What is a placebo response? 

A placebo response is an improvement in symptoms after treatment that would not normally help the condition, such as a sugar pill or a fake (“sham”) injection. 

Why would migraine get better with a sugar pill or sham injection? 

Biological placebo: 
Our brains are able to induce pain relief. We all have natural pain control pathways. Just think about athletes able to finish marathons with a broken foot! These pain control networks use opioid signaling and natural endorphins. Science suggests that the placebo response is an activation of our natural networks leading to an improvement in symptoms. 

Natural fluctuations: 
Another reason for improvement in migraine world is that migraine frequency fluctuates a lot naturally. For example, people with migraine might be most motivated to try something at the peak of a bad phase. Things were going to improve anyway, but the improvement is then linked to the treatment. This phenomenon can be seen with other health issues that improve naturally, like colds. 

Other factors happening during the study, also known as «confounders»: 
People who enter studies sometimes modify their behaviors for the best. They may be reassured by the caring research team and frequent visits All of this can positively influence migraine… but also confuse the study results. 

What factors can boost the placebo response?

The placebo response can be increased by high expectations. Expectations can be increased by different things: an empathetic and trusted health care provider, enthusiastic advertisement, and an impressive treatment like a coloured pill, complicated device, or invasive needling. Personal, familial and social beliefs have an influence.

Children tend to have stronger placebo responses than adults. 

Genetic factors play a role. Some people are born with stronger placebo responses. 

Some treatments are difficult to study compared to placebo: 

• There are no perfect placebos for diets, body manipulations, or exercise programs. It’s very difficult to do a placebo massage. Placebo needling is feasible, for example sham acupuncture. 
• The placebos for injections are still active, meaning that just the needling could produce a result. 
• Behavioral treatments require that the patient sticks to the plan or behavior studied, and that is often more difficult to do than taking a pill. Drop out rates (people who leave the study before the end) in behavioral studies are often high because it is hard to stick to exercise 3-4 times per week or maintain ideal sleep habits. 
• Some treatments are not sold by companies looking for profit and therefore funding is limited for good studies on them. Many behavioral treatments are in this category (Cognitive behavioural therapy, sleep education, meditation, exercise). 

What is the nocebo response? 

The nocebo is the dark side of the placebo. It is a bad reaction happening with a sugar pill or sham device. Some people seem to develop side effects with every pill, and may be prone to a nocebo response. Certain symptoms may also occur with no relation to the treatment but be attributed to it. Common side effects like fatigue, weight fluctuations, hair loss, dizziness and of course headache are frequently observed in the placebo groups in studies. 

The nocebo effect is very much influenced by perceptions and social learning. Seeing negative testimonials on social media can be useful, but may also boost the nocebo effect. Learning about the nocebo effect might decrease it. 

So who cares if it’s a placebo or if it only works for me? It will still work! 

That way of thinking makes perfect sense. Physicians tend to consider the placebo effect as ineffective because they have a professional obligation to recommend treatments that are scientifically proven. Patients may pay more attention to results, even if they are the result of a placebo response or an anecdotal improvement in a particular person. 

Part of the problem with placebos is that they can still be used for undue financial gain (See this post). Is it acceptable to pay for sugar pills based on a pseudoscientific concept? Should sugar pills be sold as legitimate treatments? A perfect exemple is homeopathy in France. Socially it was accepted. Physicians were prescribing it. Now that the World Health Organization has made clear that homeopathy is only placebo medicine, it will not be reimbursed as a legitimate medical treatment anymore (as of July 2019). This multi-billion industry will probably collapse. 

We still have a lot to learn on the placebo and nocebo responses. Communication between patients and health care providers should be open, and people with migraine should be aware of all treatment options, with their pros and cons. 

REFERENCES

Meissner K, Fassler M, Rucker G, Kleijnen J, Hrobjartsson A, Schneider A, et al. Differential effectiveness of placebo treatments: a systematic review of migraine prophylaxis. JAMA Intern Med. 2013;173(21):1941-51.

Marchant J. Placebos: Honest fakery. Nature. 2016;535(7611):S14-5.

Horing B, Weimer K, Muth ER, Enck P. Prediction of placebo responses: a systematic review of the literature. Front Psychol. 2014;5:1079.

Faasse K, Petrie KJ. The nocebo effect: patient expectations and medication side effects. Postgrad Med J. 2013;89(1055):540-6.

Benedetti F. Placebo and the new physiology of the doctor-patient relationship. Physiol Rev. 2013;93(3):1207-46.

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