Myofascial trigger points in migraine and tension-type headache

Background A myofascial trigger point is defined as a hyperirritable spot in skeletal muscle that is associated with a hypersensitive palpable nodule in a taut band. It has been suggested that myofascial trigger points take part in chronic pain conditions including primary headache disorders. The aim of this narrative review is to present an overview of the current imaging modalities used for the detection of myofascial trigger points and to review studies of myofascial trigger points in migraine and tension-type headache. Findings Different modalities have been used to assess myofascial trigger points including ultrasound, microdialysis, electromyography, infrared thermography, and magnetic resonance imaging. Ultrasound is the most promising of these modalities and may be used to identify MTrPs if specific methods are used, but there is no precise description of a gold standard using these techniques, and they have yet to be evaluated in headache patients. Active myofascial trigger points are prevalent in migraine patients. Manual palpation can trigger migraine attacks. All intervention studies aiming at trigger points are positive, but this needs to be further verified in placebo-controlled environments. These findings may imply a causal bottom-up association, but studies of migraine patients with comorbid fibromyalgia syndrome suggest otherwise. Whether myofascial trigger points contribute to an increased migraine burden in terms of frequency and intensity is unclear. Active myofascial trigger points are prevalent in tension-type headache coherent with the hypothesis that peripheral mechanisms are involved in the pathophysiology of this headache disorder. Active myofascial trigger points in pericranial muscles in tension-type headache patients are correlated with generalized lower pain pressure thresholds indicating they may contribute to a central sensitization. However, the number of active myofascial trigger points is higher in adults compared with adolescents regardless of no significant association with headache parameters. This suggests myofascial trigger points are accumulated over time as a consequence of TTH rather than contributing to the pathophysiology. Conclusions Myofascial trigger points are prevalent in both migraine and tension-type headache, but the role they play in the pathophysiology of each disorder and to which degree is unclarified. In the future, ultrasound elastography may be an acceptable diagnostic test.


Background
Migraine affects 16% of the population in Europe [1] with high individual and socioeconomic costs [2,3]. Several mechanisms have been proposed to be involved in its pathophysiology including vascular, peripheral and central mechanisms [4][5][6][7][8][9]. Jes Olesen systematically described pericranial tenderness in migraine patients, both during and outside of migraine attacks [10,11], leading to speculations that myofascial mechanisms may be involved in migraine [12].
Tension-type headache (TTH) is the most prevalent primary headache disorder worldwide [13]. Tenderness in pericranial myofascial tissue is correlated with the intensity and frequency of headache in TTH [14][15][16], and studies show increased muscle stiffness in TTH patients [17,18]. Thus, myofascial structures may be associated with TTH pathophysiology.
The term myofascial trigger point (MTrP) was popularized in the 1950s and is defined as a hyperirritable spot in skeletal muscle that is associated with a hypersensitive palpable nodule in a taut band [19,20]. The spot is painful on compression and can cause referred pain, referred tenderness, motor dysfunction and autonomic phenomena. The interest in myofascial symptoms has been ongoing for centuries with similar descriptions of localized thickenings of muscles with regional pain [21]. There have been inconsistencies and controversies in the literature on the underlying pathology, and even the existence of MTrPs [22]. While attempts have been made to visualize MTrPs [22], the gold standard for detection of MTrPs has been unchanged since the 1950s [22] and remains to be by way of palpation of the affected muscles. However, this technique proves to be poorly reproducible as practitioners disagree on the location of MTrPs when blindly examining different patient groups [23]. Nevertheless, MTrPs have come to play a central role in the diagnosis and treatment of myofascial pain syndrome [19]. Furthermore, MTrPs have been proposed to take part in primary headache disorders and other chronic pain conditions [12]. The aim of this narrative review is to present an up-to-date overview on MTrPs in general and then in migraine and TTH, respectively.

