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Dextropropoxyphene
Dextropropoxyphene is often used in combination with paracetamol but this combination
does not lead to better pain relief compared with paracetamol alone and increases the
incidence of dizziness (Li Wan Po & Zhang, 1997 Level I). A later study comparing this combination
with paracetamol alone in the treatment of pain after third molar surgery confirmed the lack
of analgesic benefit (Sorich et al, 2004 Level II).
The use of this compound is discouraged, not only because of its low efficacy, but also
because of a number of risks related to its use (Barkin et al, 2006). These include a euphorigenic
component with risk of abuse and complex pharmacokinetics (particularly in the elderly), with
the risk of accumulation and QT‐interval prolongation and possibility of Torsades de Pointes
(TdP) and cardiogenic death. For these reasons, it was announced that a phased withdrawal of
dextropropoxyphene combination preparations would commence in the United Kingdom from
January 2005 (Hawton et al, 2009). A marked decrease in prescribing of this combination was
followed by a major reduction in deaths (accidental and suicide) related to its use, and
while prescriptions of other analgesics increased significantly during this time, there was
no evidence of a corresponding increase in deaths related to use of these other drugs (Hawton
et al, 2009).
The major metabolite of dextropropoxyphene is nordextropropoxyphene, which has a mean
half‐life of 29 hours (compared with 16 hours for the parent drug) and is renally excreted
(Brosen et al, 1985); accumulation of nordextropropoxyphene can lead to CNS, respiratory and
cardiac depression (Davies et al, 1996). CHAPTER 4
Diamorphine
Diamorphine (diacetylmorphine, heroin) is rapidly hydrolysed to monoacetylmorphine (MAM)
and morphine; diamorphine and MAM are more lipid soluble than morphine and penetrate
the CNS more rapidly, although it is MAM and morphine that are thought to be responsible for
the analgesic effects of diamorphine (Miyoshi & Lackband, 2001).
There was no difference between parenteral diamorphine and morphine in terms of analgesia
and side effects after hip surgery (Robinson et al, 1991 Level II). Epidurally administered
diamorphine resulted in a longer time to first PCA use and lower total 24‐hour morphine
requirements compared with the same dose given as an IM injection (Green et al, 2007 Level II).
Dihydrocodeine
Dihydrocodeine is a semi‐synthetic derivative of codeine and has similar mu‐opioid agonist
activity. However, unlike codeine, inhibition of CYP2D6 by quinine does not alter its analgesic
effect, even though the CYP2D6‐dependant active metabolite, dihydromorphine, has a much
higher mu‐opioid receptor affinity than the parent drug (Lotsch, 2005).
Fentanyl
Fentanyl is a highly potent phenylpiperidine derivative, structurally related to pethidine. It is
metabolised almost exclusively in the liver to minimally active metabolites. Less than 10% of
unmetabolised fentanyl is renally excreted. Fentanyl is commonly used in the treatment of
acute pain, especially when its lack of active metabolites and fast onset of action may be of
clinical benefit (Peng & Sandler, 1999).
Mu‐opioid receptor A304G polymorphisms can affect pain relief after fentanyl administration.
Intrathecal fentanyl requirements in labour were reduced in women with the 304G allele but
increased in those with the 304A allele of genes encoding the mu‐opioid receptor (Landau et al,
2008 Level III‐3).
Acute pain management: scientific evidence 57
