Different Routes of Administration in Chronic Migraine Prevention Lead to Different Placebo Responses

A Meta-analysis

Diego Belandrino Swerts; Fabrizio Benedetti; Mario Fernando Prieto Peres


Pain. 2022;163(3):415-424. 

In This Article

Abstract and Introduction


Placebo response is a powerful determinant of health outcomes in several disorders. Meta-analysis of clinical trials in pain conditions shows that it can contribute up to 75% of the overall treatment effect. Placebo response deriving from different routes of administration is poorly understood in primary headaches' pharmacological prevention. Thus, this meta-analysis aims to analyze how different routes of administration affect the placebo response in chronic migraine (CM). We conducted a meta-analysis with 7 randomized, double-blind, placebo-controlled clinical trials, with 5672 patients older than 18 years who suffer from CM without associated comorbidities. We compared those who received a placebo-administered agent for the preventive treatment of CM subcutaneous, endovenous, or oral against those who received multiple head injections. The primary outcome was reduction in the number of days with migraine in the month assessed at 12, 16, and 24 weeks of treatment compared with baseline. Our study shows that placebo responses were greater when botulinum toxin was applied to the head, followed by intravenous injection of the anti-calcitonin gene-related peptide monoclonal antibody eptinezumab. Oral topiramate and subcutaneous monoclonal showed no difference, being inferior to head injection. Administration route affects placebo responses in CM preventive treatment. Elucidating the underlying mechanisms that mediate a placebo response in migraine treatment is beneficial to clinical practice and drug development, especially when comparing drugs with different routes of administration, with the effect of application to the head being superior to the other routes in this study. In our study the placebo response accounted for approximately 75% of the therapeutic gain in the treatment of CM.


Chronic migraine (CM) is a debilitating neurological condition, estimated to affect 2% of the world population.[29] It is defined as a headache occurring on 15 or more days/month for more than 3 months.[9] Chronic migraine therapeutic approach is more complex than episodic migraine.[8,16,17] Comorbid conditions are common, particularly psychiatric and sleep disorders,[22,28] with significant reduction in quality of life[35] and frequent analgesic use. Patients often need a multifactorial approach, adding pharmacological treatments to nonpharmacological options.

Placebo response is a powerful determinant of health outcomes in several disorders and may directly interfere with tolerance and efficacy of pharmacological therapy.[1,2] High-evidence studies have demonstrated the importance of placebo and nocebo effects, with symptom relief in conditions such as pain, depression, Parkinson disease, hypertension, arthritis, migraine, cancer, and asthma.[20] This result reaches 75% of the overall treatment in conditions such as fibromyalgia[37] and osteoarthritis.[38] In the management of acute headache, these results ranged between 21% and 30% of remission with placebo.[25,26,30]

In a consensus of experts in placebo and nocebo,[13] the importance of differentiating between the placebo effect and the placebo response[14] was emphasized. The placebo response includes all health changes that result after the application of an inactive treatment, whereas the placebo effect refers to changes specifically attributable to the placebo mechanism, including patient's expectation, genetics, disease severity, patient–physician relationship, environmental circumstances, and external factors such as the route of administration and treatment aggressiveness.[24]

Previous studies show that different routes of administration and placebo procedures result in different outcomes. Intra-articular and topical placebo had a significantly greater response than oral placebo in osteoarthritis.[5] Pain threshold was not different in an experiment comparing placebo pills, sham acupuncture, and cue conditioning.[21] In high-altitude headache, placebo oxygen inhaled through a mask was superior to placebo aspirin pills.[6]

In migraine, subcutaneous placebo was superior to the oral route,[9,26] another meta-analysis showed greater effect with intranasal route,[30] and finally sham acupuncture surgery and sham surgery had more pronounced reduction of migraine frequency than oral placebos.[27]

Such studies corroborate the hypothesis that a good part of the clinical treatment of migraine might be due to nonspecific effects and that the size of such effects might differ between different routes of administration. Therefore, we aim to answer the question: Do different routes of administration have different placebo effects in migraine?

Chronic migraine is a good model for studying placebo response. It is a well-defined disease, affects a large population, and a great number of clinical trials have been performed. We aimed to estimate the difference between placebo response in application on specific areas in the head and neck (botulinum toxin)[3,4,12] vs administered orally (topiramate),[33] intravenous (eptinezumab),[23,31] and subcutaneous (erenumab,[36] galcanezumab,[11,15] and fremanezumab)[7,32] in CM preventive treatment, by collecting data from completed randomized double-blind placebo-controlled trials in adults. This knowledge would benefit both clinical practice and drug development.