A PRISMA-compliant systematic review of the endpoints employed to evaluate symptomatic treatments for primary headaches

Abstract

Background: Primary headache are prevalent and debilitating disorders. Acute pain cessation is one of the key points in their treatment. Many drugs have been studied but the design of the trials is not usually homogeneous. Efficacy of the trial is determined depending on the selected primary endpoint and usually other different outcomes are measured. We aim to critically appraise which were the employed outcomes through a systematic review.

Methods: We conducted a systematic review of literature focusing on studies on primary headache evaluating acute relief of pain, following the PRISMA guideline. The study population included patients participating in a controlled study about symptomatic treatment. The comparator could be placebo or the standard of care. The collected information was the primary outcome of the study and all secondary outcomes. We evaluated the studied drug, the year of publication and the type of journal. We performed a search and we screened all the potential papers and reviewed them considering inclusion/exclusion criteria.

Results: The search showed 4288 clinical trials that were screened and 794 full articles were assessed for eligibility for a final inclusion of 495 papers. The studies were published in headache specific journals (58%), general journals (21.6%) and neuroscience journals (20.4%). Migraine was the most studied headache, in 87.8% studies, followed by tension type headache in 4.7%. Regarding the most evaluated drug, triptans represented 68.6% of all studies, followed by non-steroidal anti-inflammatories (25.1%). Only 4.6% of the papers evaluated ergots and 1.6% analyzed opioids. The most frequent primary endpoint was the relief of the headache at a determinate moment, in 54.1%. Primary endpoint was evaluated at 2-h in 69.9% of the studies. Concerning other endpoints, tolerance was the most frequently addressed (83%), followed by headache relief (71.1%), improvement of other symptoms (62.5%) and presence of relapse (54%). The number of secondary endpoints increased from 4.2 (SD = 2.0) before 1991 to 6.39 after 2013 (p = 0.001).

Conclusion: Headache relief has been the most employed primary endpoint but headache disappearance starts to be firmly considered. The number of secondary endpoints increases over time and other outcomes such as disability, quality of life and patients' preference are receiving attention.

Keywords: Acute; Clinical trials; Endpoints; Non-steroidal anti-inflammatory; Primary headaches; Prisma-guidelines; Triptans.

Fig. 1

PRISMA 2009 guidelines flow chart showing the flow of the search and analysis

Fig. 2

Number of publications per year depending on the type of journal. On the upper part, Headache specific journals, in the middle Neurology journals and in the lower part General medicine journals. Y-axis represent the number of publications and X-axis the year

Fig. 3

Number of studies evaluating different pharmacological groups. X-axis represents the time period and Y the number of studies

Fig. 4

Percentage of studies with a determinate primary endpoint per 5-year periods. Y-axis shows the percentages per each endpoint of the total studies of each period, X-axis shows the different periods. AE = Adverse Events

Fig. 5

Percentage of studies evaluated at each determined time. X-axis shows the predefined time points. Y-axis represents the number of papers. Percentage of the total appears squared

Fig. 6

Percentage of studies that fulfilled each of the proposed endpoints. Blue represents articles that satisfied it and red the percentage of studies that did not. AE: Adverse Events

Fig. 7

Percentage of studies addressing the recommended efficacy endpoints per period, dividing X-axis in the periods pre-IHS recommendations and after each version. Y-axis represents the percentage of studies. Considered endpoints are: complete headache resolution, headache relief, complete migraine resolution, time to the improvement, and percentage of improved patients