Page 120 Acute Pain Management

1000 mg was superior to 500 mg (McQuay & Moore, 2007 Level I). However, in a broader meta‐
analysis, no dose‐response was noted between doses of 500 mg, 600 to 650 mg and 975 to
1000 mg; the rate of adverse effects was comparable to placebo (Toms et al, 2008 Level I). A
comparison of two high‐dose regimens of oral paracetamol in young adults undergoing third
molar extractions showed no difference between doses of 90 mg/kg and 60 mg/kg (Zacharias et
al, 2007 Level II). Another comparison of single doses of IV doses of 2 g and 1 g showed better
pain relief following third molar surgery with the 2 g dose (Juhl et al, 2006 Level II).
Paracetamol is also an effective adjunct to opioid analgesia, opioid requirements being
reduced by 20% to 30% when combined with a regular regimen of oral or rectal paracetamol
(Romsing et al, 2002 Level I). The use of oral paracetamol in higher daily doses (1 g every 4 hours)
in addition to PCA morphine lowered pain scores, shortened the duration of PCA use and
improved patient satisfaction (Schug et al, 1998 Level II). Meta‐analyses looking at paracetamol
as an adjunct to PCA opioids also showed that PCA morphine requirements were decreased
but that there was no improvement in pain relief or decrease in opioid‐related adverse effects
(Elia et al, 2005 Level I; Remy et al, 2005 Level I).
In the same doses, orally administered paracetamol was less effective and of slower onset
than paracetamol given by IV injection, but more effective and of faster onset than
paracetamol administered by the rectal route, when subtherapeutic blood concentrations are
CHAPTER 4 IV paracetamol was an effective analgesic after surgery (Sinatra et al, 2005 Level II). It was as
common (see Section 6).

effective as ketorolac (Varrassi et al, 1999 Level II; Zhou et al, 2001 Level II), diclofenac (Hynes et al,
2006 Level II) and metamizol (Landwehr et al, 2005 Level II) and was equivalent to morphine and
better tolerated after dental surgery (Van Aken et al, 2004 Level II), although there was evidence
of a ceiling effect (Hahn et al, 2003 Level II). Compared with parecoxib, propacetamol (the IV
prodrug of paracetamol) led to the same degree of opioid‐sparing after surgery, although
patients receiving parecoxib were more likely to rate their pain relief as ‘good’ or ‘excellent’
(Beaussier et al, 2005 Level II).
The combination of paracetamol and NSAID was clearly more effective than paracetamol
alone, but evidence for superiority relative to the NSAID alone was more limited and of
uncertain clinical significance (Hyllested et al, 2002 Level I; Romsing et al, 2002 Level I).
Adverse effects
Paracetamol has fewer side effects than NSAIDs and can be used when the latter are
contraindicated (eg patients with a history of asthma or peptic ulcers). It is commonly
recommended that paracetamol should be used with caution or in reduced doses in patients
with active liver disease, history of heavy alcohol intake and glucose‐6‐phosphate
dehydrogenase deficiency. However, others report that it can be used safely in patients with
liver disease and is preferred to NSAIDs, and that therapeutic doses of paracetamol, at least
for short‐term use, are an unlikely cause of hepatotoxicity in patients who ingest moderate to
large amounts of alcohol (Benson et al, 2005; Graham et al, 2005; Oscier & Milner, 2009). There is no
evidence that patients who have depleted glutathione stores (eg patients who are
malnourished, or who have cirrhosis, hepatitis C or human immunodeficiency virus [HIV]) are
at increased risk of liver dysfunction when exposed to therapeutic doses of paracetamol
(Benson et al, 2005 Graham et al, 2005; Oscier & Milner, 2009).
Paracetamol interacts with warfarin to increase the International Normalised Ratio (INR)
(Mahe et al, 2005 Level II; Parra et al, 2007 Level II).

72 Acute Pain Management: Scientific Evidence