In an important, exhaustive study, Hahnenkamp et al.  1found that remifentanil, in clinically relevant concentrations, directly activates recombinantly expressed human N -methyl-d-aspartate (NMDA) receptors. As evidenced by Hahnenkamp et al. ,1NMDA receptors are thought to play a critical role in the development of opioid tolerance and secondary hyperalgesia and also in neuroprotection, because antagonists of NMDA glutamate receptors can protect the brain against some injuries (such as stroke and trauma).2The NR1/2B subunit is the focus of increasing interest as a therapeutic target in a wide range of central nervous system pathologies, including acute and chronic pain, ischemic brain injury, and head trauma.3,4It could be concluded that administration of remifentanil is disadvantageous.

Nevertheless, it should be considered that in modern clinical practice, remifentanil-based anesthesia is performed administering either propofol or sevoflurane as adjuvants. Propofol inhibits the NMDA glutamate receptor subtype, possibly through an allosteric modulation of channel gating.5Nagels et al.  4could not demonstrate that ketamine, an NMDA antagonist, resulted in greater neuroprotective effects compared with remifentanil during cardiopulmonary bypass procedures when both were combined with propofol, and Luginbuhl et al.  6reported that adding a small dose of ketamine to opioids may prevent acute tolerance to opioids. It is thought that the NR1/2A complex in particular displays a higher affinity for competitive NMDA antagonists than for agonists. Sevoflurane also exerts an NMDA receptor antagonism effect in a dose-dependent manner, producing an inhibition of NMDA-gated currents and partially inhibiting NMDA-induced mitochondrial membrane depolarization.7,8 

These data, taken together, support the hypothesis that propofol or sevoflurane, coadministered with remifentanil during anesthesia, produced an inhibiting effect at NMDA receptors antagonizing remifentanil-related stimulation.

It is also in accord with a number of recent clinical studies suggesting that administration of remifentanil is also safe in neurosurgery, neuro–intensive care unit sedation, and postoperative analgesia after craniotomy.9–11Based on the cerebral effects of remifentanil and the evidence currently available, Hancock and Nathanson2argue that remifentanil should replace nitrous oxide in the “at-risk” brain. As stated by Hahnenkamp et al. ,1the clinical use of remifentanil has gained wide clinical acceptance by anesthesiologists.1 

The clinical relevance is that during anesthesia, the coadministered anesthetics, especially the NMDA antagonists propofol and sevoflurane, should antagonize the remifentanil stimulation of NMDA receptors. We would like to ask for the authors’ thoughts on this possibility.

* University of Messina, Policlinico Universitario “G. Martino,” Messina, Italy.

Hahnenkamp K, Nollet J, Van Aken HK, Buerkle H, Halene T, Schauerte S, Hahnenkamp A, Hollmann MW, Strumper D, Durieux ME, Hoenemann CW: Remifentanil directly activates human N -methyl-d-aspartate receptors expressed in Xenopus laevis  oocytes. Anesthesiology 2004; 100:1531–7
Hancock SM, Nathanson MH: Nitrous oxide or remifentanil for the “at risk” brain. Anaesthesia 2004; 59:313–5
Chazot PL: The NMDA receptor NR2B subunit: A valid therapeutic target for multiple CNS pathologies. Curr Med Chem 2004; 11:389–96
Nagels W, Demeyere R, Van Hemelrijck J, Vandenbussche E, Gijbels K, Vandermeersch E: Evaluation of the neuroprotective effects of S(+)-ketamine during open-heart surgery. Anesth Analg 2004; 98:1595–603
Orser BA, Bertlik M, Wang LY, MacDonald JF: Inhibition by propofol (2,6 di-isopropylphenol) of the N-methyl-D-aspartate subtype of glutamate receptor in cultured hippocampal neurones. Br J Pharmacol 1995; 116:1761–8
Luginbuhl M, Gerber A, Schnider TW, Petersen-Felix S, Arendt-Nielsen L, Curatolo M: Modulation of remifentanil-induced analgesia, hyperalgesia, and tolerance by small-dose ketamine in humans. Anesth Analg 2003; 96:726–32
Criswell HE, Ming Z, Pleasant N, Griffith BL, Mueller RA, Breese GR: Macrokinetic analysis of blockade of NMDA-gated currents by substituted alcohols, alkanes and ethers. Brain Res 2004; 1015:107–13
Kudo M, Aono M, Lee Y, Massey G, Pearlstein RD, Warner DS: Effects of volatile anesthetics on N -methyl-d-aspartate excitotoxicity in primary rat neuronal–glial cultures. Anesthesiology 2001; 95:756–65
Karabinis A, Mandragos K, Stergiopoulos S, Komnos A, Soukup J, Speelberg B, Kirkham AJ: Safety and efficacy of analgesia-based sedation with remifentanil versus standard hypnotic-based regimens in intensive care unit patients with brain injuries: A randomised, controlled trial. Crit Care 2004; 8:R268–80
Verchere E, Grenier B: Pain and postoperative analgesia after craniotomy. Ann Fr Anesth Reanim 2004; 23:417–21
Viviand X, Garnier F: Opioid anesthetics (sufentanil and remifentanil) in neuro-anaesthesia. Ann Fr Anesth Reanim 2004; 23:383–8