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Abstract

Background

Clear definitions of study populations in clinical trials may facilitate application of evidence to clinical populations. This review aimed to explore definitions of study populations in clinical trials on migraine, tension-type headache, cluster headache, and cervicogenic headache.

Methods

We performed a systematic review of clinical trials investigating treatment efficacy for migraine, tension-type headache, cluster headache, and cervicogenic headache. We extracted data on diagnosis, inclusion criteria and baseline headache characteristics.

Results

Of the 229 studies reviewed, 205 studies (89.5%) defined their populations in adherence to the International Classification of Headache Disorders (ICHD) criteria. Some studies (n = 127, 55.5%) specified diagnosing through interview, clinical examination and diary entry. The most commonly reported inclusion criteria were pain intensity for migraine and tension-type headache studies (n = 123, 66.1% and n = 21, 67.7%, respectively), episode frequency (n = 5, 71.4%) for cluster headache studies, and neck-related pain for cervicogenic headache studies (n = 3, 60%). Few studies reported details on the extent to which diagnostic criteria were present at baseline.

Conclusions

ICHD is routinely used in defining populations in headache studies. Details of baseline headache characteristics were not as consistently reported.

Keywords

Patient selection International Classification of Headache Disorders migraine tension-type headache cluster headache cervicogenic headache

Introduction

Migraine, tension-type headache, cluster headache (1) and cervicogenic headache (2) are among the most commonly seen headaches in primary care and specialist clinics. Effective treatment of these headaches relies on correct diagnostic classification. Increased headache research over the past two decades (3) has contributed to improving the classification system for headaches such as the International Classification of Headache Disorders (ICHD). The ICHD, now on its third edition (beta version), provides a framework to standardize headache classification (4,5) and addresses the challenge of distinguishing headache types. A classification framework such as ICHD is important to ensure homogeneity of participants in clinical studies investigating treatment efficacy.

Despite this improvement, classification of headaches using ICHD may be challenging for certain cases, given that the classification system is based on clinical features (6). For one, a headache type may coexist with one or more other headache types (7). Further, symptoms vary within and between individuals with the same headache type (8). Additionally, some headache features may overlap, especially for frequent recurrent and disabling headaches such as migraine, tension-type headache, cluster headache and cervicogenic headache (6,9). It is therefore important to examine how study populations are defined in clinical trials. Details on definitions of study populations may confer better understanding of current criteria used to classify headaches. This understanding, in turn, would potentially increase awareness on the nature of headaches between study populations and guide to whom the inferences from the trials could be applied.

The primary objective of this systematic review, therefore, was to explore and describe the definitions of study populations in clinical trials. In particular, this review aimed to explore the eligibility criteria for study populations of frequent recurrent headaches, namely migraine, tension-type headache, cluster headache, and cervicogenic headache. The secondary objective of this review was to describe baseline characteristics of participants enrolled in clinical trials in terms of headache features listed as ICHD diagnostic criteria.

Methods

Protocol registration

The protocol for this systematic review was registered with PROSPERO (registration number CRD42014009167).

Eligibility criteria

We included research articles that were intervention studies (controlled studies or prospective cohort studies) that described participants as having ‘primary headache’, ‘migraine’, ‘tension-type headache’, ‘cluster headache’ or ‘cervicogenic headache’. Inclusion was limited to studies published in English in peer-reviewed journals from the time of introduction of ICHD-II in 2004. When this second edition of classification was released, it was recommended for use as standard definitions of headaches for clinics and research (4).

We excluded articles that had cohorts other than the diagnoses of interest for this review and articles that presented data for the same cohort as an earlier publication already included in the review.

Information sources

Relevant articles were identified by searching the following electronic databases from 2005 to April 2015: Cochrane Library, Medical Literature Analysis and Retrieval System Online (MEDLINE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), The Allied and Complementary Medicine Database (AMED), Embase, Physiotherapy Evidence Database (PEDro), and Web of Science. In addition, researchers scanned the “related articles” link of databases and SCOPUS to identify reports citing the included studies.

Search strategy

We used a sensitive search strategy using a combination of Medical Subject Headings (MeSH) and words “primary headache” OR “migraine” OR “tension-type headache” OR “cluster headache” OR “cervicogenic headache” and related terms. The search was limited to ‘peer-reviewed publication, 2005 to 2015’ and ‘humans’ (Supplementary material: Appendix A) and conducted by a single investigator (MA).

