Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ORIGINAL ARTICLE Hyperalgesia and increased sevoflurane minimum alveolar concentration induced by opioids in the rat A randomised experimental study Mariana Abreu, Delia Aguado, Javier Benito, Javier Garcı ´a-Ferna ´ ndez and Ignacio A. Go ´ mez de Segura BACKGROUND Perioperative opioids reduce inhalational anaesthetic requirements. The initial hypoalgesia may, how- ever, be followed by a rebound hyperalgesia. OBJECTIVES To determine whether prior opioid adminis- tration influences inhalational anaesthetic requirements, which might be associated with opioid-induced hyperalgesia. DESIGN A prospective, randomised, experimental study. SETTING Experimental Surgery, La Paz University Hospital, Madrid, Spain. ANIMALS Seventy-nine adult male Wistar rats. INTERVENTIONS Sevoflurane minimum alveolar concen- tration (MAC) and mechanical nociceptive thresholds (MNTs) were assessed at baseline and 7 days later following opioid treatment with remifentanil 120 mg kg 1 h 1 , bupre- norphine 150 mg kg 1 , methadone 8 mg kg 1 or morphine 10 mg kg 1 . The duration of the effect of remifentanil on MAC and MNT was evaluated in addition to the preventive effect of ketamine 10 mg kg 1 on remifentanil-induced hyperalgesia. MAIN OUTCOME MEASURES The effect of different opioid treatments on MAC and MNT was evaluated using analysis of variance (ANOVA). RESULTS All studied opioids produced an immediate reduction in sevoflurane MAC, followed by an increase (16%) in baseline MAC 7 days later (P < 0.05), although the immediate MAC reduction produced by these opioids at that time was not different. Remifentanil produced a decrease in MNT (P < 0.05), which was associated with an increase in the MAC (P < 0.05) that persisted at 21 days. The effect of remifentanil on MNT and MAC was blocked by ketamine. CONCLUSION Opioid-induced hyperalgesia was associ- ated with an increase in the MAC in normal rats who had not undergone surgery. Both effects lasted 21 days and were prevented by ketamine. Published online 5 December 2014 Introduction Opioids are widely used analgesics to treat moderate to severe pain. There is evidence, however, suggesting that opioids activate not only antinociceptive but also prono- ciceptive mechanisms leading to an increase in pain sensitivity, also known as opioid-induced hyperalgesia (OIH). Opioid-induced hyperalgesia has been defined as a state of nociceptive sensitisation caused by exposure to Eur J Anaesthesiol 2015; 32:232–241 From the Laboratory of Respiration Physiology, Carlos Chagas Filho Institute of Biophysics, CCS, Federal University of Rio de Janeiro, Rio de Janeiro, Brasil (MA), Department of Animal Medicine and Surgery, Veterinary Faculty, Complutense University of Madrid (UCM), Madrid, Spain (IAGS, DA), Department of Clinical Sciences. Faculty of Veterinary Medicine, University of Montreal (UdM), Saint Hyacinthe, Quebec, Canada (JB) and Department of Anaesthesiology and Critical Care, Puerta de Hierro University Hospital, Madrid, Spain (JGF) Correspondence to Dr Ignacio A. Go ´ mez de Segura, Department of Animal Medicine and Surgery, Veterinary Faculty, Complutense University of Madrid (UCM), Avda. Puerta de Hierro s/n, 28040 Madrid, Spain Tel: +34 913 943 858; fax: +34 913 943 808; e-mail: iagsegura@vet.ucm.es This article is accompanied by the following Invited Commentary: Weinbroum AA. Role of anaesthetics and opioids in perioperative hyperalgesia: One step towards familiarisation. Eur J Anaesthesiol 2015; 32:230–231. 0265-0215 ß 2015 Copyright European Society of Anaesthesiology DOI:10.1097/EJA.0000000000000188