Cited by 352Anesthesia and Pain ManagementPain Mechanisms and TreatmentsPain Management and Opioid Use

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Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans

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Koppert, Wolfgang, Sittl, Reinhard, Scheuber, Karin, Alsheimer, Monika, Schmelz, Martin, Schüttler, Jürgen·2003·Anesthesiology

DOI 10.1097/00000542-200307000-00025

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Abstract

Background: Experimental studies and clinical observations suggest a possible role for opioids to induce pain and hyperalgesia on withdrawal. The authors used a new experimental pain model in human skin to determine the time course of analgesic and hyperalgesic effects of the mu-receptor agonist remifentanil alone or in combination with the N-methyl-D-aspartate-receptor antagonist S-ketamine or the alpha(2)-receptor agonist clonidine. Methods: Thirteen volunteers were enrolled in this randomized, double-blind, placebo-controlled study. Transcutaneous electrical stimulation at a high current density (2 Hz, 67.3 +/- 16.8 mA, mean +/- SD) induced acute pain (numerical 11-point rating scale: 5-6 out of 10) and stable areas of mechanical hyperalgesia to punctate stimuli and touch (allodynia). The magnitude of pain and area of hyperalgesia were assessed before, during, and after drug infusion (remifentanil at 0.1 microg x kg-1 x min-1 and S-ketamine at 5 microg x kg-1 x min-1 over a period of 30 min, respectively; clonidine infusion at 2 microg/kg for 5 min). Results: Remifentanil reduced pain and areas of punctate hyperalgesia during infusion. In contrast, postinfusion pain and hyperalgesia were significantly higher than control. During infusion of S-ketamine, pain and hyperalgesia decreased and gradually normalized after infusion. When given in combination, S-ketamine abolished postinfusion increase of punctate hyperalgesia but did not reduce increased pain ratings. Clonidine alone did not significantly attenuate pain or areas of hyperalgesia. However, when given in combination with remifentanil, clonidine attenuated postinfusion increase of pain ratings. Conclusions: Opioid-induced postinfusion hyperalgesia could be abolished by S-ketamine, suggesting an N-methyl-d-aspartate-receptor mechanism. In contrast, elevated pain ratings after infusion were not reduced by ketamine but were alleviated by the alpha(2)-receptor agonist clonidine. The results of this study suggest different mechanisms of opioid-induced postinfusion antianalgesia and secondary hyperalgesia.

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Authors: Koppert, W., Sittl, R., Scheuber, K., Alsheimer, M., Schmelz, M., & Schüttler, J.
Affiliations: Universitätsklinikum Erlangen (DE)
Staff Anesthesiologist.
Visiting Research Fellow.
Heidelberg University (DE)
ORCID: Schmelz, Martin
Schüttler, Jürgen
Venue: Anesthesiology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2003-07-01
Volume: 99
Issue: 1
Pages: 152-159
ISSN: 0003-3022 (ISSN-L)
DOI: 10.1097/00000542-200307000-00025
OpenAlex: W2037762739
Cited by: 352
References: 49
Citations by year: 2026: 4 · 2025: 14 · 2024: 9 · 2023: 11 · 2022: 10 · 2021: 10 · 2020: 44 · 2019: 11 · 2018: 10 · 2017: 9 · 2016: 13 · 2015: 17 · 2014: 20 · 2013: 19 · 2012: 22
FWCI: 14.38
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Anesthesiology (publishedVersion)
PubMed (publishedVersion)
Funders: Deutsche Forschungsgemeinschaft
Topics: Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Pain Management
Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
Keywords: remifentanil, opioid-induced hyperalgesia, esketamine, clonidine, NMDA receptor antagonism, secondary hyperalgesia, allodynia, mu-opioid receptor
MeSH terms: Remifentanil, Adrenergic alpha-Agonists, Adult, Analgesics, Opioid, Anesthetics, Dissociative, Blood Pressure, Clonidine, Double-Blind Method, Electric Stimulation, Half-Life, Humans, Hyperalgesia, Infusions, Intravenous, Ketamine, Male, Oxygen, Pain Measurement, Physical Stimulation, Piperidines, Substance Withdrawal Syndrome, Receptors, Opioid, mu, Cross-Over Studies

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Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans

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