Advances in the Understanding of Pathophysiology of TTH and its Management
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.315986
Source of Support: None, Conflict of Interest: None
Keywords: Central sensitization, chronic tension-type headache, episodic tension-type headache, pathophysiology, tension-type headache
Tension-type headache (TTH) is the most common of the primary headaches, although less well understood and less medical attention is sought than the other headache subtypes. Patients usually self-diagnose and self-treat unless they have a concurrent migraine or transition from episodic to frequent or the chronic form of TTH.
The characteristic feature of TTH is mild-to-moderate head pain lasting minutes to weeks. The typical pain is pressing or tightening in quality, bilateral in location, and does not worsen with routine physical activity. The hallmark of TTH is the absence of systemic features such as nausea, vomiting, photo- and phonophobia found in other headache types such as migraine. Hence, TTH is also called a “featureless” headache. The diagnosis requires the exclusion of other organic disorders. The treatment options for TTH especially the CTTH are not too many and the outcome is not rewarding, resulting from the lag in scientific understanding of TTH pathophysiology as compared to migraine. In recent decades, researches relating to structural and functional brain alterations in TTH patients however have helped to understand the pathophysiological aspects better. Unfortunately, there is no recent breakthrough in the major therapeutics of TTH, though it is much awaited for this neglected subgroup of headache patients. Although few reviews have been published in the recent past on TTH,, we present an update on TTH focusing on its pathophysiology and management.
Widespread epidemiologic studies on TTH is not available when compared to migraine, though it is the most prevalent headache subtype. The 1-year prevalence of TTH in 12–41 year age group from a population-based study in Denmark was high (86%), but the majority had infrequent episodic TTH. Similarly, a population-based study from the United States showed the prevalence of episodic TTH peaking in the third decade (30–39 years) and decreased slightly with age.
The Global Burden of Disease (GBD 2016) rated TTH as the third most prevalent disorder with 1.89 billion individuals estimated to have TTH. The global age-standardized prevalence was 26.1% (30.8% for women and 21.4% for men). A peak in the prevalence and years lived with disability (YLD) occurred between ages 35 and 39. Data from South East Asia and particularly from India is sparse. In a south Indian population-based survey from Karnataka state found the crude 1-year prevalence of TTH to be 34.8% (age-standardized 1-year prevalence was 35%). The prevalence was higher among rural areas but was similar between genders. The prevalence is 40% in those aged 18–25 years and declined with age to 28.7% in those over 56. A population-based study from Denmark reported higher prevalence (78%), but the majority had episodic infrequent TTH (1 day a month or less). It reported “about 24% to 37% had TTH several times a month, 10% had it weekly, and 2% to 3% had chronic TTH, usually lasting for the greater part of a lifetime”. In a 12-year longitudinal epidemiologic study from Denmark, good outcome was experienced by 84% and poor outcome by 16%. The poor outcome was also attributed to “baseline chronic TTH, coexisting migraine, being unmarried, and having insomnia”.
Psychiatric comorbidities are common in chronic daily headaches, the prevalence ranging from 64 to 90% (mostly in the form of anxiety and mood disorders)., In general, CTTH patients have increased incidence of affective disorders, like depression or anxiety, anger and they also have more disability due to headache. Greater depressive symptomatology is more common in female, older age group population and in persons with more prolonged duration of headache. In an Indian study, psychiatric co-morbidity was reported in 36.4% of the patients with CTTH. This may complicate headache management and also portends a poorer prognosis for headache treatment. It is also linked with various other painful conditions like lower back pain, fibromyalgia or local muscle pain.
Relationship with migraine
Migraine and TTH may be considered related conditions with shared environmental and lifestyle factors. In general population, 94% of migraineurs reported to have TTH, and among these population 56% have frequent episodic TTH. In “contrast, TTH occurs with similar prevalence in patients with and without migraine, leading to an assumption that migraine can trigger TTH, whereas TTH may not trigger a migraine”. A population-based study “compared the clinical characters of TTH found that 1-year prevalence and male to female ratio of TTH was similar in persons with or without migraine though the duration and frequency of TTH episodes were greater in migraineurs”.,
Circadian and sleep disturbances
Using a computerized ecological momentary assessment (EMA) a significant diurnal variation in headache intensity was shown in TTH, with headache being weakest in the morning, worsening toward the evening, and peaking afterward. Sleep disturbances are common in both TTH and migraine, which may contribute to the overall disability and reduced quality of life. A Korean study reported CTTH being associated with higher EDS (excessive daytime somnolence) prevalence compared to ETTH and without headache. Furthermore, subjects with TTH with EDS had more severe TTH symptoms compared to TTH without EDS.
