Noradrenergic system involvement as a major driver of tension-type headache: a systematic review of the current evidence

Abstract

Background

Tension-type headache (TTH) is the most prevalent primary headache disorder, affecting individuals of all ages and imposing a substantial global burden. While traditionally considered a peripheral skeletomuscular condition, current evidence suggests a prominent role for central mechanisms and neurotransmitter dysregulation. In this context, growing evidence highlights the noradrenergic system as a key contributor, both for the TTH genesis and maintenance.

Methods

A systematic literature search was performed according to PRISMA guidelines. A comprehensive search of PubMed/MEDLINE and EMBASE via Scopus up to March 2024 identified studies examining the relationship between TTH and the noradrenergic system.

Results

Forty-three eligible studies were included and categorized according to their focus on pathophysiology or treatment. Biochemical studies consistently reported reduced noradrenergic activity, including reduced plasma norepinephrine/epinephrine levels and dopamine-β-hydroxylase activity in TTH patients, often correlating with headache severity and chronicity. Neurophysiological and autonomic investigations further supported noradrenergic involvement, revealing altered reflex suppression, impaired sympathetic habituation, and reduced central autonomic responsiveness in TTH. Pharmacological studies indicated that medication enhancing noradrenergic transmission achieved superior clinical efficacy compared to those acting on the serotonergic system only.

Discussion

Overall, the body of evidence underscores the noradrenergic system’s integral role in TTH. The dysregulated noradrenergic system appears to contribute to central sensitization and impaired pain inhibition. These findings, along with the consistent efficacy of noradrenergic-targeting treatments, support a shift towards a more mechanistically specific and personalized approaches. Future research is needed to clarify the specific noradrenergic pathways implicated in TTH, in order to refine treatment strategies and enhance efficacy through precision medicine.

Supplementary Information

The online version contains supplementary material available at 10.1186/s10194-026-02274-6.

Background

Tension-type headache (TTH) is the most common primary headache disorder worldwide, affecting individuals across all age groups and imposing a substantial personal, social and economic burden [1]. Epidemiological evidence consistently demonstrates a high lifetime prevalence [2], reaching up to 86%, with a substantial proportion of affected individuals experiencing recurrent episodes [3]. Although migraine is typically more debilitating, the disability associated with TTH often arises from its high frequency and persistently mild-to-moderate intensity. This chronic burden leads to reduced productivity, impaired quality of life, and increased healthcare resource utilization [4].

The pathophysiology of TTH is multifactorial and not fully elucidated. Traditional models have shifted from an exclusively peripheral muscular origin, characterized by increased pericranial muscle tenderness [5, 6], to a more complex, centrally-mediated pain processing dysfunction [7, 8]. Central sensitization mechanisms, possibly involving alterations in nociceptive transmission, dysregulation of descending inhibitory pathways and changes in cortical excitability, are increasingly recognized as key contributors [9–16]. Neurochemical imbalances, involving various neurotransmitters have also been proposed, however their precise mechanistic roles remain incompletely elucidated [17, 18].

Among the neurotransmitter systems implicated in TTH, the noradrenergic system has garnered increasing scientific attention. Norepinephrine (NE), a key modulator of pain processing, stress responses and peripheral-central nervous system integration, is thought to be relevant to TTH [19]. NE is an endogenous catecholamine that functions as both a neurotransmitter in the nervous system and a circulating hormone in the body [20]. The adrenergic system encompasses the sympathetic neural pathways and related endocrine components that utilize NE and its counterpart epinephrine, including NE-producing neurons in the central nervous system and postganglionic sympathetic neurons: in particular, NE is the primary neurotransmitter of sympathetic postganglionic fibers, making it a key mediator of autonomic responses [21]. The brainstem locus coeruleus (LC) is a principal source of descending noradrenergic modulation of pain, sending projections to the spinal dorsal horn that exert potent inhibitory control over nociceptive processing by engaging spinal α₂-adrenergic receptors, which mediate both presynaptic inhibition of neurotransmitter release from primary afferent terminals and postsynaptic inhibition of dorsal horn nociceptive neurons [22]. Higher-order cortical structures such as the prefrontal cortex and the central amygdala help regulate this descending analgesic system by modulating LC activity, thereby integrating cognitive–affective influences into noradrenergic pain control [23]. Chronic pain states are often marked by dysfunction in this noradrenergic modulatory network, including plastic changes that weaken descending NE inhibition or even render LC activity facilitatory to pain [24].

Clinical support for the noradrenergic system in TTH comes from the approved pharmacological treatments for TTH, such as venlafaxine, amitriptyline and mirtazapine, all of which exert pro-noradrenergic effects [25]. Preliminary findings have indeed suggested that noradrenergic dysregulation could be significantly involved in TTH pathogenesis [26–28]. However, these indications have not yet been comprehensively evaluated reviewed or synthesized and no consensus currently exists regarding the extent or clinical significance of noradrenergic dysfunction in TTH. Understanding the extent of the noradrenergic contribution could lead to the development of more targeted, mechanism-based therapies, potentially improving outcomes for those who do not adequately respond to existing treatments. This systematic review aims to elucidate the role of the adrenergic system in the pathophysiology of TTH and its potential mechanistic associations, while providing a comprehensive synthesis of the current body of evidence.

Methods

This review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) statement [29]. A systematic literature search was conducted up to March 2024 to identify original research articles for TTH and the noradrenergic system as a whole. The following electronic bibliographic databases were searched from inception until 1 March 2024: PubMed/MEDLINE and Embase. The literature search was repeated in November 2025 to ensure currency of the evidence. No new eligible or clinically relevant studies were identified compared with the prior search. Three investigators (SB, GC, CD) independently examined all titles and abstracts retrieved from the search. The search term “tension-type headache” was used in combination with the terms “noradrenaline”, “adrenaline”, “norepinephrine”, “epinephrine”, “noradrenergic”, and “adrenergic”. The full search strategy and inclusion/exclusion criteria is available in Supplementary Material Tables S1 and S2. The full texts of articles identified as relevant during the first screening stage were obtained and reviewed. In case of disagreement during the eligibility assessment, a fourth investigator (TM) reviewed the abstract/full text in question and made a final approval. Risk of bias was assessed for all included studies using appropriate design-specific tools (RoB 2 for randomized trials; ROBINS-I for non-randomized studies).

