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Respiratory depression has been reported to occur in up to 5.4% of patients depending on the
definition used (Carvalho et al, 2005 Level II; Gambling et al, 2005 Level II; Viscusi et al, 2005 Level II;
Martin et al, 2006 Level II) and it may require prolonged treatment; in one patient naloxone was
required for 62 hours (Martin et al, 2006 Level II).
It has been recommended that the liposome preparation of Depodur® not be administered
while local anaesthetics are present in the epidural space as this may cause early release of
the morphine (Viscusi et al, 2009 Level II). When Depodur® was administered within 3 to
15 minutes of a 3 mL test dose of 1.5% lignocaine with adrenaline, higher C max values for
morphine were indeed reported compared with C max values when no lignocaine was
administered; there was no difference in morphine C max if the interval was greater than
30 minutes (Viscusi et al, 2009 Level II). The C max of morphine was unchanged when Depodur®
doses were given 15, 30 and 60 minutes after an anaesthetic dose of epidural bupivacaine –
20 ml of 0.25% (Gambling et al, 2009 Level II).

5.2.2 Peripheral opioids
Opioid receptors on sensory unmyelinated C nerve fibres mediate peripheral antinociceptive
effects in animal studies (Stein et al, 1990). In the presence of inflammation, opioid receptors
are transported to the periphery and increased amounts of endogenous opioid peptides are
present in infiltrating immune cells (Schafer, 1999; Smith, 2008; Stein, 1995). An experimental
model of inflammatory hyperalgesia caused by ultraviolet light showed that analgesia
mediated via peripheral opioid mechanisms could also occur in humans (Koppert et al, 1999
Level II). In joint studies, the increase in opioid receptors and their endogenous peptides
correlated with the degree of inflammation, being more abundant in rheumatoid arthritis than
in osteoarthritis and joint trauma (Mousa et al, 2007), consistent with the clinical observation CHAPTER 5
that peripheral opioids are more effective in the presence of inflammation. Intra‐articular
bupivacaine was less effective than morphine in providing analgesia in patients having ‘high
inflammatory arthroscopic knee surgery’, whereas bupivacaine was more effective than
morphine in those having ‘low inflammatory surgery’ (Marchal et al, 2003 Level II) (see also
Section 7.5).
In clinical practice, morphine injected as a single dose into the knee intra‐articular space
produced analgesia that lasted up to 24 hours, but evidence for a peripheral rather than a
systemic effect was not conclusive (Gupta et al, 2001 Level I; Kalso et al, 2002 Level I).
Confounding variables that hinder analysis included the pre‐existing degree of inflammation,
type of surgery, the baseline pain severity and the overall relatively weak clinical effect (Gupta
et al, 2001 Level I). When published trials were analysed taking these confounding factors into
consideration, including the intensity of early postoperative pain, the data did not support an
analgesic effect for intra‐articular morphine following arthroscopy compared with placebo
(Rosseland, 2005 Level I).

Note: reversal of conclusions
This reverses the Level 1 conclusion in the previous edition of this
document; the earlier meta‐analyses performed without taking
confounding factors into consideration had reported improved
pain relief with intra‐articular morphine.

Acute pain management: scientific evidence 129