Emergency department visits due to TTH
In the TEDDi study, TTH was over-diagnosed in emergency visits due to headache; the majority had another primary headache and some had secondary headaches including life-threatening conditions. ICHD criteria of TTH was fulfilled in minority of patients. Inconsistent prior medical history or anamnesis were frequent and may be attributed for this.
Disability and economic burden of TTH
The prevalence of TTH is greater than migraine and the overall the economic cost of TTH is higher. The effects of TTH includes “physical suffering, loss of quality of life, and economic effects, though these are difficult to quantify”. The absenteeism from TTH is considerable and almost three times more than that seen in migraine. The disability is higher in patients with psychiatric co-morbidities. Globally TTH accounts for 6.5% of all YLDs (7.7% in females and 5.1% in males) (GBD 2016).
As per ICHD-3, there are three main subtypes of TTH based on the frequency of headache episodes [Table 1].
This division is relevant from multiple aspects. The “underlying pathophysiology, impact on daily living and therapeutic options differ among the subtypes”. “Each of the subtypes is additionally classified as occurring with or without pericranial muscle tenderness”. There is also a category of probable TTH involving all the above three categories where all the criteria for diagnosis are fulfilled except one.
The pathogenesis is probably multifactorial and varies between the subtypes of TTH [Table 1]. It has been suggested that the peripheral and environmental factors are more important in episodic TTH, whereas genetic and central factors possibly play a significant role in the chronic variety [Figure 1].
Hereditary factors seem to play a minor role in the pathogenesis of episodic TTH, which is in sharp contrast to migraine. However, genetic factors play an important role in the pathophysiology of chronic TTH. In a study investigating twin family data, it was seen that migraine in one twin was significantly associated with TTH in the other twin, indicating that a shared etiology is plausible. A stronger cross-trait, cross-twin association in monozygotic than dizygotic twins suggested that this comorbidity may also be partly due to shared genetic factors, although the difference in associations was not significant.
Peripheral sensitization of myofascial nociceptors plays an important role in the development of episodic TTH. Myofascial factors can be further described in two groups, namely pericranial tenderness and myofascial trigger points.
A. Pericranial tenderness
Pericranial tenderness most probably arises from the activation of peripheral nociceptors. Nociceptors around the blood vessels in striated muscle, tendon insertions, and fascia have been suggested as the source of pain., Clinically, there are two ways to measure muscle tenderness: by manual palpation and using a device called a palpometer. Tenderness is calculated using the Total Tenderness Scoring System (TTS): total score of 8 pairs of pericranial muscle and tender insertion points, each scored on a 4-point scale (0–3) at each location., The frequency and intensity of TTH correlate positively with pericranial muscle tenderness. The possible peripheral mechanisms include inflammatory reaction, decreased blood flow, increased muscle activity, and muscle atrophy., Though the studies on the role of these putative mechanisms have not yielded uniform and consistent findings, these findings warrant further research in this field.
B. Myofascial trigger points (TrP)
Myofascial trigger point is a hyperirritable spot associated with a taut band of a skeletal muscle, painful on compression and stretch. Active TrPs cause clinical symptoms, whereas latent TrPs might produce other muscle dysfunctions like fatigue, and restricted range of motion rather than pain. A non-blinded study found that TTH subjects had a greater number of either active or latent TrPs than healthy subjects. In a further blinded study, chronic TTH was associated with active TrPs in various head and neck muscles. Chronic Tension-Type Headache (CTTH) subjects with active TrPs had greater headache intensity, duration, and frequency than those with latent TrPs. They have also reported a greater forward head posture (FHP) in CTTH patients with active TrPs than those with latent TrPs in both standing and sitting positions. A therapeutic approach based on TrP management needs to be evaluated in chronic TTH patients.