Results

Results of the systematic search

Forty-three articles met the prespecified eligibility criteria and were included in the qualitative analysis as depicted in the PRISMA flow diagram (Fig. 1). Risk of bias assessment was made using RoB 2 (for randomized trials) and ROBINS-I (for non-randomized studies). Most non-randomized studies were rated at serious risk of bias (mainly confounding), whereas RCTs were predominantly judged as having some concerns. All the relative detailed tables are available in the Supplementary Material (Tables S3 and S4).

Fig. 1.

PRISMA diagram

The findings are presented below, stratified into ‘Pathophysiology’ and ‘Treatment’ and are additional summarised in Table 1.

Table 1.

Summary of studies investigating the relationship between TTH and the noradrenergic system

Authors	Year	Type of study	Study population	Criteria	Drugs tested / test assessed	Main findings
Castillo et al. [26]	1994	Case-Control	30 adult ETTH patients versus 20 adult healthy controls.	1st edition 1988 IHS criteria	Plasma monoamines measured (NE, epinephrine)	Lower mean plasma NE/epinephrine in ETTH; epinephrine levels negatively correlated with headache severity
Ashina et al. [27]	2004	Randomized, placebo-controlled	40 adult CTTH patients.	1st edition 1988 IHS criteria	Amitriptyline vs. Citalopram vs. Placebo	Only amitriptyline significantly reduced headache, despite citalopram being more effective at increasing 5-HT levels
Denaro et al. [28]	1985	Randomized, placebo-controlled	20 adult “tension headache” patients.	Ad Hoc Committee classification	Clonidine (α₂-stimulant) vs. Mianserin (α₂-antagonist) vs. Placebo	Only Mianserin significantly improved headache
Gallai et al. [30]	1992	Case-Control	10 adult TTH patients (frequency unspecified) versus 38 adult controls.	1st edition 1988 IHS criteria	Serum Dopamine P-hydroxylase (DBH) activity	Lower DBH activity in TTH patients compared to healthy controls
Leistad et al. [31]	2007	Case-Control	16 adult TTH patients (both chronic and episodic) versus 34 adult controls.	1st edition 1988 IHS criteria	NE and cortisol measured during cognitive stress	TTH patients showed attenuated NE response to stress and delayed headache recovery
Gallai et al. [32]	1994	Case-Control	15 paediatric ETTH patients versus 20 paediatric controls.	1st edition 1988 IHS criteria	Plasma neuropeptide Y (NPY) measurement	Children with ETTH had lower NPY levels vs. controls
D’Andrea et al. [33]	2013	Case-Control	13 adult CTTH patients versus 37 adult controls.	ICHD-2 criteria	Tyrosine and amine level measurements	Found no significant NE or amine differences in a small CTTH subgroup, possibly due to limited sample size.
Martignoni et al. [34]	1989	Case-Control	25 adult “migraine without aura with CTTH” patients versus 10 adult controls.	1st edition 1988 IHS criteria	Clonidine stimulation test (β-endorphin response)	CTTH patients had lower baseline β-endorphin and no increase after clonidine
Shimomura et al. [35]	1991	Prospective Observational	78 adult TTH patients (frequency unspecified) versus 18 adult controls.	1st edition 1988 IHS criteria	Tizanidine	TTH patients with higher baseline MHPG (NE metabolite) responded better; MHPG levels decreased post-treatment.
Jensen LB et al. [36]	1982	Single arm, Crossover	16 adult “tension headache” patients (frequency unspecified).	Clinical Assessment	Acupuncture	Acupuncture reduced urinary epinephrine /NE levels significantly more than control
Grazzi & Bussone [37]	1993	Prospective Observational	14 ETTH adult patients.	1st edition 1988 IHS criteria	Biofeedback	Biofeedback did not alter plasma NE or improve ETTH symptoms
Bendtsen et al. [38]	1996	Randomized, placebo-controlled	27 CTTH adult patients.	1st edition 1988 IHS criteria	Amitriptyline vs. Placebo vs. Citalopram	Amitriptyline shortened the late exteroceptive suppression period (ES2), while citalopram did not; no correlation with headache frequency.
Göbel et al. [39]	1994	Randomized, placebo-controlled	78 CTTH adult patients.	1st edition 1988 IHS criteria	Amitriptyline vs. Placebo	Amitriptyline significantly reduced monthly headache days/duration but did not alter pericranial EMG parameters.
Nakashima et al. [40]	1994	Prospective Observational	18 CTTH adult patients.	1st edition 1988 IHS criteria	Tizanidine	Tizanidine prolonged ES2 duration at lower stimulation intensities
Fogelholm & Murros [41]	1992	Double-blind, placebo-controlled, crossover	45 CTTH adult patients.	1st edition 1988 IHS criteria	Tizanidine vs. Placebo	Tizanidine reduced headache frequency/severity vs. placebo in CTTH.
Ozkul & Ay [42]	2007	Case-Control	28 ETTH adult patients versus 30 adult controls.	ICHD-2 criteria	Sympathetic skin response (SSR)	ETTH patients exhibited impaired habituation of SSR
Yerdelen et al. [43]	2007	Case-Control	37 adult TTH patients (15 episodic, 22 chronic) versus 37 adult controls.	ICHD-2 criteria	Resting HR & HR recovery	ETTH group had a lower resting HR than CTTH and controls
Battistella et al. [44]	1989	Case-Control	8 paediatric “tension headache” patients versus 12 healthy children versus 15 healthy adults.	Ad Hoc Committee classification	Pupillary phenylephrine test	Pupillary response to phenylephrine did not differ significantly vs. controls.
Di Piero et al. [45]	2001	Case-Control	42 adult TTH patients (both chronic and episodic).	1st edition 1988 IHS criteria	Tridimensional personality questionnaire	No significant differences in personality dimensions linked to aminergic tone in TTH vs. controls.
Diamond & Baltes [46]	1971	Randomized, placebo-controlled	90 adult “chronic tension headache” patients.	American Association for the Study of Headache	Amitriptyline vs. Placebo	Amitriptyline effectively reduced headache in patients
