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6.4.3 Paracetamol

Paracetamol is effective when given by the rectal route (Romsing et al, 2002 Level I)
although rectal absorption of paracetamol was slower and less predictable than after oral
administration, with a bioavailability of between 24% and 98% (Oscier & Milner, 2009). It was
also less effective than the same dose administered by the oral route (Anderson et al, 1996
Level II; Anderson et al, 1999 Level IV). Doses of 1 g rectally after cardiac surgery (Holmer
Pettersson et al, 2006 Level II) and hysterectomy (Kvalsvik et al, 2003 Level II) as well as 2 g given
rectally to patients undergoing laparoscopic gynaecological surgery (Hahn, Mogensen et al,
2000 Level II) also resulted in subtherapeutic blood levels, although levels may increase to
within the therapeutic range after repeat administration (Holmer Pettersson et al, 2006 Level II).
In children, similar results have been noted. Initial administration of doses of 25 mg/kg
achieved average blood concentrations at the lower end of the therapeutic range and large
variations in absorption were reported (Hahn, Henneberg et al, 2000 Level IV).
Higher doses may be more effective. Blood concentrations in the therapeutic range have been
reported in adults after doses of 40 mg/kg but not 20 mg/kg (Beck et al, 2000 Level IV) and
sustained therapeutic levels followed the use of 35 mg/kg and 45 mg/kg but not 15 mg/kg and
25 mg/kg (Stocker & Montgomery, 2001 Level IV). In children, initial doses of 40 mg/kg followed
by 20 mg/kg also provided therapeutic blood levels without evidence of accumulation
(Birmingham et al, 2001 Level IV).
When available, the oral route is therefore preferable.

6.5 TRANSDERMAL ROUTE

Not all medications applied topically have a local, peripheral action. The term ‘transdermal’
will be used to describe drugs that while applied to the skin, have predominantly central CHAPTER 6
effects that are the result of systemic absorption of the drug. The term ‘topical’ will be used in
the discussion of drugs — primarily NSAIDs — that are applied topically (including to skin) but
have a predominantly peripheral effect.

6.5.1 Opioids
The stratum corneum of the epidermis forms a major barrier to the entry of drugs. However,
drugs such fentanyl (Sathyan et al, 2005) and buprenorphine (Skaer, 2006) are available as
transdermal preparations. The analgesic effects are a result of systemic effects rather than
local peripheral opioid analgesia (Worrich et al, 2007 Level IV). The original transdermal fentanyl
patches consisted of a reservoir system and rate‐controlling membrane. In the newer system,
which has the same bioequivalence, the fentanyl is dissolved in the adhesive matrix; the
patient’s stratum corneum and the characteristics of the drug‐in‐adhesive matrix control the
rate of systemic delivery (Sathyan et al, 2005).
Transdermal fentanyl is commonly used in the management of cancer and chronic pain.
Due to the formation of a significant intradermal ‘reservoir’, onset and offset times of this
preparation are slow and this makes short‐term titration impossible. The time to peak blood
concentration is generally between 24 and 72 hours after initial patch application and after
the patch is removed, serum fentanyl concentrations decline gradually, with a mean terminal
half‐life ranging from 22 to 25 hours (MIMS, 2008).
Transdermal fentanyl patches are currently specifically contraindicated for the management of
acute or postoperative pain in many countries (FDA, 2007; eCompendium, 2008; MIMS, 2008) and

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