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Other analgesic drugs
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. 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
(Chong et al, 2009).

6.6.3 Inhaled

Opioids
Opioids are rapidly absorbed after nebulised inhalation, reflecting the high blood flow,
surface area, and permeability of the lungs.
Clinical data exist for the effectiveness of several opioids administered via the pulmonary
route including morphine (Masood & Thomas, 1996 Level II; Ward et al, 1997 Level II; Dershwitz et al,
2000 Level IV; Thipphawong et al, 2003 Level II) and fentanyl (Worsley et al, 1990 Level II; Miner et al,
2007 Level II). In a small study of 44 patients with post‐traumatic thoracic pain, there was no
difference in the pain relief obtained from nebulised morphine and PCA morphine (Fulda et al,
2005 Level II). In another study of only 28 patients in an emergency department, no patient
experienced pain relief 10 minutes after inhalation of morphine (Bounes et al, 2009 Level III‐3).
In children requiring pain relief in an emergency department, nebulised fentanyl was also as
effective as IV fentanyl (Miner et al, 2007 Level II) (see Sections 9.3 and 10.4.4).
Peak plasma concentrations following administration of morphine via a standard nebuliser CHAPTER 6
occured within 10 minutes but bioavailability was low with a mean of only 5% (Masood &
Thomas, 1996 Level II). Bioavailability may be improved (up to 59 to 100%) with peak plasma
concentrations occurring at 2 minutes using pulmonary drug delivery systems (Ward et al, 1997
Level II; Dershwitz et al, 2000 Level IV). Similarly, bioavailability of inhaled fentanyl may approach
100% (Mather et al, 1998 Level IV).
These systems await further development and thus these data are insufficient to support the
routine use of inhaled opioids in acute pain management.
Other analgesic drugs
See Section 4.3.1 for inhaled nitrous oxide and methoxyflurane.

Key messages
1. Paracetamol combined with codeine is more effective than either drug alone and shows a
dose‐response effect (N) (Level I [Cochrane Review]).

2. NSAIDs (both nsNSAIDs and coxibs) given parenterally or rectally are not more effective
and do not result in fewer side effects than the same drug given orally (U) (Level I
[Cochrane Review]).
3. Paracetamol combined with tramadol is more effective than either drug alone and shows a
dose‐response effect (N) (Level I).
4. Early postoperative oral administration of paracetamol results in highly variable plasma
concentrations that may remain subtherapeutic in some patients (N) (Level II).

Acute pain management: scientific evidence 163