Indaco & Carrieri [47]	1988	Randomized, placebo-controlled	36 “muscle contraction headache” adult patients (frequency unspecified).	Ad Hoc Committee	Amitriptyline vs. Placebo	In Parkinson’s disease patients with “muscle contraction headache”, amitriptyline significantly reduced headache frequency/severity.
Cerbo et al. [48]	1998	Prospective Observational	48 adult CTTH patients versus 34 adult ETTH patients.	1st edition 1988 IHS criteria	Amitriptyline (dose not specified)	Amitriptyline significantly improved CTTH (frequency/duration) but not ETTH.
Oguzhanoglu et al. [49]	1999	Prospective Observational	13 adult CTTH patients versus 19 adult ETTH patients.	1st edition 1988 IHS criteria	Amitriptyline vs. Fluoxetine	Amitriptyline more effective than Fluoxetine in CTTH. No sustained advantage of amitriptyline over fluoxetine in ETTH.
Holroyd et al. [50]	2001	Randomized, placebo-controlled	203 adult CTTH patients.	1st edition 1988 IHS criteria	Amitriptyline (or nortriptyline) vs. Stress management vs. Combination	Combination therapy more likely to achieve ≥ 50% reduction in headache index than either tricyclic alone or stress management alone.
Rampello et al. [51]	2004	Prospective Observational	88 adult TTH patients (frequency unspecified).	1st edition 1988 IHS criteria	Amitriptyline vs. Citalopram	Amitriptyline reduced headache more effectively; both improved depression similarly.
Bendtsen et al. [52]	1996	Randomized, placebo-controlled	40 adult CTTH patients.	1st edition 1988 IHS criteria	Amitriptyline vs. Citalopram vs. Placebo	Amitriptyline significantly improved CTTH, while citalopram did not outperform placebo.
Boz et al. [53]	2003	Randomized, placebo-controlled	90 adult CTTH patients.	1st edition 1988 IHS criteria	Amitriptyline vs. Sertraline vs. Placebo	Amitriptyline produced greater headache reduction and higher ≥ 50% response rates in CTTH vs. sertraline.
Nappi et al. [54]	1990	Randomized, placebo-controlled	38 adult CTTH patients.	1st edition 1988 IHS criteria	Amitriptyline vs. Ritanserin vs. Placebo	Both treatments improved headache and depression symptoms in chronic headache; no significant difference between arms.
Mitsikostas et al. [55]	1997	Prospective Observational	58 adult CTTH patients.	1st edition 1988 IHS criteria	Buspirone vs. Amitriptyline	Amitriptyline showed greater reduction in analgesic use and was generally rated more favorably by patients.
Saper et al. [56]	2002	Randomized, placebo-controlled	134 adult “chronic daily headache” patients.	1st edition 1988 IHS criteria	Tizanidine vs. Placebo	In chronic daily headache (including TTH), tizanidine reduced headache frequency/severity; specific TTH-only data were limited.
Bettucci et al. [57]	2006	Prospective Observational	134 adult CTTH patients.	ICHD-2 criteria	Tizanidine + Amitriptyline vs. Amitriptyline alone	Combo therapy gave added benefit at 1 month in CTTH, but differences vanished by 3 months.
Murros et al. [58]	2000	Randomized, placebo-controlled	185 adult TTH patients (both cronic and episodic).	1st edition 1988 IHS criteria	Modified-release Tizanidine (6 mg or 12 mg) vs. Placebo	No significant advantage of tizanidine over placebo in CTTH prophylaxis.
Bendtsen et al. [59]	2007	Randomized, placebo-controlled	93 adult CTTH patients.	1st edition 1988 IHS criteria	Low-dose Mirtazapine + Ibuprofen vs. Placebo	No significant improvement vs. placebo in CTTH prophylaxis; combination was well tolerated but not efficacious.
Bendtsen & Jensen [60]	2004	Randomized, placebo-controlled	24 adult CTTH patients.	1st edition 1988 IHS criteria	Mirtazapine (30 mg) vs. Placebo	Mirtazapine significantly more effective than placebo in CTTH.
Martín-Araguz et al. [61]	2003	Prospective Observational	60 adult CTTH patients.	1st edition 1988 IHS criteria	Mirtazapine vs. Amitriptyline	Both improved CTTH frequency/intensity similarly; fewer side effects and higher subjective benefit with mirtazapine.
Adelman et al. [62]	2000	Retrospective Observational	56 adult CTTH patients.	1st edition 1988 IHS criteria	Venlafaxine XR	Monthly headache frequency significantly dropped: effect was independent of anxiety/depression status.
Zissis et al. [63]	2007	Randomized, placebo-controlled	60 adult TTH patients (both cronic and episodic).	ICHD-2 criteria	Venlafaxine XR vs. Placebo	Venlafaxine more effective than placebo in tension-type headache, and generally well tolerated.
Langemark et al. [64]	1990	Randomized, placebo-controlled	114 chronic “muscle contraction headache” adult patients.	Ad Hoc Committee	Clomipramine vs. Mianserin vs. Placebo	Both active drugs improved headache vs. placebo, but a strong placebo effect was noted.
Manna et al. [65]	1994	Randomized, placebo-controlled	40 adult CTTH patients.	1st edition 1988 IHS criteria	Fluvoxamine vs. Mianserin vs. Placebo	Both agents reduced headache in CTTH; no major difference in efficacy.
Fogelholm & Murros [66]	1985	Randomized, placebo-controlled, crossover	34 adult “Chronic Tension Headache” patients.	Clinical Assessment	Maprotiline vs. Placebo	Maprotiline (potent NE reuptake inhibitor) significantly improved headache parameters with minimal mood changes.
Mousavi et al. [67]	2011	Prospective Observational	138 adult CTTH patients.	ICHD-2 criteria	Imipramine vs. Transcutaneous electrical nerve stimulation (TENS)	Imipramine was more effective than TENS in reducing severity/frequency of CTTH.
Walker et al. [68]	1998	Prospective Observational	37 adult CTTH patients.	1st edition 1988 IHS criteria	Fluoxetine vs. Desipramine	Both showed equivalent improvements in pain relief and mood for CTTH.
Holroyd et al. [69]	2003	Prospective Observational	31 adult CTTH patients.	1st edition 1988 IHS criteria	Paroxetine (after failing amitriptyline)	Only 15% achieved ≥ 50% headache reduction with paroxetine, suggesting limited benefit in amitriptyline nonresponders.

