Has the Phase of the Menstrual Cycle Been Considered in Studies Investigating Pressure Pain Sensitivity in Migraine and Tension-Type Headache: A Scoping Review

Objective: The aim of this scoping review was to identify if the phase of the menstrual cycle was considered in observational studies comparing pressure pain sensitivity between women with migraine or tension-type headache (TTH) and headache-free women. Methods: A systematic electronic literature search in PubMed, Medline, Web of Science, Scopus, and CINAHL databases was conducted. Observational studies including one or more groups with TTH and/or migraine comparing pressure pain thresholds (PPTs) were included. The methodological quality (risk of bias) was assessed with the Newcastle-Ottawa Scale. Authors, objectives, inclusion/exclusion criteria, size sample, female sample, tool to assess PPTs, mean age, and the use of any medication were extracted and analyzed independently by two authors. Results: From a total of 1404 and 1832 identified articles for TTH and migraine, 30 and 18 studies satisfied the criteria and were included. Nineteen (63.4%) studies assessing TTH patients and eleven (61.1%) assessing migraine patients showed a high risk of bias. The most common flaws were attributed to improper selection of control and control over other additional factors. Based on the systematic review, just one study including TTH and one including migraine patients considered the menstrual cycle. Conclusion: The results of this scoping review identified that the phase of the menstrual cycle has been rarely considered in studies investigating sensitivity to pressure pain in primary headaches, such as TTH or migraine, although there is evidence showing the relevance of the phase of the menstrual cycle in pain perception.


Introduction
Headache is a condition ranked among the top ten causes of disability-adjusted-lifeyears (DALYs) [1]. Migraine and tension-type headache are probably the most prevalent primary headaches. Tension-type headache (TTH) is the second most prevalent disorder worldwide [2]. Similarly, migraine has been ranked the third-highest cause of disability worldwide in both genders under the age of 50 years [3]. Both headaches feature the presence of pressure pain hyperalgesia [4,5]. This assumption is based on the results from several studies investigating sensitivity to pressure pain in both TTH [5][6][7][8][9][10][11] and migraine [12][13][14][15]. Additionally, migraine is also characterized by an increased sensitivity to visual or auditory stimulus during but also outside of the headache attack [4,16].

Inclusion Criteria
(1) A group of women (age >18 years) diagnosed with TTH or migraine according to the IHS criteria. Studies including both women and men were also included but the main analysis, obviously, considered just the female group. (2) A control group of healthy women without history of headache.
(3) Full text report published in Spanish or English as a journal article. (4) Pressure pain sensitivity evaluated with PPTs assessed with a pressure algometer or dynamometer as the primary outcome.

Exclusion Criteria
(1) Studies assessing pain sensitivity with manual palpation or with other outcomes rather than an algometer (e.g., Von-Frey monofilament). (2) Experimental-induced pain models (healthy subjects receiving a hypertonic saline injection or similar) of TTH or migraine. (3) In those studies, evaluating different quantitative sensory tests, such as thermal or electrical pain thresholds, only PPTs measured with an algometer or dynamometer were included.

Data Charting Process
Data extraction was conducted using the Mendeley Desktop program. A data chart-ing form was developed for this scoping review to identify the variables that correspond with the research question. Data were extracted independently by two authors (FCM, DPRdS) using a data charting form, including title, authors, objectives, inclusion and exclusion criteria, size sample, size female sample, recruitment process, tool to assess PPT, average age of sample, and the use of any medication. Two researchers (FCM, DPRdS) completed the chart data and had to achieve a consensus on every item. In case of disagreement, a third researcher (FAS) participated in the decision to reach a resolution.

Methodological Quality
We used the Newcastle-Ottawa Scale, a star rating system, for evaluating the quality and the risk of bias of observational studies included in the review. The Newcastle-Ottawa Scale for case control studies consists of three items: selection (with 4 sections), comparability (1 section), and exposure (3 sections). Every section is formed by 2, 3, or 4 options and some of them are awarded a star if that criterion is clearly satisfied. The maximum score is nine stars. A score ≥7 stars means a study with low risk of bias [30].

