Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ORIGINAL ARTICLE Amitriptyline, minocycline and maropitant reduce the sevoflurane minimum alveolar concentration and potentiate remifentanil but do not prevent acute opioid tolerance and hyperalgesia in the rat A randomised laboratory study Delia Aguado, Mariana Abreu, Javier Benito, Javier Garcı ´a-Ferna ´ ndez and Ignacio A. Go ´ mez de Segura BACKGROUND The antidepressant amitriptyline, the inhibi- tor of microglia activation minocycline, and the neurokinin-1 antagonist maropitant have all been used to prevent or treat hyperalgesia and opioid tolerance. OBJECTIVES To determine the effect of amitriptyline, minocycline, maropitant, independently or with remifentanil, on the sevoflurane minimum alveolar concentration in rats and whether these drugs may block opioid-induced hyper- algesia and acute opioid tolerance under inhalational anaes- thesia. DESIGN A randomised, laboratory study. SETTING Experimental Unit, La Paz University Hospital, Madrid, Spain. ANIMALS One hundred and fourteen adult male Wistar rats. INTERVENTIONS Intraperitoneal administration of amitripty- line (10 and 50 mg kg 1 ), minocycline (30 and 100 mg kg 1 ), maropitant (10 and 30 mg kg 1 ) or isotonic saline, combined with a constant rate intravenous infusion of remifentanil (240 mg kg 1 h 1 ) or saline. MAIN OUTCOME MEASURES Sevoflurane minimum alveolar concentration was determined before and after administration of the drugs; acute opioid tolerance was defined as a decreased ability of remifentanil to reduce the minimum alveolar concentration in the short term. In addition, mechanical nociceptive thresholds were deter- mined before and after these treatments. Opioid-induced hyperalgesia was defined as an increase in mechanical nociceptive thresholds after opioid administration. RESULTS Amitriptyline, minocycline and maropitant reduced minimum alveolar concentration up to 24 (8)%, 23 (6)% and 15 (5)%, respectively (P <0.001). Remifentanil alone reduced minimum alveolar concentration by 36 (6)% (P <0.001), and in combination with amitriptyline, minocy- cline and maropitant, the reduction was 76 (9)%, 75 (16)% and 59 (5)%, respectively (P <0.001). An acute tolerance effect (P < 0.01) and a decrease in the mechanical nocicep- tive thresholds were observed with remifentanil in all groups. CONCLUSION Amitriptyline, minocycline and maropitant reduced the minimum alveolar concentration and potentiated the remifentanil minimum alveolar concentration reduction but failed to block opioid-induced hyperalgesia and acute opioid tolerance. Published online 20 May 2014 Introduction Opioids are considered excellent analgesics for the treat- ment of mild to severe pain, but their adverse effects, such as opioid-induced hyperalgesia (OIH) and tolerance, may limit their use. 1 OIH is defined as an increased pain Eur J Anaesthesiol 2015; 32:248–254 From the Department of Animal Medicine and Surgery, Veterinary Faculty, Complutense University of Madrid (UCM), Madrid, Spain (DA, IAGDS), Laboratory of Respiration Physiology, Carlos Chagas Filho Institute of Biophysics, CCS, Federal University of Rio de Janeiro, Rio de Janeiro, Brasil (MA), Department of Clinical Sciences, Veterinary Faculty, Universite ´ de Montre ´ al, Saint Hycianthie, 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 0265-0215 ß 2015 Copyright European Society of Anaesthesiology DOI:10.1097/EJA.0000000000000098