Headache: Migraine and Tension-type : Pathophysiology and Treatments

Sunday, January 25th 2015. | Disease

Migraine is a recurring headache of moderate to severe intensity associated with gastrointestinal (GI), neurologic, and autonomic symptoms. In migraine with aura, a complex of focal neurologic symptoms precedes or accompanies the attack.


  • Neuronal dysfunction is now accepted as the primary basis of migraine pathophysiology. Symptoms of aura are thought to result from neuronal dysfunction characterized by a wave of depressed electrical activity that advances across the cerebral cortex. Aura is also associated with reduced cerebral blood flow.
  • Migraine pain is believed to result from activity within the trigeminovascular system that results in release of vasoactive neuropeptides with subsequent vasodilation, dural plasma extravasation, and perivascular inflammation.
  • The pathogenesis of migraine may be related to an imbalance in the activity of serotonin-containing neurons and/or noradrenergic pathways in brainstem nuclei that modulate cerebral vascular tone and nociception. This imbalance may result in vasodilation of intracranial blood vessels and activation of the trigeminovascular system.
  • Serotonin (5-hydroxytryptamine, or 5-HT) is an important mediator of migraine. Acute antimigraine drugs such as ergot alkaloids and triptan derivatives are agonists of vascular and neuronal 5-HT1 receptor subtypes, resulting in vasoconstriction and inhibition of vasoactive neuropeptide release and pain signal transmission. Drugs used for migraine prophylaxis stabilize serotonergic neurotransmission and raise the migraine threshold by antagonizing or down-regulating 5-HT2 receptors, or by modulating serotonergic neuronal discharge.



Migraine is a common, recurrent, severe headache that interferes with normal functioning. It is a primary headache disorder divided into two major subtypes, migraine without aura and migraine with aura.


  • Migraine is characterized by recurring episodes of throbbing head pain, frequently unilateral, that when untreated can last from 4 to 72 hours. Migraine headaches can be severe and associated with nausea, vomiting, and sensitivity to light, sound, and/or movement. Not all symptoms are present at every attack.
  • In the headache evaluation, diagnostic alarms should be identified. These include: acute onset of the “first” or “worst” headache ever, accelerating pattern of headache following subacute onset, onset of headache after age 50, headache associated with systemic illness (e.g., fever, nausea, vomiting, stiff neck, and rash), headache with focal neurologic symptoms or papilledema, and new-onset headache in a patient with cancer or human immunodeficiency virus (HIV) infection.



  • A stable pattern, absence of daily headache, positive family history for migraine, normal neurologic examination, presence of food triggers, menstrual association, long-standing history, improvement with sleep, and subacute evolution are all signs of migraine headache. Aura may signal the migraine headache but is not required for diagnosis.
  • Approximately 10% to 60% of migraineurs experience premonitory symptoms, or prodrome, in the hours or days before the onset of headache. Neurologic prodromal symptoms (phonophobia, photophobia, hyperosmia, difficulty concentrating) are most common, but psychologic (anxiety, depression, euphoria, irritability, drowsiness, hyperactivity, restlessness), autonomic (e.g., polyuria, diarrhea, constipation), and constitutional (e.g., stiff neck, yawning, thirst, food cravings, anorexia) symptoms may also occur.
  • A migraine aura is experienced by approximately 31% of migraineurs. The aura typically evolves over 5 to 20 minutes and lasts less than 60 minutes. Headache usually occurs within 60 minutes of the end of the aura. Visual auras can include both positive features (e.g., scintillations, photopsia, teichopsia, fortification spectrum) and negative features (e.g., scotoma, hemianopsia). Sensory and motor symptoms such as paresthesias or numbness of the arms and face, dysphasia or aphasia, weakness, and hemiparesis may also occur.
  • The actual migraine headache may occur at any time of day or night but usually occurs in the early morning hours on awakening. Pain is usually gradual in onset, peaking in intensity over minutes to hours, and lasting between 4 and 72 hours. Pain is typically reported as moderate to severe and most often involves the frontotemporal region. The headache is usually unilateral and throbbing or pulsating in nature. GI symptoms (e.g., nausea, vomiting) almost invariably accompany the headache. Other systemic symptoms include anorexia, constipation, diarrhea, abdominal cramps, nasal stuffiness, blurred vision, diaphoresis, facial pallor, and localized facial or periorbital edema. Sensory hyperacuity (photophobia, phonophobia, osmophobia) is frequently reported. Physical activity may aggravate the pain, and many patients seek a dark, quiet place for rest and relief.
  • Once the headache pain wanes, a resolution phase characterized by exhaustion, malaise, and irritability ensues.