Continuous myofascial nociception may induce central changes (central sensitization) probably at both the supraspinal level and spinal dorsal horn/trigeminal nucleus in patients with chronic TTH. The likely changes include both increased central excitability and attenuated central pain inhibition. This in turn may lead to a further increase in pericranial tenderness. Thus, in the chronic pain state, “increased tenderness is caused by both peripheral nociception and central sensitization”.
Pain perception studies in TTH
Pain thresholds can be checked by applying pressure, electrical and thermal (heat and/or cold) stimuli. For each stimulus modality pain detection threshold and pain tolerance threshold can be measured. The pain ”detection threshold is the lowest possible stimulus causing the sensation of pain”. The “Pressure tolerance threshold is the maximal painful stimulus that a person can tolerate”.
Pain report is another measure that includes fixed stimulus (threshold and suprathreshold), temporal summation and DNIC (descending inhibitory control studies). Studies of pain threshold in patients with episodic TTH (ETTH) revealed mixed responses. While the majority of these studies reported normal pain detection threshold,,, only two studies reported decreased pressure pain detection threshold in ETTH of frequent type., In contrast, the majority of studies reported lower pressure, thermal and electrical pain threshold in CTTH patients as compared with the controls.,, Studies on pressure pain tolerance threshold and suprathreshold testing have also demonstrated similar results in CTTH patient and might be even more sensitive than threshold measurement in the evaluation of central sensitization (increased excitability of neurons in the CNS) in TTH patients.,
Few studies on temporal summation have been reported in TTH; two of these did not find any significant difference,, whereas a recent study by Cachart et al. has demonstrated increased temporal summation in CTTH patients. Descending Inhibitory Control Studies (DNIC studies) found decreased Nociceptive flexion reflex (NFR) thresholds in patients with CTTH compared to controls, pointing to dysfunction of DNIC in CTTH.,,
Abnormal brain functions have been demonstrated in TTH patients using resting-state fMRI study and functional connectivity study., Using Voxel-based morphometry (VBM), Schmidt-Wilcke et al. have demonstrated a decrease in the volume of gray matter brain structures involved in pain processing in patients with chronic TTH. This decrease correlated positively with the duration of the headache. The most likely explanation put forward was that the central sensitization generated by prolonged input from pericranial myofascial structures might have caused these changes. Other studies have also suggested alteration in brain structure and grey matter volume in TTH patients., Further white matter tracking has shown abnormalities in patients with TTH., Overall, these studies need to be interpreted in the context of central mechanisms of pain generation in CTTH and to be integrated with the existing models for the current understanding of TTH pathophysiology.
From the above discussion, it is apparent that the pathophysiology of TTH remains unclear. However, the available studies suggest the possible role of continuous nociceptive inputs from pericranial muscles and myofascial tissues in causing central sensitization involving dorsal horn, trigeminal nucleus, and supraspinal neurons. Also descending inhibitory processes may be altered in CTTH.
The diagnosis of TTH relies only upon clinical profile and no diagnostic tests are specific for TTH. Thus, a detailed history taking along with a thorough clinical examination is mandatory to rule out secondary causes.
Head pain in TTH is usually described as dull, pressure-like, and wearing a tight band around their head or heaviness of head. The headache does not worsen during routine physical activities, which is in sharp contrast to migraine.,, The head pain location is usually bilateral in 90% of the patients, mild to moderate in intensity. The headache starts at some point in the day with possible aggravation toward the end of the day.
While photophobia and phonophobia can often be present, only one of them is allowed by the diagnostic criteria for episodic TTH. Nausea and vomiting, if present rules out the diagnosis of TTH, though mild to moderate anorexia may be present in 20% of TTH patients. Mild nausea may be allowed for chronic TTH patients as long as there is no photophobia or phonophobia. Cranial autonomic features are uncommon. Precipitating and aggravating factors are similar to migraine, like stress, lack of sleep, fasting, and are not very helpful to distinguish the two subtypes.