Myofascial trigger points
In the comprehensive trigger point manual by Travell and Simons [19], MTrPs are subclassified into different types, e.g., active and latent amongst others. An active MTrP produces a constant pain complaint while a latent only produces pain during manual palpation [19]. It was hypothesized that a sustained muscle contraction in MTrPs promotes hypoxia and ischemia with a following increase in concentrations of substances such as calcitonin gene-related peptide (CGRP) and substance P (SP) [24]. Consequently, this would lead to increased peripheral nociceptive transmission [24]. This hypothesis is only supported in active MTrPs, as they have been shown to be associated with higher levels of these substances in the local milieu compared to latent MTrPs [25,26]. Other properties such as the consistency of the tissue have also been suggested to play a key role in MTrPs [27].

Investigations of myofascial trigger points Ultrasound imaging
Different ultrasound modalities in ultrasound imaging have visualized MTrPs. Lewis et al. [28] conducted a pilot study to assess the use of ultrasound in determining soft tissue changes in the region of active MTrPs in 11 subjects. They found no correlation between clinical identified active MTrPs and ultrasound. In contrast, Turo et al. [29] were able to differentiate between symptomatic MTrPs and asymptomatic muscle tissue with texture-based analysis. Sikdar et al. investigated the stiffness of active and latent MTrPs, using ultrasound elastography by Doppler variance imaging in nine subjects while inducing vibrations with an external handheld massage vibrator [27]. MTrPs appeared as focal, hypoechoic regions on two-dimensional ultrasound images and with reduced vibration amplitude, indicating increased stiffness. Furthermore, they describe hypoechoic regions that were not identified during palpation prior to ultrasound. In another study by the same group, MTrPs showed reduced vibration amplitude on elastography indicating increased stiffness and distinct blood flow waveform patterns [30]. Ballyns et al. [31] used elastography to investigate MTrPs in 44 subjects with acute cervical pain. They were able to measure the size and distinguish type (active, latent) of MTrPs with elastography. In addition, Doppler waveforms of blood flow showed different characteristics in active sites compared to normal tissue. Takla et al. [32] compared elastography with two-dimensional grayscale ultrasound in identifying MTrPs. They found that MTrPs had an accuracy of 100% for both active and latent MTrPs while two-dimensional grayscale ultrasound could only identify 33 and 35%, respectively.

Microdialysis
Microdialysis has been used to measure endogenous and exogenous molecules in the local milieu of MTrPs. Shah et al. [25] used microdialysis to investigate subjects with active or latent MTrP, and controls without MTrP were detected by manual palpation by two experienced clinicians. The authors measured selected substances (pH, bradykinin (BK), CGRP, SP, tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), serotonin, and norepinephrine (NE)) in standardized locations of the trapezius muscle and gastrocnemius muscle. Subjects with active MTrPs in the trapezius muscle showed increased concentrations of all substances compared to the other groups. Shah et al. [26] found similar results in the trapezius muscle of subjects with neck pain and active MTrP compared to a group with neck pain and no MTrP present and healthy controls. The results showed that the active MTrP group had higher concentrations of BK, CGRP, SP, TNF-α, IL-1β, serotonin, NE.

Electromyography
Electromyography (EMG) can be used to measure the electrical activity of skeletal muscles. Simons et al. compared the prevalence of motor endplate potentials in active MTrPs, endplate zones, and taut bands of skeletal muscles in subjects with palpable MTrPs [33]. The authors found that endplate noise was more common in MTrPs than in sites outside of the trigger point, even within the same endplate zone. Ge et al. evaluated intramuscular muscle activity in a synergistic muscle during isometric contraction in 15 subjects with latent MTrPs [34]. The needle was inserted into a latent MTrP or a non-MTrP in the upper trapezius at rest and during contraction. The EMG activities were recorded from the middle deltoid muscle and the upper, middle, and lower parts of the trapezius muscle. The intramuscular EMG activity in the upper trapezius muscle was significantly higher at rest and during contraction at latent MTrPs compared with non-MTrPs. Yu et al. measured maximum voluntary isometric contraction, endurance, median frequency, and muscle fatigue index in three groups of participants: an active MTrP group, a latent MTrP group, and a control group [35]. The active MTrP group had a higher median frequency and muscle fatigue index than the control group. Wytrążek et al. compared the EMG activity of muscle motor units at rest and maximal contraction with surface EMG recordings [36]. The results showed MTrPs correlated with an increase in EMG amplitude at rest.