In selected circumstances and secondary headache presentation, serum chemistries, urine toxicology profiles, thyroid function tests, lyme studies, and other blood tests such as a complete blood count, antinuclear antibody titer, erythrocyte sedimentation rate, and antiphospholipid antibody titer may be considered.


  • Perform a general medical and neurologic physical examination. Check for abnormalities: vital signs (fever, hypertension), funduscopy (papilledema, hemorrhage, and exudates), palpation and auscultation of the head and neck (sinus tenderness, hardened or tender temporal arteries, trigger points, temporomandibular joint tenderness, bruits, nuchal rigidity, and cervical spine tenderness), and neurologic examination (identify abnormalities or deficits in mental status, cranial nerves, deep tendon reflexes, motor strength, coordination, gait, and cerebellar function).
  • Consider neuroimaging studies in patients with abnormal neurologic examination findings of unknown etiology and in those with additional risk factors warranting imaging.
  • A comprehensive headache history is the most important element in establishing the clinical diagnosis of migraine.
  • Diagnostic and laboratory testing may be warranted if there are suspicious headache features or abnormal examination findings. Neuroimaging (computed tomography or magnetic resonance imaging) should be considered in patients with unexplained neurologic physical findings or an atypical headache history.


  • Acute therapy should provide consistent, rapid relief with minimal adverse effects and symptom recurrence, thereby enabling the patient to resume normal daily activities. Ideally, patients should be able to manage their headaches effectively without emergency department or physician office visits.
  • Clinicians and migraineurs should collaborate to create a long-term management plan that reduces attack frequency and severity, minimizes disability and emotional distress, and improves quality of life.

Nonpharmacologic Treatment

  • Application of ice to the head and periods of rest or sleep, usually in a dark, quiet environment, may be beneficial.
  • Preventive management should begin with identification and avoidance of factors that provoke migraine attacks (Table 51-1).
  • Behavioral interventions (relaxation therapy, biofeedback, cognitive therapy) are preventive options for patients who prefer nondrug therapy or when drug therapy is ineffective or not tolerated.

Pharmacologic Treatment of Acute Migraine

  • Acute migraine therapies are most effective when administered at the onset of migraine.
  • Pretreatment with antiemetics (e.g., prochlorperazine, metoclopramide) 15 to 30 minutes prior to administering abortive therapy or use of non-oral treatments (rectal suppositories, nasal spray, injections) may be advisable when nausea and vomiting are severe. In addition to its antiemetic effects, the prokinetic agent metoclopramide enhances absorption of oral medications.
  • Acute migraine therapies should generally be limited to 2 days/wk to avoid the development of medication misuse (or rebound) headache.
  • Analgesics and Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
  • Simple analgesics and NSAIDs are effective treatment for mild to moderate migraine attacks. Aspirin, ibuprofen, naproxen sodium, tolfenamic acid, and the combination of acetaminophen plus aspirin and caffeine have shown most consistent evidence of efficacy.
  • The COX-2 inhibitors and naproxen have been recently associated with cardiac events and stroke. The COX-2 inhibitors should not generally be chosen for this indication. The Food and Drug Administration (FDA) urges that the naproxen product labeled dosing be carefully followed when it is used for any indica- tion.
  • NSAIDs appear to prevent neurogenically mediated inflammation in the trigeminovascular system by inhibiting prostaglandin synthesis.
  • In general, NSAIDs with a long half-life that preclude their frequent use are preferred. Rectal suppositories and intramuscular ketorolac are options for patients with severe nausea and vomiting.
  • The nonprescription combination of acetaminophen, aspirin, and caffeine is approved in the United States for relieving migraine pain and associated symptoms.
  • Aspirin and acetaminophen are also available by prescription in combination with a short-acting barbiturate (butalbital) or an opioid (e.g., codeine). No randomized, placebo-controlled studies support the efficacy of butalbital-containing formulations for migraine.
  • Midrin is a proprietary combination of acetaminophen, isometheptene mucate (a sympathomimetic amine), and dichloralphenazone (a chloral hydrate derivative) that has shown modest benefits in placebo-controlled trials. It may be an alternative for patients with mild to moderate migraine attacks.