Study Selection
The initial search for TTH revealed a total of 1404 identified articles. After removing duplicates (n = 634), 770 were initially screened. A total of 611 studies were excluded after reading the title and another 116 after reading the abstract since they were not directly related to pressure pain sensitivity in TTH. After reading the full-text of the remaining 43 studies, the last 13 were excluded because: results were not provided by TTH or migraine [31][32][33][34], text did not provide the required data [35], they were experimentalinduced pain models [36][37][38], it was written in Korean [39], results were not separated by gender [40][41][42], or PPT was not assessed with an algometer or dynamometer [43]. Finally, 30 studies satisfied all inclusion criteria and were included in the review of TTH ( Figure 1) [6][7][8][9][10][11].
Individuals who reported at least 1 episode of headache per month for FETTH according to the ICHD criteria, second edition (2004) Individuals with a history of migraine and those who took prescribed medication to treat their headaches or any other medical condition.    To compare differences in widespread PPT between women with FEETH, CTTH and healthy controls.
Patients with a diagnosis of FETTH or CTTH according to the ICHD criteria, third edition (2013).
(1) other primary/secondary headache; (2) medication overuse headache as defined by the ICHD-III; (3) cervical or head trauma; (4) pregnancy; (5)   To determine PPT in pericranial muscles as well as at an extracephalic site, the Achilles tendon, in patients with CTTH, migraineurs or healthy controls.
Females presenting with CTTH according to the ICHD criteria, first edition (1988).
Patients taking more than 3 analgesic tablets/week or treated with psychotropic drugs or patients who had taken such drugs less than 24 h before investigation.       The average age of the sample with migraine was 39.7 with an SD of 8.77 years. Most of the selected studies used the pressure algometer, except for some of them reporting the use of dynamometer [14,73]. A diagnostic headache diary over two or four weeks [80] was not used in any study of migraine.
Several studies excluded patients who had taken medication, such as analgesics or muscle relaxants, 24-48 h before examination [7,[12][13][14][15]52,60,[72][73][74][75][77][78][79], except for four in which this consideration was not taken into account [55,63,66,76]. Garrigós-Pedrón et al. [77] permitted the use of abortive pharmacological treatment during the assessment. Table 5 shows the Newcastle-Ottawa Scale on each TTH study included in the review. A total of 19 (63.4%) studies showed a high risk of bias and the remaining 11 (36.7%) had aa low risk of bias according to the Newcastle-Ottawa Scale. The most common flaws were a failure to observe proper selection of controls and to control for other additional factors ( Figure 3).  Table 6 shows the Newcastle-Ottawa Scale on each migraine study included in the review. A total of 11 (61.1%) studies showed a high risk of bias and the remaining seven (38.9%) had a low risk of bias according to the Newcastle-Ottawa Scale. The most common flaw was a failure to properly select controls (Figure 4).

Consideration of Menstrual Cycle
The days since the last menstruation were just recorded in one of the thirty studies (3.3%) investigating pressure pain sensitivity in TTH [47]. No other data of menstrual information were recorded in any other study. Importantly, the lack of consideration of the menstrual cycle was not considered as a limitation in any of the articles. Engstrom et al. collected the days since last menstruation in both women with and without TTH [47]. Twenty TTH patients (11 females) and 29 controls (15 females), comparable for age and sex, were included in this study. In the control group, the average number days since menstrual cycle was 16.7 (SD 9.2) days, whereas in the TTH group it was 11.3 (6.4) days. Menstrual data were not compared or associated with any other feature. Nothing else related with menstrual cycle was reported [47].
Similarly, the number of days since last menstruation were only recorded in one study including women with migraine, interestingly conducted by the same group [74]. In this case, two studies recognized that not recording the menstrual aspect was considered as a limitation [77,78]. In addition, Garridos-Pedrón et al. also considered as a limitation not reporting oral contraceptive use of the female participants [77]. Engstrom et al. [74] collected data about the number of days since last menstruation in controls (mean: 18.9 days, SD: 8.6 days), interictal migraine (mean: 14.2, SD: 7.6 days), preictal migraine (mean: 15.0, SD: 13.9 days), and postictal migraine (mean: 13.8, SD: 10.1 days) moments. Again, this menstrual data were not compared or associated with anything and no further data related with menstrual cycle were provided.
Interestingly, Strupf et al. included four patients (20% of their total sample size) with menstrual migraine [79], whereas Sales Pinto et al. included women with menstrual migraine associated with another primary headache [13]. Neither study considered the moment of the menstrual cycle in their assessments.