Infrared thermography
Infrared thermography can be used to measure the skin temperature. Dibai-Filho et al. [37] have reviewed the literature on infrared thermography investigations of MTrPs. The authors included three comparative studies [38][39][40] and one accuracy study [41]. The conclusion of the review is that the included studies do not agree on skin temperature patterns in the presence of MTrPs. The included studies of the review are briefly presented in the following. Merla et al. [38] found that individuals with myofascial pain had a greater difference between the right and left side in skin temperature over the masseter and sternocleidomastoid muscles before and after maximal voluntary clenching compared to healthy volunteers. They also found that the myofascial pain group had a greater temperature change over the measured muscles after maximum voluntary clenching. Kimura et al. [39] evaluated the vasoconstrictor response after provoking pain in MTrPs with an intramuscular glutamate injection. Furthermore, they activated the sympathetic outflow by using a breath-holding maneuver. They found a decrease in skin temperature over time in latent MTrPs. In contrast, Zhang et al. [40] did not find that the skin temperature was affected following an intramuscular glutamate injection into latent MTrPs. Haddad et al. [41] compared infrared thermography and algometer measurements of MTrPs in the masticatory muscles. The authors found a positive correlation between skin surface temperature and pressure pain threshold. Regarding diagnosing MTrPs, infrared thermography had an accuracy of 0.564 to 0.609 (area under the receiver operating characteristic curve).

Magnetic resonance imaging
Chen et al. [42] examined 65 patients with myofascial pain-associated taut bands using magnetic resonance elastography. They found that agreement between physicians and imaging raters were relatively poor (63%; 95% CI, 50%-75%), but that these bands could be assessed quantitatively using magnetic resonance elastography. The authors suggest that clinicians might overestimate while magnetic resonance elastography may underestimate MTrPs.

Migraine and myofascial trigger points
Pericranial tenderness in migraine patients was systematically described by Jes Olesen in 1978, both during and outside of attacks [10,11] leading to speculations that myofascial mechanisms may be involved in migraine [12]. The bottom-up model states that increased peripheral nociceptive transmission sensitizes the central nervous system to lower the threshold for perceiving pain while the top-down model suggests these changes are already present in the central nervous system [43]. While it can be argued that pericranial tenderness in migraine may be caused by a top-down central sensitization, a bottom-up association was implied in 1981 when Tfelt-Hansen et al. [44] demonstrated that injections of lidocaine and saline into tender trigger points could relieve migraine attacks. They infiltrated the most tender spots of 26 cranial and neck muscles and tendon insertions in 50 migraine patients. The most frequent sites of tenderness were sternocleidomastoid, anterior temporal, neck and shoulder muscles, the coronoid process and occipital insertions. The tender points in the mentioned study do not necessarily overlap with Travell and Simons' definition of MTrPs, but the implication stands that peripheral myofascial mechanisms may be involved in migraine pathophysiology. Consequently, there has been an interest in exploring MTrPs in migraine (Table 1) [45][46][47][48][49][50][51][52][53][54][55][56][57][58].

The occurrence of myofascial trigger points in migraine
Several studies have demonstrated a high occurrence of active and latent MTrPs in migraine patients [45][46][47][48][49]. Studies show that there is a significantly higher prevalence of active MTrPs in migraine patients compared to healthy controls [45,46,58]. There are conflicting results in which muscles are the most affected [47,48]. Fernández-de-Las-Peñas et al. [46] observed that active MTrPs were most prevalent ipsilateral to the migraine headaches. More unclear is whether the amount of MTrPs is correlated with the frequency and intensity of headache attacks. Calandre et al. [45] found a positive correlation between the number of MTrPs and • Active MTrPs in the temporalis and masseter muscle were most prevalent in both groups.
• MTrPs in all the muscles.
• Active MTrPs was positively associated with a reduction in cervical lordosis and head extension of the head on the neck.
• No association between the number of active MTrPs and clinical features of migraine was observed. Not reported MTrPs were considered to be active if 1) referred pain due to palpation reproduced the subjects' headache.

