Page 104 Acute Pain Management

In clinically relevant doses, buprenorphine appears to behave like a full mu‐opioid receptor
agonist, and in animals as well as humans in low doses (ie transdermal buprenorphine), there
also appears to be no antagonism of other concurrently administered mu‐agonist drugs (Kress,
2009). Contrary to earlier concerns, there was a ceiling effect found for respiratory depression
but not for analgesia (Dahan et al, 2005 Level III‐2; Dahan et al, 2006 Level III‐2). The risk of
respiratory depression is low compared with morphine, methadone, hydromorphone and
fentanyl, even in the doses used for the treatment of opioid addiction, as long as concurrent
sedative medications are not given (Kress, 2009). Should buprenorphine‐induced respiratory
depression occur, reversal is possible although higher‐than‐usual doses and a longer duration
infusion of naloxone may be required (van Dorp, Yassen et al, 2006 Level III‐2).
In animal models of pain, buprenorphine appears to have good efficacy for neuropathic pain
(Hans, 2007). In the clinical setting, case reports have suggested that buprenorphine is also
effective (Kress, 2009). Using experimental pain stimuli in humans, and unlike pure mu‐opioid
agonists, buprenorphine has been shown to be antihyperalgesic (ie the area of hyperalgesia
was reduced), which may be related in part to its kappa‐opioid antagonist activity (Koppert
et al, 2005).
Withdrawal symptoms, which may be seen if the drug is ceased after long‐term treatment,
are milder and more delayed in onset (72 hours or more) than other opioids (Kress, 2009).
CHAPTER 4 Codeine is classified as a weak opioid. However, it is only a very weak mu‐receptor agonist and
Codeine

its analgesic action depends on the metabolism of about 10% of the dose given to morphine,
via the CYP2D6 cytochrome P450 isoenzyme (Lotsch, 2005).
Over 100 allelic variants of CYP2D6 have been identified, resulting in wide variability in enzyme
activity (Somogyi et al, 2007). Individuals carrying two wild type alleles display normal enzyme
activity and are known as extensive metabolisers; intermediate metabolisers are
heterozygotes with two variant alleles known to decrease enzymatic capacity; and poor
metabolisers have no functionally active alleles and have minimal or no enzyme activity
(Stamer & Stuber, 2007). In Caucasian populations, 8% to 10% of people are poor metabolisers;
however 3% to 5% are ultrarapid metabolisers (Stamer & Stuber, 2007; Madadi et al, 2009). Those
who are ultrarapid metabolisers (carriers of the CYP2D6 gene duplication) have significantly
higher levels of morphine and morphine metabolites after the same dose of codeine
(Kirchheiner et al, 2007 Level IV).
There are large inter‐ethnic differences in the frequencies of the variant alleles. For example,
the proportion of ultrarapid metabolisers is higher (up to 29%) in Middle Eastern and Northern
African populations, and lower (0.5%) in Asians (Stamer & Stuber, 2007); the proportion of poor
metabolisers is lower in Asians and African Americans (Holmquist, 2009).
A case‐control study including a case of a newborn dying while breastfed by a mother taking
codeine has highlighted that breastfed infants of mothers who are ultrarapid metabolisers are
at increased risk of life‐threatening CNS depression (Madadi et al, 2009 Level III‐2). A number of
similar cases have been reported and health care workers and mothers of breastfeeding
infants should be aware of this risk (Madadi et al, 2008 Level IV). CYP2D6 genotyping predicts
subjects with reduced metabolism to morphine, but must be combined with additional
phenotyping to accurately predict patients at risk of morphine toxicity (Lotsch et al, 2009
Level III‐2).
The principal metabolite of codeine is codeine‐6‐glucuronide, which has a similar low potency
to the parent drug and is renally excreted.

56 Acute Pain Management: Scientific Evidence