Pathophysiology

Biochemical alterations of noradrenergic system in TTH

Four independent studies investigating biomarkers have consistently reported dysregulated noradrenergic function in TTH. Measurements of serum dopamine-β-hydroxylase (DBH), a key enzyme in NE synthesis, obtained by the one-step photometric procedure, revealed significantly lower interictal DBH levels in individuals with TTH compared with controls [30]. Similarly, studies examining catecholamines have consistently demonstrated reduced ictal NE and epinephrine concentrations in TTH. Specifically, Castillo et al. reported lower mean plasma NE in individuals with TTH when compared with healthy controls (359.93 ± 276.28 pg/mL vs. 655.90 ± 461.25 pg/mL p < 0.05, respectively) using high-pressure liquid chromatography [26]. Comparable reductions were observed in epinephrine levels, along with a negative correlation between epinephrine concentrations and headache severity (r = -0.51, p < 0.01). Moreover, dopamine levels were positively correlated with headache duration (r = 0.55, p < 0.05), suggesting progressive catecholaminergic alterations over time. Leistad et al. investigated the relationship between NE dynamics and the development and resolution of headache pain under a low-grade stress task. The authors observed that, in patients with TTH, attenuated plasma NE increases in response to the stress test were significantly correlated with delayed or impaired recovery from stress-induced pain (r = − 0.64, p = 0.01) [31]. The same TTH population exhibited stable cortisol levels during stress, in contrast to controls and individuals with migraine, who showed the expected circadian decline. This suggests an abnormal Hypothalamic–pituitary–adrenal axis (HPA axis) response to stress, potentially reflecting dysregulated stress-adaptation mechanisms. In a pediatric population with TTH, Gallai et al. observed a trend towards lower plasma levels of neuropeptide Y (NPY) – a peptide co-stored and co-released with NE, serving as an indirect biomarker [70] - compared with healthy controls, although this difference did not reach statistical significance [32]. In contrast to these trends, a single study reported no significant differences in NE or other amines in chronic TTH (CTTH), although it was mainly designed and powered for migraine and included only a very small sample of TTH patients [33].

Modulation of the adrenergic system

Further insights emerged from studies examining neurotransmitter changes following pharmacological treatments. Ashina et al., compared amitriptyline with the selective serotonin reuptake inhibitor (SSRI) citalopram and placebo to determine whether serotonin (5-HT) reuptake inhibition correlates with pain relief. While both active drugs reduced platelet serotonin, with citalopram having a greater effect, only amitriptyline produced a significant reduction in headache area under the curve (AUC) (p = 0.04), suggesting differential involvement of noradrenergic pathways [27]. Furthermore, no significant correlation was observed between headache severity reduction and platelet 5-HT levels, indicating that 5-HT reuptake inhibition is unlikely to be the primary mechanism of amitriptyline’s analgesic effects. Examination of β-endorphin (β-EP), a marker of opioidergic function, and an indirect marker of noradrenergic function in response to clonidine stimulation [71], showed lower baseline β-EP levels when compared to healthy controls (4.79 ± 0.52 fmol/mL vs. 7.35 ± 0.84 fmol/mL respectively, p < 0.05), consistent with altered presynaptic adrenoceptor sensitivity [34]. Clonidine administration (an α₂-adrenergic agonist) failed to increase β-EP levels in TTH patients, indicating blunted adrenergic-opioidergic responses. In contrast, patients with migraine exhibited a moderate β-EP response to clonidine, suggesting partial preservation of adrenergic function in migraine [34]. Shimomura et al., demonstrated that response to tizanidine, another α₂-adrenergic agonist, was interictally significantly greater in TTH patients with elevated levels of baseline plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), a marker of NE metabolism and turnover. Post-treatment, MHPG levels significantly decreased in responders, suggesting a tizanidine-mediated reduction in central noradrenergic turnover. Moreover, serum free fatty acids (FFA) levels were also higher in responders and decreased after treatment, further indicating increased beta adrenergic drive and reduced α₂ adrenergic activity in TTH [35].

Non-pharmacological interventions have provided additional perspectives. Jensen et al., evaluated the effect of acupuncture on sympathetic nervous system activity, measured by urinary catecholamine (adrenaline and NE) excretion [36]. Acupuncture resulted in a significantly greater reduction of urinary adrenaline and NE levels compared to control, suggesting that acupuncture exerts its effect partly by modulating autonomic nervous system activity, particularly by reducing sympathetic overactivity [36]. In contrast, biofeedback treatments did not alter plasma NE or sympathetic activity indices, nor did it improve TTH symptoms, indicating that not all interventions influence catecholamine profiles [37]. It should be noted that these studies were performed in episodic TTH (ETTH), and there is little evidence of non-pharmacologic modulation in CTTH.

Neurophysiological and autonomic dysregulation in TTH

Neurophysiological and autonomic studies have provided insights into the pathophysiological mechanisms of TTH and its association with the noradrenergic system.

