Page 142 - The clinical aspects and management of chronic migraine Judith Anne Pijpers

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Chapter 7
before administration of CGRP-antibodies, or whether CGRP antibodies enhance efficacy of withdrawal. Therefore, further research is warranted, which is also emphasized by the European headache federation guideline on the use of CGRP-antibodies.73 A design as used in chapter 4 for BTA would be feasible to answer some of these questions.
Methodology in this thesis – placebo effect
Apart from the contentual contribution to our knowledge on migraine chronification and its treatment, this thesis is unique in its methodology. Most chapters comprise longitudinal study designs, enhancing the establishment of causal associations. More specifically, the randomized controlled trials both contained new techniques to ensure blinding of participants, using a low dose versus high dose principle. In Chapter 4 blinding was ensured by using a low dose of BTA in the forehead region in the placebo group. In this manner, one of the major limitations of the previous BTA trials was tackled.74,75 Placebo-controlled trials and adequate blinding of participants are particularly complicated in behavioural interventions, due to the nature of the treatment. In chapter 5, this was accomplished by the concealment of the behavioural intervention in another trial, so patients were unaware of the existence of two treatment arms. Also in this chapter, a low dose versus high dose principle was applied with minimal versus intensive support by a headache nurse.
These techniques aim to reduce bias by placebo effect due to unblinding, which is particularly important in the research field of pain conditions due to the high placebo response. Placebo response is a complex phenomenon, often referring to various types of effects like regression to the mean, reporting-bias, and psychologically induced responses to treatment.76 Studies investigating the mechanisms of placebo response suggest anti-nociceptive effects by enhancement of endogenous opioid-related analgesia and activation of the descending pain modulation pathway, initiated in limbic regions of the brain and transmitted to the brainstem nuclei by the periaqueductal grey.76,78 The placebo response would be largely independent from ascending nociceptive processing.79 The anti-nociceptive effects might to some extend explain the high placebo responses in pain studies, and the designs described in this thesis can be used to improve discernment between the intervention induced response from the placebo response.