Trigeminocervical complex pathophysiologies are considered the main source of headaches. Secondary causes include an identifiable pathology, infection, medication side effect, space-occupying lesions, spinal pathology, or inflammation. Headaches can be nociceptive, neurogenic, or neurohumoral. The pain of headaches results from vasodilation or muscle spasm and can be self-perpetuating. In more than 90% of patients, the primary type of head pain is migraine, cluster, or tension-type/daily headache.





Migraines may affect 30 million Americans.[4] The prevalence of migraine in the United States is highest among white women at 20.4%, followed by 16.2% for black women, 9.2% for Asian American women, 8.6% for white men, 7.2% for black men, and 4.2% for Asian American men.[70]



Although the exact cause of migraine is uncertain, the results of experimental studies and the success of some migraine-specific therapies have helped define the pathology as a cervical-trigeminal-vascular disorder. Sensitization and activation of the trigeminal ganglia nerves release the calcitonin gene-related peptide and cause inflammation in the nerves serving meningeal blood vessels.

In a 1993 study on the pathogenesis of migraine, Kaube et al.[42] found that stimulating the sagittal sinus (a trigeminally innervated structure) in cats increased cervical cord activity, including expression of c-fos immunoreactivity. This allowed visualization of the neurons that likely play a role in a vascular headache such as migraine. A few years later, Goadsby and Hoskin[33] stimulated the sinuses of monkeys and mapped the resulting evoked expression of c-fos in laminae of the trigeminal nucleus and C1 dorsal horn. Because they found that the amount evoked at the C2 level was closer to the control, they concluded that C1 trigeminovascular afferents may have a specialized role in mediating the pain of migraine.

In addition, serotonin levels are higher centrally and lower peripherally during migraines. In 1993, Marcus[51] reviewed reports on the role of serotonin in migraine and concluded that changes in serotonin levels may precede the cerebral vascular dilation and muscular changes noted in both migraine and tension-type headache. Further implicating serotonin, triptans designed to activate two receptors in the 5-HT1 serotonin family, the 5-HT1B receptors that constrict meningeal vessels (reversing migraine-associated vasodilation) and the 5-HT1D receptors that may block the secretion of the trigeminal neuropeptides which may play a role in the neurogenic inflammatory response, can relieve migraine pain.[36]

Spreading oligemia has been observed in studies of cerebral blood flow during the aura phase of migraine. The time course and relationship of the changes in cerebral blood flow and the symptomatology of the migraine are as follows. As the aura phase gives way to the headache, cerebral blood flow diminishes. Depressed cortical spreading may induce neurogenic inflammation and vasodilation. This inflammation, in turn, irritates the perivascular trigeminal sensory fiber, increasing capillary permeability, vasodilation, and hypothalamic and cervical cord activation. After approximately 1 hour of headache pain, the brain becomes hyperperfused with blood. This continues for less than 2 hours beyond cessation of pain, when blood flow returns to normal.

Another hypothesis is that a “hyperexcitable” brain may be predisposed to cause an imbalance between neuronal inhibition and excitation and that this imbalance has an important role in migraine pathophysiology.[45]

As we learn more about the pathogenesis of migraine, we will be able to improve its management.



Migraines may proceed through four phases: (1) a prodromal phase characterized by depression, irritability, and anorexia; (2) an aura phase that occurs in approximately 15% of cases, is transient and reversible, and may involve visual, somatosensory, or motor or language deficit of neurologic origin (generally, hypersensitivity to normally non-noxious stimuli, such as light or noise); (3) the headache phase marked by unilateral throbbing pain of moderate-to-severe intensity that lasts 4 to 72 hours, sometimes accompanied by nausea; and (4) a resolution phase, marked by fatigue. Migraine is never a daily occurrence, but it is a recurring syndrome.

Like all painful conditions, migraine is underdiagnosed. A pilot study indicates that as many as 96% of patients with migraine (according to the International Headache Society criteria) also have nasal symptoms and, thus, mistakenly believe they are experiecing sinus headaches.[41]

Several migraine triggers can cause pain within 12 hours of exposure, including alcohol and foods that trigger tyramine (cheese, fermented food), aspartame (diet soft drinks), monosodium glutamate (used as a flavor enhancer), phenylethylamine (chocolate), and, possibly, sinus inflammation. Additional triggers are changes in hormone levels, sleep patterns, and stress. Even a minor degree of trauma, such as whiplash,[77] concussion with subsequent normal neurologic examination,[50] or trauma causing only a brief loss of consciousness,[74] can trigger migraines.