Florencio
2) There was a jump sign that was the characteristic behavioral response to pressure on a trigger point. All subjects included had active trigger points. Subjects (al were randomly assigned to one of two groups: 1) Medication only 2) Medication + positional release therapy The treatment phase lasted 2 weeks and medication included NSAIDs, nortriptyline, propranolol and depakine. Subjects completed a daily headache diary throughout the study and tablet count was recorded. After a baseline period of 2 weeks the sensitivity of trigger points (using a digital force gauge) and cervical range of motion were assessed. This was repeated after the treatment phase and as a follow up after 1, 2 and 4 months (counting from start of treatment) Suboccipital, sternocleidomastoid, upper trapezius, cervical multifidus, rotators and interspinales • Both groups showed significant reduction in headache intensity, frequency, duration and tablet count after 4 months follow up.
• The sensitivity of trigger points was significantly reduced in the medication positional release therapy group, while it remained unchanged in the medicine only group.
Do et al. were significantly lower than in controls at baseline. In group one pain threshold increased significantly during treatment. In group two there was no significant change. In the control group there was no significant variation.
• In group 1 maximal intensity and number of migraine attacks decreased significantly. In group 2 the change was not significant.
• The mean number of rescue medication taken fell significantly in group 1, but not in group 2.
• The group that participated in the second experiment also had a pain threshold lower than normal.
Landgraf (2017 Not specified MTrPs were identified by palpation and the PPT on these points was measured using an algometer. Manual pressure was applied to the trigger points, and the occurrence and duration of induced headache were recorded. At a second consultation (4 weeks after the first), manual pressure with the detected pressure threshold was applied to non-trigger points within the same trapezius muscle (control).
Trapezius muscle • Manual pressure to MTrPs in the trapezius muscle led to lasting headache after termination of the manual pressure in 13 (50%) patients (from 5 s to over 30 min).
• No patient experienced headache when manual pressure was applied to non-trigger points at the control visit.
• Headache was induced significantly more often in children ≥12 years and those with internalizing behavioral disorder.

Neck mobility and specific muscles
There appears to be an association between neck mobility and MTrPs [46,48,49,58]. Ferracini et al. [48] found that a higher number of active MTrPs was positively correlated with a reduction in cervical lordosis and head extension of the head on the neck. In addition, that lower cervical angles were correlated higher then the number of active MTrPs. Florencio et al. [49] hypothesized that active MTrPs in the cervical musculature alters the activity of the related muscles and that this would be reflected in EMG readings. They observed that the presence of active MTrPs in the cervical musculature had different activation in the neck flexor muscles compared to those without active MTrPs in the same muscles regardless of the presence of pain. Palacios-Ceña et al. [55] found that the number of active MTrPs in head, neck and shoulder muscles were associated with widespread pressure hypersensitivity in a migraine population.

Provocation and intervention studies
Two unblinded studies show that manual palpation of MTrPs can provoke a migraine attack [45,53]. Calandre et al. provoked a migraine attack in one-third of a migraine population by palpating MTrPs [45]. Landgraf et al. provoked migraine headache by inducing pressure to MTrPs and could not replicate this by pressure to non-trigger points in the trapezius in an adolescent migraine population [53].
Interventions targeted at MTrPs show promising results [50-52, 56, 57], but the quality of studies varies greatly and lack placebo-control. Giambierardino et al. demonstrated that local anesthetic infiltration of MTrPs resulted in a reduction of migraine symptomatology in terms of frequency and intensity [52]. Furthermore, there was a reduction of hyperalgesia, not only at the injection site but also in referred areas overlapping with migraine pain sites. Similar, Ranoux et al. injected botulinum toxin in MTrPs with similar results in terms of reduction in headache days [56]. Gandolfi et al. improved the outcome of prophylactic botulinum toxin treatment in chronic migraine patients with manipulative treatment of MTrPs [50]. The outcome was a lower consumption of analgesics, improvement in pressure pain threshold and increased cervical range of motion. Likewise, Ghanbari et al. reported that combined positional release therapy targeted at MTrPs with medical therapy is more effective than the sole pharmacological treatment [51]. Interestingly, sessions of magnetic stimulation of active MTrPs reduced headache frequency and intensity in adolescent migraineurs [57]. Though these findings need to be verified in a placebo-controlled study. There has not been any studies on the effect of systemic musculoskeletal analgesics on MTrPs [59], which would be of interest for future studies.