Study selection

Two reviewers (MA and MD) removed duplicate citations and independently determined the eligibility of retrieved articles by applying the inclusion criteria through title and abstract screening in EndNote™ X7.3 (Thomson Reuters. Endnote. New York: Thomson Reuters; 2015). Two other reviewers (TR and AL) were consulted for articles that did not clearly meet the inclusion criteria. The full text of the remaining citations was retrieved and independently assessed by two reviewers (MA and AL or TR or KM or MD). Disagreement between the reviewers on study selection was resolved by a third researcher (TR or AL).

Data extraction

A data extraction spreadsheet was designed and pilot tested by all reviewers. Data were extracted independently by two reviewers (MA and AL or TR or KM or MD). Disagreement between the reviewers on extracted data was resolved by a third researcher (TR or AL).

Data extracted included study and participant characteristics (Supplementary material: Appendix B). Study characteristics included research design, sample size, intervention and control, method of headache diagnosis, and inclusion and exclusion criteria for the study. Participant characteristics comprised demographic information and headache features of the participants at baseline. Headache features included the diagnostic criteria for each headache type according to ICHD-II (4). Studies were grouped by diagnosis for descriptive analysis. Data on the process of diagnosis and inclusion criteria used in the clinical studies were analyzed to define the patient populations. Frequency distribution of studies that reported the ICHD clinical features as baseline characteristics of participants, and the means and standard deviations of these features or percentage of participants demonstrating these reported baseline characteristics, were also described.

Results

Two hundred and twenty nine studies met the selection criteria for this review (Figure 1). The list of studies included in this review appears in the Supplementary material as Appendix C. Of these studies, 222 (96.9%) were randomized controlled trials and seven (3.1 %) were controlled clinical trials. Sample sizes ranged from 11 to 1935 [mean (SD) 243.31 (336.30)] (Table 1), with a total of 48,661 participants across all studies. Migraine was the most studied headache type, while cervicogenic headache was the least studied. Most investigated pharmacologic interventions (n = 158, 69.0%). Non-pharmacologic interventions (n = 71, 31.0%) included complementary and alternative medicine (n = 29, 12.7%), psychotherapeutic intervention (n = 15, 6.6%), neurostimulation and nerve blockade (n = 16, 7.0%).

Figure 1.

Flow diagram of study selection.

Table 1.

Characteristics of studies and participants in the review.

Study characteristics
Design
RCT (n, %)	222 (96.9)
CCT (n, %)	7 (3.1)
Number of participants (mean, SD)	243.31 (336.30)
Headache classification studied [n (%) of total studies reviewed]
Migraine	186 (81.2)
Tension-type headache	31 (13.5)
Cluster headache	7 (3.1)
Cervicogenic headache	5 (2.2)
Participant characteristics
% female (mean, SD)	78.74 (17.88)
Age, years (mean, SD)	39.43 (0.48)
History of headaches, years (mean, SD)	11.2 (12.85)

Definition of study population and selection of participants in clinical trials

Two hundred and ten studies (91.7%) used a classification system to define their study populations, with 205 studies (89.5%) reporting adherence to the ICHD. One hundred and twenty seven studies (55.5%) diagnosed participants through interview, clinical examination and diary entry (Table 2). It is unclear how diagnoses were arrived at or how the classification system was used in the other 102 studies, as these details were not provided.

Table 2.

Process of diagnosing headaches used in clinical studies.

Process of diagnosis	n (%) of studies
Use of classification system
Used a classification system	210 (91.7)
ICHD	205 (89.5)
Guidelines for controlled studies of drugs in migraine by the International Headache Society Clinical Trial Subcommittee	3 (1.3)
Silberstein-Lipton criteria for chronic migraine	2 (0.9)
Sjaastad criteria for cervicogenic headache	2 (0.9)
Did not report	19 (8.3)
Method of diagnosis
Interview	81 (35.4)
Clinical examination	55 (24.0)
Diary	40 (17.5)
Diagnosed by health professional/s	26 (11.4)
Questionnaire	15 (6.6)
Diagnostic and laboratory tests	13 (5.7)
Self-identified	2 (0.9)
“Screening”	12 (5.2)
Did not report	102 (44.5)

Not all clinical features listed as ICHD diagnostic criteria for the headache types were routinely specified among the inclusion criteria (Figure 2). For migraine studies, the most commonly reported inclusion criterion was pain intensity (n = 123, 66.1%) and the least common was pulsating quality of headache (n = 22, 11.8%). For tension-type headache studies, the most commonly reported inclusion criteria were pain intensity (n = 21, 67.7%) and frequency of attacks (n = 17, 54.8%) while the least common were bilateral location, non-pulsating quality of headache and not affected by physical activity (all n = 7, 22.6%). For cluster headache studies, the most commonly reported inclusion criteria were frequency of attacks (n = 5, 71.4%) and severity, location and duration of headache (n = 4, 57.1%). For cervicogenic headache studies, the most commonly reported inclusion criteria were pain referred from the neck (n = 4, 80%) and evidence of cervical spine or muscle disorder (n = 3, 60%). No cervicogenic headache study specified improvement or resolution of pain in parallel with the resolution of the neck disorder or lesion as an inclusion criterion.

