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Low‐dose parenteral ketamine may also improve analgesia in patients with opioid‐induced
tolerance or hyperalgesia. 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 (Bell, 1999; Eilers 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). The evidence for the ability of
ketamine to attenuate the acute tolerance and/or OIH seen after intraoperative use of
remifentanil infusions is conflicting. Ketamine infusion reduced the area of punctate
mechanical hyperalgesia around the wound and postoperative morphine consumption,
following high‐dose remifentanil infusion during laparotomy (Joly et al, 2005 Level II). In
paediatric scoliosis surgery, ketamine did not decrease postoperative morphine requirements
after remifentanil‐based anaesthesia (Engelhardt et al, 2008 Level II).
Perioperative ketamine has ‘preventive’ (Katz & Clarke, 2008 Level I), but not ‘pre‐emptive’ (Ong
et al, 2005 Level I) analgesic effects in the immediate postoperative period. Ketamine reduced
the area of wound hyperalgesia and allodynia after nephrectomy (Stubhaug et al, 1997 Level II)
and laparotomy (De Kock et al, 2001 Level II). Perioperative ketamine administration reduced the
incidence of CPSP following thoracotomy (Suzuki et al, 2006 Level II) and laparotomy (De Kock et
al, 2001 Level II), possibly reflecting a prolonged ‘preventive analgesia’ effect. However, there
was no significant effect on CPSP following total knee replacement (Adam et al, 2005 Level II) or
radical prostatectomy (Katz et al, 2004 Level II), or on the incidence of phantom or stump pain
6 months after lower limb amputation (Hayes et al, 2004 Level II), although this latter study may
have been underpowered. CHAPTER 4
Ketamine showed a significant analgesic effect in patients with neuropathic pain after spinal
cord injury (Kvarnstrom et al, 2004 Level II).
Adverse effects with short‐term systemic administration of ketamine
The addition of low‐dose ketamine did not alter the overall incidence of adverse effects
compared with opioids alone (Elia & Tramer, 2005 Level I). When used in conjunction with PCA
morphine, adverse effects were noted to be mild or absent (Bell et al, 2006 Level I).
Routes of systemic administration and bioavailability
Ketamine is most commonly administered as a continuous low‐dose intravenous infusion,
however SC infusion is also used, especially in palliative care, with a bioavailability (similar to
IM) of approximately 90% (Clements et al, 1982). Sublingual, intranasal (IN) and transdermal
routes have also been used for acute pain management (see Section 6).
A pharmacokinetic study in healthy volunteers calculated the bioavailability of oral ketamine
as 20%, sublingual 30% and IN 45%: the pharmacodynamic effects of the active metabolite
norketamine were thought to be of potential significance (Yanagihara et al, 2003). The
bioavailability of a 25 mg ketamine lozenge was 24% when given by both sublingual and oral
routes; peak plasma levels were seen at 30 minutes and 120 minutes respectively and terminal
half‐lives were similar at around 5 hours (Chong et al, 2009). For both routes, norketamine
concentrations exceeded the concentrations of ketamine, and given its pharmacological
activity profile, norketamine is therefore likely to be a major contributor to the overall
analgesic effect.
Dextromethorphan
A review of dextromethorphan for perioperative analgesia concluded that while some studies
showed a decrease in opioid consumption and opioid‐related side effects, any reduction in
pain was not clinically significant and that, ‘the consistency of the potential opioid‐sparing and
pain reducing effect must be questioned’ (Duedahl et al, 2006). A meta‐analysis was not

Acute pain management: scientific evidence 85