Physical examination should include manual palpation of the pericranial muscles to identify tender points and trigger points, as described earlier in the pathophysiological subsection, which is increased in TTH patients. Manual palpation is performed by “applying firm pressure with second and third digits with small rotatory movements on the pericranial muscles; frontal, temporal, masseter, pterygoid, sternocleidomastoid, splenius, and trapezius muscles”. EMG studies have shown decreased relaxation of pericranial muscles at rest. Pericranial tenderness is associated with both the intensity and frequency of TTH attacks. Rest of the physical examination should be normal and should be thoroughly looked into to rule out the secondary causes. Neuroimaging is not indicated in most patients who have a stable headache pattern for over 6 months and a normal neurological examination.
Episodic tension-type headache
Differentiating TTH from mild migraine without aura is sometimes challenging when patients under-report symptoms by poorly describing them or when TTH headache is more severe than the typical TTH and associated with photophobia or phonophobia. In the Spectrum study, 32% of the patients initially diagnosed as episodic TTH were re-diagnosed as migraine or probable migraine when their headache record book were reviewed.
Chronic tension-type headache
CTTH must be differentiated clinically from other primary chronic daily headaches of long duration and from secondary headache disorders. One of the three clinical situations can occur in patients presenting with long-duration headaches equal to or more than 15 days a month with migrainous and/or TTH phenotype. They can have any of these 3 diagnoses and the clinicians must be careful to diagnose them correctly.
New daily persistent headache, an uncommon primary headache disorder that is characterized by headache that, unambiguously, is daily and is remembered as an unremitting headache from less than 24 h after its first onset is clearly distinguishable from CTTH if proper history is taken.
These may pose a diagnostic challenge for both episodic and chronic TTH. The features of a slowly growing brain tumor may be nonspecific and vary widely with tumor location and size. One should carefully look for subtle neurological deficits on physical examination.
Medication overuse headache
It should be suspected in patients having frequent or daily headaches despite or because of the regular use of headache medications. In clinical practice it is preceded by an episodic headache disorder, usually migraine or TTH, that required frequent and excessive amounts of acute symptomatic medications for management.
The treatment of TTH can be divided into two broad groups: namely pharmacologic and non-pharmacologic. The usefulness of a headache diary cannot be overemphasized and often helpful for the physician. It helps to document the progression of the frequency and severity and sometimes specific headache triggers can be identified. While suspecting medication overuse, it can be very useful in the true estimation of drug intake and reality check.
Acute pharmacotherapy: Most of the patients of infrequent ETTH do not report to the physician and self-medicate with over the counter analgesics.
For patients with frequent ETTH, simple analgesics, and NSAIDs are the mainstays of acute management. Aspirin (500 mg or 1000 mg), acetaminophen (1000 mg) both are as effective for acute pain management and superior to placebo. NSAIDs like ibuprofen (200–400 mg), naproxen sodium (375–550 mg) can be used and have been demonstrated to be more effective and better tolerated than other NSAIDs.
The addition of caffeine, codeine, sedatives, and tranquilizers in the combination therapy should be avoided to prevent the risk of dependency, abuse, and chronification of headache. Opiate and muscle relaxants also need to be avoided.
Frequent intake of NSAIDs and simple analgesics (≥10 days/month) and combination analgesics should be avoided to prevent the development of medication overuse headache. Some patients with ETTH may also have associated migraine which may respond to triptans. These patients need careful education to identify their attack phenotype and to take the appropriate drug. Relaxation training can be of benefit in recurrent ETTH. The effectiveness of analgesics tends to decrease with increasing headache frequency.
Chronic pharmacotherapy: It should be considered in all patients with CTTH, in those with ETTH and frequent attack (>8 headache days/month), and in those with headache-related disability.
Amitriptyline: It is the most extensively used and efficacious drug for the preventive treatment of TTH. Since 1964, it has been the mainstay in the treatment of CTTH patients and several studies support its use.,,, It is generally well tolerated, though some side effects like dry mouth, drowsiness, and weight gain can be seen. Mechanism of action in TTH prevention includes “serotonin reuptake inhibition, potentiation of endogenous opioids, NMDA receptor antagonism, and blockade of ion channels”. The treatment should be started at a low dose (10 mg to 25 mg/day) and titrated by 10-25 mg weekly till therapeutic effect is seen or side effects appear.