Findings
This scoping review aimed to identify if the phase (menstruation-bleeding, luteal phase, ovulation, or follicular phase) of the menstrual cycle was considered as a cofounder factor in studies investigating pressure pain sensitivity between patients with TTH or migraine and healthy controls. The results of this review identified that the phase of the menstrual cycle has not been consistently considered in studies published to date investigating sensitivity to pressure pain in primary headaches, such as TTH or migraine, although evidence supports a potential relevance of the menstrual cycle in pain percep-tion [17,18,81]. Only one study including individuals with TTH [47] and one including migraine patients [74] considered it relevant to include data about the last day since menstruation (but without specifying more data about this). However, these data were not compared or associated with anything else in these studies.
Similarly, an interesting finding was that just two studies including women with migraine considered the lack of menstrual information as a limitation [77,78]. Considering that more women are included in studies investigating primary headache, menstruation could be an important factor influencing pain sensitivity. We do not currently know if differences between women with migraine or TTH and headache-free women are due to "pain status" or influenced by a "menstrual status". For instance, if headache patients are assessed in a follicular phase or other of the menstrual cycle, whereas control women are assessed during menstruation, ovulation, or a different phase of the menstrual cycle, between-group differences observed in PPTs can be related to the headache status (headache or control) but also to the menstrual cycle. In fact, this would be highly important in studies investigating pain sensitivity in women with chronic migraine, since menstrualcycle disorders and dysmenorrhea are more prevalent in this population [82]. Future studies comparing women with migraine or TTH (no menstrual migraine) and healthy women should consider this and evaluate all participants, either patients or controls, in the same phase of the menstrual cycle and if differences between patients and controls are different depending on the phase of the menstrual cycle. This could be highly relevant since the menstrual cycle exhibits cyclic variations with an increased pain sensitivity during menstruation, suggesting that females could have lower PPTs during luteal and ovulation phases due to low levels of progesterone [81].
In fact, it has been already considered that females and males could have comparable detection thresholds for cold pain and ischemic pain while PPTs could be lower in females than males [83]. Similarly, Teepker et al. found that conditioned pain modulation inhibition neither differed between women with migraine and healthy women nor varied over the menstrual cycle [84].

Strengths and Limitations
The result from this scoping review should be extrapolated according to its strengths and limitations. The first strength was the use of different databases to avoid limiting the search and to include all articles fulfilling eligibility criteria. The second strength was the inclusion of studies without a limit date of publication. Third, we systematically evaluated all studies for determining the risk of bias and the inclusion of phase of menstrual cycle as a factor for being considered in PPT assessments. Among the limitations, although we included a total of 30 studies with TTH and 18 with migraine, almost 60% of the studies exhibited high risk of bias. Secondly, most studies were cross-sectional and no longitudinal studies investigating the time course of PPT have been conducted. Finally, the sample size of some of the studies was small, although this limitation does not restrict the extrapolation of our results in relation to the consideration of the phase of the menstrual cycle. In fact, the lack of information in relation to the investigated topic permits to determine different research lines for future studies.