Ergot Alkaloids and Derivatives

  • Ergot alkaloids are nonselective 5-HT1 receptor agonists that constrict intracranial blood vessels and inhibit the development of neurogenic inflammation in the trigeminovascular system. They also have activity at α-adrenergic, β-adrenergic, and dopaminergic receptors.
  • Ergotamine tartrate is available for oral, sublingual, and rectal administration. Oral and rectal preparations contain caffeine to enhance absorption and potentiate analgesia. Because oral ergotamine undergoes extensive first-pass hepatic metabolism, rectal administration is preferred. Dosage should be titrated to produce an effective but subnauseating dose.
  • Dihydroergotamine (DHE) is available for intranasal and parenteral (intramuscular [IM], intravenous [IV], subcutaneous [SC]) administration. Patients can be trained to self-administer DHE by the IM or SC routes. The efficacy of intranasal DHE has been consistently demonstrated.
  • Nausea and vomiting are common adverse effects of ergotamine derivatives. Ergotamine is 12 times more emetogenic than DHE; pretreatment with an antiemetic should be considered with ergotamine and IV DHE therapy. Other side effects include abdominal pain, weakness, fatigue, paresthesias, muscle pain, diarrhea, and chest tightness. Symptoms of severe peripheral ischemia (ergotism) include cold, numb, painful extremities; continuous paresthesias; diminished peripheral pulses; and claudication. Gangrenous extremities, myocardial infarction, hepatic necrosis, and bowel and brain ischemia have been reported rarely with ergotamine. Ergotamine derivatives and triptans should not be used within 24 hours of each other.
  • Contraindications include renal and hepatic failure; coronary, cerebral, or peripheral vascular disease; uncontrolled hypertension; sepsis; and women who are pregnant or nursing.
  • DHE does not appear to cause rebound headache, but dosage restrictions for ergotamine tartrate should be strictly observed to prevent this complication.

Serotonin Receptor Agonists (Triptans)

  • Sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, frovatriptan, and eletriptan are appropriate first-line therapy for patients with moderate to severe migraine or as rescue therapy when nonspecific medications are ineffective.
  • These drugs are selective agonists of the 5-HT1B and 5-HT1D receptors. Relief of migraine headache results from (1) vasoconstriction of intracranial blood vessels through stimulation of vascular 5-HT1B receptors; (2) inhibition of vasoactive neuropeptide release from trigeminal perivascular nerves through stimulation of presynpatic 5-HT1D receptors; and (3) interruption of pain signal transmission within the brainstem through stimulation of 5-HT1D receptors. They also display varying affinity for 5-HT1A, 5-HT1E, and 5-HT1F receptors.
  • Sumatriptan is available for oral, intranasal, and SC administration. The SC injection is packaged as an autoinjector device for self-administration by patients. The efficacies of 50-mg and 100-mg doses are comparable. When compared with the oral formulation, SC administration offers enhanced efficacy and a more rapid onset of action (10 vs. 30 minutes). Intranasal sumatriptan also has a faster onset of effect (15 minutes) than the oral formulation and produces similar rates of response. Approximately 30% to 40% of patients who respond to sumatriptan experience headache recurrence within 24 hours; a second dose given at the time of recurrence is usually effective. However, routine administration of a second oral or SC dose does not improve initial efficacy rates or prevent subsequent recurrence.
  • Second-generation agents have higher oral bioavailability and longer half-lives than oral sumatriptan, which could theoretically improve within-patient treatment consistency and reduce headache recurrence. However, comparative clinical trials are necessary to determine their relative efficacy.
  • Pharmacokinetic characteristics of the triptans are shown in Table 51-3.
  • Clinical response to triptans varies among individual patients, and lack of response to one agent does not preclude effective therapy with another member of the class.
  • Side effects of triptans include paresthesias, fatigue, dizziness, flushing, warm sensations, and somnolence. Minor injection site reactions are reported with SC use, and taste perversion and nasal discomfort may occur with intranasal administration. Up to 15% of patients report chest tightness, pressure, heaviness, or pain in the chest, neck, or throat; although the mechanism of these symptoms is unknown, a cardiac source is unlikely in most patients. Isolated cases of myocardial infarction and coronary vasospasm with ischemia have been reported.
  • Contraindications include ischemic heart disease, uncontrolled hypertension, cerebrovascular disease, and hemiplegic and basilar migraine. Triptans should not be given within 24 hours of ergotamine derivatives administration. Administration within 2 weeks of therapy with monoamine oxidase inhibitors is not recommended.


