We review the therapies for primary headache disorders: migraine, chronic migraine, tension-type headache, and cluster headache. Recommendations follow the evidence-based treatments so far as is possible with expert opinion to give clinical guidance. Headache has 2 levels of care: acute treatments designed to stop a headache from progressing and alleviate all symptoms associated with the headache and preventive therapies for patients whose headache frequency is such that by itself produces significant disability and impact on quality of life, or where the frequency of use of acute medications, regardless of efficacy, poses risks in terms of overuse or adverse events.
Key points
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Simple analgesics may suffice for migraine with little disability, but triptans are essential for many with migraine.
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Chronic migraine is a complication of episodic migraine with numerous other risk factors.
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Medication overuse of acute treatments plays a critical role in many patients.
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Preventive therapies for migraine are not as effective here, but OnabotulinumtoxinA has strong evidence for efficacy.
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Therapies for tension-type headache are focused on prevention, most commonly with older tricyclic antidepressants. Migraine medications are not typically useful for tension-type headache.
Introduction
In previous articles it is apparent that not all headaches are the same. Therefore, in examining treatment of headache with medical therapies it is necessary to subdivide headache into its component parts and focus on each individually. In this article, we focus on the primary headache disorders, those in which there is no underlying primary causation, save the patient’s own natural physiology and genetics. These are migraine, tension-type headache, and cluster headache, as well as chronic migraine, a complication of episodic migraine, and one that can perplex even headache experts. Treatments focus on evidence-based approaches to management insofar as possible with expert opinion where evidence is insufficient to provide guidance.
| NSAID | Non-steroidal anti-inflammatory agents |
| DHE | Dihydroergotamine |
| SUNCT Syndrome | Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing |
| TTHA | Tension type headache |
| CM | Chronic Migraine |
| MO | Medication Overuse |
| onaBoNTA | OnabotulinumtoxinA |
| TCA | Tricyclic antidepressants |
| SSRI | Serotonin specific reuptake inhibitors |
| PREEMPT | Phase III REsearch Evaluating Migraine Prophylaxis Therapy |
Introduction
In previous articles it is apparent that not all headaches are the same. Therefore, in examining treatment of headache with medical therapies it is necessary to subdivide headache into its component parts and focus on each individually. In this article, we focus on the primary headache disorders, those in which there is no underlying primary causation, save the patient’s own natural physiology and genetics. These are migraine, tension-type headache, and cluster headache, as well as chronic migraine, a complication of episodic migraine, and one that can perplex even headache experts. Treatments focus on evidence-based approaches to management insofar as possible with expert opinion where evidence is insufficient to provide guidance.
| NSAID | Non-steroidal anti-inflammatory agents |
| DHE | Dihydroergotamine |
| SUNCT Syndrome | Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing |
| TTHA | Tension type headache |
| CM | Chronic Migraine |
| MO | Medication Overuse |
| onaBoNTA | OnabotulinumtoxinA |
| TCA | Tricyclic antidepressants |
| SSRI | Serotonin specific reuptake inhibitors |
| PREEMPT | Phase III REsearch Evaluating Migraine Prophylaxis Therapy |
Episodic migraine
Acute Treatment
Acute treatments for migraine are designed to relieve the symptom complex of pain, photophobia, phonophobia, and nausea. Ideally, these treatments provide relief within 2 hours, without recurrence and with minimal adverse events. In 2000, the US Headache Consortium produced an evidence-based guideline for acute treatment and report summary. The guideline has not been updated.
Migraine is highly variable within an individual and in the population. Selection of treatments use stratified care based on levels of disability and symptoms, such as nausea or vomiting. Additionally, selecting treatments or route of administration is based on specific attack characteristics to a stepped care approach within and between attacks. Frequency of use is the limiting factor for these agents, as frequent use leads to medication overuse (MO) and chronification of migraine.
Simple analgesics, combination analgesics, and prescription nonsteroidal anti-inflammatory agents (NSAIDs) ( Table 1 ) are considered first-line therapy for migraine. Of the NSAIDs, naproxen may have the least risk of cardiovascular concerns. For those patients who fail to respond to these agents consistently, then oral triptans are used. Triptans are used as first-line agents before analgesics for more severely impacted patients. Nonoral administration of triptans or dihydroergotamine (DHE) is preferred for those who do not respond to oral triptans consistently or have early onset of nausea or vomiting.
