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18. In clinically relevant doses, there is a ceiling effect for respiratory depression with
buprenorphine but not for analgesia (N) (Level III‐2).
19. Assessment of sedation is a more reliable way of detecting early opioid‐induced respiratory
depression than a decreased respiratory rate (S) (Level III‐3).
20. The evidence for risk of cardiac arrhythmias following low‐dose droperidol is poor (N)
(Level III‐3).
21. In adults, patient age rather than weight is a better predictor of opioid requirements,
although there is a large interpatient variation (U) (Level IV).
22. Impaired renal function and the oral route of administration result in higher levels of the
morphine metabolites morphine‐3‐glucuronide and morphine‐6‐glucuronide with
increased risk of sedation and respiratory depression (S) (Level IV).
The following tick box represents conclusions based on clinical experience and expert
opinion.
The use of pethidine (U) and dextropropoxyphene (N) should be discouraged in favour of
other opioids.
4.2 PARACETAMOL, NON-SELECTIVE NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS AND COXIBS CHAPTER 4
4.2.1 Paracetamol
Paracetamol (acetaminophen) is the only remaining para‐aminophenol used in clinical practice
and is an effective analgesic (see below) and antipyretic. It is absorbed rapidly and well from
the small intestine after oral administration with a bioavailability of between 63% and 89%
(Oscier & Milner, 2009). It can also be given rectally and intravenously (see below and Section 6).
The mechanism of action of paracetamol remains unclear. In contrast with opioids,
paracetamol has no known endogenous binding sites, and unlike NSAIDs, apparently does not
inhibit peripheral cyclo‐oxygenase activity. There is increasing evidence of a central
antinociceptive effect. Although the mechanism of analgesic efficacy of paracetamol remains
elusive, it may involve direct and indirect inhibition of central cyclo‐oxygenases, but the
activation of the endocannabinoid system and spinal serotonergic pathways also appear to be
essential (Bertolini et al, 2006; Botting, 2006; Pickering et al, 2006; Mallet et al, 2008; Pickering et al,
2008). Paracetamol has also been shown to prevent prostaglandin production at the cellular
transcriptional level, independent of cyclo‐oxygenase activity (Mancini et al, 2003).
As one of the mechanisms of action of paracetamol appears to be linked to the serotonergic
system, it is possible that other drugs with serotonergic effects could affect pain relief. In
volunteers, coadministration of tropisetron or granisetron blocked the analgesic effects of
paracetamol (Pickering et al, 2006 Level II; Pickering et al, 2008 Level II). The significance of this in
the clinical setting has not yet been elucidated.
Efficacy
Single doses of paracetamol are effective in the treatment of postoperative pain. The NNTs for
a variety of doses as well as combinations of paracetamol with other analgesic drugs such as
codeine are discussed and listed in Section 6 and Table 6.1.
Superiority of an oral dose of 1000 mg over doses below 1000 mg was shown after wisdom
tooth extraction (Weil et al, 2007 Level I). In a meta‐analysis designed to look at dose response,
Acute pain management: scientific evidence 71
