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17 Articles in Volume 19, Issue #4
Analgesics of the Future: Inside the Potential of Nerve Growth Factor Antagonists
Best Practices Are Still Largely Undefined in Task Force Report
Brief Behavioral Interventions for Chronic Pain
Cervicogenic Headache: Diagnosis and Management
Chronic Headache and Central Pain Conditions
Considering Comorbidities When Selecting Medications for Pain (Part 4)
For APPs: How to Contribute to Clinical Research
Gabapentin and Suicidal Ideation: Is There a Link?
Intranasal Ketamine for the Relief of Cluster Headache
Letters: Slipping Rib Syndrome; Burning Leg Pain; CGRP Complications
Pain Assessment Tools for Malingering in Patients with Chronic Pain
Refractory Chronic Migraine: Mild, Moderate, or Severe
Should Probuphine be considered for MAT?
Special Report: The Abuse Potential of Gabapentin & Pregabalin
Tension-Type Headache: Evidence for Trigger Points
Treatment Alternatives for Migraine
Trigeminal Neuralgia: Current Diagnosis and Treatment Options

Chronic Headache and Central Pain Conditions

Understanding the overlap between chronic migraine or tension-type headache and central pain conditions may help clinicians offer patients more effective long-term care.
Pages 30-35

Chronic headache is one of the most common medical problems. The vast majority of headaches fall into one of three primary headache categories: tension-type, migraine, or cluster headaches. Tension-type headaches (TTH) are the most common, with a yearly prevalence of 60 to 80% (see Figure 1).1 TTH are usually mild or modest, associated with cranial and/or cervical muscle tenderness, and often do not prompt a healthcare visit. Migraine headaches are usually unilateral, throbbing, and often associated with aura, nausea, photophobia, and phonophobia. Migraine headaches are sub-divided into those with or without aura and affect 10 to 15% of the population, with women affected three times as often.2 Cluster headaches are now part of a new headache category termed trigeminal autonomic cephalgia by the International Classification of Headache Disorders, 3rd edition. These headaches are characterized by sudden, severe, recurrent headaches with autonomic symptoms on the same side, which may include ptosis, miosis, rhinorrhea, and nasal congestion. Cluster headaches are present in less than 1% of the population and are more common in males. Many patients experience both migraine and TTH; migraine typically worsens a tension headache.

Each of these primary headache types is, by definition, central in nature. Headaches may also be secondary, such as from a space-occupying mass, a vascular abnormality, an infection, or a systemic or metabolic disease.

This article focuses on the role of central pain in TTH and migraine. Central pain, also termed central sensitization, is defined as localized or generalized pain generated solely in the central nervous system (CNS). Central pain is characterized by hyperalgesia – an increased response to a painful stimulus – and allodynia – that is, pain following a stimulus that is typically not irritating.

The Clinical Link Between Headache and Fibromyalgia/Chronic Widespread Pain

Chronic headache is present in 30 to 80% of patients with fibromyalgia, also known as chronic widespread pain (CWP).3 In one study of 100 fibromyalgia patients, chronic headache was present in more than 50% of the patients; types were equally divided between migraine and TTH.3

Unsurprisingly, a number of studies have found a high prevalence of fibromyalgia in patients with chronic headache. Fibromyalgia was present in one-third of 118 consecutive patients with migraine followed at a university headache clinic.4 The presence of fibromyalgia correlated with migraine severity and anxiety. In another report on 1,000-plus subjects at a tertiary headache clinic, fibromyalgia was diagnosed in 40% of subjects with chronic migraine and TTH (see Figure 2).5 The prevalence was much lower in those with cluster headaches. Concurrent fibromyalgia correlated with headache frequency, anxiety, pericranial tenderness, poor sleep quality, and physical disability.

In a study from a university neurology clinic, fibromyalgia was diagnosed in 70% of patients with chronic migraine and in 30% of those with TTH.6 In those subjects with migraine, the presence of fibromyalgia correlated with increased photophobia, phonophobia, anxiety, depression, and sleep disturbances. There was a significant increase in clinical fibromyalgia flare-ups in patients with episodic or chronic migraine.7 In patients with chronic migraine and fibromyalgia, there were three times as many flares of the chronic widespread pain monthly compared to patients with fibromyalgia but no chronic headache (see Figure 3).

In a population-based study of 1,500 subjects with chronic migraine and 8,000 controls, there was a 2.4 odds ratio of fibromyalgia in those with migraine compared to controls.8 Depression was twice as common in the subjects with chronic migraine compared to controls. In 157 subjects with comorbid fibromyalgia and migraine, greater depressive symptoms, higher headache intensity, and more severe headache-related disability were present compared to subjects without fibromyalgia.9 The presence of fibromyalgia correlated with headache frequency and intensity, anxiety, depression, sleep disturbance, and quality of life. Another study found that concurrent fibromyalgia was a risk factor for suicide in patients with migraine.10 The odds ratio was 2.6 for suicidal ideation and 2.0 for suicide attempts in the headache group with concurrent fibromyalgia.

