Opioid-induced Hyperalgesia : A Qualitative Systematic Review

1. The possible involvement of nitric oxide (NO) in the induction and expression of morphine tolerance and dependence was studied in mice. A two-day repeated injection regimen was used to induce morphine tolerance and dependence. Tolerance was assessed by the tail flick test and physical dependence by naloxone challenge, on the third day. 2. Two days pretreatment with L-arginine (20 mg kg-1, twice daily) or D-NG-nitro arginine methyl ester (D-NAME, 20 mg kg-1, twice daily) alone had no effect on subsequent morphine antinociception. L-NG-monomethyl arginine (L-NMMA, 10 mg kg-1, twice daily) for two days led to a slight increase (not statistically significant) in morphine antinociception; while L-NG-nitro arginine methyl ester (L-NAME, 10 mg kg-1, twice daily) for two days led to attenuation of morphine analgesia. None of the animals treated with these drugs alone showed signs characteristic of the opioid withdrawal syndrome upon naloxone challenge. 3. Induction phase L-arginine slowed the development of opioid tolerance and physical dependence, while L-NAME and L-NMMA led to a higher degree of tolerance but had no effect on the development of physical dependence. 4. L-Arginine and D-NAME had no effect on the expression of morphine tolerance and physical dependence. Expression phase L-NAME and L-NMMA, on the other hand, attenuated morphine tolerance and reduced the incidence of withdrawal signs. 5. NO may, therefore, play a role in both phases of morphine tolerance and dependence: elevation of NO levels during the induction phase delays the development of opioid tolerance/dependence, while inhibition of NO synthase accelerates the development of tolerance. Inhibition of NO attenuates the expression of both tolerance and physical dependence.

We have examined the hypothesis that intrathecal fentanyl at operation can increase postoperative i.v. morphine requirements. We studied 60 patients undergoing Caesarean section. All received intrathecal 0.5% plain bupivacaine 2 ml combined with either fentanyl 0.5 ml (25 micrograms) (group F) (n = 30) or normal saline 0.5 ml (group S) (n = 30). In addition, 10 ml of an extradural solution (fentanyl 1 ml (50 micrograms) combined with 0.5% bupivacaine 9 ml) was administered after delivery. Extradural solution was only given before delivery if the intrathecal injection failed to produce a block above T6 or the patient required further analgesia. Postoperative analgesia was provided with i.v. morphine patient-controlled analgesia. At operation, intrathecal fentanyl reduced the need to administer extradural solution before delivery, increased the anaesthetist's satisfaction with analgesia and reduced nausea, but increased pruritus. Up to 6 h after delivery there was no difference in postoperative morphine requirements or pain scores. Between 6 h and 23 h there was a 63% increase in morphine requirements in group F. We consider the most likely explanation for this finding to be that intrathecal fentanyl induced acute spinal opioid tolerance.