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pethidine compared with morphine (Adunsky et al, 2002 Level III‐3) and a variety of other opioids
(Morrison et al, 2003 Level III‐2). Pethidine use postoperatively was associated with an increased
risk of delirium in the postoperative period; there was no difference between various other
opioids (Fong et al, 2006 Level I).
Tolerance and hyperalgesia
In the absence of disease progression, a decrease in the effectiveness of opioid analgesia has
traditionally been attributed to opioid tolerance. It is now known that administration of
opioids can lead to both opioid‐tolerance (a desensitisation of antinociceptive pathways to
opioids) and, paradoxically, to opioid‐induced hyperalgesia (OIH) (a sensitisation of
pronociceptive pathways leading to pain hypersensitivity), and that both these phenomena
can significantly reduce the analgesic effect of opioids (Angst & Clark, 2006; Chu LF et al, 2008).
The mechanisms underlying the development of tolerance and OIH are still not fully
understood but, as with neuropathic pain, are thought to include activation of the
glutaminergic system via the NMDA receptor, as well as other transmitter and receptor
systems (Angst & Clark, 2006; Mao, 2008).
Mao (Chang et al, 2007; Mao, 2008) distinguishes between ‘pharmacological tolerance’
(ie tolerance, as defined in Section 11.7 — the predictable and physiological decrease in the
effect of a drug over time) and ‘apparent tolerance’, where both tolerance and OIH contribute
CHAPTER 4 relevant contribution of pharmacological tolerance and OIH to ‘apparent tolerance’ in any
to a decrease in the effectiveness of opioids. The clinical significance of this mix, and the

particular patient, is difficult if not impossible to determine (Angst & Clark, 2006). Inadequate
pain relief because of pharmacological tolerance may improve with opioid dose escalation,
while improvements in analgesia in the presence of OIH may follow a reduction in opioid dose
(Chang et al, 2007; Mao, 2008; Chu LF et al, 2008).
It is probable that the degree of OIH varies between opioids. Morphine, in high doses, may be
more likely to result in OIH than other opioids; experimental data and a very limited number
of case reports have shown an improvement when morphine doses were reduced or a change
to methadone, fentanyl or sufentanil was made (Angst & Clark, 2006). Similarly, it appears that
opioids differ in their ability to induce tolerance and, at least in part, this may reflect their
varying ability to promote receptor internalisation and recycling. While drugs such as
methadone, fentanyl and sufentanil promote receptor internalisation and thereby recycling,
activation of opioid receptors by morphine leads to little or no receptor internalisation and an
increased risk of development of tolerance (Joo, 2007).
The difference between opioids is one reason why opioid‐rotation may be a useful strategy in
the clinical setting in attempts to improve pain relief (see Section 11.7.3).
Studies using experimental pain stimuli
Many animal studies have shown that opioid administration can lead to OIH (Angst & Clark,
2006). A number of human studies have also investigated changes in pain sensitivity following
long‐term opioid use and reported increases in sensitivity to certain pain stimuli.
Patients taking methadone as part of a drug‐dependence treatment program have been
shown to have an increased sensitivity to cold pressor pain stimuli (Compton et al, 2000 Level IV;
Doverty et al, 2001 Level III‐2; Athanasos et al, 2006 Level III‐2). Similarly, pain sensitivity to cold
pressor but not heat stimuli was noted in patients 1 month after starting oral morphine
therapy (Chu et al, 2006 Level III‐2), and to cold pressor but not electrical pain stimuli in patients
with chronic non‐cancer pain taking either methadone or morphine (Hay et al, 2009 Level III‐2).
In a comparison of methadone‐maintained and buprenorphine‐maintained patients, pain
sensitivity to cold pressor pain stimuli was increased in both groups and overall there was no

68 Acute Pain Management: Scientific Evidence