The occurrence of myofascial trigger points in tension-type headache
There is a high occurrence of active and latent MTrPs in patients with TTH [63-67, 69-72, 79] Active MTrPs are found almost only in TTH patients compared to controls [63,65,69,72,80]. MTrPs are more prevalent on the dominant side of the patients [66]. The number of active MTrPs is higher in adults in comparison to adolescents regardless of no significant association between the number of active MTrPs and headache frequency, duration and intensity [62]. Other studies have found that active MTrPs are correlated with the severity of TTH [65,67,78,80] with a greater occurrence of MTrPs in chronic TTH in comparison to episodic TTH [80]. Furthermore, studies show that active MTrPs are correlated with the intensity, duration and frequency of headache episodes in TTH [65,80]. In contrast, other studies failed to show a correlation between MTrPs and chronic and frequent episodic TTH [78] and showed no correlation between MTrPs and headache parameters either in episodic TTH patients [69].

Neck mobility and specific muscles
Episodic TTH patients had less neck mobility compared to controls [69]. Patients with active MTrPs had a greater forward head position than subjects only with latent MTrPs [69]. However, neither forward head position or neck mobility was correlated with headache parameters [69]. In a different study, active MTrPs in the right upper trapezius muscle and left sternocleidomastoid muscle was correlated with a greater headache intensity and duration [72]. Furthermore, active MTrPs in the right and left  [89] PPT was assessed using an algometer.
Temporalis (9 landmarks total, 3 each respectively in the anterior, medial and posterior part) • The analysis of variance did not detect significant differences in the referred pain pattern between active MTrPs.
• The topographical pressure pain sensitivity maps showed the distinct distribution of the MTrPs indicated by locations with low PPTs. • Patients with bilateral MTrPs reported a greater headache intensity and duration than those with unilateral TrPs.
• CCTH subjects showed a decreased PPT compared to controls.

Suboccipital
• Active MTrPs were only found in CTTH patients.
• CTTH patients with active MTrPs reported greater headache intensity and frequency than those with latent.
• A craniovertebral smaller angle was positively correlated with increased headache frequency and negatively correlated with headache duration. Superior oblique • 86% CTTH patients and 60% ETTH patients reported referred pain from MTrPs.
• The pain was perceived as a deep ache located at the retro-orbital region -sometimes extending to the supraorbital region or the homolateral forehead.
• Pain intensity was greater in CTTH patients than in ETTH patients.  EMG examination before and after injections.

Occipitalis and trapezius
• Responders (70%) had an average of 8,1 weeks free of pain following treatment.
• The EMG recorded immediately after injection in all cases showed that the hyperactivity in the trapezius muscle was completely abolished. PPT was assessed using an algometer.

Moraska
MTrP diagnosis was performed following the criteria described by Simons et al. [19] Suboccipital and upper trapezius • PPT increased across the study timeframe in all four muscle sites tested for massage, but not sham ultrasound or wait-list groups. PPT was assessed using an algometer.

Moraska
MTrP diagnosis was performed following the criteria described by Simons et al. [19] Suboccipital, sternocleidomastoid, and upper trapezius • Headache frequency fell in both the massage and the placebo group.
• PPT improved in the massage group.
Do et al.  temporalis muscles correlated with longer headache duration and greater headache intensity, respectively [72]. Suboccipital active MTrPs correlated with increased intensity and frequency of headache [65]. Chronic TTH patients with active MTrPs in the analyzed muscles had a greater forward head position than those subjects only with latent MTrPs [65,72]. Sohn et al. [80] identified a greater occurrence of MTrPs in chronic TTH compared to episodic TTH and that the number of active MTrPs correlated with the frequency and duration of headache, although they did not find any correlations for forward head posture and neck mobility in contrast to Fernández-de-las-Peñas et al. [65,72].