Studies in CTTH patients involving the late exteroceptive suppression period (ES2), a brainstem-mediated inhibitory reflex in jaw muscles, have demonstrated alterations following noradrenergic drug treatments. In particular, shorter ES2 durations were observed during amitriptyline treatment compared to placebo (p = 0.02), while citalopram did not result in a statistically significant change when administered alone (p = 0.34). These findings suggest central modulation of this reflex, possibly driven by noradrenergic input. However, ES2 alterations did not correlate with changes in headache frequency or intensity [38]. Conversely, Gobel et al. observed that, following amitriptyline administration, there was no significant change in ES2 duration, contingent negative variation (CNV) amplitude, or pericranial EMG activity, although ES2 showed a non-significant trend toward prolongation [39]. Nakashima et al., investigated the effects of tizanidine (α2-adrenergic agonist), on ES2 of the temporalis muscle in TTH patients. Tizanidine prolonged ES2 duration when lower-intensity stimulation was applied compared with higher stimulation which did not affect ES2 (four vs. ten times the sensory threshold). This suggests a mild, centrally mediated modulatory effect of tizanidine, and thus of a2 adrenergic receptors, on brainstem inhibitory interneurons, detectable only under lower intensity stimulation conditions [40]. Additionally, Folgelholm et al. demonstrated that, following tizanidine administration, electromyographic (EMG) activity of the trapezius muscle did not significantly change, nor did it correlate with clinical improvement, suggesting a central mechanism of action rather than a peripheral myogenic one [41].

Similarly, autonomic dysfunction – of which NE is key mediator - has been reported in TTH patients, although autonomic measurements have produced mixed results. An impaired sympathetic skin response (SSR) habituation, which primarily reflects the efferent postganglionic sympathetic fibers, has been demonstrated in TTH patients, indicating dysfunction in central autonomic regulation and processing [42]. In another study, with a specific focus on heart rate recovery (parasympathetic activity) and resting heart rate (sympathetic tone), a significantly lower resting heart rate was found in ETTH compared to CTTH and controls (p = 0.001 and p = 0.008, respectively), suggesting reduced sympathetic tone in ETTH. On the other hand, heart rate recovery measurements were similar across all groups, indicating preserved vagal function [43]. In contrast, in a small study of pediatric patients with TTH, pupillary response to phenylephrine did not differ significantly from healthy controls, highlighting the need for larger studies to elucidate this mechanism [44].

Behavioural studies

Assessments of personality dimensions possibly linked to noradrenergic function did not reveal distinguishing features in TTH. A single study found no significant differences between TTH patients and controls on personality scales associated with proposed aminergic neurochemical domains [45].

Treatment

Amitriptyline-nortriptyline

The mechanisms of action of amitriptyline and nortriptyline are not fully elucidated, however it is suggested they inhibit membrane pump mechanisms responsible for the re-uptake of transmitter amines and serotonin. Multiple randomized and observational studies have documented the effects of amitriptyline in TTH. Gobel et al., investigated the effects of amitriptyline in a double-blind, randomized trial including 53 patients with CTTH. They reported a 30% reduction in monthly headache days and episode duration after six weeks of 75 mg amitriptyline (p < 0.01) along with a significant reduction in pain sensitivity to severe experimental pain [39]. Studies exploring the effect of amitriptyline on TTH in the presence of other comorbid conditions have also been conducted. In patients with CTTH and comorbid anxiety and/or depression, amitriptyline significantly reduced headache frequency, depression, anxiety, insomnia, and psychosomatic complaints even at a 10 mg dose [46]. Moreover, amitriptyline 25 mg twice daily significantly reduced headache frequency, severity and analgesic consumption in patients with TTH and Parkinson’s disease [47]. These improvements occurred independently of changes in mood or depression scores, suggesting that analgesia was not mediated by antidepressant effects [47].

There have been conflicting results when comparing the efficacy of amitriptyline in chronic and ETTH. Specifically Cerbo et al., showed significant reductions in headache frequency, duration and acute headache medication consumption in CTTH patients, whereas these effects were not seen in ETTH [48]. In a separate study, amitriptyline did not show a sustained advantage over fluoxetine in reducing headache frequency and intensity among patients with ETTH [49]. Similar outcomes have been demonstrated with both amitriptyline and nortriptyline monotherapy, as well as with their use in combination with stress management interventions [50]. Tricyclic antidepressant medication with amitriptyline up to 100 mg/day or nortriptyline up to 75 mg/day, yielded significant reductions in headache frequency, severity, analgesic use and disability in patients with CTTH [50]. Combined TCA and stress management treatment was more likely to produce a ≥ 50% reduction in headache index than either monotherapy, suggesting complementary biological and behavioural mechanisms [50].

When compared to other antidepressants, amitriptyline has generally shown superior efficacy. In one study of 88 patients with comorbid depression, migraine and TTH, amitriptyline (50 mg) reduced headache attacks more than citalopram (20 mg). Patients who did not respond to citalopram improved when amitriptyline was added, while both drugs were similarly effective in improving depressive symptoms [51]. Similar results emerged from another study, where amitriptyline resulted in a greater reduction in the headache AUC (intensity x duration) (30%) compared with citalopram (12%) or placebo (10%), while both drugs were similarly effective in improving depressive symptoms [52]. Amitriptyline also significantly reduced headache duration (p = 0.01), frequency (p = 0.01) and acute medication consumption (p = 0.02) [52]. Amitriptyline was also found to be superior to fluoxetine (20 mg), but only in CTTH [49]. Consistent results were observed in a trial where amitriptyline (25 mg) was compared with sertraline (50 mg) [53]. Amitriptyline produced significantly greater reductions in headache index (frequency × intensity × duration / 28 days) and acute medication use at 8 and 12 weeks (p < 0.05), while 70.3% of patients in the amitriptyline group had ≥ 50% reduction in headache index vs. 44.4% in the sertraline group (p = 0.009) [53]. Additionally, both amitriptyline and ritanserin, an indirect NE booster via antagonism of the 5-HT2C receptor, improved headache outcomes without statistically significant differences [54]. Lastly, Mitsikostas et al. showed that amitriptyline compared favourably to buspirone, a partial 5-HT1A agonist with no effect on NE reuptake [55]. While both treatments significantly reduced headache frequency and analgesic medication use, amitriptyline led to a significantly greater reduction in analgesic use and was rated more favourably by patients (p < 0.05) [55].

