Adding Caffeine to OTC Pain Relievers Improves Analgesic Efficacy
Pressures to reduce opioid analgesic prescribing has resulted in an increased use of nonsteroidal anti-inflammatories and acetaminophen. With this uptick in use of over-the-counter ibuprofen and acetaminophen, the addition of caffeine to the doses has received recent evaluation for analgesic effectiveness.
Two Cochrane Review reports have concluded that caffeine given with ibuprofen or acetaminophen significantly improved the drugs' pain relieving properties. Combinations of caffeine and acetaminophen in the same pill are commercially available over the counter in the U.S. A fixed combination of ibuprofen and caffeine is not available in the U.S, but can be achieved by taking an ibuprofen tablet with a caffeine source such as a cup of coffee or caffeine tablets. Fixed combinations of aspirin, acetaminophen, and caffeine are also available as over-the-counter pain relievers in the U.S.
First Caffeine Study
The first Cochrane Review report can be accessed at: Derry CJ, Derry S, Moore RA. “Caffeine as an analgesic adjuvant for acute pain in adults.” Cochrane Database Syst Rev, Dec 11, 2014; (12): CD009281. Doi:10.1002/14651858.CD009281.pub3.
Caffeine has been a component of common analgesic products containing acetaminophen or aspirin (and ibuprofen outside the U.S.) in the belief that it enhances analgesic efficacy. The authors stated that evidence to support this belief has been limited up until now and often based on invalid comparisons.
The reason for this Cochrane Review was to assess the relative efficacy of a single dose of an analgesic plus caffeine against the same dose of the analgesic alone, without restriction on the analgesic used or the pain condition studied. Serious adverse events were also assessed.
Search methods and data collection
The authors searched CENTRAL, MEDLINE, and EMBASE from inception to August 28, 2014; the Oxford Pain Relief Database; carried out Internet searches; and contacted pharmaceutical companies known to have carried out trials that have not been published. The data they collected included trials that were randomized, double-blind studies comparing a single dose of analgesic plus caffeine with the same dose of the analgesic alone in the treatment of acute pain.
Two review authors independently assessed the eligibility of studies and extracted data. The analgesic efficacy measure of interest was the number of participants experiencing at least 50% of the maximum pain relief over four to six hours, participants reporting a global evaluation of treatment of very good or excellent, or headache relief after two hours. Numbers needed to treat to benefit (NNT) with caffeine was calculated, and the authors looked for any numerical superiority associated with the addition of caffeine. Finally, information about any serious adverse event was obtained.
This was an updated version of a previous review from 2012, which included 20 studies and 7,238 participants in valid comparisons. This present review identified no new studies. Because the authors used different outcomes for some headache studies, the number of participants in the analysis of the effects of caffeine in this review was 4,262.
The caffeine component was 100 mg to 130 mg in combination with either acetaminophen or ibuprofen. The most common pain condition studies were postoperative dental pain, postpartum pain, and headache.
There was a statistically significant benefit with caffeine used at doses of 100 mg or more, which was not dependent on the pain condition or type of analgesic.
Five percent to 10% more participants achieved a good level of pain relief defined as at least 50% of the maximum over four to six hours with the addition of caffeine. NNT was about 14 with high quality evidence.
Only one serious adverse event was reported with caffeine, but was considered unrelated to any study medication.
The authors indicated the existence of around 25 additional studies with almost 12,500 participants for which data for analysis were not obtainable. According to the authors, the bulk of the unobtainable data are reported to have similar results as this review.
The authors concluded that the addition of 100 mg to 130 mg of caffeine to a standard dose of commonly used analgesic provided a small but important increase in the proportion of participants who experienced a good level of pain relief.
Follow-up Caffeine Review
The second Cochrane review can be accessed at: Derry CJ, Derry S, Moore RA. “Single dose oral ibuprofen plus caffeine for acute postoperative pain in adults.” Cochrane Database Syst Rev, Jul 14, 2015; (7): CD011509,doi:10.1002/14651858.CD011509.pub 2.
This review was done to assess the analgesic efficacy and adverse effects of a single oral dose of ibuprofen plus caffeine for moderate-to-severe postoperative pain, using methods that permit comparison with other pain relievers evaluated in standardized trials using almost identical methods and outcome.
The authors searched CENTRAL, MEDLINE, EMBASE, the Oxford Pain Relief Database, two clinical trial registries, and the reference lists of articles. The date of the most recent search was February 1, 2015.
The selection criteria were randomized, double-blind, placebo, or active controlled clinical trials of single dose oral ibuprofen plus caffeine for acute postoperative pain in adults. The authors calculated pain relief versus time to derive the proportion of participants with at least 50% pain relief over six hours given either ibuprofen plus caffeine or placebo. Risk ratio (RR) and NNT were calculated. Information on the use of rescue medication was used to calculate the proportion of participants requiring rescue medication and the median time to use. They also collected information on adverse effects.
Five randomized, double-blind studies with 1,501 participants were identified, but only four had been published and had relevant outcome data.
Study subjects who took ibuprofen 200 mg plus caffeine 100 mg and ibuprofen 100 mg plus caffeine 100 mg were far more likely to achieve at least 50% of the maximum pain relief over six hours than those on placebo. Both dose combinations also significantly reduced remedication rates.
For at least 50% of maximum pain relief, the NNT was 2.1 for ibuprofen 200 mg plus caffeine 100 mg and 2.4 for ibuprofen 100 mg plus caffeine 100 mg.
Adverse event rates were low and no reliable analysis was possible.
According to the authors, this analgesic effect was among the best values for analgesics in this model.
The study authors found that for ibuprofen 200 mg plus caffeine 100 mg, the low NNT value was among the best values for pain relievers in the pain model. Although a fixed combination of ibuprofen and caffeine is not available in the U.S., the dose can be achieved by taking a single 200 mg ibuprofen tablet with a cup of coffee or caffeine tablets. In principle, this can deliver good analgesia at lower doses of ibuprofen and avoid the potential pitfalls of more problematic analgesics.
Richard L. Wynn, BS Pharm, PhD, is professor of pharmacology at the Baltimore College of Dental Surgery, Dental School, University of Maryland Baltimore.
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