Nine studies compared 1 or more types of NSAIDs with acetaminophen, of which 6 are of high-quality.17,30-34,45
Quantitative analysis. The pooled analysis of 5 high-quality studies30-34,45 and 2 low-quality studies31,41 showed a significant difference in short-term pain relief in favor of NSAIDs (TABLE 1).
Qualitative analysis. Six high-quality studies showed that in 9 out of 13 comparisons (69%) NSAIDs were not significantly more effective than acetaminophen for short-term pain relief in patients with acute episodes of TTH (conflicting evidence).
Adverse events. Seven studies reported data on adverse events. The pooled RR for number of patients reporting side effects was 1.3 (95% CI, 0.97–1.6), indicating no significant difference.
4. Comparison between different NSAIDs
Seven studies compared different types of NSAIDs,15,26,28,29,35-37 of which 4 provided data.
Quantitative and qualitative analysis. The analysis the between different types of NSAIDs no differences in short-term pain relief can be found; RR vary between 0.9 and 1.5 (TABLE 1).
Adverse events. The adverse effects were reported involving the central nervous system (ie, dizziness, drowsiness, vertigo), gastrointestinal system (ie, nausea, vomiting, gastrointestinal upset or discomfort), and the body as a whole (ie, light-headed, fatigue, cramps, asthenia, chills).
Naproxen and zomepirac gave more adverse events involving the central nervous system than aspirin, ibuprofen, and ketoprofen. Naproxen and zomepirac were also more often associated with gastrointestinal side effects than ibuprofen and ketoprofen.
Furthermore, aspirin was more associated with gastrointestinal complaints than ibuprofen. Side effects such as fatigue and cramps (body as whole) occurred significantly more often with ketoprofen compared with aspirin and ibuprofen, naproxen compared with ketoprofen, and zomepirac compared with aspirin.
5. Other analgesics vs placebo
Qualitative analysis. There is insufficient evidence to either support or refute the effectiveness of all other analgesics compared with placebo, due to the fact that most analgesics were a unique combination of analgesics with caffeine or peppermint oil. Also, the low methodological quality of nearly all these studies and the low number of studies per comparison made drawing conclusions difficult.
Optalidon and Tonopan were compared with placebo in 3 substudies of 1 high-quality study, and we found significant more pain relief using these analgesics than placebo.15 No adverse events were stated in these studies.
The combination of acetaminophen and caffeine was compared with placebo in 2 studies of high quality25,49 showed that the combination of acetaminophen with caffeine is more effective than placebo (moderate evidence).
The combination of acetaminophen, aspirin, and caffeine was compared with placebo in 4 substudies of the same high-quality study.25 Data from these studies suggest that this combination is significantly more effective than placebo. All groups reported low numbers of side effects as stomach discomfort, nervousness, and dizziness.
Relation between funding source and effect estimates
The pooled effect estimates in placebo-controlled trials stratified by funding are shown in TABLE 2. No major differences in effect sizes were found between the different funding sources.
TABLE 2
Relation between funding source and effect estimate, intervention vs placebo only
| NUMBER OF COMPARISONS (TRIALS) | NUMBER OF COMPARISONS IN HIGH QUALITY STUDIES (TRIALS) | EFFECT ESTIMATE ALLSTUDIES: RR (95% CI) | EFFECT ESTIMATE HIGH QUALITY STUDIES: RR (95% CI) | |
|---|---|---|---|---|
| Non-profit organizations | 0 | 0 | — | — |
| Not reported | 4 (2) | 0 | 1.4 (0.8–2.6) | — |
| Non-profit and for-profit organizations | 26 (11) | 11 (4) | 1.7 (1.4–2.1) | 1.4 (1.1–1.7) |
| For-profit organizations | 14 (7) | 8 (3) | 1.4 (1.2–1.6) | 1.2 (1.06–1.4) |
| All studies | 44 (20) | 19 (7) | 1.5 (1.3–1.8) | 1.4 (1.1–1.7) |
| *P=.006 using χ2 test | ||||
Methodological quality of included studies
This review shows that many RCTs on the efficacy of analgesics in TTH have methodological shortcomings. Using a cut-off point of 6 out of 10 criteria, only 35% of the included studies were found to be of high quality. Most authors failed to explicitly specify the method of treatment allocation and blinding procedure. In many studies authors stated that the trial had a double-blind procedure, however, when the blinding procedure was not explicitly reported (ie, identical looking tablets) we did not score 1 or more blinding items positive. These flaws can be prevented in future trials.
We are unaware of any prior systematic reviews or meta-analyses that have assessed the efficacy and tolerability of analgesics in the treatment of acute episodes of tension-type headache in adults. We conducted the review according to the high Cochrane standard, resulting in a review of high validity. Our review succeeded in identifying a large number of only randomized trials. Also the methodological quality did not explain the possible association between funding and effect estimates.
Although systematic reviews offer the least biased method of summarizing research literature, our review should be considered with the following limitations in mind. First, we decided not to contact the authors for additional information, because most trials were published before 1995. Second, some of the medications have only been evaluated in 1 or 2 studies, which may limit the generalizability of the findings. We do not think these factors have influences our conclusions.