Newly Published
Pain Medicine  |   May 2019
Dextromethorphan Analgesia in a Human Experimental Model of Hyperalgesia
Author Notes
  • From University Clermont Auvergne, Department of Fundamental and Clinical Pharmacology of Pain, NeuroDol, F-63000 Clermont-Ferrand, France (E.M., C.D., G.P.); Inserm UMR-S1147, Saints-Pères University Centre, Paris, France (C.N., M.-A.L.); University Paris Descartes, Sorbonne Paris Cité, Paris, France (C.N., M.-A.L.); Assistance Publique—Paris Hospital (AP-HP), Georges Pompidou European Hospital, Biochemistry Department, Paris, France (C.N., M.-A.L.); Cochin Hospital, HUPC, Hôpitaux de Paris (AP-HP) Paris, France (X.D., L.L.); Pharmacy Faculty, University Paris Descartes Inserm UMR-S1144, Paris, France (X.D.); Clermont-Ferrand, Research and Innovation Department, Clermont-Ferrand, France (C.L., B.P.); and University Hospital Clermont-Ferrand, Clinical Pharmacology Department/Clinical Research Centre, Inserm 1405, F-63003 Clermont-Ferrand, France (G.D., C.D., G.P).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Submitted for publication March 8, 2018. Accepted for publication March 13, 2019.
    Submitted for publication March 8, 2018. Accepted for publication March 13, 2019.×
  • Correspondence: Address correspondence to Dr. Pickering, Centre de Pharmacologie Clinique, Bâtiment 3C, CIC Inserm 1405, CHU Clermont-Ferrand, BP 69, F-63003 Clermont-Ferrand Cedex 1, France. gisele.pickering@uca.fr. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Central and Peripheral Nervous Systems / Pain Medicine
Pain Medicine   |   May 2019
Dextromethorphan Analgesia in a Human Experimental Model of Hyperalgesia
Anesthesiology Newly Published on May 10, 2019. doi:10.1097/ALN.0000000000002736
Anesthesiology Newly Published on May 10, 2019. doi:10.1097/ALN.0000000000002736
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Neuropathic pain, which presents abnormal pain manifestations including allodynia and hyperalgesia, is associated with central sensitization involving N-methyl-d-aspartate receptors

  • In the freeze-injury hyperalgesia model, a cold burn leads to development of both primary hyperalgesia and secondary hyperalgesia, which develops away from the site of injury without apparent tissue modification, and is associated with central sensitization and activation of N-methyl-d-aspartate receptors in the spinal cord

  • Dextromethorphan, which is an N-methyl-d-aspartate receptor antagonist, is antihyperalgesic in preclinical pain models

What This Article Tells Us That Is New:

  • Using the freeze-injury pain model in a randomized, double-blind, placebo-controlled crossover trial of 30-mg doses of oral dextromethorphan in 20 male volunteers, dextromethorphan was antihyperalgesic and reversed peripheral and central neuronal sensitization

  • Because dextromethorphan had no intrinsic antinociceptive effect in acute pain on healthy skin, N-methyl-d-aspartate receptors may need to be sensitized by pain for dextromethorphan to be effective

Background: Central pain sensitization is often refractory to drug treatment. Dextromethorphan, an N-methyl-d-aspartate receptor antagonist, is antihyperalgesic in preclinical pain models. The hypothesis is that dextromethorphan is also antihyperalgesic in humans.

Methods: This randomized, double-blind, placebo-controlled, crossover study explores the antihyperalgesic effect of single and repeated 30-mg dose of oral dextromethorphan in 20 volunteers, using the freeze-injury pain model. This model leads to development of primary and secondary hyperalgesia, which develops away from the site of injury and is associated with central sensitization and activation of N-methyl-d-aspartate receptor in the spinal cord. The primary outcome was antihyperalgesia calculated with the area under the curve of the percentage change in mechanical pain threshold (electronic von Frey) on the area of secondary hyperalgesia. The secondary outcomes were mechanical pain threshold on the area of primary hyperalgesia and cognitive (reaction time) effect.

Results: Single 30-mg results are reported. Antihyperalgesia (% · min) is significantly higher on the area of secondary hyperalgesia with dextromethorphan than placebo (median [interquartile range]: 3,029 [746; 6,195] vs. 710 [–3,248; 4,439], P = 0.009, Hedge’s g = 0.8, 95% CI [0.1; 1.4]). On primary hyperalgesia area, mechanical pain threshold 2 h after drug intake is significantly higher with dextromethorphan (P = 0.011, Hedge’s g = 0.63, 95% CI [0.01; 1.25]). No difference in antinociception is observed after thermal painful stimuli on healthy skin between groups. Reaction time (ms) is shorter with placebo than with dextromethorphan (median [interquartile range]: 21.6 [–37.4; 0.1] vs. –1.2 [–24.3; 15.4], P = 0.015, Hedge’s g = 0.75, 95% CI [0.12; 1.39]). Nonserious adverse events occurrence (15%, 3 of 20 volunteers) was similar in both groups.

Conclusions: This study shows that low-dose (30-mg) dextromethorphan is antihyperalgesic in humans on the areas of primary and secondary hyperalgesia and reverses peripheral and central neuronal sensitization. Because dextromethorphan had no intrinsic antinociceptive effect in acute pain on healthy skin, N-methyl-d-aspartate receptor may need to be sensitized by pain for dextromethorphan to be effective.