  • Opioids and derivatives (e.g., meperidine, butorphanol, oxycodone, hydromorphone) provide effective relief of intractable migraine but should be reserved for patients with moderate to severe infrequent headaches in whom conventional therapies are contraindicated or as rescue medication after failure to respond to conventional therapies.
  • Intranasal butorphanol may provide an alternative to frequent office or emergency department visits for injectable migraine therapies. Onset of analgesia occurs within 15 minutes of administration. Adverse effects include dizziness, nausea, vomiting, drowsiness, and taste perversion. It is also a controlled substance that carries the potential for dependence and addiction.


  • Short courses of oral or parenteral glucocorticoids (e.g., prednisone, dexamethasone, hydrocortisone) appear to be useful for refractory headache that has persisted for several days.
  • Corticosteroids may be an effective rescue therapy for status migrainosus, which is a severe migraine that may last up to 1 week.

Pharmacologic Prophylaxis of Migraine

  • Prophylactic therapies are administered on a daily basis to reduce the frequency, severity, and duration of attacks, as well as to increase responsiveness to acute symptomatic therapies. A treatment algorithm for prophylactic management of migraine headache .
  • Prophylaxis should be considered in the setting of recurring migraines that produce significant disability; frequent attacks requiring symptomatic medication more than twice per week; symptomatic therapies that are ineffective, contraindicated, or produce serious side effects; uncommon migraine variants that cause profound disruption and/or risk of neurologic injury; and patient preference to limit the number of attacks.
  • Preventive therapy may also be administered intermittently when headaches recur in a predictable pattern (e.g., exercise-induced or menstrual migraine).
  • Because efficacy of various prophylactic agents appears to be similar, drug selection is based on side-effect profiles and comorbid conditions of the patient. Individual response to a particular agent is unpredictable, and a trial of 2 to 3 months is necessary to judge the efficacy of each medication.
  • Only propranolol, timolol, and valproic acid are approved by the FDA for this indication.
  • Prophylaxis should be initiated with low doses and advanced slowly until a therapeutic effect is achieved or side effects become intolerable.
  • Prophylaxis is usually continued for at least 3 to 6 months after headache frequency and severity have diminished, and then gradually tapered and discontinued, if possible.

β-Adrenergic Antagonists

  • β Blockers (propranolol, nadolol, timolol, atenolol, and metoprolol) are the most widely used treatment for prevention of migraine. β Blockers with intrinsic sympathomimetic activity are ineffective.
  • Side effects include drowsiness, fatigue, sleep disturbances, vivid dreams, memory disturbance, depression, GI intolerance, sexual dysfunction, bradycardia, and hypotension.
  • β Blockers should be used with caution in patients with heart failure, peripheral vascular disease, atrioventricular conduction disturbances, asthma, depression, and diabetes.


  • Amitriptyline appears to be the tricyclic antidepressant (TCA) of choice, but imipramine, doxepin, nortriptyline, and protriptyline have also been used.
  • Their beneficial effects in migraine prophylaxis are independent of antidepressant activity and may be related to down-regulation of central 5-HT2 and adrenergic receptors.
  • TCAs are usually well tolerated at the lower doses used for migraine prophylaxis, but anticholinergic effects may limit use, especially in patients with benign prostatic hyperplasia or glaucoma. Evening doses are preferred because of sedation.
  • Selective serotonin reuptake inhibitors (SSRIs) have not been extensively studied for migraine prophylaxis. There are inconsistent data for fluoxetine, and prospective data evaluating sertraline, paroxetine, fluvoxamine, and citalopram are lacking.
  • SSRIs are considered to be less effective than TCAs for migraine prophylaxis and should not be considered first- or second-line therapy. However, they may be beneficial when depression is a significant contributor to headache.


