Relief of cluster headache and cranial neuralgias

Promising prophylactic and symptomatic treatments

Donald J. Dalessio, MD

VOL 109 / NO 1 / JANUARY 2001 / POSTGRADUATE MEDICINE

CME learning objectives

• To learn to diagnose and differentiate cluster headache from the major cranial neuralgias
• To be able to develop treatment strategies for these diagnoses
• To become aware of new approaches to advanced medical and surgical management of difficult cases

The author discloses no financial interests in this article.

This is the third of four articles on headache

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Preview: Cluster headaches and trigeminal and glossopharyngeal neuralgias produce intermittent, debilitating pain. The episodic nature of the symptoms of these conditions remains enigmatic, but a number of effective treatments have been developed that offer hope to patients. In this article, Dr Dalessio discusses the presentation, course, and treatment indications for each of these disorders.
Dalessio DJ. Relief of cluster headache and cranial neuralgias: promising prophylactic and symptomatic treatments. Postgrad Med 2001;109(1):69-78

The intense pain that characterizes cluster headaches and trigeminal and glosso-pharyngeal neuralgias usually can be relieved--or prevented--through use of oxygen, drug therapy, or surgery. However, treatment relies on the physician's recognition of these disorders, each of which has a unique presentation and course.

Cluster headaches

Three enigmas surround cluster headaches:

• Why do they begin?
• Why do they stop?
• Why do they start again?

No one has been able to explain the peculiar periodicity of cluster headaches, even though, as with all headache types, theories abound.

Goadsby (1) suggests that cluster headache should be termed neurovascular headache. He used a nitroglycerin spray to initiate typical cluster attacks in nine patients with chronic cluster headaches. The patients' brains were then studied by using positron emission tomography. He found that the cluster headaches affected three areas of the brain, two of which are associated with any painful stimulus. The area most activated by cluster headache was the ipsilateral hypothalamic gray matter. Because the hypothalamus can be associated with periodic illness of any sort, it could be postulated that an explanation for the intermittent nature of cluster headache is at hand.

Goadsby also noted that the vasodilation associated with cluster headache is a "secondary phenomenon," a result of activation of the trigeminal vascular system. It remains to be resolved whether this is correct or whether the vasodilation is primary and the other changes are secondary.

Clinical findings
Cluster headaches are characterized by excruciating, sharp, penetrating pain that typically lasts 30 to 45 minutes (range, 10 minutes to 4 hours). They usually occur once or twice a day (but may occur up to 10 times per day) for 1 to 4 months. Most patients then experience a remission of months or years.

Cluster headaches and migraine have many similarities but also many differences. In contrast to migraine, cluster headaches are more prevalent in men, are not preceded by an aura, always occur unilaterally with pain recurring on the same side in subsequent headaches, and usually are not associated with a positive family history of cluster headache.

The headache often occurs during sleep (usually within 1 hour after falling asleep) and is severe enough to wake the patient. The mean age at onset is 27 to 30 years. Characteristically, cluster headache is associated with ipsilateral lacrimation, rhinorrhea, nasal congestion, and conjunctival injection. The pain is distributed unilaterally over the oculotemporal, oculofrontal, or temporal facial region. A partial Horner's syndrome with miosis and ptosis may occur on the ipsilateral side.

Short-term treatment
Oxygen inhalation is effective and relatively safe for the symptomatic treatment of cluster headache (2). I generally prescribe it as first-line treatment. The mechanism of action is unknown but probably involves a marked reduction in cerebral blood flow that results in concomitant pain reduction. Patients should be told to begin therapy at the onset of an attack by administering 100% oxygen through a face mask at a rate of 7 to 8 L/min for 10 to 15 minutes. A nasal cannula should not be used because nasal congestion may impede inhalation. Patients should assume a sitting position, either upright or leaning forward, and should avoid hyperventilation, which may limit oxygen saturation.

Ergotamine preparations are more convenient than oxygen treatment, but the relatively slow onset of action of the oral products often limits their usefulness in cluster headache treatment (3). Sublingual ergotamine has a more rapid onset of action, which may render it useful for cluster headache treatment. A single dihydroergotamine meslyate (D.H.E. 45) injection may be useful in an emergency department or office setting.

Nonsteroidal anti-inflammatory drugs: Theoretically, many drugs used in the abortive or symptomatic treatment of migraine also should be effective in cluster headaches. However, because of the extremely brief nature of cluster headaches, most oral preparations do not provide relief. The nonsteroidal anti-inflammatory drug (NSAID) naproxen sodium given in a 550-mg dose at the onset of an attack may be of some use in these situations because of its relatively fast absorption. This drug's usefulness is limited, however, to those patients whose headaches last longer than 45 minutes. Because of NSAIDs' potential to cause serious gastrointestinal bleeding and ulcers, patients experiencing several attacks a day must carefully adhere to the manufacturer's recommendations for total daily dose.