Pressure pain threshold
The number of active and latent MTrPs was significantly and negatively associated with pressure pain thresholds on the temporalis muscle, C5/C6 zygapophyseal joint, second metacarpal, and tibialis anterior muscle [78]. Thus, a higher number was associated with a more generalized sensitization regardless of the frequency of headache. Another study observed that the location of active MTrPs in the temporalis muscle corresponded to areas with lower pain pressure thresholds which establishes a relationship between the two [68]. The same group found that chronic TTH patients with bilateral active MTrPs in the trapezius muscles have a significantly lower pain pressure threshold compared to patients with only unilateral active MTrPs [70]. Minimum clinical differences in pressure pain thresholds in TTH patients may be used to evaluate treatment of MTrPs [79].

Therapeutic studies targeting myofascial trigger points
Karadas et al. [81] investigated pericranial lidocaine injections in MTrPs in 108 patients with frequent episodic TTH using a double-blind placebo-controlled randomized study design. Repeated local lidocaine injections into the MTrPs in the pericranial muscles reduced both the frequency and intensity of pain compared to placebo. Another placebo-controlled study found similar results with lidocaine injections in MTrPs in chronic TTH with a reduction in pain frequency, pain intensity, and analgesic use [74]. In addition, there was a significant effect on anxiety and depression of the subjects. A randomized, double-blind, placebo-controlled pilot study of botulinum toxin A injections in MTrPs included 23 patients with chronic TTH [73]. The subjects were assessed at 2 weeks, 1, 2 and 3 months after injection. The botulinum toxin A group reported a reduction in headache frequency that disappeared by week 12. There was no difference in intensity between the groups. In a randomized, placebo-controlled clinical trial, Moraska et al. applied massage focused on MTrPs of patients with TTH [77]. For both active and placebo groups, there was a decrease in headache frequency, but not for intensity or duration. Thus, there was no difference between massage and placebo [81].