Reliability and Validity of Pressure Pain Thresholds
Pressure pain threshold (PPT) is a static measure of pain reflecting the basal state of pain perception in relation to the pressure experienced a patient [85]. In fact, PPT is one of the quantitative sensory tests most commonly used for characterization of TTH [5] and migraine [4]. Nevertheless, its reliability and validity are controversial. Several studies reported good to excellent intra-and inter-rater reliability (intraclass correlation coefficient (ICC) > 0.70) when PPT are assessed on healthy subjects [86] or in individuals with different pain conditions [87,88]. Most studies calculate PPT as the mean of three consecutive trials assessed on the same point. However, evidence suggests that scores obtained at the first assessment are usually significantly higher than the two succeeding ones [89]. If this difference reaches 50kPa, it is recommended to conduct a fourth measurement and discard the highest value, although this is a recommendation not justified by evidence. More recent studies suggest that two measurements reduces the measurement error and presents excellent reliability (ICC ranging from 0.80 to 0.97) [90,91]. Most studies included in this scoping review conducted three measurements and calculated the means, but they did not calculate their internal reliability of PPT assessments. Therefore, results should be considered with caution. It would be recommended that futures studies comparing pressure sensitivity between women with headache and headache-free women calculate their own reliability data.
Another important topic is to determine if differences between headache patients and controls are clinically relevant and should be considered real. This is a topic of current debate since minimal detectable change (MDC) for PPT depends on the area of assessment and the population. For instance, Mailloux et al. 2021 [91] reported that the MDC for PPT ranged from 28.71 to 50.56 kPa in healthy subjects in the lumbar spine and the upper extremity. Walton et al. 2011 [87] found an MDC of 42.7 kPa for the cervical spine and of 86.3kPa for the tibialis anterior in asymptomatic subjects. In headache patients, Romero-Morales et al. [59] determined that a difference of 16.18kPa in the temporalis muscle and of 78.94kPa within the upper trapezius could be considered as real difference between people with TTH and headache-free subjects. Therefore, the comparison of pressure pain hyperalgesia between women with TTH or migraine against headache-free women should be accounted for according to these considerations.
This discussion increases in relevance when, in addition, considering the phase of the menstrual cycle, since some between-group variations could be related to the fact that two participating women are in a different phase of the cycle. Nevertheless, as will be discussed in the next section, studies determining the time course of pressure pain sensitivity throughout the different phases of the menstrual cycle are clearly needed. According to available data on MDC, the variations observed in PPTs between the different phases of the menstrual cycle should range between 50kPa and 100kPa depending on the area of assessment for determining real differences in sensitivity to pressure pain during the different phases of the menstrual cycle.

Future Research Directions
This review highlights the lack of information regarding consideration of the phase of the menstrual cycle in studies comparing pressure pain sensitivity between women with primary headaches, such as TTH or migraine, and healthy women and opens several questions for future research. First, further studies are needed to systematically determine if pain sensitivity is different throughout the different phases, e.g., menstruation-bleeding, luteal phase, ovulation, or follicular phase, of the menstrual cycle in both healthy women and women with headaches. In such a scenario, proper determination of the phase of the menstrual cycle when women are assessed will be highly important. For instance, determining the phase of the cycle by monitoring follicular development with ultrasound and measurement of estrogen/progestin blood measurements would be of high importance. With that information, future studies assessing pain sensitivity in women with migraine or TTH should evaluate all participants in the same phase of the menstrual cycle for avoiding an effect of this cofounder factor.
Similarly, medication intake of analgesics or muscle relaxants modifies pain perception as assessed with PPTs. In fact, a high proportion of studies included in this scoping review excluded patients who had taken analgesics or muscle relaxants 24-48 h before examination. However, regular consumption was not regularly controlled in most studies. This cofounder factor should be also considered in future studies. In such a scenario, another aspect to consider would be the use of hormonal contraception. Although the use of oral contraceptives is associated with an increased migraine intensity (at least at the end of menstruation), no effects on detection and pain thresholds has been observed in a small sample of migraineurs [81]. We believe that the differences in pain sensitivity in this group of women using any type of contraception may require separate studies.
Similarly, another subgroup of women to be considered is those with menstrual migraine. A review of studies applying neurophysiological procedures to test pain-related changes during the menstrual cycle in women with menstrual migraine found a fluctuation of the central modulation of pain across the menstrual phases, with a prevalence of excitatory versus inhibitory control in the premenstrual period [17]. Therefore, we do not know if the effect of menstrual cycle would be similar in this group of patients.

Conclusions
This scoping review found that observational studies examining sensitivity to pressure pain in women with TTH or migraine did not consistently consider the phase of the menstrual cycle, suggesting that the influence of menstrual cycle phase in observational studies on headache may likely be underestimated. Consequently, ignoring the effects of this cofounder factor may result in differences in PPTs between these primary headaches and healthy controls that could be related to the phase of the menstrual cycle and not just to the patient condition. Future studies investigating pressure pain sensitivity in TTH or migraine should consider the phase of the menstrual cycle in their evaluations.

Data Availability Statement:
The data presented in this study are available on request from the corresponding author.

Conflicts of Interest:
The authors declare no conflict of interest.