Use of a fixed combination of acetylsalicylic acid, acetaminophen and caffeine compared with acetaminophen alone in episodic tension-type headache: meta-analysis of four randomized, double-blind, placebo-controlled, crossover studies

Tension-type headache (TTH) is by far the most prevalent primary headache [1, 2]. In general, most patients with episodic TTH never consult a physician [3] and treat the headache episodes with over-the-counter (OTC) medication [4]. The most frequently used drugs are acetylsalicylic acid (ASA), acetaminophen (APAP; paracetamol) and non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. In fact, such drugs are the only options available, as specific migraine medications such as triptans are not effective in TTH [5], while opioids increase the risk of medication-overuse headache [6]; neither is recommended for use in TTH [7]. However, some patients or headache episodes might not respond to monotherapy, and patients may overuse an analgesic in order to relieve their pain. Therefore, combination therapies with ASA, APAP and caffeine were developed to provide superior efficacy using lower doses of analgesics compared with therapeutic doses of monotherapy [8, 9].

In this paper, we describe four multicenter, randomized, double-blind, crossover studies comparing the effectiveness of a single dose of a combination analgesic containing ASA, APAP and caffeine vs. APAP alone or placebo in patients with moderate or severe episodic TTH. These studies were pooled for a meta-analysis of the efficacy of the triple combination. The original studies were conducted in the 1980s, and the results were published by Migliardi et al. [10]. The purpose of the Migliardi paper was to evaluate the effect of caffeine in TTH and therefore included the results of all studies in TTH that used an analgesic–caffeine combination. However, we wanted to concentrate only on the efficacy of the triple combination (ASA, APAP and caffeine) and hence only included four of the studies assessed in the Migliardi paper [10]. Furthermore, the efficacy analysis was updated to reflect endpoints that have recently been recommended to better differentiate among treatments in clinical trials of TTH, i.e. pain-free after 2 h (Y/N) and headache response after 2 h (Y/N) [11, 12]. These endpoints are particularly appropriate to guide therapeutic choices [11]. In addition, it was decided to see how effective the triple combination was in the subset of patients with severe pain at baseline.

This post-hoc meta-analysis employed new efficacy endpoints to update the results of four randomized studies that were performed in 1986. These endpoints (i.e. pain-free and headache response after 2 h) have been recommended to better differentiate among treatments in clinical trials of TTH [11, 12]. Results demonstrate that AAC is effective in the treatment of episodic TTH, and significantly superior to APAP with respect to being pain-free at 2 h, having headache response at 2 h and being able to return to daily activities. The beneficial effects on pain are in agreement with other studies; the reduction in headache pain was greater with the triple combination vs. monotherapy, using lower doses of analgesic [9, 15]. However, the double combination of APAP plus caffeine was not effective than monotherapy with naproxen [16].

Migliardi et al. [10] found that the triple combination is well tolerated, with AEs that were consistent with the known profile of the drug [10]. It was speculated that the greater incidence of ‘nervousness’ and ‘dizziness’ could be attributed to the caffeine content; on the other hand, the greater incidence of ‘stomach discomfort’ with AAC was probably caused by the presence of ASA. In contrast, the study by Diener at al. [9] included a subgroup of patients with episodic TTH; although the results of this subgroup were not reported, the triple combination was well tolerated in episodic TTH, and did not result in more AEs than monotherapy (HC Diener, unpublished data, [9]). A favorable risk-benefit ratio was also observed in a previous study that used this triple combination in TTH, albeit with a lower dose of caffeine (50 mg) [15].

Clearly, the combination offers an important alternative when APAP alone is not effective enough. Caffeine, in particular, contributes to the greater efficacy of the combination vs. APAP alone; patients with TTH or other pain conditions who take an analgesic without caffeine need about 40% more medication to get the same relief as patients taking the same analgesic with caffeine [17]. Analgesic combinations containing caffeine have been recommended as first-line [18] or Level I [19] therapies to manage episodic TTH.