Lidocaine nose drops: Some patients may feel relief with the local anesthetic lidocaine hydrochloride in the form of nose drops. Lidocaine 4% topical solution (Xylocaine) is available by prescription and may be dispensed in a dropper bottle (4). With the head tilted backward and turned toward the ipsilateral side, patients should instill 15 drops in the nostril on the affected side at the onset of headache. The dose may be repeated after 15 minutes, if needed.

Lidocaine may be used two times per headache, up to four times per day. To facilitate the administration of lidocaine, phenylephrine hydrochloride 0.5% nasal drops may be used to clear congested nasal passages. Side effects of lidocaine nasal drops may include nervousness and dizziness. Some patients allergic to lidocaine may show signs of hypersensitivity.

Triptans: The triptans, particularly sumatriptan succinate (Imitrex), are effective for short-term treatment of cluster headache (5). Generally, sumatriptan is used in patients who experience one or two cluster headaches each day.

Prophylactic treatment
Because of both the limited usefulness of drugs for cluster headache pain and the intense nature of the pain, prophylactic treatment is essential. Cluster headaches that occur only during sleep may be treated with nightly administration of ergotamine. However, attacks that occur at various times of day or night may be prevented by routine use of methysergide maleate (Sansert), verapamil hydrochloride (Calan, Isoptin, Verelan), lithium, or prednisone, either alone or in combination (6-8). For example, I may prescribe a combination of prednisone (60 to 80 mg/day) and verapamil (240 mg/day) first (figure 1: not shown). I am careful to limit prednisone use to 7 to 14 days. It may be necessary to increase the verapamil dose or to continue the therapy through the cluster headache period.

If this combination fails, I usually try methysergide (2 mg three times daily), but again, I limit treatment to 1 to 2 months. Methysergide should not be given with other drugs except pain relievers such as hydrocodone bitartrate (Vicodin). If methysergide is ineffective, lithium or valproic acid (Depakene, Depakote), or both, can be used, often with verapamil. Treatment must be individualized if multiple drug failures occur.

Chronic cluster headache can be treated prophylactically with verapamil or lithium, or both. Valproic acid used alone or with verapamil often is effective. Occasionally, a patient responds to intranasal application of capsaicin five or six times per day. Occipital nerve blocks may relieve cluster attacks briefly, but I have found that subsequent injections become less effective. Patients with chronic cluster headache may become resistant to a previously successful prophylactic medication. These patients may require polypharmacy or, eventually, inpatient treatment.

For hospitalized patients with the rare intractable cluster headache, I use dihydroergotamine given intravenously every 8 hours. Some patients become headache-free during treatment, and remission is often sustained after discharge from the hospital. If hospitalization and all prophylactic efforts fail, neuroablative procedures may be considered. At this point, I sometimes refer patients to the Diamond Headache Clinic for histamine desensitization (9), a benign procedure that can produce striking results.

Surgical procedures include sphenopalatine ganglionectomy, radiofrequency thermocoagulation of the trigeminal ganglion, and section of the trigeminal nerve (10-12). However, the corneal anesthesia that results from these procedures puts the ipsilateral eye at risk. Use of glycerol injection into the trigeminal cistern to treat intractable cluster headache has resulted in significant pain relief and poses no risk to the cornea (10).

Major cranial neuralgias

The major cranial neuralgias are trigeminal neuralgia and glossopharyngeal neuralgia.

Trigeminal neuralgia
Trigeminal neuralgia (tic douloureux) is an episodic, unilateral pain syndrome that occurs in the elderly. It almost never begins before age 30 and then only in patients with multiple sclerosis. The pain is of high intensity and usually occurs in association with trigger zones. These are areas of increased sensitivity on the face, particularly around the nostrils and mouth, that initiate the attack when they are stimulated by even trivial sensations. Thus, the behavioral characteristic of patients with trigeminal neuralgia is avoidance of touching the face, washing, shaving, biting, chewing, or any other actions that stimulate the trigger zones and produce the pain. This avoidance is an invaluable clue to the diagnosis. In nearly every other facial pain syndrome, patients are seen massaging the pain area, abrading it, or applying heat or cold; however, in trigeminal neuralgia, the patient goes to great lengths to avoid any stimulation of the face or mouth.

The pain usually is a jab that lasts less than 20 to 30 seconds followed at times by a period of relief of a few seconds to 1 minute, then by another jab of pain. Episodes of pain may recur, but the pain is not as long-lived as other chronic facial pains.

