A systematic review of adverse events in placebo groups of anti-migraine clinical trials

Abstract

In analgesic clinical trials, adverse events are reported for the painkiller under evaluation and compared with adverse events in the placebo group. Interestingly, patients who receive the placebo often report a high frequency of adverse events, but little is understood about the nature of these negative effects. In the present study, we compared the rates of adverse events reported in the placebo arms of clinical trials for three classes of anti-migraine drugs: NSAIDs, triptans and anticonvulsants. We identified 73 clinical trials in 69 studies describing adverse events in placebo groups: 8 were clinical trials with NSAIDs, 56 were trials with triptans, and 9 were trials with anticonvulsants. Studies were selected of all Medline/PubMed or CENTRAL referenced trials published until 2007. Adverse event profiles of the three classes were compared using a systematic review approach. We found that the rate of adverse events in the placebo arms of trials with anti-migraine drugs was high. In addition, and most interestingly, the adverse events in the placebo arms corresponded to those of the anti-migraine medication against which the placebo was compared. For example, anorexia and memory difficulties, which are typical adverse events of anticonvulsants, were present only in the placebo arm of these trials. These results suggest that the adverse events in placebo arms of clinical trials of anti-migraine medications depend on the adverse events of the active medication against which the placebo is compared. These findings are in accordance with the expectation theory of placebo and nocebo effects.

Preventive Pharmacologic Treatments for Episodic Migraine in Adults

“…26 Previously published systematic reviews focused on the efficacy of specific drugs rather than comparative effectiveness and tolerability of all pharmacologic options. 27,28 In addition, the Institute of Medicine recommends basing treatment decisions on post-marketing studies tracking drug benefits and harms after FDA approval. [29][30][31] Thus, we conducted a systematic literature review of the comparative effectiveness and tolerability of the available preventive medications for episodic migraine in adults in outpatient settings to inform treatment and policy decisions (CRD42012001918).…”

The influence of the nocebo effect in clinical trials

“…[30][31][32] Amanzio et al performed a systematic review of adverse effects of anti-migraine randomized placebo-controlled clinical trials. 32 The final sample consisted of 69 studies including 56 trials for triptans, 9 trials for anticonvulsants, and 8 trials for nonsteroidal anti-inflammatory drugs. The researchers found a high rate of adverse events in the placebo arms of trials, with the effects noted after taking antimigraine drugs matching those described for real drugs.…”

“…For example, anticonvulsant placebos produced anorexia, memory difficulties, paresthesia and upper respiratory tract infections -all of which were adverse events reported in the side effect profile of the three classes of antimigraine drugs. 32 The linkage between reported side effects in the placebo groups and the known side effects of particular drugs suggests genuine nocebo effects that arose from the informed consent process.…”

Placebo effects in chronic pain conditions. Can placebo components enhance the efficacy of active treatments?

“…Importantly, however, the negative information completely abolished the effect of the analgesic treatment, thereby showing that negative expectations may block the efficacy of a welldocumented analgesic treatment. In line with this, a systematic review showed a high incidence of adverse events in placebo treated groups of anti-migraine clinical trials (Amanzio, Corazzini, Vase & Benedetti 2009). Noteworthy, the adverse events experienced in different placebo arms corresponded to the adverse events produced by the actual drug against which the placebo was compared.…”

“…Studies investigating how patients' negative perception and expectations towards treatment contribute to treatment outcomes are also emerging (Amanzio, Corazzini, Vase & Benedetti 2009;Bingel et al 2011;Rief, Avorn & Barsky 2006).…”