Hyperalgesia

Widespread skin and muscle allodynia have been noted in all forms of chronic headache but particularly in migraine.11 Allodynia has been correlated with headache frequency, depression, and body mass index. In most studies of chronic headache, depression, cognitive and sleep disturbances—all classic features of fibromyalgia/CWP—have correlated with generalized allodynia.11

In 151 migraine subjects aged 8 to 15, allodynia was present in 97% and pericranial tenderness was present in 69%.12 Increased migraine frequency and severity correlated with allodynia and fibromyalgia pain. Allodynia was associated with mood disturbances, pain catastrophizing, and disability.

Another study compared 176 consecutive subjects with migraine to 132 age- and sex-matched controls and determined widespread pressure pain threshold using the fibromyalgia manual tender point examination.13 Widespread tenderness was present in 65% and allodynia in 42%. Widespread tender points correlated with female gender, higher frequency of migraine attack and younger age at onset. Chronic low back pain was present in more than 80% of chronic headache subjects compared to 65% without headaches.14 In subjects with chronic headache and chronic low back pain, there was evidence of neck and diffuse lower pressure pain threshold, suggesting central sensitization.

The Evidence for Central Pain
Migraine

The vascular theory that migraine is caused by altered cerebral blood vessel dilatation and constriction has been disproven and it has been made clear that migraine is a disorder of neuronal dysfunction.15 The headaches and visual aura characteristic of migraine have been linked to a self-propagating neuronal wave termed cortical spreading depression.15 These neuronal events involve activation of trigeminal nerve afferents and central sensitization.

Neuroimaging studies have demonstrated structural and functional brain changes in subjects with migraine. Compared to controls, patients with migraine had decreased grey matter in the cingulate cortex, an area important in pain perception.16 Another report noted focal gray matter reduction in the right superior temporal gyrus, right inferior frontal gyrus, and left precentral gyrus.17 Researchers also found a correlation of reduced gray matter volume in the anterior cingulate cortex with frequency of migraine. Another study of 73 migraine patients and 46 controls found changes in gray matter volume in various brain regions in the migraine group.18 Over time, there were further structural differences, including in pain regions. These changes varied with migraine duration and severity. White matter hyperintensities were present in one-third of patients with migraine and correlated with increased severity of attacks and a poor prognosis.19

Functional imaging studies in patients with migraine have revealed abnormal pain processing and altered functional connectivity of sensory processing regions, similar to results seen in patients with other chronic pain disorders, such as fibromyalgia and vulvodynia.20 These results have included abnormal brain response to various stimuli and an absence of the normal habituating response between migraine attacks. A topologic brain atlas analysis demonstrated disrupted brain functional activity in female migraine patients compared to controls.21 The authors suggested that the posterior insula plays an important role in migraine, similar to what has been proposed for fibromyalgia.

Brainstem function following painful orofacial stimuli was measured in 31 patients with migraine and compared to 31 controls.22 Researchers found that pain sensitivity increased over the interictal period and then dramatically decreased just before a migraine attack. They also noted changes in functional connectivity, including enhanced periaqueductal gray connectivity with the rostral ventromedial medulla. The investigators concluded that brainstem sensitivity fluctuates throughout the migraine cycle and that, immediately prior to a migraine attack, endogenous pain mechanisms are activated. Other studies have further suggested that pain perception alterations vary dramatically during a migraine attack, worsening just before and then disappearing during the attack.23 The more frequent the attacks, the more this central pain sensitization becomes persistent and difficult to treat. An increased thalamic level of thalamic glutamate/glutamine was found in migraine patients compared to controls, further evidence of central sensitization.24

The author uses fibromyalgia as a comparative example to central pain conditions in chronic headache patients. (Source: 123RF)

Chronic Tension-Type and Cluster Headaches

Peripheral factors, particularly muscle tension/spasm, and central factors, similar to those discussed in migraine, jointly are linked to the pathophysiology of tension-type headaches. These local muscle factors are often termed myofascial trigger points. Patients with TTH have increased the number of active and latent tender points as well as decreased head and neck mobility and increased muscle tenderness.25 Although pericranial and cervical muscle spasm and tenderness are prominent in TTH, and in migraine, the role of myofascial trigger points in the etiology of TTH has been controversial.26 Most investigators have concluded that myofascial trigger points develop over time as a consequence of the headaches rather than causing them.26

Physiologic studies and neuroimaging have demonstrated similar abnormalities in pain processing in TTH as in migraine.27-30 Brain MRI studies demonstrated loss of gray matter in pain processing regions in TTH.27 This change correlated with the duration and severity of the TTH. Generalized allodynia has been demonstrated in subjects with TTH28 and, as noted in migraine, functional imaging studies demonstrate alterations in pain transmission with diffuse noxious inhibitory control function reduction in TTH.29,30

Abnormal pain processing has been demonstrated in individuals with cluster headaches as well.31 Following cold water exposure, abnormal activity of the diffuse noxious activity control network was noted in subjects with cluster headaches compared to controls.

