PMC:7507645 / 24270-31837
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7507645","sourcedb":"PMC","sourceid":"7507645","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7507645","text":"Discussion\nThese post hoc analyses demonstrated that fremanezumab, compared with placebo, significantly reduced the monthly average number of headache days of at least moderate severity and led to a significantly greater proportion of patients who had a clinically meaningful ≥ 50% response rate, independently of the presence of MO in patients with CM. Similar reductions were also seen for migraine days. In patients with baseline MO, significantly more fremanezumab-treated patients reverted to no MO during the 12-week treatment period compared with those who received placebo. Significant reductions in days using acute headache medication were also observed in patients with and without MO at baseline, with the greatest numerical reductions noted in those who reverted from MO to no MO during the 12-week treatment period.\nMigraine preventive therapy is recommended for patients with frequent and chronic migraine, but the effectiveness of preventive medications was believed to be affected by MO [6]. Topiramate, a migraine preventive treatment, significantly reduced migraine days in patients with CM, but failed to reach significance in a post hoc analysis of patients with CM and MO, possibly due to a small sample size [21]. In one study of patients with MO who were unresponsive to preventive therapy, withdrawal of the overused medication increased the efficacy of preventive therapy [22]. However, in our study, more patients treated with fremanezumab had a ≥ 50% reduction in the monthly number of headache days of at least moderate severity, independent of baseline MO. This strongly suggests that MO has minimal, if any, impact on the efficacy of fremanezumab.\nNotable differences were observed between patients with and without MO at baseline, including several differences in disease characteristics. By definition, monthly number of days using acute headache medication differed between subgroups. The defining feature of the subgroups may also underlie the differences in monthly number of headache days of at least moderate severity and migraine days, because a day with acute migraine-specific medication use to treat a headache of any severity or duration was included in the count for these variables. Disease characteristics that did not notably differ at baseline included levels of disability, quality of life, and depression as measured by HIT-6, MSQoL domain, and PHQ-9 scores, respectively. Previous studies have shown that patients with chronic daily headache (CDH; an umbrella term that encompasses CM) and MO have more disability and quality-of-life impairment compared with patients with CDH without MO; however, because these studies looked at MO in a heterogenous group of headache disorders, they may not be generalizable to patients with CM [1]. Similarly to CM, medication overuse headache, a secondary headache attributable to MO, is associated with psychiatric comorbidities such as depression, although whether it could be a cause or an effect is not known [23, 24]. Baseline characteristics in this study suggest that MO does not increase the severity of depression in patients with CM. The impact of fremanezumab on disability, quality of life, and depression was positive in patients with and without MO, with significant differences from placebo observed for HIT-6 and MSQoL domain scores. PHQ-9 scores were reduced from baseline; however, only the reduction among patients without MO in the fremanezumab quarterly group reached statistical significance. A greater difference over placebo may not have been observed due to the majority of patients (69.1% to 79.2%) already having PHQ-9 scores in the no to minimal depression range (R.B. Lipton, unpublished data, 2019), creating a floor effect. In a separate subgroup analysis of patients in this population with moderate to severe depression, reductions in mean PHQ-9 scores were numerically greater, although not statistically significant, potentially due to the modest sample size (R.B. Lipton, unpublished data, 2019).\nIn this study, patients with MO saw improvements in the measured outcomes without undergoing withdrawal therapy or so-called “detoxification,” which is often believed to be important in managing MO [2]. Several strategies are available for detoxification, including early abrupt withdrawal, restricted intake, discontinuation therapy with rescue medication (different analgesic than the overused medication), or intravenous hydration [2, 3, 25]. During detoxification, most patients experience an initial worsening of headaches and additional withdrawal symptoms such as nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, and anxiety, which typically last up to 10 days, but may persist for up to 4 weeks [3, 26, 27]. Studies have demonstrated variable rates of success in discontinuing medications, with percentages of patients achieving detoxification ranging from 57% to 100% [28]. Even after successful discontinuation of overused medication, 17% to 43% of patients relapse back to MO just 1 year after detoxification [28]. Our results suggest that patients treated with fremanezumab do not need to discontinue overused drugs to experience the benefit of preventive treatment and achieve reduced acute medication use. Fremanezumab treatment resulted in 58% of patients reverting from MO to no MO, compared with 46% for patients given placebo, suggesting that patients receiving fremanezumab may achieve reversion from MO, avoid detoxification and its associated symptoms, and still achieve fewer headache days and migraine days. Together, this suggests the potential for a paradigm shift to an effective and more humane approach for treating CM with MO: prevent first and detoxify later if necessary.\nThese findings have certain limitations. These subgroup analyses were not prespecified in the HALO CM protocol; however, the measures evaluated were generally consistent with the observed effects in the FAS population, and all data points in these subgroups were collected a priori. In addition, this study did not consider the intensity of MO, differentiate between the types or combination of medications taken, nor did it consider the presence and severity of comborbid psychiatric disorders that may contribute to MO, such as anxiety or cephalophobia. Future studies to determine whether the type of overused medication impacts outcomes would be beneficial. Due to exclusion criteria, patients using opioids or barbiturates on more than 4 days per month were not included in this trial; therefore, inferences cannot be drawn about patients overusing these drugs. Furthermore, one cannot rule out that the routine observation by doctors over the course of the trial may have contributed to some of the observed reductions in MO; however, placebo-treated patients were observed in a similar manner with smaller improvements. The current understanding of the pathophysiology of MO also supports the role of fremanezumab in reducing MO. Increased CGRP expression and release is hypothesized to play a role in the development of the increased sensitivity to pain perception that MO fosters [29, 30]. This sensitization may be reversed by blocking CGRP with fremanezumab. In triptan- or morphine-sensitized rats, a single administration of fremanezumab was able to prevent cutaneous allodynia resulting from triggers associated with migraine attacks [31]. Lastly, headache data were captured using a patient self-reported diary, which can vary in terms of content recorded, reading and writing skill, and 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