Migraine is an undertreated and inadequately treated syndrome because patients generally rely on over-the-counter medication, and physicians have little to guide them in prescribing for this condition.[18]

Migraine treatment can be prophylactic (including avoiding triggers), abortive (using specific or nonspecific analgesics), or acute. Treatment choices include the administration of prescription or over-the-counter pharmaceuticals, physical therapy, alternative therapies, or interventional therapies (neural blockade or modulation: trigeminal blockade, C1–3 blockade, botulinum toxin A injections).



Patients who experience frequent migraines or are unable to relieve their severe migraine pain may benefit from prophylaxis.[45] The first step, eliminating or reducing exposure to triggers, can lead to a 50% improvement in 50% of intractable migraines. After that, first-line pharmacologic prophylactic treatment includes the administration of β-blockers, calcium blockers, antidepressants, or NSAIDs. The efficacy of these drugs for migraine prophylaxis was discovered by chance; their mechanism of action for this indication remains unknown.[45]

The prophylactic β-blockers include propranolol (adverse effects: hypotension, bradycardia, depression, sedation), timolol, nadolol, metoprolol, and atenolol (data suggest care in prescribing these drugs to patients with chronic heart failure or asthma). Common adverse effects of β-blockers include fatigue, depression, exacerbation of Raynaud’s phenomenon, sleep disturbance, and diarrhea.

Prophylactic calcium-channel blockers include verapamil (adverse effects: hypotension, fatigue, constipation), diltiazem, nimodipine, and nicardipine (adverse effects: flushing, edema). Use of calcium-channel blockers should be avoided in patients with cardiac rhythm disorders or chronic heart failure.

Tricyclic antidepressants (TCAs), such as amitriptyline, nortriptyline, and doxepin, may be effective but their use can be limited by their adverse effect profiles.[59] Amitriptyline is one of the most anticholinergic TCAs (adverse effects dry mouth, constipation, blurred vision, and urinary retention) and nortriptyline the least. Amitriptyline also has a strong sedative effect but is least likely to cause an autonomic effect leading to orthostatic hypotension, whereas nortriptyline is most likely to. TCAs are contraindicated in patients with prolonged conduction times and should be used with caution in patients with cardiac disease.

The NSAIDs used as migraine prophylactic and abortive treatment are aspirin, naproxen, flurbiprofen, ketoprofen, and fenoprofen. As with all NSAIDs, adverse effects include analgesic nephropathy and gastrointestinal upset and bleeding.

Because these prophylactic drugs are not effective in a significant number of migraineurs, investigators continue to test the efficacy of additional pain treatments, including anticonvulsants, in preventing migraine.[9] When used to prevent and treat migraine and chronic daily headache, anticonvulsants, which are γ-aminobutyric acid agonists, are better considered “neuromodulating agents” or “neuronal stabilizing agents.”[44] The use of these agents is based on the hyperexcitable brain theory of migraine pathogenesis. To date, only sodium valproate has gained approval by the U.S. Food and Drug Administration for this indication, but baclofen, gabapentin, and topiramate are under investigation and may prove to be especially useful for patients with comorbidities.[1][16][25]

A 2002 literature review concurred that divalproex sodium (valproate semi-sodium) is an efficacious migraine prophylactic. This agent dilutes cerebral arteries, but its adverse effect profile includes hepatic dysfunction thrombocytopenia, gastrointestinal upset, hair loss, and weight gain.[45] The same review noted that lamotrigine may have a role in preventing migraine-associated aura, topiramate shows promise (and additional trials are underway), and only insufficient evidence points to a role for gabapentin, magnesium, lisinopril, botulinum toxin A, tiagabine, levetiracetam, zonisamide, or petasites.[45]

Abortive therapy.