Glossopharyngeal neuralgia
Glossopharyngeal tic is a phenomenon similar to trigeminal neuralgia in which the symptoms are related to the anatomic base of the glossopharyngeal nerve. In glossopharyngeal tic, pain similar to that of trigeminal neuralgia is felt in the pharynx, tonsils, and ear; it often is initiated by swallowing, yawning, or eating. Syncope may occur and is presumably related to asystole as a result of stimulation of the vagus system.

Treatment
It is now possible to relieve the pain in most cases of trigeminal neuralgia. A series of medical and surgical advances during the past decade has produced several forms of therapy that may result in semipermanent or permanent pain remission. Therapy may be medical, surgical or, more likely, both. Thus, cooperation between physician and surgeon in the management of patients with trigeminal neuralgia is essential (13,14).

Most authorities agree that medical treatment is indicated first, if for no other reason than that its use constitutes a therapeutic challenge to the diagnosis. If a patient presumed to have trigeminal neuralgia does not respond within 24 to 48 hours to carbamazepine (Tegretol), the diagnosis is doubtful. Diagnosis is made on the basis of history alone, and the patient may not be a good observer of pains or sensations.

If the patient responds to carbamazepine, it is the treatment of choice. Physicians who have monitored patients with trigeminal neuralgia for more than a decade have found that this disease often is remitting. Remission may be possible with drug therapy, which can sometimes eventually be discontinued. If response to carbamazepine is only partial, drugs such as phenytoin (Dilantin) and baclofen (Lioresal) may be used.

Some neurosurgeons report that frequent unpleasant side effects occur with carbamazepine, implying that 20% to 30% of patients should discontinue its use. This suggestion is surprising because the drug seems well tolerated when used to treat epilepsy. Nonetheless, it cannot be denied that carbamazepine may produce undesirable sedation or idiosyncratic reactions (including, rarely, blood dyscrasias); caution is needed when prescribing it (tables 1 and 2).

Table 1. Medical therapy for trigeminal neuralgia
Agent	Dose (mg/day)	Precautions	Preparation
Baclofen (Lioresal)	30-80	Drowsiness, weakness, nausea, vomiting	Oral
Carbamazepine (Tegretol)	200-600	Monitor for blood disorders	Oral
Phenytoin (Dilantin)	200-400	Monitor for CNS and hemopoietic effects and gingival hyperplasia	Oral
CNS, central nervous system.

Anticonvulsants may inhibit or reduce synaptic transmission and relieve pain. These drugs reduce the sensitivity of the trigger zones and relieve pain--often dramatically--within 4 to 24 hours. Generally, carbamazepine therapy is begun at a dosage of 100 to 200 mg two or three times daily. If this dosage is well tolerated and the pain is rapidly relieved, therapy may be continued for several weeks or months, depending on the course of the disease. The dosage should be adjusted according to the severity of the patient's pain. To keep patients pain-free, it may be necessary to continue carbamazepine at a maintenance dose (eg, 200 mg/day).

If symptoms persist despite adequate dosing and therapeutic blood levels, I add another drug to the regimen. Generally, this is baclofen, beginning at 10 mg/day and increasing to 60 to 80 mg/day (in divided doses). Rarely, if pain persists, a third drug, such as phenytoin, is added in a therapeutic dose. Other drugs, including valproic acid and clonazepam (Klonopin), may be efficacious, but formal studies have not been done. By the time the three-drug treatment level is reached, referral for appropriate surgery should be considered. Generally, these drugs are not administered parenterally.

Between 25% and 50% of patients with trigeminal neuralgia eventually stop responding to medical therapy and require neurosurgery (15,16). The type of operation performed varies widely. Patients need to be completely and clearly apprised of the nature of the operations proposed, the procedures to be undertaken, possible side effects, costs, and morbidity and mortality risk. Given the many differences between these neurosurgical procedures, informed consent must be obtained (table 3).

Table 3. Comparison of neurosurgical procedures for trigeminal neuralgia
Procedure	Advantages	Disadvantages
Percutaneous radiofrequency rhizotomy	90% effective, minor procedure, brief hospital stay	Facial sensory loss, facial weakness, corneal hypesthesia (10%-15% of patients)
Glycerol injection	No craniotomy, 85% effective, minor procedure	Masseter weakness, facial sensory loss
Microvascular decompression	90% effective, no sensory loss	Serious postoperative complications in +4% of cases, 1% mortality rate, long hospital stay, major craniotomy

Treatment of glossopharyngeal neuralgia includes the same medications as those previously described for trigeminal neuralgia. Generally, the mainstays are the anticonvulsants--especially carbamazepine--given in increasing doses to achieve the desired therapeutic effect. Section of cranial nerve IX is indicated if surgery is necessary, but this procedure is performed only rarely.