The usual goal of preventive treatment includes a reduction in headache frequency and intensity and improved response to abortive treatment. It is a reasonable practice to continue a successful preventive regimen for six months and then slowly reducing the dose observing the headache frequency. A decrease in the daily dose by 20%–25% every 2–3 days might avoid rebound headaches.
Mirtazapine: A noradrenergic and serotonergic antidepressant is efficacious in situations where amitriptyline is either ineffective or contraindicated. The usual dose is 15-30 mg/day and has been shown to reduce the headache index by 34% more than placebo in difficult to treat patients.
Muscle relaxants: Centrally acting muscle relaxants like tizanidine (6–18 mg/day) may have some benefit, though not recommended routinely. A recent open randomized study has shown that a combination of tizanidine (4 mg/day) and amitriptyline (20 mg/day) during the first 3 weeks of treatment gave faster relief of head pain than amitriptyline alone.
Anticonvulsant (Topiramate) - in an open study, has shown to be effective at a dose of 100 mg/day, although this result needs to be confirmed in a randomized controlled trial.
Botulinum toxin type A: The results of a few controlled trials have been conflicting and mostly negative. The use of botulinum toxin at present is not recommended for CTTH prevention.
Trigger point injection (lidocaine): Limited data from small randomized controlled trials suggest a promising role in decreasing headache frequency and total acute medication use infrequent ETTH and CTTH patients., It requires more research in establishing its role.
As pharmacological interventions are not optimally effective, there is an increased interest in nonpharmacologic interventions in recent years.
Behavioral treatments,, include the following methods:
Relaxation training and EMG biofeedback therapies have been shown to reduce headache activity by nearly 50%, both alone or in combination.
Cognitive-behavioral interventions like stress management programs can effectively reduce TTH activity. They have been shown to be more useful when combined with biofeedback or relaxation therapies.
The “combination of stress management therapy and amitriptyline (≤100 mg/day) was more effective than either therapy used alone”.
The headache index score was reduced by 50% in 65% of the patients on the combination arm compared with 38% on tricyclics, 35% on stress management, and 29% of the placebo arm.
The improvement seen after behavioral treatment might appear slowly compared with tricyclics; however, it is maintained for more extended periods.
Physical therapy: Its components include positioning, exercise program, hot and cold packs, massage, ultrasound, and TENS (transcutaneous electrical nerve stimulation). Adding craniocervical training to classical physiotherapy might be better than physiotherapy alone.
Acupuncture: Most trials are limited by small sample size and reported conflicting results. Acupuncture methods include needle acupuncture, as well as laser acupuncture, and both, and have shown effectiveness as compared to placebo., A recent overview of the systematic reviews has shown significant heterogeneity regarding the quality of the studies with only seven out of 36 outcome parameters providing high-quality evidence.
CGRP receptor antagonists: “Calcitonin gene-related peptide has emerged as a key neuropeptide in migraine pathophysiology”. CGRP receptor antagonists have been approved as therapies for migraine. Whether they have a role in the treatment of TTH requires future clinical trials.
Neuropeptide substance P: It co-localizes with CGRP in trigeminal ganglia neurons. The nociceptive effect is mediated by binding to G protein-coupled NK 1 receptor. The exact role of substance P in TTH, however, remains unclear.
NOS inhibitors: NG-monomethyl-L-arginine hydrochloride molecule was found to reduce headache and associated pericranial tenderness and hardness in CTTH patients., Also the NO donor glyceryl trinitrate induced TTH in these patients. Hence, inhibition of NOS may become a novel target in the treatment of CTTH.
Considering the prevalence of TTH and its socioeconomic burden, elucidation of pathophysiological mechanisms and therapeutics has received lesser attention than in migraine. In addition to the existing models of peripheral generation of pain in TTH due to excessive muscle contraction, ischemia, and inflammation of head and neck muscles, central mechanisms are being proposed based on neurophysiological and advanced neuro-imaging studies. Once there is a better understanding of how to modulate these peripheral and central sensitization processes, effective control for head pain in TTH may be achieved. Though episodic TTH is well controlled with analgesics, chronic TTH requires a combination of pharmacologic and non-pharmacologic intervention for optimal results. However, the outcome still remains less than satisfactory.
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