The choice of abortive therapy for migraine should be based on the characteristics of the pain (severity, frequency, and associated symptoms) and on the characteristics of the patient (therapeutic history, comorbidities, etc.). Most abortive therapy is pharmaceutical, but this approach can be augmented or replaced by complementary/alternative therapies or interventional treatment.

Other nonspecific medical therapies used for abortive treatment include opioids, phenothiazines, NSAIDs, intranasal lidocaine, and steroids.[18]

Vasoconstrictors such as dihydroergotamine mesylate and other ergotamine derivatives and the triptans (selective serotonin 5-HT1B/1D agonists) are the mainstay of abortive migraine therapy. These pharmaceuticals should be used with caution in patients with coronary artery disease, primary vascular disease, and hypertension. In fact, triptans are contraindicated in patients with ischemic heart disease or symptoms consistent with ischemic heart disease; coronary artery vasospasm, including Prinzmetal’s variant angina; and any other significant cardiovascular disease, including uncontrolled hypertension.

Choosing the best of the seven triptans at the best oral dose for any given patient will be difficult because the differences are small but probably clinically relevant for individual patients. One review, using the guidelines of evidence-based medicine, found that 59% of patients taking 100 mg of sumatriptan had a 2-hour improvement from moderate/severe to mild/no pain, 29% were pain free in 2 hours, and in 20% this was sustained, in 67% these results were consistent. At least one adverse event was experienced by 13% of patients. Findings were similar but not identical (some triptans offered lower efficacy but better tolerability, for example) for sumatriptan 25 mg; rizatriptan 10 and 5 mg; eletriptan 80, 40, and 20 mg; almotriptan 12.5 mg; naratriptan 2.5 mg; and zolmitriptan 2.5 and 5 mg. The investigators noted that data suggest frovatriptan may offer substantially lower efficacy and concluded that rizatriptan 10 mg, eletriptan 80 mg, and almotriptan 12.5 mg are most likely to be consistently efficacious.[24]

Another study notes that 25% to 45% of patients suffer headache recurrence on triptans, but that almotriptan 12.5 mg is associated with a recurrence rate of just 18% to 27% while offering similar efficacy to the other triptans, 75% consistency, and tolerability similar to placebo.[17] Headache recurrence is, in fact, a major reason that patients become dissatisfied with triptans. One study of this phenomenon found that headache recurrence is lowest among triptans with the longest half-lives and greatest 5-HT1B receptor potency.[32] Tizanidine has been successfully used as an adjunct to a long-acting NSAID to treat rebound headache accompanying the discontinuation of overused acute migraine therapies.[16]

Additional analgesics used to abort migraines include rectal indomethacin; Excedrin (combination of acetaminophen, aspirin, and caffeine),[46] naratriptan, or zolmitriptan, each of which can cause flushing, nausea, esophageal spasm, or angina. The goal of these drugs is to inhibit the trigeminocervical complex and, thus, interfere with the migraine pain referral pathway. Investigators have even used intranasal capsaicin to treat migraine.[29]

Highlighting the need to find the right drug for the right patient, a study of 347 patients with migraine who self-identified as nonresponders to sumatriptan found that 36% obtained pain relief at 2 hours with a second dose of sumatriptan when the drug was masked. The group of actual nonresponders was then randomly assigned to receive 2.5 mg naratriptan vs placebo, which led to pain relief at 2 hours for 25% and at 4 hours for 42%. The placebo relieved pain in 10% at 2 hours and 20% at 4 hours.[69]

Acute therapy.


When migraine is especially severe or refractory, its victims may appear in emergency rooms. Treatment options will be dictated by which pharmaceuticals the patient has recently consumed and by the associated symptoms.[34]

For acute migraine therapy, 80% efficacy can be gained with 12.5 to 37.5 mg of intravenous chlorpromazine or 10 mg of intravenous prochlorperazine.[15] However, one study showed that 16 of 28 patients treated with prochlorperazine needed rescue medication after 1 hour,[39] which is associated with a risk of hypotension, sedation, and dystonia. Other agents that are commonly administered but are only 50% to 65% effective are metoclopramide, lidocaine, transnasal butorphanol, propofol, sumatriptan (chest pressure and a sensation of heaviness are common adverse effects, and headache recurrence is as high as 40%), and intravenous valproic acid. Using dihydroergotamine or ergotamine for migraine abortive therapy is associated with a minor risk of angina, cramps, nausea, and vomiting.