Figure 2.

ICHD diagnostic criteria reported as inclusion criteria for study populations.

Other inclusion criteria unrelated to the ICHD criteria but necessary to control for potential confounders were frequently used in the headache studies. In general, participants were included in studies if they belonged to a specific age group (mostly 18 to 65 years old), were younger than 50 years old on their first headache attack, were experiencing a single headache type or able to differentiate attacks according to headache types, were experiencing headaches for at least 1 year, and had no comorbidities such as malignancy or depression. Other selection criteria for study populations were related to the intervention investigated. For example, many studies excluded participants who were pregnant or lactating, had taken or were responsive to certain medications, or were taking other medications considered to be prophylactic or contraindicated to the intervention.

Description of participants at baseline in terms of ICHD criteria

Not all clinical features listed as ICHD criteria for the headache types were routinely reported as baseline characteristics of participants in the studies (Table 3). Nevertheless, among the migraine studies that reported the baseline clinical features, the most reported characteristics were the severity of the headache (n = 64, 34.4%) and presence of photophobia and/or photophobia (n = 44, 23.7%). Where reported, most participants demonstrated moderate to severe pain intensity (92.5% of participants) and photophobia and/or phonophobia (79.4% of participants) at baseline. For tension-type headache studies, the baseline headache characteristic most reported was severity of the headache (n = 15, 46.9%). It was not possible to pool severity data because different headache intensity scales were used. For cluster headache studies, only two ICHD clinical features were reported as baseline characteristic of participants: duration and frequency of attacks. Participants in the cluster headache studies had about three attacks per day lasting for about an hour. For cervicogenic headache, the only clinical feature reported as a baseline characteristic of participants was abolition of headache following nerve blockade (n = 1, 20%).

Table 3.

ICHD diagnostic criteria described among baseline characteristics of participants with recurrent headache.

ICHD clinical features	n (%) of studies that measured and reported the feature as a baseline characteristic	Mean (SD) of the reported headache feature or % of participants demonstrating the feature at baseline
(a) Migraine
Headache attacks lasting 4–72 hours (untreated or unsuccessfully treated)	29 (15.6)	21.31 (18.14) hours
Unilateral location	11 (5.9)	59.8%
Pulsating quality	8 (4.3)	85.9%
Moderate or severe pain intensity	64 (34.4)	92.5%
Aggravation by or causing avoidance of routine physical activity	6 (3.2)	76.9%
Nausea and/or vomiting	36 (19.4)	52.4%
Photophobia and phonophobia	44 (23.7)	79.4%
At least five attacks
(b) Tension-type headache
Headache occurring on ≥15 days/month on average for >3 months (≥180 days/year)	1 (3.1)	21 days
Headache lasting from 30 minutes to seven days	5 (15.6)	11.46 (4.89) hours
Bilateral location	0 (0)
Pressing/tightening (non-pulsating) quality	1 (3.1)	67%
Mild or moderate intensity	14 (45.2)	5.81 (1.70) (out of 10)
Not aggravated by routine physical activity such as walking or climbing stairs	0 (0)
No nausea or vomiting (anorexia may occur)	1 (3.1)	100%
No more than one of photophobia or phonophobia	1 (3.1)	100%
(c) Cluster headache
Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15–180 minutes if untreated	3 (50)	82.75 (37.89) minutes
Conjunctival injection and/or lacrimation	0 (0)
Nasal congestion and/or rhinorrhoea	0 (0)
Eyelid oedema	0 (0)
Forehead and facial sweating	0 (0)
Forehead and facial flushing	0 (0)
Sensation of fullness in the ear	0 (0)
Miosis and/or ptosis	0 (0)
A sense of restlessness or agitation	0 (0)
Attacks have a frequency between one every other day and eight per day for more than half the time when the disorder is active	1 (16.67)	3.33 (0.77) per day
(d) Cervicogenic headache
Pain, referred from a source in the neck and perceived in one or more regions of the head and/or face	0 (0)
Clinical, laboratory and/or imaging evidence of a disorder or lesion within the cervical spine or soft tissues of the neck known to be, or generally accepted as, a valid cause of headache	0 (0)
Abolition of headache following diagnostic blockade of a cervical structure or its nerve supply using placebo- or other adequate controls	1 (20)	61.0 (5.4) % reduction in pain
Pain resolves within three months after successful treatment of the causative disorder or lesion	0 (0)