| Drug | Quality of Evidence a | Clinical Uses b | Types and Relative Risk of Adverse Events c |
|---|---|---|---|
| Simple analgesics/combination analgesics/nonsteroidal anti-inflammatory drugs | |||
| Acetaminophen | B | Nondisabling migraine | Nonspecific/infrequent |
| Aspirin | A | First line: mild to moderate migraine | Gastrointestinal and bleeding/occasional |
| Acetaminophen, aspirin, caffeine | A | First line: mild to moderate migraine | Cardiovascular, gastrointestinal, and bleeding/occasional |
| Diclofenac potassium | B | First line: mild to moderate migraine | Gastrointestinal and bleeding/occasional |
| Flurbiprofen | B | First line: mild to moderate migraine | Gastrointestinal and bleeding/occasional |
| Ibuprofen | A | First line: mild to moderate migraine | Gastrointestinal and bleeding/occasional |
| Naproxen | B | First line: mild to moderate migraine | Gastrointestinal and bleeding/occasional |
| Naproxen sodium | A | First line: mild to moderate migraine | Gastrointestinal and bleeding/occasional |
| Ketorolac IM | B | Rescue therapy/severe migraine with contraindications to 5HT agonists | Gastrointestinal and bleeding/infrequent |
| 5HT 1B/1D agonists | |||
| Naratriptan | A | Migraine nonresponding to analgesics/moderate to severe migraine | Nausea, paresthesia, chest discomfort/infrequent when used early in attack |
| Rizatriptan | A | Migraine nonresponding to analgesics/moderate to severe migraine | Nausea, paresthesia, chest discomfort/infrequent when used early in attack |
| Sumatriptan | A | Migraine nonresponding to analgesics/moderate to severe migraine | Nausea, paresthesia, chest discomfort/infrequent when used early in attack |
| Zolmitriptan | A | Migraine nonresponding to analgesics/moderate to severe migraine | Nausea, paresthesia, chest discomfort/infrequent when used early in attack |
| Sumatriptan nasal spray | A | Migraine nonresponding to analgesics/moderate to severe migraine | Nausea, paresthesia, chest discomfort unpleasant taste/occasional |
| Sumatriptan SC | A | Moderate to severe migraine/oral nonresponders/early-onset nausea | Nausea, paresthesia, chest discomfort/frequent |
| DHE: intravenous/intramuscular/subcutaneous | B | Moderate to severe migraine/oral nonresponders/rescue/headache recurrence/bridge therapy for CM and MO | Nausea, paresthesia, chest discomfort/frequent |
| DHE nasal spray | A | Moderate to severe migraine/oral nonresponders/headache recurrence | Nausea, paresthesia, chest discomfort, nasal congestion/occasional |
a US Headache Consortium Guideline Evidence Classification. Level A: Medications with well-established efficacy. Level B: Medications that are probably effective.
c After US Consortium Headache Guideline evidence with author opinion.
Newer Acute Treatments
A number of treatments were not available at the time of the 2000 guideline but have evidence similar to those agents in category A of the guidelines for consistent efficacy and tolerability. One involves innovative delivery improving effectiveness, such as diclofenac powder (Cambia). Three other triptans have come on the market: almotriptan, eletriptan, and frovatriptan, and all bear similarity to the 4 reviewed triptans. A novel tablet design combines sumatriptan and naproxen sodium, altering the pharmacokinetics of both drugs for favorable outcomes. An easy to use method is available especially in the patient with nausea, with a recently approved sumatriptan patch (Zelrix). When a nonoral treatment of migraine is needed in which there is early onset of nausea or if the patient does not have a consistent response to oral triptans, then zolmitriptan nasal spray or subcutaneous administration of sumatriptan without a needle (Sumavel DosePro sumatriptan, zogenix pharmaceuticals, emeryville, CA) is available. The NSAID, ketorolac, is used as a parenteral rescue medication.
Preventive Treatments
Preventive treatment should be considered if migraine attacks occur 4 or 5 days per month with normal functioning or if there are 2 to 3 migraine days per month that have some impairment or disability. The choice of preventive medications ( Table 2 ) has been recently reviewed in 2 evidence-based guidelines. These include “natural” treatments and prescriptive agents. The treatments of first choice are 3 beta blockers: propranolol, timolol, and metoprolol; 3 antiepileptic agents: valproic acid, divalproex, and topiramate; the triptan: frovatriptan for preventive treatment of menstrual migraine; and the herbal preparation: Petadolex brand of butterbur (Linpharma Inc. Oldsmar, FL), as it is the only formulation that has been subjected to clinical trials. Other agents can be considered based on comorbidities, patient preference, and tolerability. The doses used for all of these agents should be titrated upward to an effective dose over the first month and maintained for 3 months before considering increasing the dose or changing drugs. Titrating the dose minimizes the adverse event burden, common for many patients. Treatment should reduce the migraine burden optimally, then be maintained for a year before attempting to taper the medications, which occurs over several months. Education of the patient in a headache-healthy lifestyle and nonpharmacologic strategies should be encouraged.