Interventional therapy.


Botulinum toxin type A inhibits acetylcholine release at nerve terminals and may also block parasympathetic nervous system action. In a double-blind, controlled trial of the safety and efficacy of botulinum toxin A as a migraine prophylactic, 123 patients who suffered 2 to 8 migraines per month were randomly assigned to receive injections of either 25 or 75 U botulinum A.[65] The injections occurred during a single visit and were made into various pericranial muscles. Participants kept migraine diaries for 1 month before and 3 months after the injections. In each botulinum group, the neurotoxin reduced the frequency and severity of migraines, use of migraine medication, and migraine-induced vomiting. The 75-U group, however, had a higher rate of adverse events than did the control group. Specific features of the headache (frequency, severity, etc.) may influence response.[10]

A literature review that classified this trial as negative for the 75-U group and positive for the 25-U group, the other controlled study as “partly positive,” and the four open studies as negative, however, concluded that until further studies are conducted, there is insufficient evidence to recommend botulinum toxin A treatment for migraine.[22] This conclusion is echoed by other investigators who note the trials reported few significant adverse events, but more research is needed to determine the mechanism of action of botulinum toxin A in migraines as well as the optimal treatment schedule and injection sites for specific headaches.[16]

Another interventional approach is to treat moderate to severe migraines by removing the corrugator supercilii muscles, transecting the zygomaticotemporal branch of the trigeminal nerve, and repositioning the soft tissue in the temple. In a prospective study, investigators injected 25 U botulinum toxin A into each corrugator supercilii muscle of 24 female and 5 male patients. Of the 24 patients with a positive response, 22 went on to the surgical treatment. Of these, during a follow-up of 222 to 494 days, headaches were eliminated in 10 patients and considerably improved in intensity and frequency in 11. The remaining patient experienced no change. These investigators concluded that the surgical approach was a success and that the botulinum injection was a reliable predictor of that success.[35]

Psychological aspects.


As noted above, all pain has an emotional component, and migraine is sometimes treated with psychological interventions such as biofeedback or cognitive therapy. The placebo response also has an emotional component and, if we can expect a portion of study subjects to have an active response to a placebo, it is equally reasonable to expect a portion of study subjects to fail to respond to an active drug simply because they know they are taking part in a placebo-controlled trial. In other words, if some patients optimistically but mistakenly believe they are receiving the active drug and have a positive response to a placebo, other patients may pessimistically but mistakenly believe they are receiving a placebo and block their body’s ability to have a response to the active drug. Investigators are beginning to examine this aspect of the placebo response. One such study compared the effectiveness of an active drug for migraine in trials that had a placebo control with those that did not and found a significantly lower response to the active drug in the placebo-controlled trials (61% vs 71%).[20] Findings such as these should lead investigators both to consider ways to enhance the action of migraine therapies and to develop new psychological approaches to treatment.[21]

Cluster Headache




Unlike migraine, cluster-type headache is uncommon, occurring in only 1 in 1000 individuals. Also unlike migraine, this headache occurs six times more often in males than females. Cycles of cluster headaches can last 1 to 4 months, and remissions range from 6 to 24 months.



The symptoms of cluster headache are excruciating unilateral pain involving the eye/temple/upper jaw. Attacks of pain are 15 minutes to 2 hours in duration and may occur 1 to 4 times/day. Additional symptoms include pacing the floor, lacrimation, ptosis, nasal stuffiness, and rhinorrhea.





Verapamil (240–480 mg) is the drug of choice to prevent cluster headaches and may be combined with prednisone or 1 mg qhs Wigraine. Additional pharmaceuticals include lithium (300 mg/day divided), methysergide (2–8 mg/day). Episodic cluster headache is commonly treated with prednisone (40 mg qd tapered down every week by 10 mg).

Acute therapy.


When patients with cluster headache come to the emergency room, appropriate acute therapy includes administration of oxygen 8 to 10 L/min for 10 minutes, ergotamine, DHE-45, triptans, lidocaine, or a sphenopalatine block.