Cervicogenic headache

Assessment of cervicogenic headache, a secondary headache disorder, is considered a confusing and controversial category by many clinicians; in fact, many headache experts have abandoned this area of diagnosis and treatment. The type implies that the source of the headache is an anatomic structure in the cervical spine or soft tissues. There is evidence that headache attacks may be caused by referred pain from the cervical spine, usually from encroachment of one or more of the first three cervical nerve roots.32 Otherwise, most headaches related to cervical muscle tension are now considered to fall under the TTH category. (Editor’s Note: for more on cervicogenic headache, see our online exclusive review.)

Diagnostic and Treatment Considerations for Central Pain Comorbidities

A detailed discussion of headache diagnosis and management is beyond the scope of this paper. However, readers may find Ready’s article, "Discussing Migraine: What to Try When Nothing is Working," and Robbins’ article, "Migraine Treatment: What’s Old, What’s New," in the June 2017 issue of PPM, as well as the articles within this special headache issue to be useful. The following section focuses on the impact of central sensitization on the diagnosis and therapy of patients with chronic headache.

Based on the prevalence of fibromyalgia/CWP in patients with migraine or TTH, it is reasonable to screen any patient with chronic headache for fibromyalgia. This step may be especially important for those patients presenting with severe headache attacks, multiple somatic symptoms, and/or concurrent moderate or severe depression (see Table I). Depression, sleep disturbances, and catastrophizing are considered to be strong risk factors for both chronic headache and fibromyalgia/CWP. In a group of patients with chronic migraine, the odds ratio for severe migraine-related disability was 3.5 for moderate to severe depression and 2.0 for pain catastrophizing.33

Screening patients with chronic headache for fibromyalgia/CWP is often quick and inexpensive (see Table II). The cardinal symptom is chronic, widespread pain, lasting more than three months. There should be no systemic inflammatory or neurologic disorder present that would be the cause of the pain.34 In the author’s clinical experience, physical examination is typically unremarkable except for widespread tenderness to palpation. Patients almost always report exhaustion and sleep disturbances, and, as discussed, many have concurrent mood disturbances, as well as cognitive disturbances, catastrophizing and neuropathic symptoms. Extensive laboratory testing may not be cost-effective, other than blood tests for acute phase reactants, ESR or CRP, which should be normal. Some healthcare providers may be fearful that patients with widespread pain and multiple somatic symptoms may have headaches secondary to an undiagnosed systemic disease or malignancy. However, the co-existence of chronic headache with fibromyalgia/CWP is much more likely to be the situation.

In patients with TTH, it may make sense to treat any associated muscle spasm/tenderness with benign physical modalities, such as ice, heat, massage, and stretching. Trigger point injections, either with dry needling or lidocaine or botulinum toxin-A (Botox) have been effective in some trials in patients with TTH.35-37 Botox may work by blocking the release of pain-related neurotransmitters, such as glutamate and substance P, at the dorsal horn of the spinal cord (see Figure 4).37

In migraine and tension headache, both pharmacologic and non-pharmacologic treatments are typically used to manage and prevent chronic attacks – this approach is similar to managing fibromyalgia. Standard care includes the use of tricyclic medications, such as amitriptyline and gabapentin,38,39 as well as biofeedback, acupuncture, and cognitive behavioral therapy. Lifestyle modification, including stress reduction and exercise, are often strongly recommended as well for both fibromyalgia and chronic headache. There is evidence to support a multidisciplinary approach to the treatment of chronic headache, particularly in patients with co-existing fibromyalgia.39

Conclusion

Chronic widespread pain/fibromyalgia are commonly present in patients with chronic migraine and tension-type headache. This comorbidity correlates with headache frequency and intensity, mood disturbances, sleep disturbance, as well as quality of life.

There is also strong evidence that chronic headache is a central pain disorder, overlapping with fibromyalgia, irritable bowel syndrome, temporomandibular joint disorder, and chronic pelvic and bladder pain disorders. It is advised that patients with migraine and TTH be routinely screened for fibromyalgia/CWP.

As in each of these chronic pain conditions, patients with chronic migraine and TTH often exhibit widespread allodynia and hyperalgesia. Neuroimaging studies may help to demonstrate structural and functional evidence of central sensitivity. Imaging tools are likely to have direct applicability to new therapies for chronic headache in the near future. Many of the treatment principles that are effective in fibromyalgia/CWP have shown to be helpful in the prophylaxis and long-term management of chronic headache. When viewing chronic headache as a central pain condition, therefore, clinicians may be less likely to miss comorbidities such as fibromyalgia, and to approach treatment with a multidisciplinary pain management framework.

Last updated on: June 21, 2019
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Tension-Type Headache: Evidence for Trigger Points
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