Tizanidine

Tizanidine is an alpha-2 receptor agonist and its anti-nociceptive actions have been attributed to agonist action on the alpha-2 receptors in sensory fibers. Tizanidine also reduces spasticity by activating alpha-2 receptors pre-synaptically on motor neurons. The drug also acts centrally and leads to a reduction in the release of excitatory amino acids like glutamate. The therapeutic effects of tizanidine have varied across clinical studies. In a study by Saper et al., which included patients with CTTH, tizanidine hydrochloride (mean dose 18 mg) significantly reduced headache frequency, severity and duration over 12 weeks. A major limitation of this study was the inclusion of patients with various subtypes of chronic daily headache—namely, chronic migraine, migrainous headache, and CTTH— without conducting or reporting stratified subgroup analyses. This lack of diagnostic differentiation significantly limits the generalizability of these findings specifically to the CTTH population [56]. Similar beneficial effects of tizanidine compared with placebo in CTTH have been reported in several open-label and double-blind studies [35, 41, 57]. Dosing regimens varied widely across these trials, ranging from 3 mg to 18 mg per day. Notably, in a small study of 18 CTTH patients, adjunctive tizanidine (4 mg/day for 3 weeks) combined with amitriptyline (20 mg/day) resulted in significantly greater reductions in headache frequency, intensity, and duration after one month of treatment, compared with amitriptyline alone [57]. However, by the end of the 3-month treatment period, these between-group differences had attenuated and were no longer statistically significant, suggesting only a transient additive benefit of short-term tizanidine co-administration [57]. Conversely, in a larger randomized controlled trial, modified-release tizanidine, administered at either 6 mg or 12 mg per day, did not demonstrate clinical superiority over placebo, showing no statistically significant therapeutic advantage in CTTH management [58].

Mirtazapine

Studies on mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA) that blocks α2-adrenergic autoreceptors, have shown dose-dependent effects. Low-dose mirtazapine (4.5 mg/day) alone or in combination with ibuprofen (400 mg/day) did not reduce the headache AUC compared with placebo [59]. Combination therapy was well tolerated, though associated with more drowsiness and weight gain than placebo [59]. The same authors subsequently evaluated the effects of mirtazapine at a higher dose (30 mg/day) and reported a 34% reduction in the AUC compared to placebo (p = 0.01), indicating a statistically significant prophylactic effect in patients with CTTH [60]. In a separate randomized controlled trial on CTTH patients, mirtazapine (30 mg/day) and amitriptyline (25 mg/day) both improved headache frequency and intensity, with no significant difference between groups. However, subjective improvement was greater with mirtazapine (66% vs. 34%; p < 0.05) and adverse effects (notably dry mouth and drowsiness) were significantly less frequent (p < 0.001) [61].

Venlafaxine

Studies on venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI) that increases synaptic concentrations of both 5-HT and NE, reported favorable results in CTTH. In an open-label retrospective study, venlafaxine XR (150 mg/day; range 37.5–300 mg/day) significantly reduced mean monthly headaches from 24 to 15.2 (p < 0.001). Over 50% of patients with pure CTTH achieved ≥ 50% reduction in total or moderate-to-severe headache frequency. Notably, no significant differences in response were observed between those with and without comorbid depression or anxiety, suggesting that venlafaxine’s efficacy was independent of its antidepressant effect [62]. In a subsequent 12-week, randomized, parallel, placebo-controlled, multicenter trial involving 60 patients with chronic and ETTH and no concurrent depression or anxiety disorders, venlafaxine XR 150 mg/day reduced the number of days with headache from baseline by 44.8% at weeks 9–12, compared with 15.7% in the placebo group (p = 0.023). The number needed to treat (NNT) for achieving ≥ 50% reduction in monthly headache days was 3.48, while the number needed to harm (NNH) for any adverse event was 5.58 [63].

Mianserin

Mianserin is a tetracyclic antidepressant that has antihistaminic effects, but also it is a weak inhibitor of NE reuptake and strongly stimulates the release of NE. Studies involving mianserin have demonstrated potential therapeutic efficacy, suggesting possible clinical utility in the management of TTH via modulation of central noradrenergic pathways. Langemark et al. examined the use of mianserin (tetracyclic antidepressant with noradrenergic action) and clomipramine (tricyclic antidepressant) in CTTH. Both clomipramine (30–60 mg/day) and mianserin (30–60 mg/day) significantly reduced VAS scores compared with placebo (p < 0.02), although no statistically significant differences were observed in the proportions of patients achieving ≥ 50% pain reduction due to a strong placebo effect (49%) [64]. In earlier clinical investigations, mianserin at a dosage of 30 mg/day demonstrated a statistically significant reduction in both headache intensity (p < 0.001) and frequency (p < 0.01), whereas clonidine at 0.150 mg/day did not show a comparable therapeutic effect [28]. However, similar efficacy in reducing headache frequency, severity and analgesic use was observed between mianserin and Fluvoxamine, a selective serotonin reuptake inhibitor [65].

Others

Investigations involving maprotiline, a tetracyclic antidepressant that acts primarily as a SNRI, with minimal serotonergic activity and high affinity as a potent NE transporter (NET) inhibitor, have demonstrated statistically significant improvements in headache-related outcomes. In contrast, the improvement of depressive symptoms was mild and did not reach statistical significance, suggesting that maprotiline’s analgesic effects in CTTH are likely mediated through noradrenergic modulation independent of its antidepressant properties [66]. Imipramine, a tricyclic antidepressant, at a dose of 25 mg twice daily, significantly reduced headache severity compared with transcutaneous electrical nerve stimulation (TENS) (p < 0.05) in CTTH [67]. Conversely, Desipramine (a SNRI) and Fluoxetine (a SSRI) produced comparable improvements in pain reduction, mood, and quality-of-life measures in CTTH [68].

