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profile, adverse effects and use of parenteral forms (eg parecoxib) of coxibs have not been
adequately studied in children.
10.5.4 Opioids and tramadol
As there are significant developmental changes in the pharmacokinetic handling (Bouwmeester
et al, 2004) and pharmacodynamic response to opioids (Nandi & Fitzgerald, 2005), doses must be
adjusted according to age and individual response. Routine and regular assessment of pain
severity, the analgesic response, and the incidence of side effects (particularly nausea and
vomiting and sedation) is essential, with titration of opioid treatment according to individual
needs. As with adult patients, appropriate dose regimens, guidelines for monitoring,
documentation, management of side effects, and education of staff and carers are required
(Wrona et al, 2007 Level IV) (see Section 4).
Morphine
The clearance of morphine is reduced and half‐life prolonged in neonates and infants
(Bouwmeester et al, 2004; Anand et al, 2008). Within age groups, individual variability in kinetics
results in 2 to 3‐fold differences in plasma concentration with the same rate of infusion (Lynn
et al, 1998). In neonates, infants and children to 3 years, age was the most important factor
affecting morphine requirements and plasma morphine concentrations (Bouwmeester, van den
Anker et al, 2003 Level II), and in older children average patient‐controlled morphine
requirements also change with age (Hansen et al, 1996 Level IV).
The risk of respiratory depression is reduced when infusions are targeted to plasma morphine
concentrations less than 20 ng/mL. However, no minimum effective concentration for
analgesia has been determined (Kart, Christrup et al, 1997). No clear relationship between
plasma concentration and analgesia has been identified due to variability in individual
requirements, the clinical state of the child, the type of surgery, the assessment measure used
and the small sample size in many studies (Bouwmeester, Hop et al, 2003 Level II; Anand et al, 2008
Level II). Analysis of 35 paediatric RCTs of morphine, administered via IV, epidural, IM and
intrathecal routes, reported analgesic efficacy in comparison with inactive controls, but with
significantly increased vomiting and sedation. The majority of studies analysed compared
single perioperative doses and only one study evaluated a postoperative infusion of morphine
(Duedahl & Hansen, 2007 Level II).
CHAPTER 10 Fentanyl is a potent mu‐opioid agonist and highly lipophilic. Rapid redistribution contributes
Fentanyl
to offset of action, fentanyl is metabolised by CYP3A4 to inactive metabolites, and clearance is
only 70‐80% of adult levels in neonates but rapidly matures (Tibboel et al, 2005). Fentanyl has
been administered by multiple routes for perioperative pain management in neonates (Simons
& Anand, 2006) and children (Howard et al, 2008), including: IV infusion or PCA (Antila et al, 2006
Level II; Butkovic et al, 2007 Level III‐1); intrathecal (Batra et al, 2008 Level II) injection; epidural
infusion (Lerman et al, 2003 Level II) and patient‐controlled epidural analgesia (PCEA) (Saudan et
al, 2008 Level III‐3). Prolonged IV infusion of fentanyl during neonatal intensive care has been
associated with more rapid dose escalation than morphine, but both can produce opioid
withdrawal symptoms following rapid cessation (Simons & Anand, 2006).
Due to its rapid onset and short duration of action, fentanyl can be used alone or in
combination with sedatives, to control procedural pain (Tibboel et al, 2005), but opioid‐related
side effects, such as nausea and vomiting and respiratory complications may also be increased
(Migita et al, 2006 Level I). Due to its high lipophilicity, fentanyl can also be administered via
transmucosal, IN, and inhaled routes (Robert et al, 2003 Level II) (Borland et al, 2005 Level II).
Transdermal fentanyl has approximately 30% of the IV bioavailability (Tibboel et al, 2005).
350 Acute Pain Management: Scientific Evidence
