Chronic migraine, one of the chronic pain diseases, commonly involves symptoms like periodical attacks of headache, hypersensitivity to sensory stimuli, nausea, and vomiting (Schwedt, 2014). It may also sometimes be accompanied by certain degrees of mental health disorders, sleep disorders, gastrointestinal dysfunction, aura experience, and cutaneous allodynia (Aurora & Brin, 2017). It differentiates from episodic migraine by having more frequent headache attacks: with at least 15 days of headache and 8 days with other associated symptoms each month (Headache Classification Committee of the International Headache Society, 2013).
On the individual level, chronic migraine normally has detrimental influences on a patient’s life. Studies have suggested that most patients with chronic migraine were severely impacted on their socioeconomic functioning, mental health, and quality of life (Buse et al., 2012; D’Amico et al., 2003; Wiendels et al., 2006). They also “had statistically significant lower levels of household income, were less likely to be employed full time and were more likely to be occupationally disabled” (Buse, Manack, Serrano, Turkel, & Lipton, 2010, p. 428).
On the socioeconomic level, the direct and indirect annual costs on headache are estimated to be $20bn in the US (Stewart, 2003) and €27bn in Europe (Andrée & Stovner, 2008), which are considerable amounts for governmental spending. Furthermore, according to a research done by Bigal, Serrano, Reed, & Lipton (2008), 57% of people with chronic migraine have missed at least five days of work or school within three months. This might lead to a substantial loss in overall productivity.
In this paper, we will first review some of the recent research findings on the etiology and mechanisms of chronic migraine. Then, we will shift to a discussion on the treatments existing nowadays and the potential of placebo to become an effective treatment option in the future.
Epidemiology
According to Natoli et al. (2010), the prevalence of chronic migraine is about 0.9% to 5.1%, with estimates around 2% of the whole world population. Regarding age stratification, data from the US show that the prevalence of chronic migraine typically increases throughout adolescence, peaks in midlife, decreases after the age of 50 years, and is highest among women aged 18-49 years (Buse et al., 2012). Multiple studies have reported the same significant gender difference, with the prevalence being 2.5 – 6.5 times higher in women comparing to men (Natoli et al., 2010; Peterlin, Gupta, Ward, & MacGregor, 2011). Although the detailed explanation for this difference has not yet been discovered, fluctuations in sex hormones, changes in receptor binding, genetic factors, differences in response to environmental stressors, and pain perception have all be proposed to be possible reasons behind this phenomenon (Peterlin et al., 2011).
Mechanisms and Etiology
Chronic pain disorders are notorious for their mysterious and complex underlying mechanisms. Unlike pain caused by normal lesions, the direct stimulus or cause of pain cannot be simply determined by doctors and scientists. Nowadays, with more advanced technology, scientists are able to find multiple structural and functional abnormalities in the chronic pain patients and raise different theories to explain their origins. For chronic migraine specifically, atypical pain processing, central sensitization, and cortical hyperexcitability are considered to be the major explanations for the disorder (Schwedt, 2014).
As nociceptors do not exist in the brain itself, the subjective feeling of pain is more probably aroused from variations in meninges and ventricular systems. In a review, Noseda & Burstein (2013) have proposed the origin of headache to be mechanical, electrical, or chemical activation of nociceptors innervating pial, arachnoid, dural blood vessels, large cerebral arteries and sinuses. Additionally, the pain processing system of migraine patients have been shown to be atypical. The descending pain modulatory pathway has been identified to show reduced inhibition, and the normal inhibitory capacity of the cortex is indicated to be reduced (Aurora, Barrodale, Tipton, & Khodavirdi, 2007).
Several neuroimaging studies have discovered other malfunctions in migraine patients, including lateralized pons dysfunction (Afridi, 2005), pons glucose metabolism increase (Aurora et al., 2007), and gray matter volume decrease (Valfrè, Rainero, Bergui, & Pinessi, 2007). A study conducted by Kim et al. (2008) have also found that bilateral insula, motor/premotor, prefrontal, cingulate cortex, right posterior parietal cortex, and orbitofrontal cortex have significant reduction of gray matter volume in migraineurs comparing to normal controls.
To conclude, although the exact mechanism behind chronic migraine is still not strictly determined, the highly productive field of neuroimaging has already offered us numerous interesting and valuable findings which shed light on the etiology of this disease.
Current Pharmacological Treatments
As the etiology of chronic migraine is not well-defined, finding effective treatments is a relatively challenging task for researchers. Until now, multiple modalities of treatment have been suggested, including both pharmacological ones and non-pharmacological ones (e.g., CBT, neuromodulation, biofeedback, acupuncture). For the purpose of this paper, we will mainly focus on two pharmacological medicines that are currently available and evaluate their efficacy through summarizing the results of multiple clinical trials and reviews.
Topiramate
The efficacy of topiramate has been supported by various randomized controlled trials (RCTs) (Bussone, Diener, Pfeil, & Schwalen, 2005; Diener et al., 2007; Mathew & Jaffri, 2009; Silberstein et al., 2007). Silberstein has also concluded in a recent review that “topiramate reduces migraine frequency and acute medication use, improves quality of life, and reduces disability in patients with episodic migraine and in those with chronic migraine with or without medication overuse headache” (Silberstein, 2017, p. 165). Nevertheless, Silberstein also mentioned in the same review that patients may experience side effects such as fatigue, dizziness, mood changes, slowed mental processing, and memory difficulties after taking topiramate, which should be taken into the consideration of the overall effectiveness.
