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Attenuation of tolerance and opioid-induced hyperalgesia
There are a number of strategies that may help attenuate opioid tolerance and OIH, at least to
a certain degree. These include:
• use of NMDA‐ or opioid‐receptor antagonists;
• opioid rotation; and
• other adjuvant drugs.
NMDA and opioid-receptor antagonists
As noted in Section 4.1.3, the NMDA receptor is thought to be involved in the development of
tolerance and OIH (Chang et al, 2007). In rodents, use of the NMDA‐receptor antagonist
ketamine has been shown to attenuate both the development of tolerance (Shimoyama et al,
1996; Laulin et al, 2002) and OIH (Laulin et al, 2002; Haugan et al, 2008).
Angst and Clark (Angst & Clark, 2006) summarised a number of RCTs that investigated the
effects of a short remifentanil infusion in volunteer subjects with pre‐existing experimentally
induced mechanical hyperalgesia; the use of remifentanil was shown to aggravate
hyperalgesia, the magnitude of the effect was directly related to the dose given, and
coadministration of ketamine abolished the effect of remifentanil. However, the evidence for
the ability of ketamine to attenuate the acute tolerance and/or OIH seen after intraoperative
use of remifentanil infusions is conflicting, with both no benefit (Engelhardt et al, 2008 Level II)
and prevention of OIH (Joly et al, 2005 Level II) shown. In patients taking opioids on a long‐term
basis, the administration of ketamine has been reported to lead to improved pain relief and
reduced opioid requirements (Eilers et al, 2001; Sator‐Katzenschlager et al, 2001; Mitra, 2008). After
spinal fusion in opioid‐tolerant patients, use of a continuous ketamine infusion resulted in
significantly less pain but did not reduce PCA opioid requirements (Urban et al, 2008 Level II).
Similarly, in rodents, ultra low doses of naloxone have been shown to attenuate opioid
tolerance (Crain & Shen, 1995; Crain & Shen, 2000; Wang et al, 2005). Clinical studies have
concentrated on the effects of both naloxone and an opioid given acutely, with conflicting
results; both improved postoperative pain and reduced opioid requirements and no
differences in either have been reported (Angst & Clark, 2006; Sloan & Hamann, 2006). There was
no analgesic benefit of adding naloxone to the PCA morphine solution (Sartain & Barry, 1999
Level II; Cepeda et al, 2002 Level II; Cepeda et al, 2004 Level II); in ‘ultra low doses’ but not in the
higher dose studies, the incidence of nausea and pruritus was decreased (Cepeda et al, 2004
Level II). In the experimental pain setting in volunteers, the coadministration of ultra‐low doses
of naloxone to patients given buprenorphine significantly increased tolerance to cold pressor
pain (La Vincente et al, 2008 Level II). There is no information about the effect of naloxone in
patients taking opioids in the longer term.
Use over 3 months of a formulation combining oxycodone and ultra‐low‐dose naltrexone in CHAPTER 11
the same tablet in patients with chronic pain, in comparison with oxycodone alone, showed
that those given the combination had similar pain relief but with significantly smaller doses as
well as less constipation, sedation, itching and physical dependence as assessed by a
withdrawal scale (Webster et al, 2006 Level II).
Opioid rotation
Opioid rotation is commonly used in the treatment of chronic non‐cancer and cancer pain
when a change to another opioid can improve analgesia and reduce side effects (Quigley, 2004;
Mercadante & Arcuri, 2005; Angst & Clark, 2006). Opioid rotation (eg using an opioid that is
different from the preadmission opioid) may also be of use in the acute pain setting (Hadi et al,
2006). The concept is based on the rationale that the different opioids do not act to the same
degree on different opioid receptor subtypes and are metabolised differently, and also takes
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