment of 1% amitriptyline, 0.5% ketamine, combination amitriptyline 1%/ketamine 0.5%, or placebo. Blood amitriptyline levels for patients not taking oral amitriptyline were <50 nmol/L in every case (8 patients), which was below the limit of detection. In 3 patients who were taking oral amitriptyline, post-treatment amitriptyline levels were not increased compared with pre-treatment amitriptyline levels. Ketamine levels were below the limit of detection (<21 nmol/L) in 8/11 subjects while norketamine levels were below the limit of detection in 5/11 patients. No patient described any side effects related to ketamine.

Minimal drug and metabolite levels, along with no reported systemic side effects related to either drug, suggests that there was no clinically significant absorption of amitriptyline or ketamine when used in these doses.

A double-blind, randomized, placebo-controlled 3-week study (3) was performed to evaluate the efficacy of topical 2% amitriptyline, 1% ketamine, and a combination of both compared to placebo in treating patients with neuropathic pain. Ninety-two patients with diabetic neuropathy, postherpetic neuralgia, or postsurgical/posttraumatic neuropathic pain were randomly assigned to receive one of four creams. Subjects were instructed to apply 4 ml cream to the site of maximum pain (size of the area of pain varied) three times per day for 3 weeks. Plasma concentrations of amitriptyline and ketamine indicated no or minimal detectable concentrations of either active agent or metabolite, suggesting a lack of systemic effect. Only three subjects exhibited detectable ketamine concentrations, and the concentrations were generally less than 30 ng/ml (20, 22, 30 ng/ml), none of whom reported any systemic side effects.

An open label prospective trial (4) found that, with use of topical 2% amitriptyline/ 1% ketamine cream for treatment of neuropathic pain. Subjects were instructed to apply 4 ml cream to the site of maximum pain (size of the area of pain varied) three times per day for 6-12 months. In the 21 subjects who completed the trial, there was no detectable ketamine or norketamine. In 14 subjects, there was no amitriptyline or nortriptyline detected. Five of the 7 subjects exhibiting detectable blood amitriptyline or nortriptyline were taking oral amitriptyline concurrently. Overall, there was no significant systemic absorption of amitriptyline or ketamine.

However, a case of systemic absorption and subsequent toxic encephalopathy following application of topical high concentration of amitriptyline (5%), ketamine (10%), and lidocaine (5%) for recalcitrant pruritus was reported (5). Following initial application to small test areas with subsequent improvement, the patient gradually increased coverage to include most of his upper body on the evening prior to presentation at the emergency department. Amitriptyline, and ketamine, lidocaine (2360 ng/mL; 0 ng/mL, normal level,) along with their respective metabolites including norketamine were detected via a mass spectroscopy–based urine toxicology test. It has been suggested that elderly patients, or those with pre-existing neurologic illness, especially in the setting of impaired skin barrier function, may be at an increased risk for systemic absorption.

Evidence that systemic absorption may occur with topical 10% cream amitriptyline, possibly leading to adverse effects, was reported (6).

1. Vårt produktregister - APL
2. Lynch ME, Clark AJ, Sawynok J. A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain. Clin J Pain. 2003 Sep-Oct;19(5):323-8
3. Lynch ME, Clark AJ, Sawynok J, Sullivan MJ. Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes: a randomized, double-blind, placebo-controlled trial. Anesthesiology. 2005 Jul;103(1):140-6
4. Lynch ME, Clark AJ, Sawynok J, Sullivan MJ. Topical amitriptyline and ketamine in neuropathic pain syndromes: an open-label study. J Pain. 2005 Oct;6(10):644-9.
5. Cardis MA, Pasieka HB. Safety of Topical Neuromodulators for the Treatment of Pruritus. JAMA Dermatol. 2016;152(12):1390–1391.ndoi:10.1001/jamadermatol.2016.3118
6. Thompson DF, Brooks KG. Systematic review of topical amitriptyline for the treatment of neuropathic pain. J Clin Pharm Ther. 2015 Oct;40(5):496-503. doi: 10.1111/jcpt.12297. Epub 2015 Jun 7. PMID: 26059975.