Interventional therapy.


In a study of the efficacy of radiofrequency lesioning of the sphenopalatine ganglion to treat and prevent cluster headache in patients refractory to pharmaceuticals, 34 of 56 patients with episodic and 3 of 10 patients with chronic cluster headache achieved complete pain relief. The remaining patients gained no relief. Eight patients had temporary postoperative epistaxis, and 11 experienced a cheek hematoma. In four patients, the maxillary nerve was partially lesioned. Hypesthesia of the palate, which occurred in nine patients, resolved within 3 months. The investigators concluded that this approach is reasonable in this population of patients.[62]

Intractable chronic cluster headaches can resolve with blockade of the trigeminal ganglion[37] or the sphenopalatine ganglion. One follow-up study found sphenopalatine ganglion neurolysis to be 60% effective in 56 patients with episodic cluster headache and 30% in 10 with chronic cluster headache.[62]

Chronic Tension-Type/Daily Headache




Chronic tension-type/daily headache is a relatively common condition, occurring in approximately 3% to 5% of the U.S. population and in women more often than men.



The pathophysiology of this headache type is unknown, but overactive pericranial muscles may play a role. Because chronic daily headache can be transformed migraine, new-onset daily headache, or tension-type headache,[30] achieving an exact diagnosis can be difficult.[13]



These headaches occur more than 15 days a month and consist of a constant band-like pain that feels like mild to moderate pressure, tightness, or dull ache. The pain is bilateral and contained in the forehead.



Some patients benefit from psychological techniques, including strengthening exercises, self-hypnosis, cognitive therapy, and biofeedback to relax muscles.[55] Most patients can achieve adequate relief from tension-type headache with over-the-counter analgesics, such as NSAIDs. Things become more complicated for headaches that are a daily occurrence.

Prophylactic drugs for chronic daily headache include antidepressants (amitriptyline, doxepin, fluoxetine), neuromodulating agents (divalproex), β-blockers (propranolol, nadolol, etc.), calcium-channel blockers (verapamil), and miscellaneous agents, such as methysergide.

Acute treatment relies on pharmaceutical regimens that may include tizanidine (for chronic cases or prophylaxis) or depend on augmenting standard analgesics with sedating antihistamines, antiemetics, butalbital, or opiates. Muscle relaxants may be useful for acute cases.

Regular analgesic use has been implicated as a cause of chronic headache because approximately 2% of those with daily headache use analgesics on a routine basis. In these patients, analgesic withdrawal can lead to improvement in symptoms. One study designed to shed light on this possibility examined headache history in 110 patients using daily analgesics for rheumatoid arthritis, seronegative arthritis, or miscellaneous rheumatology-related disorders and concluded that regular analgesic use in patients with a history of migraine will likely lead to chronic daily headache.[6]

The results of botulinum toxin A injections are mixed. For example, in four patients, tension-type refractory headaches improved in terms of severity, frequency, and subsequent medical interventions for control of headaches with injection of 20 U botulinum toxin A in symptomatic areas.[76] In a double-blind, randomized controlled trial involving 21 patients with acute tension headaches who received 10 pericranial injections of 20 U botulinum toxin A or saline placebo, however, no significant differences were found at 4, 6, and 12 weeks in visual analog scale pain scores, frequency and duration of attacks, analgesic use, pressure pain threshold, total tenderness score, or quality of life. These investigators concluded that peripheral mechanisms play only a minor role in the pathogenesis of tension-type headache.[61] Another double-blind, randomized controlled trial involving the injection of 100 U botulinum toxin A or 2 cc saline into temporal or cervical muscles found a 25% to greater than 50% improvement in the number of headache-free days, headache severity score, and quality of life at 3 months’ follow-up in 13 treatment patients vs only 2 control subjects.[67]

Paroxysmal Hemicrania




Hemicrania is rare and occurs more often in women than in men.



As its name indicates, this is a unilateral headache. It causes excruciating pain in the ocular and frontotemporal area for 10 to 30 minutes, 10 to 30 times/day, and is provoked by certain neck movements and pressure in the upper back. Each occurrence can last up to 20 hours. Because additional symptoms include nasal congestion, conjunctival injection, lacrimation, and rhinorrhea, hemicrania is often misdiagnosed as sinus headache.