Botulinum Toxin Type A (BoNT-A)
Multiple randomized placebo-controlled clinical trials have suggested the efficacy of Botulinum Toxin Type A in treating chronic migraine (Aurora et al., 2011; Dodick et al., 2010; Matharu et al., 2017; Mathew et al., 2005; Mathew & Jaffri, 2009; Silberstein et al., 2006). However, the results are not always consistent. In the several trials conducted by Mathew et al. (2005) and Silberstein (2006), although BoNT-A was shown to reduce total headache days in chronic migraine patients, they are not always significantly more effective than placebos. An up-to-date review, after analyzing the data from 90 articles (including 28 trials and 4190 participants), also concluded with that “Botulinum toxin was not proven to be better than placebo at reducing the number of attacks suffered per month” (Herd et al., 2018, p. 3). To conclude, the effectiveness of BoNT-A seems to remain controversial.
The Undervalued Role of Placebos
Two drugs for treating chronic migraine have been introduced in the previous section. However, although their efficacy has been revealed by various randomized clinical trials, they still either sometimes fail to demonstrate better effectiveness comparing to placebos or have undesirable side effects on patients’ health.
Mainly concentrating on the development of pharmacological treatments, researchers nowadays are more often using the placebo effect as a parameter of measuring effectiveness of other treatments in clinical trials, instead of viewing it as a possibility for further exploration and understanding of the genuine nature underlying the treatment of disease. Having reviewed various research and data on this topic, I am more and more convinced that the placebo effect and other psychological factors should be given more credit in the treatment of chronic migraine, and also in other similar diseases.
In the following discussion, the potential effectiveness of placebo treatment will be analyzed by viewing data from previous pharmacological studies, studies focusing on pediatric chronic migraines, and studies on the treatments of other chronic pains. Then, the discussion will be broaden to the role of other psychological factors and the possible ethical concerns regarding the prescription of placebos.
Placebo-Controlled Studies
Analyzing data presented in the previous studies of BoNT-A and topiramate, we have found impressive placebo responses. For example, in Mathew et al.’s study (2005), after 180 days, patients treated with BoNT-A have a mean change of 6.7 more headache-free days comparing to baseline, but those treated with placebo also achieved 5.2 more headache-free days, which does not suggest a significant difference. As he described in his paper, placebo responses were not only able to sustain for 9 months, but also were able to produce remission rates higher than 40%. Although placebos do not always yield such positive results, the absence of other side effects should also be taken into consideration when deciding their overall benefits.
Pediatric Chronic Migraine Treatment
The specific discussion on pediatric chronic migraine is important because of the higher placebo response rates in children. Whereas the typical placebo response is around 35% in adult migraine trials, pediatric trails normally have response rates higher than 50% (Lewis, Winner, & Wasiewski, 2005). Also, a meta-analysis has indicated that placebo pills can effectively decrease the average occurrence of headaches by half from the original 6 times a month in children (El-Chammas et al., 2013). This differential response rates might be explained by the delayed prefrontal maturation (Casey, Tottenham, Liston, & Durston, 2005) and more flexible belief systems among children (German & Defeyter, 2000). As placebos can generate more positive treatment outcomes in children than adults and will not create any negative pharmacological side effects that might influence children’s physical or mental development, they ought to be considered as a well-rounded candidate for treatment of pediatric chronic migraine.
Placebo Treatments for Other Chronic Pains
Although no existing research has directly tested the efficacy of placebos in treating chronic migraine, its positive effect in treating other chronic pain disorders can also strongly demonstrate its potential. For instance, an open-label placebo (OLP) treatment for chronic low back pain has been shown to be effective recently (Carvalho et al., 2016). Furthermore, two studies using OLPs to treat irritable bowel syndrome (IBS) have both generated positive outcomes (Ballou et al., 2017; Kaptchuk et al., 2010).
Role of Other Psychological Effects
Placebo effect itself is a psychological effect, including factors like patients’ mood, expectation, cognition, and so on. Therefore, aiming to generate more positive outcomes of treatments, harnessing these psychological effects might also be beneficial in the treatment process.
For example, as stress and stress related psychiatric disorders are closely related to migraine, it has been shown that cognitive behavioral therapy (CBT) may significantly boost the outcomes of pharmacological treatments for adolescents (Powers et al., 2013).
Aspects like doctor-patient relationship and communication skills have also been shown to play an essential role in the reduction of chronic pain symptoms and improvement of patients’ mental health (Bensing & Verheul, 2010; Faria, Linnman, Lebel, & Borsook, 2014; Verheul, Sanders, & Bensing, 2010). According Verheul et al. (2010), physicians’ warm, empathetic, affect-oriented communication style combined with the raising of patients’ positive expectations can generate the optimal outcome of treatment.
Ethical Concerns
In the past, prescription of placebos has been avoided typically because of certain ethical concerns on the nature of deception (Gold & Lichtenberg, 2014; Louhiala, 2009). However, as suggested in the previous section, studies have demonstrated the effectiveness of OLPs in treating both lower back pain and IBS (Ballou et al., 2017; Carvalho et al., 2016; Kaptchuk et al., 2010). As a result, deception is no longer a necessary condition for placebos to function. Although no current clinical trial has yet demonstrated the effect of OLPs on the treatment of chronic migraine, based on the outcomes of preceding studies, it is not unreasonable to assume they may as well result in successful responses.
Conclusion
Pharmacological and psychological modalities, instead of being in a dichotomy, are inseparable in the treatment of chronic migraine. And as we are paying too much attention to the pharmacological aspect, placebos and other psychological factors should be given more credit in the treatment process, maybe for other chronic pain disorders generally.
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