Finally, Paroxetine – a SSRI with only weak and non-significant NET inhibition properties - exhibited limited efficacy in patients with CTTH who were refractory to amitriptyline. Among those transitioned to paroxetine, only 15% (2/13) achieved ≥ 50% reduction in headache frequency, a response rate that was not statistically significant, indicating a modest and clinically limited benefit in this treatment-resistant subgroup [69].

Discussion

The collective body of evidence presented herein suggests that alterations in the noradrenergic system may play a central role in the pathophysiology of TTH. Across multiple lines of investigation, an emerging narrative supports the notion that a reduced noradrenergic tone contributes to TTH. While the role of serotonin in headache disorders is well-established [72, 73], the results examined in this review indicate that TTH may be more closely aligned with deficits in noradrenergic transmission. Additionally, data from pharmacological interventions support that treatments modulating NE reuptake often yield greater clinical benefits than those targeting serotonin alone, placing the noradrenergic system at the forefront of TTH pathophysiology and therapy.

Biochemical studies provide some of the strongest evidence that noradrenergic dysfunction underpins TTH. Reduced DBH activity – a key enzyme that converts dopamine into NE - and lower plasma catecholamine levels have been reported in TTH patients compared to healthy controls [30]. Similarly, significantly lower plasma NE and epinephrine concentrations have been reported in TTH patients, along with a negative correlation between epinephrine levels and headache severity both in chronic and episodic patients [26, 31]. Collectively, these findings strongly suggest that diminished noradrenergic output contributes to TTH pathogenesis.

Pharmacological studies further highlight how modulating neurotransmission impacts TTH. Several studies that directly compared drugs targeting both NE and serotonin reuptake against those targeting serotonin alone found that dual-action drugs often confer greater clinical improvements. Amitriptyline, a tricyclic antidepressant with robust inhibition of both NET and the serotonin transporter (SERT), consistently outperforms agents that are predominantly serotonergic, such as citalopram or other SSRIs [49, 51–53], especially in chronic cohorts. Notably, while both amitriptyline and citalopram reduce platelet 5-HT levels, only amitriptyline significantly improved TTH clinical outcomes compared to placebo, suggesting that its therapeutic benefit may be primarily mediated through the noradrenergic system.

Interestingly, amitriptyline appears more effective in CTTH than in ETTH [48]. The lack of comparable efficacy in ETH, generally thought to involve more peripheral pathophysiological mechanisms (e.g., myofascial tenderness), supports that noradrenergic analgesia depends on enhanced central descending inhibitory pathways.

Tizanidine, an α2-adrenergic agonist, has shown variable efficacy across clinical studies in TTH. While several open-label and double-blind trials reported significant reductions in headache frequency, severity, and duration [35, 41, 57], mostly in CTTH cohorts, one larger randomized controlled trial – including both ETTH and CTTH patients - did not find any significant advantage over placebo [58]. Notably, patients with higher baseline 3-Methoxy-4-hydroxyphenylglycol (MHPG), a marker of noradrenergic turnover, responded better to tizanidine, with post-treatment declines in MHPG [35]. This suggests α₂-agonists may normalise dysregulated catecholamine metabolism in a subset of CTTH, supporting a precision-medicine approach guided by baseline noradrenergic activity.

Additionally, other pharmacological studies suggest the centrality of NE in TTH. Mirtazapine, which enhances NE release, has shown efficacy in reducing CTTH burden [60, 61]. Similarly, mianserin, which modulates adrenergic function, and maprotiline, a potent NET inhibitor, have demonstrated superior outcomes compared with placebo in CTTH [28, 64, 66]. Venlafaxine, an agent that inhibits both serotonin and NE reuptake, has also consistently reduced headache frequency in CTTH [62, 63]. Notably, patients with CTTH - especially those with “pure” TTH - showed a greater absolute reduction in headache days than patients with migraine, suggesting that enhancing noradrenergic transmission may be especially beneficial in CTTH. Furthermore, the clinical response appeared independent of comorbid mood disorders, indicating that venlafaxine’s analgesic effect is not solely attributable to its antidepressant properties [62]. In contrast, SSRIs like fluoxetine, citalopram, and paroxetine, which have minimal effect on NE reuptake, generally yield less robust improvements [49, 51–53] particularly in chronic cohorts.

Neurophysiological measures, such as the late exteroceptive suppression period (ES2), reinforce how noradrenergic mechanisms may regulate muscle activity and pain processing in TTH. In particular, they suggest that amitriptyline’s ability to modulate brainstem inhibitory circuits may hinge on its noradrenergic component, rather than on serotonin reuptake inhibition alone, in chronic patients [38]. However, no correlation emerged between ES2 alterations and headache frequency or intensity, indicating that while ES2 may reflect underlying neurochemical modulation, it might not directly predict clinical outcomes in TTH. Interestingly, in CTTH Tizanidine showed prolonged ES2 duration under lower stimulation intensities, but not at higher intensities [40]. This pattern supports the hypothesis that α2-receptor activation can modulate inhibitory circuits in the brainstem, reducing polysynaptic reflexes and promoting muscle relaxation without excessively suppressing normal reflex activity.

Finally, autonomic function studies further underscore potential noradrenergic dysregulation. An impaired SSR habituation was documented in ETTH [42], indicating a dysfunction in central autonomic regulation and processing. SSR is regulated by supraspinal structures such as the posterior hypothalamus and mesencephalic reticular formation—regions with a high density of noradrenergic pathways—and defective habituation suggests that noradrenergic dysfunction may impair the adaptive response to repeated sensory stimuli. Another investigation focusing on heart rate recovery (parasympathetic activity) and resting heart rate (sympathetic tone) noted that ETTH patients have a significantly lower resting heart rate compared to CTTH patients and controls, indicating reduced sympathetic output [43] reinforcing the concept that central sympathetic dysfunction, likely reflecting blunted noradrenergic activity, contributes to the condition.