| Drug | Quality of Evidence a | Special Clinical Considerations b | Types and Relative Risk of Adverse Events b |
|---|---|---|---|
| Alpha agonists | |||
| Clonidine | C | Also used for reducing opioid withdrawal | Fatigue, hypotension/occasional |
| Guanfacine | C | Fatigue, hypotension/occasional | |
| ACE inhibitors | |||
| Lisinopril | C | Maybe useful for preservation of renal function in patients with diabetes | Dizziness/infrequent |
| ACE blocking agents | |||
| Candesartan | C | Dizziness/infrequent | |
| Antidepressants | |||
| Amitriptyline | B | Coexisting depression | Somnolence, anticholinergic, weight gain/frequent |
| Venlafaxine | B | Coexisting depression, anxiety, perimenopausal | Sexual dysfunction, mood disorders especially teenagers/infrequent |
| Antiepileptic agents | |||
| Carbamazepine | C | Coexisting seizure disorder, trigeminal neuralgia | Aplastic anemia, dizziness, somnolence, extreme caution in women of childbearing potential/frequent |
| Divalproex sodium/valproate | A | Coexisting mood disorder or seizure disorder | Weight gain, hair loss, tremor, extreme caution in women of childbearing potential/frequent |
| Topiramate | A | Coexisting seizure disorder | Mood changes, paresthesias, nephrolithiasis, acute glaucoma, weight loss/frequent |
| Beta adrenergic blocking agents | |||
| Atenolol | B | Bradycardia, hypotension/occasional | |
| Metoprolol | A | Hypotension/infrequent | |
| Nadolol | B | Hypotension, mood dish orders/occasional | |
| Nebivolol | C | Hypotension/infrequent | |
| Pindolol | C | Raynaud disease | Hypotension/infrequent |
| Propranolol | A | Acute anxiety disorder | Hypotension, mood disorder/occasional |
| Timolol | A | Hypotension, mood disorder/occasional | |
| 5HT1B/1D agonists | |||
| Frovatriptan | A | Menstrual-associated migraine | Nausea, paresthesia, chest discomfort/infrequent |
| Naratriptan | B | Menstrual-associated migraine | Nausea, paresthesia, chest discomfort/infrequent |
| Zolmitriptan | B | Menstrual-associated migraine | Nausea, paresthesia, chest discomfort/infrequent |
| Herbal therapies | |||
| Feverfew | B | MIG-99 only formulation shown effective | Gastrointestinal/infrequent |
| Petasites | A | Petadolux only formulation studied. Processing differences between brands may increase risk of adverse events | Gastrointestinal/infrequent. Other formulations may contain derivatives that are hepatotoxic. |
| Histaminic agents | |||
| Cyproheptadine | C | Children, cluster headache, category B in pregnancy | Sedation, weight gain/occasional |
| Histamine subcutaneous | B | Cluster headache, must be compounded | Flushing, itching/infrequent |
| Hormones | |||
| Estrogen (soy isoflavones, dong quai, and black cohosh)/estradiol | C | Menstrually associated migraine | Alteration of menstrual blood loss/occasional |
| Minerals and Vitamins | |||
| Co-Q 10 | C | Rare | |
| Magnesium | B | Menstrually associated migraine | Gastrointestinal/occasional based on formulation |
| Riboflavin | B | Urine discoloration/frequent | |
| Nonsteroidal anti-inflammatory drugs | |||
| Flurbiprofen | C | Also menstrually associated migraine | Gastrointestinal and bleeding/occasional |
| Fenoprofen | B | Also menstrually associated migraine | Gastrointestinal and bleeding/occasional |
| Ibuprofen | B | Also menstrually associated migraine | Gastrointestinal and bleeding/occasional |
| Ketoprofen | B | Also menstrually associated migraine | Gastrointestinal and bleeding/occasional |
| Mefenamic acid | C | Also menstrually associated migraine | Gastrointestinal and bleeding/occasional |
| Naproxen | B | Also menstrually associated migraine | Lowest risk of cardiovascular disease complications, gastrointestinal and bleeding/occasional |
| Naproxen sodium | B | Also menstrually associated migraine | Lowest risk of cardiovascular disease complications, gastrointestinal and bleeding/occasional |
a After the Reports of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Level A: Medications with well-established efficacy. Level B: Medications that are probably effective. Level C: Medications that are possibly effective.
Cluster headache
Given the unilateral nature of cluster headache, it is important to consider in the differential diagnosis paroxysmal hemicrania, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT syndrome), primary stabbing headache, and trigeminal neuralgia. The first 3 of these, along with hemicrania continua, share a preventive treatment response to indomethacin, although they are rare conditions even by comparison with cluster headache.
Acute Treatment
Treatment of cluster headache is primarily pharmacologic. There has been some success with behavioral approaches, occipital nerve procedures, and deep brain stimulation. Given its severity and debilitating features, although attention to acute treatment is important, the focus is on preventive treatment. Both the American Academy of Neurology and the European Federation of Neurologic Societies have published evidence-based recommendations.
The current guidelines ( Table 3 ) suggest that 100% oxygen at a rate of 6 to 12 L per minute for up to 15 minutes per attack, subcutaneous injection of sumatriptan, and zolmitriptan nasal spray are the first-line treatments for the acute treatment of cluster headache. Oxygen is the treatment of choice, given its side-effect profile and safety; however, the triptans may be more effective acute medications and can be used with greater convenience. Rapid onset of action is essential. This makes injectable and intranasal formulations preferred over the oral triptans. There is limited evidence for the local anesthetic agents lidocaine and cocaine being effective. There is no evidence for the opioid analgesics.