In our pooled population, over 30% of treated headaches had pain rated severe at baseline – much higher than reported by Rasmussen et al. [20]. Nevertheless, several other studies in episodic TTH have reported comparably higher proportions of episodic TTH patients with severe pain [16, 21, 22]. However, we cannot absolutely exclude the possibility that some of the treated headaches were migraine attacks, as it is not clear whether associated symptoms were recorded. The phenotype of treated headache attacks might have deviated from the diagnosis made by prior history. This problem, inherent to studies of this type, has been noted previously [23]. Nevertheless, subjects were only included in the studies if they met criteria that adhered to the definition of TTH at the time, matching at least two of the criteria of episodic TTH used today [14]. In addition, patients were excluded if they had a history of “vascular headache of migraine type” – although it should be noted that prior to inclusion in the studies, headache attacks were described as throbbing (or a combination of throbbing/non-throbbing) in some patients. This type of ‘pulsating’ pain is more commonly associated with migraine, however the IHS classification does not preclude it as a characteristic of episodic TTH [14]. Therefore, it is not unreasonable to assume that the majority of ‘severe’ headaches were in fact tension-type.

There is also a common perception that the pain associated with episodic TTH can only be mild to moderate. However, while it is true that the IHS states that the pain intensity associated with episodic TTH is typically mild to moderate (particularly in contrast to the pain of a migraine, for example, which is classed as moderate to severe), the criteria do not specify that the pain has to be mild to moderate [14]. Only two of the four characteristics need to be met to diagnose episodic TTH (i.e. bilateral location, pressing/tightening (non-pulsating) quality, mild or moderate intensity, not aggravated by routine physical activity such as walking or climbing stairs [14]), so the pain might indeed be severe. Especially considering that the way in which patients rate the severity of their pain can vary considerably, depending on perception – each patient has different pain thresholds and moderate pain in one patient may be regarded as severe by another. In the studies in our meta-analysis, the patients rated their own pain and may simply have perceived it to be severe, whereas a physician might have rated it as moderate. Despite these uncertainties, our meta-analysis demonstrates that the triple combination was superior to monotherapy in the subset of headache episodes with severe pain at baseline; the proportion of severe headache episodes treated that were pain-free after 2 h was 67% higher with AAC compared with APAP.

Our meta-analysis also evaluated the impact of the triple combination on daily activities, an aspect that is rarely studied in the literature. Even mild episodic TTH can have an impact on cognition and attention, which can impair performance and successful completion of general tasks [24] and lead to reduced productivity [3, 25, 26]. Therefore, any analgesic that is effective in this regard will be of interest to patients. Our results demonstrate that daily activities were ‘no more difficult than normal’ from as little as 1 h after treatment with the triple combination (Table 2).

The strength of the present study is the sample size and the large number of treated headache episodes. The crossover design increases the power of the trial [27]. A limitation of the study is the long time period that has passed since these studies were performed. Consequently, operational criteria for the conduct and analysis of studies for the treatment of TTH were not available. Although the design limitations cannot be addressed at this late date, we consider them to have modest impact. In addition, it cannot be ignored that some of the headache attacks during the studies may have been migraine rather than episodic TTH, as noted above. Either way, the combination of ASA, APAP and caffeine is superior to APAP monotherapy and placebo even in patients with severe headache and is well tolerated.

Pooled data from 6,861 treated headache episodes confirms the efficacy of the fixed combination of acetylsalicylic acid, acetaminophen and placebo in the treatment of episodic TTH. AAC was significantly superior to 1000 mg APAP and to placebo with respect to the percent pain-free at 2 h, as well as the percent with headache response (mild or no pain) at this point. Similar superiority was observed in the subset of treated headaches with pain rated severe at baseline. In addition, significantly more AAC patients were able to return to their daily activities 1 h after dosing vs. either 1000 mg APAP or placebo. AAC was generally well tolerated, with a predictable safety profile.