On further examination of the reported baseline characteristics of participants, there was little to no information describing the extent to which participants demonstrated the clinical features that were thought to least overlap with other headache types. For migraine studies, nausea and/or vomiting, photophobia and phonophobia, and aggravation of the attack by routine physical activity (8,10) were reported in less than a quarter of the studies. Similarly, the following features were not reported as baseline characteristics: headaches not aggravated by routine physical activity for tension-type headache (8,11,12); presence of autonomic symptoms for cluster headache (13); and pain, referred from the neck and evidence of a cervical spine lesion for cervicogenic headache (2).

Discussion

This review reveals that the ICHD is routinely used to define study populations in headache studies, suggesting consensus and endorsement among researchers of ICHD in providing a framework for selecting participants. The use of a common framework such as the ICHD in defining study populations, in turn, allows for better comparison and synthesis of data across clinical trials. The methods of applying the ICHD criteria varied between studies, with most conforming to the “gold standard” for diagnosing headaches of using the ICHD through interview and physical examination (14).

Study populations across studies were homogenous beyond their headache features because participants were also selected based on other criteria. These selection criteria, such as being of a certain age at first headache episode and enrolment in the study, gender, health status, medication use, and frequency of attacks, were apparently used to fit outcomes of interest and to control for potential confounders. Whereas these selection criteria do not reflect the validity of the diagnostic criteria used in the studies, they conform to guidelines for clinical trials (15,16). The use of these guidelines in conjunction with the ICHD reflects how well these tools complement each other in defining study populations. While study populations were generally selected based on headache features listed in the ICHD, the results of this review did not make it possible to describe the extent to which these features were demonstrated by participants at baseline. Few studies have provided this level of detail. Of the ICHD features reported at baseline, the most reported were intensity, severity and frequency of headaches. These headache features were consistent with some of the recommended outcome measures for headache trials (15 –18).

It is reasonable to think that not all headache features were reported as baseline characteristics because the researchers of the studies already mentioned adhering to the ICHD criteria in selecting the participants. Although selection criteria provide some information on participant characteristics, further details on baseline headache characteristics may be helpful. Because diagnosing using the ICHD is based on combinations of headache features, details on which and to what extent headache features were demonstrated at baseline would clarify participant features and potentially improve understanding and confidence in headache classification in studies. Ultimately, such details may aid translation of research findings to clinical populations.

Nevertheless, this large review presents a comprehensive snapshot of the landscape of definitions of study populations in headache trials. The limitations of this review were that we could not pool data for meta-analysis due to lack of standardization of outcome measures used, and we did not assess risk of bias within studies. However, these were redundant because this review did not aim to evaluate treatment efficacy nor report pooled effect sizes for treatment outcome. A step forward may be to explore the importance and impact of reporting baseline headache characteristics of participants in headache trials.

In summary, study populations of treatment efficacy studies investigating migraine, tension-type headache, cluster headache, and cervicogenic headache were generally defined based on the ICHD criteria. It is unclear to what extent participants demonstrated the ICHD criteria at baseline. This review provides a comprehensive snapshot of how study populations are defined in headache trials. Results of this review also provide a starting point for discussing the level of detail in reporting diagnostic headache features at baseline in clinical trials.

Footnotes

Article highlights

Definitions of study populations in most treatment efficacy studies of frequent recurrent headaches, namely, migraine, tension-type headache, cluster headache, and cervicogenic headache strictly adhered to the International Classification of Headache Disorders.

It is unclear to what extent participants demonstrated the diagnostic criteria at baseline, as few studies provided this level of detail.

Results of this review provide a starting point for discussing the level of detail in reporting diagnostic headache features at baseline in clinical trials.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Maria-Eliza Aguila was supported by a fellowship through the Doctoral Studies Fund under the Expanded Modernization Program of the University of the Philippines. Trudy Rebbeck was supported by a fellowship from the Australian National Health and Medical Research Council (NHMRC).

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Supplementary Material

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Definitions and participant characteristics of frequent recurrent headache types in clinical trials: A systematic review

Abstract

Background

Methods

Results

Conclusions

Keywords

Introduction

Methods

Protocol registration

Eligibility criteria

Information sources

Search strategy

Study selection

Data extraction

Results

Definition of study population and selection of participants in clinical trials

Description of participants at baseline in terms of ICHD criteria

Discussion

Footnotes

Article highlights

Declaration of conflicting interests

Funding

References

Supplementary Material