Both hemicrania continua and chronic paroxysmal hemicrania respond to 150 to 200 mg divided doses of indomethacin. In fact, this response confirms the diagnosis: a patient may have all the symptoms of hemicrania but respond only to triptans and pizotifen, which usually work for cluster headache.[28]

Cervicogenic Headache




Cervicogenic headaches are common. One such headache, occipital neuralgia, results from injury to the occipital nerve caused by stress, trauma, or repetitive muscular contraction. Pain arising from the C2–C3 facet joints also generally radiates to the occiput and can be reproduced with ipsilateral rotation and extension of the cervical spine. Facet joint syndrome is difficult to diagnose because it arises from the same types of degenerative changes that show up in x-rays of asymptomatic joints. The patient’s response to a nerve block helps in the diagnosis of cervical facet joint syndrome. Facet joint syndrome can be differentiated by the response to radiographically guided injections of local anesthetics into the zygapophyseal joints or around the dorsal medial branches of the posterior primary rami.



In 1990, Sjaastad[66] described cervicogenic headache as a variant of migraine that originates in the back of the head and spreads to the front. Pain is unilateral, of moderate severity, and, because it is triggered by neck movement, can be precipitated mechanically. He noted that occipital nerve blocks effectively stop the pain. Edmeads[19] had previously associated this phenomenon with photophobia, phonophobia, nausea, and dizziness. Cervicogenic headaches are difficult to distinguish clinically from migraine and tension-type headache.



Treatment ranges from conservative therapy, such as massage and rest, to interventional therapy, including nerve blocks and steroid injections.

An open study with masked outcome assessment sought to determine the efficacy of manipulation therapy and exercise alone and in combination compared with controls by randomly assigning 200 patients into four groups. By 1-year follow-up, manipulative therapy and exercise therapy alone reduced the frequency and intensity of headaches and neck pain compared with control subjects. Although the combined therapy showed no significant benefit over either single therapy, 10% more of the patients in this group improved. The patients maintained the positive effects.[40]

A double-blind, randomized controlled trial examined the effects of injecting 100 U botulinum toxin A in five cervical trigger points (14 patients) vs injecting 1 mL of saline placebo (12 patients). At 2- and 4-week follow-ups, the treatment group showed a significant improvement in pain and range of motion compared with their preinjection levels, whereas the placebo group demonstrated no significant changes.[26]

A case report describes excellent but temporary results in a patient with refractory retroorbital headaches using three consecutive C2 ganglion blocks with 0.5 mL of local anesthetic administered under fluoroscopy. After the clinicians subsequently performed percutaneous radiofrequency ganglionectomy with multiple C2 lesions at 60°C for 90 seconds, the patient remained pain free throughout 4 years of follow-up.[5]

To determine the efficacy of treating intractable occipital neuralgia using percutaneous peripheral nerve electrostimulation, 13 patients had an electrode implanted transversely at the C1 level across the base of the occipital nerve trunk. With 18- to 72-month follow-ups, 12 patients reported greater than 50% pain control and required little or no medication. In the remaining patient, the symptoms resolved and the electrode was removed. The investigators concluded that electrostimulation in such cases is a reasonable therapy.[73]

Trigeminal Neuralgia




Trigeminal neuralgia is found more often in women than in men and generally in people over the age of 50 years.



Trigeminal neuralgia causes a sudden, severe pain that feels like an electric shock or stab. The pain generally affects only one side of the jaw or cheek and can last only 20 to 30 seconds or occur in rapid sequence. This pain may continue off and on for a day or several months and then might disappear only to recur months or even years later. The pain may be triggered by trivial, everyday stimuli, such as brushing teeth or touching the face.



Magnetic resonance imaging (MRI) of the ganglion can be used to diagnose this condition.



Pharmaceuticals used to treat this condition include Tegretol (carbamazepine), Dilantin (phenytoin), baclofen, clonazepam, gabapentin, and valproic acid alone or in combination.

If pain is refractory, a single percutaneous stereotactic radiofrequency rhizotomy can be effective. Barring that, patients undergo a surgical intervention.



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