Finally, oxcarbazepine (Trileptal) was recently approved by the US Food and Drug Administration. This drug has been used in Europe for treatment of the major neuralgias for the last decade (17). Experience with oxcarbazepine is lacking in the United States, but given the efficacy of the drug and the absence of serious side effects, it should prove useful in the treatment of major neuralgias.

Summary

When a patient presents with persistently unilateral head or face pain, cluster headache and trigeminal neuralgia should be considered. Diagnosis is based on the patient's history; anatomical studies are performed only to rule out problems other than tumor or stroke.

A patient who presents with pain in the pharynx, tonsils, and ear--particularly if it is initiated by swallowing, yawning, or eating--may have glossopharyngeal neuralgia. Treatment with carbamazepine is indicated; if the patient does not respond to this drug, the diagnosis is doubtful.

Several effective treatments are available for these conditions. Oxygen, drug therapy, or surgery may be indicated depending on the course of the disease.

References

1. Goadsby PJ. Cluster headache: new perspectives. Cephalalgia 1999;19 Suppl 25:39-41
2. Kudrow L. Response of cluster headache attacks to oxygen inhalation. Headache 1981;21(1):1-4
3. Kudrow L. Diagnosis and treatment of cluster headache. Med Clin North Am 1991;75(3):579-94
4. Kittrelle JP, Grouse DS, Seybold ME. Cluster headache: local anesthetic abortive agents. Arch Neurol 1985;42(5):496-8
5. Treatment of acute cluster headache with sumatriptan. The Sumatriptan Cluster Headache Study Group. N Engl J Med 1991;325(5):322-6
6. Friedman AP, Elkind A. Appraisal of methysergide in treatment of vascular headaches of migraine type. JAMA 1963;184:125-8
7. Gabai IJ, Spierings EL. Prophylactic treatment of cluster headache with verapamil. Headache 1989;29(3):167-8
8. Meyer JS, Hardenberg J. Clinical effectiveness of calcium entry blockers in prophylactic treatment of migraine and cluster headaches. Headache 1983;23(6):266-77
9. Diamond S, Freitag FG, Bhambhvani S. IV histamine desensitization therapy in recidivist chronic cluster headache patients. Cephalalgia 1997;17:456
10. Hassenbusch SJ, Kunkel RS, Kosmorsky GS, et al. Trigeminal cisternal injection of glycerol for treatment of chronic intractable cluster headaches. Neurosurgery 1991;29(4):504-8
11. Onofrio BM, Campbell JK. Surgical treatment of chronic cluster headache. Mayo Clinic Proc 1986;61(7):537-44
12. Maxwell RE. Surgical control of chronic migrainous neuralgia by trigeminal ganglio-rhizolysis. J Neurosurg 1982;57(4):459-66
13. Dalessio DJ. Medical treatment of trigeminal neuralgia. Clin Neurosurg 1977;24:579-83
14. Dalessio DJ. Trigeminal neuralgia: a practical approach to treatment. Drugs 1982;24(3):248-55
15. Jannetta PJ. Treatment of trigeminal neuralgia by suboccipital and transtentorial cranial operations. Clin Neurosurg 1977;24:538-49
16. Waltz TA, Dalessio DJ, Copeland B, et al. Percutaneous injection of glycerol for the treatment of trigeminal neuralgia. Clin J Pain 1989;5(2):195-8
17. Zakrzewska JM, Patsalos PN. Oxcarbazepine: a new drug in the management of intractable trigeminal neuralgia. J Neurol Neurosurg Psychiatry 1988;52(4):472-6

For a helpful guide to electronic and print resources on headache for physicians and patients, see the Resource Guide in this issue.

Dr Dalessio is senior consultant, division of neurology, Scripps Clinic, La Jolla, California. Correspondence: Donald J. Dalessio, MD, Senior Consultant, Division of Neurology, Scripps Clinic, 10666 N Torrey Pines Rd, MS313, La Jolla, CA 92037.

Symposium Index

• HEADACHE: Introduction to a four-article symposium by Seymour Diamond, MD
• MIGRAINE'S IMPACT TODAY: Burden of illness, patterns of care by Richard B. Lipton, MD, Walter F. Stewart, MPH, PhD, Michael Reed, PhD, Seymour Diamond, MD
• A FRESH LOOK AT MIGRAINE THERAPY: New treatments promise improved management by Seymour Diamond, MD
• RELIEF OF CLUSTER HEADACHE AND CRANIAL NEURALGIAS: Promising prophylactic and symptomatic treatments by Donald J. Dalessio, MD
• SEXUAL ASPECTS OF HEADACHE: How sexual function relates to headaches and their causes and treatment by Jerome Goldstein, MD

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