  • Valproic acid and divalproex sodium (a 1:1 molar combination of valproate sodium and valproic acid) can reduce the frequency, severity, and duration of headaches by at least 50% in up to 65% of migraineurs.
  • Efficacy of valproic acid may be due in part to inhibition of serotonergic neurons of the dorsal raphe nuclei.
  • Side effects include nausea (less common with divalproex sodium and gradual dosing titration), tremor, somnolence, weight gain, hair loss, and hepatotoxicity (rare).
  • Topiramate is undergoing FDA review for migraine prophylaxis. Gabapentin and other anticonvulsants may also have a role, but further study is required to establish their utility.


  • Methysergide is a semisynthetic ergot alkaloid that is a potent 5-HT2 receptor antagonist. It appears to stabilize serotonergic neurotransmission in the trigeminovascular system to block the development of neurogenic inflammation.
  • Its use is limited by the occurrence of potentially serious retroperitoneal, endocardial, and pulmonary fibrotic complications that have occurred during long-term uninterrupted use. It is reserved for patients with refractory headaches that do not respond to other preventive therapies.
  • Consequently, a 4-week medication-free period is recommended after each 6-month treatment period. Dosage should be tapered over 1 week to prevent rebound headaches.
  • Monitoring for fibrotic complications should include periodic cardiac auscultation, chest x-ray, echocardiography, and abdominal imaging. Patients should report symptoms of flank pain, dysuria, chest pain, and shortness of breath.
  • Methysergide is best tolerated when taken with meals. Side effects other than GI intolerance are many and include insomnia, vivid dreams, hallucinations, claudication, and muscle cramps. The labeling should be consulted for additional side effects and contraindications.

Calcium Channel Blockers

Verapamil provided only modest benefit in decreasing the frequency of attacks in two placebo-controlled studies. It has little effect on the severity of migraine attacks. It is generally considered a second- or third-line prophylactic agent.
Nonsteroidal Anti-inflammatory Drugs

  • NSAIDs are modestly effective for reducing the frequency, severity, and duration of migraine attacks, but potential GI and renal toxicity limit daily or prolonged use.
  • They may be used intermittently to prevent headaches that recur in a predictable pattern (e.g., menstrual migraine). Treatment should be initiated 1 to 2 days prior to the time of headache vulnerability and continued until vulnerability is passed.



Tension-type headache is the most common type of primary headache and is more common in women than men. Pain is usually mild to moderate and nonpulsatile. Episodic headaches may become chronic.


  • Pain is thought to originate from myofascial tissues.
  • After activation of supraspinal pain perception structures, a headache occurs because of central modulation of incoming peripheral stimuli.


  • Premonitory symptoms and aura are absent, and pain is usually mild to moderate, bilateral, and in the frontal and temporal areas, but occipital and parietal areas can also be affected.
  • Mild photophobia or phonophobia may occur.
  • Pericranial or cervical muscles may have tender spots or localized nodules in some patients.


  • Simple analgesics (alone or in combination with caffeine) and NSAIDS are the mainstay of acute therapy.
  • Nonpharmacologic therapies include reassurance and counseling, stress management, relaxation training, and biofeedback. physical therapeutic options (e.g., heat or cold packs, ultrasound, electrical nerve stimulation, massage, acupuncture, trigger point injections, occipital nerve blocks) have performed inconsistently.
  • Acetaminophen, aspirin, ibuprofen, naproxen, ketoprofen, indomethacin, and ketorolac are effective.
  • High-dose NSAIDS and the combination of aspirin or acetaminophen with butalbital or, rarely, codeine are effective options. The use of butalbital and codeine combinations should be avoided when possible.
  • Acute medication for episodic headache should be taken no more often than 2 days/wk to prevent development of chronic tension-type headache.
  • There is no evidence to support the efficacy of muscle relaxants for tension-type headache.
  • Preventive treatment should be considered if headache frequency (more than 2 per week), duration (greater than 3 to 4 hours), or severity results in medication overuse or substantial disability.
  • The TCAs are used most often for prophylaxis of tension headache. injection of botulinum toxin into pericranial muscles has demonstrated efficacy in prophylaxis of chronic tension-type headache in two studies.


  • Patients should be monitored for frequency, intensity, and duration of headaches and for any change in the headache pattern.
  • Patients taking abortive therapy should be monitored for frequency of use of prescription and over-the-counter medications and for side effects of medications.
  • Patterns of abortive medication use can be documented to establish the need for prophylactic therapy. Prophylactic therapies should also be monitored closely for adverse reactions, abortive therapy needs, adequate dosing, and compliance.
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