Glasgow Meeting - May 2003

Acute opioid tolerance, facts and clinical significance

Marcel Chauvin

Pharmacological tolerance is defined as a decrease in the effect of a drug administered in repeated boluses or in continuous infusion. In clinical practice, opioid pharmacological tolerance results to a diminishing analgesic efficacy during a course of opioid therapy, resulting in an opioid dose escalating in order to restore opioid analgesic effects. This opioid tolerance is not limited to chronic therapy, it can be also observed after an acute administration. Moreover, two opposing cellular mechanisms are involved in an opioid tolerance: a desensitization process (pharmacological tolerance) and a sensitization process (opioid-induced pain sensitivity).

Different groups have published a decrease in the dose response effects of opioids on nociception during acute administrations in animals. This decline in the antinociceptive efficacy is much rapidly observed with short acting opiates such as alfentanil than with long acting opiates such as morphine (1). Interestingly, this tolerance is associated to a progressive reduction of baseline nociceptive thresholds (allodynia). This was clearly demonstrated by Mao et al in rats receiving repeated intrathecal morphine administration over a period of 7 days (2) or by Kissin et al after a 4 hour infusion of alfentanil (3). The Laulin et al’s study reported an obvious relationship between acute tolerance and hyperalgesia in rats receiving repeated once daily heroin (4). A progressive decrease in heroin analgesic effects was combined to a gradual lowering of the nociceptive threshold. This same group reported that opioid induced hyperalgesia is dose-dependent (5). Larger was the dose of subcutaneous fentanyl bolus and more marked was the reduction of baseline nociceptive thresholds.

In this study, decreased baseline nociceptive thresholds lasted as long as 5 days after the cessation of four fentanyl bolus injections. Opioid-induced hyperalgesia is also time-dependent. In a recent study, allodynia following an opioid infusion was increased with longer opioid infusions in comparison to shorter ones (6). All these studies strongly indicate that repeated opioid administration or continuous infusion could lead to a progressive progressive, long-lasting, dose and time-dependent reduction of baseline antinociceptive thresholds, hence an increase in pain sensitivity.

In volunteers, tolerance to analgesia during remifentanil infusion at a constant rate for 4 h was profound and developed very rapidly within 60-90 min after the start of infusion (7). Moreover, delayed hyperalgesia from short-acting opioid exposure was reported in volunteers by different groups (8-10). However, unlike these experimental conditions in which changes in baseline nociceptive thresholds are measured in a controlled setting, it is often difficult to determine whether changes in pain sensitivity occur clinically following opioid administration. Nevertheless, it has been observed in several studies that larger was the intraoperative opioid dose, greater was postoperative opioid consumption (11-13), and higher were the pain scores (12,13). For example, we found, in patients who had received remifentanil-based anesthesia for abdominal surgery averaging 4 h, that their demand for morphine in the first 24 h was nearly twice that of those who received desflurane-based anesthesia (13). By contrast, a lack of change in opioid analgesic efficacy under a similar condition was reported (14). However, in this study (14), remifentanil exposure was of two hours and N2O was used in the anesthetic procedure.

The neuronal mechanisms of opioid-induced pain sensitivity are complex, multiple and incompletely well known. They combined principally:

	activation of the central glutaminergic system
	increases in spinal dynorphin
	involvement of descending sensitization process.

Opioid large dose-induced hyperalgesia has important clinical consequences. It represents an argument:

2) to avoid the intra-operative use of large opioid doses. It is a supplementary reason to limit the use of opioid to doses that interferes in synergy with general anesthetics.

3) to combine opioids with NMDA antagonists such as ketamine or N2O. We observed that supplementing remifentanil-based anesthesia with smalldose ketamine decreased intraoperative remifentanil use and postoperative morphine consumption (15).

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2. Mao et al. J Neurosci 1994;14:2301-12.

3. Kissin et al. Anesth Analg 2000;91:1483-8.

4. Laulin et al. Neuroscience 1999;89 :631-6.

5. Célèrier et al. Anesthesiology 2000;92 :465-72.

6. Shung-Tai et al. Anesth Analg 2002;95 :948-51.

7. Vinik and Kissin. Anesth Analg 1998;86 :1307-11.

8. Koppert et al. Anesthesiology 2001;95 :395-402.

9. Koppert et al. Anesthesiology 2001;95 :A 861.

10. Pettersen et al. Anesthesiology 2001;94 :15-20.

11. McQuay et al. Life Sciences 1981;28 :2513-7.

12. Chia et al. Can J Anaesth 1999;46 :872-7.

13. Guignard et al. Anesthesiology 2000;93 :409-17.

14. Cortinez et al. Br J Anaesth 2001;87 :866-9.

15. Guignard et al. Anesth Analg 2002;95 :103-8.