Page 108 Acute Pain Management

In an experimental pain model comparing oxycodone, morphine and placebo, and involving
mechanical, thermal and electrical pain stimuli in skin, muscle and oesophagus, oxycodone
was more effective than morphine for pain related to mechanical and thermal stimulation of
the oesophagus, suggesting it could be better than morphine for visceral pain (Staahl et al, 2006
Level II). One explanation of this difference is that, in animal studies at least, oxycodone is
thought to act as a kappa‐receptor agonist (Nielsen et al, 2007) and these receptors may play an
important role in the mediation of visceral pain (Staahl et al, 2006).
Pethidine
Pethidine (meperidine) is a synthetic opioid still widely used even though it has multiple
disadvantages. Despite a common belief that it is the most effective opioid in the treatment of
renal colic, it was no better than morphine (O'Connor et al, 2000 Level II) or hydromorphone
(Jasani et al, 1994 Level II). Similarly, pethidine and morphine had similar effects on the sphincter
of Oddi and biliary tract and there was no evidence that pethidine was better in the treatment
of biliary colic (Latta et al, 2002 Level IV).
Pethidine induced more nausea and vomiting than morphine when used parenterally in the
emergency department (Silverman et al, 2004 Level III‐3) and in the first 2 hours after
gynaecological surgery (Ezri et al, 2002 Level II).
Accumulation of its active metabolite, norpethidine (normeperidine), is associated with
CHAPTER 4 neuroexcitatory effects that range from nervousness to tremors, twitches, multifocal
myoclonus and seizures (Simopoulos et al, 2002 Level IV). As impaired renal function increases
the half‐life of norpethidine, patients with poor renal function are at increased risk of
norpethidine toxicity. Naloxone does not reverse and may increase the problems related to
norpethidine toxicity. Overall, the use of pethidine should be discouraged in favour of other
opioids (Latta et al, 2002).
Tramadol
Tramadol is commonly referred to as an atypical centrally acting analgesic because of its
combined effects as an opioid agonist and a serotonin and noradrenaline reuptake inhibitor
(Lotsch, 2005). Although an effective analgesic, it may not provide adequate pain relief if used
as the sole agent for the management of moderate to severe acute pain in the currently
recommended doses (Thevenin et al, 2008 Level II). Tramadol is an effective treatment of
neuropathic pain with an NNT of 3.8 (Hollingshead et al, 2006 Level I).
Tramadol given with morphine to patients immediately after surgery was shown to be
morphine‐sparing, but the combination was infra‐additive (Marcou et al, 2005 Level II).
The (+) enantiomer of tramadol is the stronger inhibitor of serotonin reuptake and the (‐)
enantiomer the more potent inhibitor of noradrenaline reuptake; tramadol is metabolised by
CYP2D6 and the resultant active metabolite, O‐desmethyltramadol (or M1), is a more potent
mu‐opioid receptor agonist than the parent drug (Raffa et al, 1992; Lotsch, 2005). Patients who
are poor metabolisers may get less analgesic effect from tramadol (Stamer et al, 2003).
Conversely, carriers of a CYP2D6 gene duplication allele (ultrarapid metabolisers) may be more
sensitive to the effects of tramadol (Kirchheiner et al, 2008).
Coadministration with other drugs that inhibit CYP2D6 may also influence the effectiveness of
tramadol. For example, pretreatment with paroxetine in healthy extensive metabolisers
reduced the hypoalgesic effect of tramadol in an experimental pain model (Laugesen et al, 2005
Level II).
Inhibition of 5HT3 receptors by ondansetron also decreased the analgesic effect of tramadol
(Arcioni et al, 2002 Level II; De Witte et al, 2001 Level II).

60 Acute Pain Management: Scientific Evidence