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No hyperalgesia following opioid withdrawal after the oripavine derivative etorphine compared to remifentanil and sufentanil

Freye, Ennoa,b; Levy, Joseph Vc,*

European Journal of Anaesthesiology (EJA): February 2010 - Volume 27 - Issue 2 - p 174–180
doi: 10.1097/EJA.0b013e32832ff528
Chronic pain

Background and objective The concept of opioid-induced hyperalgesia has recently gained prominence as a contributing factor for long-term treatment failure.

Methods To evaluate possible differences of opioids used in anaesthesia, cumulative doses of sufentanil and remifentanil were compared with escalating doses of the oripavine derivative etorphine, in awake and trained canines. This was followed by naloxone unmasking a possible hyperalgesic state, which had developed during opioid administration. Heart rate, blood pressure and propagation of nociceptive volleys in somatosensory-evoked potentials as well as the skin-twitch reflex were evaluated.

Results Opioid-related hypotension and bradycardia were reversed by naloxone with a late (30 min) overshoot of +43 and +17% after remifentanil and sufentanil, respectively. Following etorphine, overshoot in mean blood pressure was +9%, whereas heart rate still remained below −9% when compared with control. Peak hyperalgesia, as detected in the somatosensory-evoked potential and skin-twitch, increased by +70% after remifentanil and by +43% after sufentanil. This reflected a significant (P < 0.005) increase in propagation of nociceptive afferents as late as 30 min after naloxone reversal. Such potentiation was not observed in the etorphine group, as peak somatosensory-evoked potential deflection and skin-twitch remained below −80% when compared with control.

Conclusion The pure μ-agonists sufentanil or remifentanil seem to induce a ‘bimodal’ inhibitory followed by an excitatory effect. The latter is unmasked by naloxone in the postadministration period. In contrast, this is not seen with etorphine, a close congener of buprenorphine. The proposed mode of action of such hyperexcitatory effects may involve second-messenger-mediated G-protein activation, originally proposed by others. Ligands of the oripavine series may present an alternative for prevention of opioid-induced hyperalgesia in patients.

aClinics of Vascular Surgery, University Clinics of Duesseldorf, Duesseldorf, Germany

bCenter of Ambulatory Pain Medicine, Neuss-Uedesheim, Germany

cDepartment of Physiology & Pharmacology, Arthur Dugoni School of Dentistry, University of the Pacific, San Francisco, California, USA

*In memory of Professor Joseph Victor Levy, a dear friend, coauthor and a renowned scientist who had passed away on 10 January 2009.

Received 4 August, 2008

Revised 5 June, 2009

Accepted 17 June, 2009

Correspondence to Enno Freye, MD, PhD, Deichstrasse 3a, 41468 Neuss-Uedesheim, Germany Tel: +49 2131 314 2421; e-mail:

© 2010 European Society of Anaesthesiology