Taken together, these data support a model in which chronically reduced noradrenergic tone weakens descending inhibitory control over nociceptive input to the trigeminal and upper cervical dorsal horn. Under physiological conditions, NE acting at α2-adrenergic receptors suppresses primary-afferent transmitter release, dampens second-order nociceptive neurons, and facilitates inhibitory interneurons; when NE availability or signaling is blunted, circuit gain increases, promoting central sensitization and the pericranial myofascial hyperexcitability typical of TTH. Mild photophobia/phonophobia without prominent cranial autonomic signs similarly aligns with adrenergic dysregulation of sensory gating, and impaired sympathetic habituation and heart-rate indices indicating central sympathetic blunting. This framework accounts for the observed superior clinical effects of NET-blocking or dual-action antidepressants over SSRIs - by restoring NE they re-establish descending inhibition.

While current evidence strongly implicates reduced noradrenergic function in TTH, it should be noted that TTH may not be explained exclusively by this mechanism. Factors such as peripheral muscle tension, stress-related triggers, and genetic predispositions may interact with central monoaminergic pathways [74]. Moreover, while pharmacological data points toward the primacy of the noradrenergic system, non-pharmacological interventions like acupuncture, biofeedback, and stress management demonstrate variable influence on catecholamine levels. For example, acupuncture-related improvements correlated with a significant reduction of urinary epinephrine and NE levels compared to controls, while biofeedback showed no significant shifts in NE or headache outcomes [36, 37]. These nuances suggest that while CTTH is characterized by persistently low NE levels, short-term interventions like acupuncture may still modulate transient stress-related autonomic activation. Consistently, NE-induced stress does not trigger headaches in healthy individuals, indicating a chronic dysregulation of noradrenergic function, rather than acute stress-induced surges in NE [75]. Finally, it should be noted that noradrenergic pathways interact with other systems, such as cognitive-emotional and pain modulatory networks, and that multiple interrelated mechanisms may influence headache expression.

Future investigations should seek to more clearly isolate and characterize the role of noradrenergic system in TTH pathophysiology and mediating therapeutic effects. Studies employing selective NE reuptake inhibitors, α2-adrenergic receptor modulators, or NE receptor agonists and antagonists might further delineate the specific adrenergic receptor subtypes involved. Such approaches could inform rational drug design, targeting NE more directly. Additionally, larger randomized controlled trials (RCTs) comparing pure noradrenergic enhancers against SSRIs or placebo can provide stronger evidence for causality and relative efficacy.

Conclusion

This review highlights the significant involvement of the noradrenergic system in the pathophysiology and treatment of TTH. A converging body of biochemical and neurophysiological evidence points to a consistent pattern of reduced noradrenergic activity, especially in CTTH, documented by reduced DBH activity, lower plasma catecholamines, late exteroceptive suppression, and autonomic habituation deficits point. Treatments enhancing noradrenergic transmission demonstrate superior efficacy compared with serotonergic agents alone, underscoring NE’s therapeutic relevance. These findings support a shift toward a more mechanism-based approach to TTH management. Future studies should focus on refining noradrenergic-targeted therapies and identifying biomarkers to guide individualized treatment.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

S.B. conceived and designed the study, conducted the literature search, performed the screening and data collection, and drafted the manuscript. G.C. assisted with screening procedures, contributed to data collection, and supported data organization. C.D. contributed to data curation and critically revised the manuscript for intellectual content. L.K. revised the manuscript, performed language editing, and assisted in harmonizing the structure and clarity of the final text. V.S.T. revised the manuscript, provided additional conceptual feedback, and contributed to refining the interpretation of the findings. A.P.A. contributed to data curation and critically reviewed the manuscript. D.D.M. assisted with data curation and contributed to the revision of the manuscript. T.M. originated the study idea, supervised all stages of the project, provided domain-specific clinical expertise, coordinated team communication, managed administrative requirements, and critically revised and corrected the final manuscript.

Funding

No funding was received for this study.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

S.B has received personal compensation from Eli Lilly for oral communications. C.D. has received travel grants and honoraria from AstraZeneca, Merck & Co, Pfizer and Teva Pharmaceuticals and research grants from the International Headache Society and the Hellenic Neurology Society. V.S.T has received travel grants from ECTRIMS and the European Academy of Neurology, as well as coverage of congress registration fees from Inovis, Genesis Pharma and Novartis. A.P.A reports advisory board at Neuresta, Zenith Scientific, Modulight. Speaker/Speaker board at AbbVie, Pfizer, Organon, TEVA. Consultant at Neuresta, Zenith Scientific, General Services Consulting. Grant support for research or education at AbbVie, Pfizer, Ipsen, Medical Research Foundation, Brain Research UK, Migraine Trust, Medical Research Council, National Institute of Health. D.D.M has received fees and travel grants from AbbVie/Allergan, Amgen, Eli Lilly and Company, ELPEN, Genesis Pharma, Lundberg, Merck & Co, Mylan, Novartis, Roche, Sanofi, Pfizer, and Teva Pharmaceuticals. He has also participated in clinical trials for Amgen, Eli Lily and Company, Lundberg, Novartis, Pfizer, and Teva Pharmaceuticals as the principal investigator. D.D.M is also the president of the Hellenic Headache Society and is a member of the Management Group of the Headache Scientific Panel of the European Academy of Neurology. He also served in the past as President of the European Headache Federation. D.D.M has also had commercial assistance and/or received honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Company, Genesis Pharma, Helion, Lundbeck, Merck and Co, Novartis, Orion Pharma, Pfizer, Roche and Teva Pharmaceuticals. T.M Received travel grant from AbbVie. L.K and G.C report no conflicts of interest.