Discussion
Ultrasound and EMG appear to be the most promising modalities to be used as a diagnostic test for MTrPs. While the use of ultrasound in headache disorders has primarily been focused on vascular changes and not on myofascial structures [82], ultrasound may also be used to identify MTrPs if specific analysis methods are applied [29] or with the use of elastography [27,30,32]. However, there is no precise description of a gold standard using these techniques, and they have yet to be evaluated in headache patients. Active MTrPs affect the electrical activity at rest and during muscle contraction in EMG studies [33][34][35][36]. Out of the two modalities, ultrasound is presumably the most viable candidate as a diagnostic test as it has an immediate availability at most treatment sites, it is time-efficient and is non-invasive. Although there are currently no studies investigating if it is possible to identify MTrPs with ultrasound without prior manual palpation. Future studies should investigate if ultrasound is comparable with manual palpation in identifying MTrPs. The other modalities do not appear to be suitable as microdialysis show mixed results regarding whether the local milieu of MTrPs is changed and needs further exploration before a conclusion can be made [25,26,83]. According to the review by Dibai-Filho et al. [37], infrared thermography appears to be a promising non-invasive method, but it should still only be used as an auxiliary tool in the evaluation of MTrPs due to conflicting results. Magnetic resonance elastography in diagnosing MTrPs has only been investigated in a few studies, and the sensitivity may be too low for suitable use as a diagnostic test [42]. Studies show a high occurrence of active and latent MTrPs [45][46][47][48][49] and correlation between neck mobility and MTrPs in migraine patients [46,48,49,58]. However, there are conflicting results in which muscles are the most affected [47,48], and it is unclear whether there is a positive correlation with the degree of headache frequency or intensity due to conflicting results. Palpation of MTrPs may provoke a migraine attack in some patients [45,53] but needs further confirmation in placebo-controlled studies. Intervention studies targeting MTrPs are mostly positive [50-52, 56, 57], but they lack placebo-control. Thus, a bottom-up association between MTrPS and migraine [44] cannot be fully supported based on the evidence (Fig. 1). In addition, in patients with migraine-fibromyalgia comorbidity, it has been shown that migraine attacks exacerbate fibromyalgia symptoms, suggesting a top-down central sensitization [84] as fibromyalgia symptoms include specific tender points [85]. Although a study showed migraine severity was similar in migraine patients with and without fibromyalgia [86]. One would expect an association between migraine severity and co-existing fibromyalgia if a top-down central is taking place in patients with this comorbidity. It is possible that MTrPs may have an important role in some subpopulations of migraine patients. This calls for therapeutic studies targeting patients with a high degree of MTrPs, but this is only speculative at this point.
The prevalence of active MTrPs in TTH [65-67, 73, 74, 77, 78, 80, 81] is coherent with the hypothesis that peripheral mechanisms are involved in the pathophysiology of TTH [14][15][16]60]. It has been speculated that an increased peripheral nociception increases the sensitization of central mechanisms resulting in an increase in the sensitivity to peripheral pain (Fig. 1). Active MTrPs may contribute to a central sensitization as they are correlated with lower pain pressure thresholds [68,70,78]. This would also provide an explanation for the efficacy of injections of lidocaine in MTrPs [74,81] as these would reduce the transmission of peripheral nociception. However, these assumptions are in contrast with a study showing that the number of active MTrPs is higher in adults in comparison to adolescents, regardless of no significant association with headache parameters [62]. This suggests that active MTrPs are accumulated over time as a consequence of TTH [62] instead of being an integrated part of the pathophysiology of TTH. Previous studies of botulinum toxin A injections in pericranial muscles have been shown to have no effect in TTH [87]. The efficacy of botulinum toxin A in MTrPs [73] might be explained by its possible action of modulating the release of nociceptive and inflammatory mediators e.g., CGRP and SP [88]. These inflammatory mediators may be increased in the local milieu of MTrPs [25,26]. This would also account for its poor efficacy in injection protocols targeting fixed landmarks in pericranial muscles instead of MTrPs [87], as these substances appear to be concentrated at MTrPs [25,26].
There are many overlapping findings in studies of MTrPs in migraine or TTH. In both disorders, MTrPs are prevalent and may be related to neck mobility. Palpation of MTrPs can, in some cases, provoke an attack in migraine patients, while palpation of MTrPs in TTH can provoke pain resembling the usual headache pattern of patients. Intervention studies are promising in both disorders. The quality of studies in both disorders varies greatly as many of the reviewed studies lacked blinding (Table 3). Furthermore, true blinding is difficult to achieve as active MTrPs by definition cause referred pain.

Conclusion
In conclusion, ultrasound elastography is the most promising tool to assess MTrPs [27,30,32], but still needs to be performed combined with palpation, which introduces risk of bias and interobserver variation. MTrPs are very frequent in both migraine patients [45][46][47][48][49] and TTH patients [65-67, 73, 74, 77, 78, 80, 81] compared to healthy controls. Active MTrPs are especially interesting as these are rarely found in control groups. However, their role in the pathophysiology of each disorder and to which degree is still unclear. The results of the provocation and intervention studies support the hypothesis of a trigemino-cervical-complex pathophysiology model in both migraine [45, 50-53, 56, 57] and TTH [73,74,81]. Whether MTrPs contribute to an increased disease burden in migraine is uncertain [45,47,48] and needs further exploration [50,52]. Future research should aim to increase the quality of studies before further speculations are made. To elucidate this, large-scale studies to stratify the headache populations into more homogenous subgroups should be conducted. Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.
Authors' contributions TPD contributed with data interpretation, drafting and revision of the manuscript for intellectual content. GFH, LTK and JH contributed with revision of the manuscript for intellectual content. HWS contributed with conceptualization, data interpretation and revision of the manuscript for intellectual content. All authors read and approved the final manuscript.
Ethics approval and consent to participate Not applicable.

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Competing interests HWS has received travel grants or speaking fees from Pfizer, Autonomic Technologies and Novartis. TPD, GFH, LTK and JH declare that they have no competing interests.