Although the epidemiology of headache disorders is only partly documented, taken together, headache disorders are extraordinarily common. It has been estimated that worldwide approximately 240 million people have migraine attacks each year. The National Headache Foundation states that more than 29.5 million Americans suffer from migraine headaches, with women being affected three times more often than men. In addition, in developed countries, tension type or “stress” headaches are estimated to affect two-thirds of all adult males and over 80% of adult females. Less well known is the prevalence of chronic daily headaches although the World Health Organization (WHO) estimates that one adult in 20 has a headache every or nearly every day. Trigeminal neuralgia is not a common disorder but the pain associated with trigeminal neuralgia attacks has been described as among the most severe known to mankind.
Not only are headaches painful, but headache disorders can be disabling to afflicted individuals. Worldwide, according to the WHO, when analyzing all causes for “years lived with disability” migraine headaches were rated 19th on the list. Headache disorders may impose substantial hardships and burdens on the afflicted individuals including personal suffering, impaired quality of life and high financial cost. Repeated headache attacks, and often the constant fear of the next one, can damage an individual's family life, social life and their productivity at their place of employment. For example, it is estimated that social activity and work capacity are reduced in almost all migraine sufferers and in 60% of tension headache sufferers. Finally, the long-term effort of coping with a chronic headache disorder may also predispose an individual to other illnesses. For example, depression is three times more common in people with migraine or severe headaches than in healthy individuals.
A wide range of headache types have been classified by the International Headache Society and among them are primary types including vascular, trigemino-autonomic and tension headaches and secondary types including headaches resulting from infection, trauma and non-vascular, intracranial disorders.
Vascular headaches refer to a group of headache conditions in which events at the interface between meningeal blood vessels and afferent nerve fibers are critical major components in the production of pain. Afferent nociceptive nerve fibers innervating meningeal blood vessels become activated in response to inflammatory and related events at the peri-vascular sheet causing a throbbing or pulsating type of pain. The most common type of vascular headache is migraine. Current pathophysiological evidence suggests that the trigemino-vascular system plays a pivotal role in the genesis of migraine headache. Migraine headache characteristics include unilateral (60%) or bilateral head pain, pain with a pulsating or throbbing quality, moderate to severe pain, pain associated with nausea or vomiting, sensitivity to light and sound, attacks that last four to 72 hours (sometimes longer) and visual disturbances or aura. Physical exertion often makes a migraine headache worse and women are more likely than men to have migraine headaches. Approximately one to two-fifths of migraine sufferers experience an aura, a sensory phenomena including visual disturbances that precede the onset of migraine headache. It is now believed that the aura is due to transient changes in the activity of specific nerve cells.
Another type of primary vascular headache is “cluster” headache, which is diagnosed by a well characterized clinical presentation. Although the syndrome is well defined from a clinical point of view, the causes are not well understood. The pathophysiology is believed to be associated with the trigemino-autonomic system. The periods during which cluster headache is experienced can last several weeks or months and then disappear completely for months or years leaving pain-free intervals between headache series. Cluster headache is characterized by frequent attacks of short lasting (15-180 minutes), severe, uniform, unilateral head pain associated with autonomic symptoms (e.g. lacrimation and nasal congestion). Pain can occur on the opposite side when a new series starts, pain may be localized behind the eye or in the eye region and may radiate to the forehead, temple, nose, cheek or upper gum on the affected side. Pain is generally extremely intense and severe and often described as a burning, boring, stabbing or piercing sensation. The headaches occur regularly, generally at the same time each day. Many individuals get one to four headaches per a day during a cluster period. Cluster headache is less common than migraine or tension headache and its cause is unknown. In contrast to migraine headaches, cluster headaches occur more in men than women and individuals suffering from these attacks may be very restless.
Tension headache, often referred to as “stress” headache, is a non-specific type of primary headache, which is of non-vascular origin and rarely is related to an organic disease. The pathophysiology of tension headaches is thought to involve the myo-facial system. For example, tension headache may be caused by the tightening of facial and neck muscles, clenching or grinding of teeth and/or poor posture. Tension headaches can be episodic and chronic in course, and typically are of mild to moderate intensity. Verbal descriptor used to characterize tension headache include pressing, dull aching and/or non-pulsating. Tension head pain is typically bilateral, and is not aggravated by physical activity.
Trigeminal neuralgia, also called “tic duloreaux” is a condition that affects the trigeminal nerves and results in severe facial and head pain. Trigeminal neuralgia most commonly is diagnosed in patients over age 50, is slightly more common in women and has an incidence of approximately 4-5 per 100,000 persons. Trigeminal neuralgia is characterized by sudden severe, sharp facial pain, which usually starts without warning. The quick bursts of pain are described as “lightening bolt-like”, “machine gun-like” or “electric shock-like”. The pain is generally on one side of the face and is spasmodic, coming in short bursts lasting a few seconds which may repeat many times over the course of a day. Trigeminal neuralgia can involve one or more branches of the trigeminal nerve and the causes are not well characterized.
Current Treatments
There are numerous treatment strategies for migraine and associated symptoms (e.g. nausea). However, to date, there is no single treatment strategy (including prevention or prophylaxis) that successfully alleviates migraine in a majority of patients. Additionally, treatment that has proven effective in one particular migraine sufferer may only be partially or intermittently effective. The current standard of care for migraine focuses on three major areas: 1) acute or abortive treatment; 2) treatment to relieve specific symptoms; and 3) preventive treatment.
