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5.2
The rationale for addition of caffeine to ibuprofen and other analgesics has been
based on the premise of raising the analgesic ceiling of the analgesic. The
addition of caffeine to NSAIDs and paracetamol has been investigated for over
three decades as an adjuvant to enhance pain relief (Aronoff and Evans 1982;
Sunshine and Olson 1989; Zhang 2011). Combinations of caffeine and sodium
salicylate and aspirin have been available in the UK since 1949, and have been
mentioned in several pharmacopoeias (Martindale The Extra Pharmacopoeia 1958;
Reynolds 1993). Caffeine is mentioned in the British National Formulary (2009) as
a weak stimulant to enhance analgesia, but the alerting effect, mild habit-forming
properties, and possible provocation of headache may not always be desirable.
Earlier studies of the efcacy due to the addition of caffeine were largely negative,
except the combination with paracetamol (Laska et al. 1983, 1984).
Ibuprofencaffeine combinations have been investigated by several workers for
efcacy compared with that of ibuprofen (Stewart and Lipton 1989; Dionne and
Cooper 1999). Combinations of ibuprofen with caffeine have been shown to be
more effective than ibuprofen alone in the dental pain model (Forbes et al. 1990,
1991; McQuay et al. 1996). In particular, enhanced pain relief has been observed
with doses of 100 mg caffeine and 200400 mg ibuprofen (Forbes et al. 1990, 1991;
McQuay et al. 1996; Dionne and Cooper 1999). Ibuprofen 400 mg with caffeine
200 mg has been found to give greater pain relief in the treatment of migraine than
ibuprofen 400 mg alone (Stewart and Lipton 1989). Caffeine has also been found to
enhance the pain relief with ibuprofen in tension headache (Diamond et al. 2000;
Sparano 2001) and in childrens headache (Dooley et al. 2007).
There are, however, several issues that are raised about the use of combinations
of caffeine with ibuprofen, as well as with other non-narcotic analgesics/nonsteroidal anti-inammatory drugs (NSAIDs) which include:
(a) The pharmacological rationale for including caffeine; what is the pharmacological basis or mechanism for the enhanced analgesic activity?
(b) The confounding effects from the intake of caffeine-containing beverages,
estimated to be of the order of 100400 mg daily (Rall 1990; Reynolds,
Martindale, The Extra Pharmacopoeia; Nawrot et al. 2003; Rainsford 2004a).
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taken 46 times daily, the amount of caffeine taken would be within the intake of
caffeine-containing beverages.
The common adverse events attributed to caffeine are: (1) associations with
increased myocardial infarction, tachycardia, and increased blood pressure, (2)
insomnia, anxiety, tremor, tenseness, and irritability, (3) increased free fatty acids
and hyperglycaemia, (4) nausea, vomiting, and stimulation of gastric acid secretion,
(5) increased diuresis, and (6) urticaria (Ellinwood and Lee 1996), gastrooesophagal reux, symptoms of anxiety and tachycardia in infants and children
(Ellinwood and Lee 1996). With long-term intake of caffeine-containing
analgesics, addiction may develop coincident with the analgesic abuse syndrome
(Ellinwood and Lee 1996; Rainsford 2004c). There has been concern that drinking
>78 cups of coffee per day may be associated with an increased incidence of
stillbirths, pre-term deliveries, low birth weights of infants and spontaneous
abortions, but other factors including intake of analgesics per se may contribute
to these states (Beers and Berkow 1999). Concerns about the possibility of the risks
of mutagenicity, genotoxicity, and carcinogenicity led to an assessment of these
risks by the US Food and Drug Administration and several reviews (Thayer
and Palm 1975). A variety of in-vitro and in-vivo experiments and studies had
been reported since 1948 from which both positive and negative observations
were recorded (Thayer and Palm 1975). A considerable number of animal studies
of genetic changes, enhancement of dominant lethal changes, and teratogenic
potential in rodents as well as in-vitro studies in cell lines, in relation to the
pharmacokinetics and tissue/organ distribution of caffeine, were analysed and
assessed by Thayer and Palm (1975) in their comprehensive review.
In conclusion, it appears that caffeine may have some moderate potentiating
effects on analgesia from NSAIDs or paracetamol, but where these combinations
are taken in large quantities for long periods of time there are risks of CNS adverse
reactions, and at extremes analgesic abuse syndrome. Considering the availability
of other combinations with ibuprofen (e.g., paracetamol, codeine) which are
probably more effective than the ibuprofencaffeine combination, it would not
seem of appreciable therapeutic benet to use ibuprofencaffeine mixtures. It
would appear just as simple and more pleasurable to take ibuprofen alone with
coffee, tea or other caffeine-containing beverages.
5.3
IbuprofenCodeine Combinations
The combination of codeine with aspirin or paracetamol has been a popular and
effective analgesic in moderate to severe pain for over 3040 years (Reynolds 1993;
Martindale; Cooper 1984). Combination of ibuprofen with codeine has been found
to be more efcacious than either the drug alone, placebo or other NSAIDs in pain
following episiotomy or gynaecological surgery (Norman et al. 1985; Cater et al.
1985; Sunshine et al. 1987), tonsillectomy (Pickering et al. 2002), post-operative
dental pain (Mitchell et al. 1985; Giles et al. 1986; McQuay et al. 1989, 1992,