Factors influencing
opioids tolerance
W. Koppert
Opioids are the drugs of choice for the treatment of
moderate to severe acute and chronic pain. However, clinical evidence suggests
that opioids can elicit increased sensitivity to noxious stimuli suggesting
that administration of opioids can activate both, pain inhibitory and pain
facilitatory systems (1-3). Acute receptor desensitization via uncoupling of
the receptor from G-proteins, upregulation of the cAMP pathway, activation of
the N-methyl-D-aspartate (NMDA) -receptor system, as well as descending
facilitation, have been proposed as potential mechanisms underlying
opioid-induced hyperalgesia (4-9). Interestingly, the same mechanisms were
identified to play a major role in the development of tolerance, leading to the
suggestion that tolerance results from a pain sensitization prozess more than
from a decrease in the opioid effectiveness (10-12).
Numerous reports exist demonstrating that opioid-induced hyperalgesia is
observed both in animal and human experimental models (13-18). Brief exposures
to m-receptor agonists induce long-lasting
hyperalgesic effects for days, which might by reflected by clinical
observations that large-doses of intraoperative m-receptor agonists increased postoperative pain and
morphine consumption. Furthermore, the prolonged use of opioids in patients
often requires increasing doses and may be accompanied by the development of
abnormal pain. Successful strategies that may decrease or prevent
opioid-induced hyperalgesia include the concomitant administration of drugs
like NMDA-antagonists, a2-agonists, or non-steroidal anti-inflammatory
drugs (NSAIDs), opioid rotation or combinations of opioids with different
receptor selectivity (19-26).
1. Vinik HR, Kissin I (1998) Rapid development
of tolerance to analgesia during remifentanil infusion in human. Anesth Analg
86:1307-1311
2. Chia YY, Liu K, Wang JJ, Kuo MC, Ho ST (1999)
Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can
J Anaesth 46:872-877
3. Guignard B, Bossard AE, Coste C, Sessler DI,
Lebrault C, Alfonsi P, Fletcher D, Chauvin M (2000) Acute opioid tolerance:
intraoperative remifentanil increases postoperative pain and morphine
requirement. Anesthesiology 93:409-417
4. Larcher A, Laulin JP, Celerier E, Le Moal M,
Simonnet G (1998) Acute tolerance associated with a single opiate
administration: involvement of N-methyl-D-aspartate-dependent pain facilitatory
systems. Neurosci 84:583-589
5. Celerier E, Laulin J, Larcher A, Le Moal M,
Simonnet G (1999) Evidence for opiate-activated NMDA processes masking opiate
analgesia in rats. Brain Res 847:18-25
6. Vanderah
TW, Gardell LR, Burgess SE, Ibrahim M, Dogrul A, Zhong CM, Zhang ET, Malan TP,
Ossipov MH, Lai J, Porreca F (2000) Dynorphin promotes abnormal pain and spinal
opioid antinociceptive tolerance. J Neurosci 20:7074-7079
7. Vanderah TW, Ossipov MH, Lai J, Malan TP,
Porreca F (2001) Mechanisms of opioid-induced pain and antinociceptive
tolerance: Descending facilitation and spinal dynorphin. Pain 92:5-9
8. Vanderah TW, Suenaga NMH, Ossipov MH, Malan
TP, Lai J, Porreca F (2001) Tonic descending facilitation from the rostral
ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive
tolerance. J Neurosci 21:279-286
9. Freye E,
Latasch L (2003) Toleranzentwicklung unter Opioidgabe - Molekulare Mechanismen
und klinische Bedeutung. Anästhesiol Intensivmed Notfallmed Schmerzther
38:14-26
10. Borgland SL (2001) Acute opioid receptor
desensitization and tolerance: is there a link? Clin Exp Pharmacol Physiol 28:147-154
11. Kieffer BL, Evans CJ (2002) Opioid tolerance -
In search of the holy grail. Cell 108:587-590
12. Simonnet G, Rivat C (2003) Opioid-induced
hyperalgesia: Abnormal or normal pain? Neuroreport 14:1-7
13. Li X, Angst MS, Clark JD (2001) A murine model
of opioid-induced hyperalgesia. Brain Res Mol Brain Res 86:56-62
14. Li X, Angst MS, Clark JD (2001) Opioid-induced
hyperalgesia and incisional pain. Anesth Analg 93:204-209
15. Angst MS, Koppert W, Pahl I, Clark JD, Schmelz M (2003) Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain 106: 49 – 57
16. Koppert W, Angst MS, Alsheimer M, Sittl R,
Albrecht S, Schüttler J, Schmelz M (2003) Naloxone provokes similar pain
facilitation as observed after short-term infusion of remifentanil in humans.
Pain 106: 91-99
17. Koppert W, Sittl R, Scheuber K, Alsheimer M,
Schmelz M, Schüttler J (2003) Differential modulation of remifentanil-induced
analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans.
Anesthesiology 99:152-159
18. Luginbühl M, Gerber A, Schnider TW,
Petersen-Felix S, Arendt-Nielsen L (2003) Modulation of remifentanil-induced
analgesia, hyperalgesia and tolerance by small-dose ketamine in humans. Anesth
Analg 96:726-732
19. Celerier E, Rivat C, Jun Y, Laulin JP, Larcher
A, Reynier P, Simonnet G (2000) Long-lasting hyperalgesia induced by fentanyl
in rats: preventive effect of ketamine. Anesthesiology 92:465-472
20. Guignard B, Coste C, Costes H, Sessler DI,
Lebrault C, Morris W, Simonnet G, Chauvin M (2002) Supplementing
desflurane-remifentanil anesthesia with small-dose ketamine reduces
perioperative opioid analgesic requirements. Anesth Analg 95:103-108
21. Rivat C, Laulin JP, Corcuff JB, Celerier E,
Pain L, Simonnet G (2002) Fentanyl Enhancement of Carrageenan-induced
Long-lasting Hyperalgesia in Rats: prevention by the N-methyl-d-aspartate
Receptor Antagonist Ketamine. Anesthesiology 96:381-391
22. Laulin JP, Maurette P, Corcuff JB, Rivat C,
Chauvin M, Simonnet G (2002) The role of ketamine in preventing fentanyl-induced
hyperalgesia and subsequent acute morphine tolerance. Anesth Analg 94:1263-9
23. Bie B, Fields HL, Williams JT, Pan ZZ (2003) Roles of a1- and a2-adrenoreceptors in the nucleus raphe magnus in opioid analgesia and opioid abstinence-induced hyperalgesia. J Neurosci 23:7950-7957
24. Mao J, Price DD, Caruso F, Mayer DJ (1996)
Oral administration of dextromethorphan prevents the development of morphine
tolerance and dependence in rats. Pain 67:361-368
25. Richebe P, Rivat C, Creton C, Maurette P,
Simonnet G (2003) Nitrous oxide revisited: preventive effects on fentanyl
induced hyperalgesia and morphine acute tolerance. Anesthesiology 99:A940
26. Bie
B, Pan ZZ (2003) Presynaptic mechanism for anti-analgesic and anti-hyperalgesic
actions of k-opioid receptors. J Neurosci 23:7262-7268