Abortive treatment is always indicated because of the disabling nature of migraine attacks. Sumitriptan and related 5-hydroxytryptamine (5-HT-1, serotonin) receptor agonists (triptans) are often considered the therapy of choice for migraine headache. To show optimal effectiveness, these agents generally have to be given early in the onset of pain. Serotonin receptor agonists are effective in up to 70% of patients and generally have few side effects when used sporadically. The number of patients benefiting from treatment with triptans may decrease to less than 50% during long-term therapy. Despite being effective, serotonin receptor agonists often only partially attenuate migraine headache. Rebound pain frequently occurs during the time period during which the drug levels are falling. Furthermore, side effects may arise including dizziness, heaviness or pressure on the chest and arms, shortness of breath, and sometimes chest pain which limit their clinical utility. Triptans are contra-indicated for patients with coronary artery disease. Other members of this class of drugs include, but are not limited to, sumatriptan, zolmitriptan, naratriptan, rizatriptan and elitriptan. Other classes of drugs that are used to treat migraine include the nonsteroidal anti-inflammatory drugs (NSAIDs), ergotamines and on occasion, neuroleptic drugs such as compazine. NSAIDS are as effective as triptans in alleviating migraine headache when given at the onset of mild migraine headache. Ergotamines, although commonly prescribed, are less effective than triptans and NSAIDS. Opioids such as codeine and butorphanol are not a first choice for the treatment of migraine because of their limited effectiveness, associated side effects including sedation and respiratory depression and the potential for dependence and abuse.
Preventive treatment strategies are considered whenever migraine attacks have occurred several times in a month or are very severe and do not respond well to abortive medication. The following classes of drugs are used for preventing migraine: beta-blockers (e.g. propranolol, metoprolol, atenolol), calcium channel blockers, NSAIDs, antidepressants, anti-convulsant drugs (e.g. divalproex sodium, topiramate) and methysergide (no longer available in the United States). Another avenue for preventive treatment is educating the migraine patient to recognize and avoid migraine triggers which may help to reduce the frequency of attacks. Common migraine triggers include, but are not limited to, weather changes, bright lights, strong odors, stress and foods.
In a significant number of patients abortive and preventive treatments for migraine headache are often either ineffective, only partially effective or associated with significant side effects including hypotension, tiredness, increased weight, breathlessness, dizziness, heaviness or pressure on the chest and arms, shortness of breath, chest pain, nausea, muscle cramps, or peripheral vasoconstriction.
Treatment strategies for cluster headache are classified as abortive or preventive. Abortive treatments are directed at stopping or reducing the severity of an attack, while preventive treatments are used to reduce the frequency and intensity of individual headache bouts. Abortive treatment strategies of cluster headache are quite successful when drugs can be injected. Drug classes used for injection include the 5HT1-agonists (e.g. sumatriptan) and the ergotamines. Alternatively, inhalation of 100% oxygen or an occipital nerve block have proven effective. However, all these treatment strategies require a visit to a doctor's office or to an emergency room.
Because of the short-lived nature of cluster headaches, preventive therapy is the cornerstone for individuals who have frequent attacks which severely affect their quality of life. Preventive therapy is initiated at the start of a cluster headache cycle and continues until the person is free of headaches for at least 2 weeks. The dosage of the preventive drug is then slowly tapered off which helps prevent relapsing headaches. Drug classes used preventively include beta-blockers, tricyclic antidepressants, anti-convulsants (e.g., divalproex sodium, topiramate), calcium channel blockers (e.g., verapamil), cyproheptadine, and NSAIDs (e.g. naproxen). Unlike drugs that ablate cluster headache (abortive drugs), most of the drugs used to prevent cluster headache have been developed for other clinical conditions and unfortunately, their effectiveness in prevention is limited.
Treatment for tension headache usually consists of nonprescription painkillers such as aspirin, acetaminophen, NSAIDs or combinations of these agents with caffeine or sedating medications. When severe muscle contraction is present and/or the tension headache becomes chronic, more powerful prescription drugs may be needed to achieve relief. Tricyclic anti-depressants including amitriptyline HCl, doxepin HCl and nortriptyline HCl are commonly used. However these drugs have significant side effects including sedation, weight gain, dry mouth and constipation.
The first line treatment of trigeminal neuralgia is pharmacological in nature and is based on the use of antiepileptic agents including gabapentin, baclofen, clonazepam, lamotrigine, oxcarbazepine, toprimate and carbamazepine. About 50% of patients initially respond to treatment with a single agent and about 70% respond to treatment with two agents. However, a significant portion of patients (>50%) eventually becomes refractory to drug treatment and adding of a third agent or an analgesic drug (opioid or a non-steroidal anti-inflammatory agent) does not improve therapeutic success. Therapy with antiepileptic agents is also associated with side effects, most prominently dizziness, drowsiness, and ataxia. Many antiepileptic agents have the potential to cause rare but serious reactions.
Considering surgical interventions is the next appropriate step in patients who are refractory to pharmacological interventions. Surgical techniques include radio-frequency ablation of the trigeminal ganglion, micro-vascular decompression of the trigeminal root and gamma-knife radiation to the trigeminal root. The success rate of surgical techniques is initially quite high (80-90%) while the longer term success is closer to 50%. Specific side effects of these surgical interventions are sensory loss (numbness) and/or dysesthesia (e.g. analgesia dolorosa) in the distribution of the trigeminal nerve. Micro-vascular decompression in particular can be complicated by the occurrence of meningitis, cerebrospinal fluid leaks, or cranial nerve deficits. This procedure requires a craniotomy and the published mortality rate for this procedure is significant at 0.2-1.2%.
It is clear that migraine, cluster and tension headaches as well as trigeminal neuralgia can be debilitating to individuals and significantly impair their quality of life. To date, there does not appear to be a class of drugs or a treatment regimen that is effective for a majority of patients suffering from primary or secondary headaches or suffering from trigeminal neuralgia. Therefore, there is still a great need for novel and more effective therapies preventing or alleviating head pain of any origin.