For Refractory Migraine, Consider Ketamine

LAS VEGAS—When first- and second-line drugs fail in the treatment of refractory migraine, ketamine may be a suitable option.

In fact, the US Headache Consortium recommended treatment of migraine includes ketamine, was well as triptans and ergot and its derivatives, antiemetics, NSAIDs and nonnarcotic analgesics, and narcotic opiate analgesias, said Natalie H. Strand, MD, Chief Medical Officer at Freedom Pain Hospital, Scottsdale, Arizona. She reviewed the diagnostic criteria for migraine, clinical presentation of migraine, ketamine pharmacology, and the clinical application of ketamine for migraine at PAINWeek 2014. 

Paroxysmal episodes of headache, with associated symptoms of nausea, vomiting, visual changes, photophobia, and phonophobia, are the hallmarks of migraine, which may be precipitated by a trigger and last from 4 to 72 hours. Phases of migraine are prodrome, aura, headache, and postdrome. Migraine may occur with or without aura and may be chronic. Status migrainosus is a migraine attack that lasts more than 72 hours, causing intense pain and disability and often refractory to usual outpatient treatments.

Of the 28 million people in the US who suffer from migraine, 75% are adult women. In fact, migraine prevalence is 18.2% among females, nearly three times that of 6.5% among males. Migraine causes an estimated $15.5 billion in lost revenue annually due to loss of work house and use of medical facilities. Common migraine comorbidities include sleep disturbance, depression, anxiety, panic disorder, bipolar disorder, epilepsy, obsessive-compulsive behavior, fibromyalgia, and cognitive impairment.

Ketamine is a noncompetitive NMDA receptor antagonist that blocks the release of excitatory neurotransmitter glutamate, providing anesthesia, amnesia, and analgesia. It works by decreasing central sensitization and the “wind-up” phenomenon. Ketamine is also a serotonin and norepinephrine reuptake inhibitor, and is lipophilic, crossing the blood-brain barrier. If administered intravenously, onset of action is 1 to 5 minutes; subcutaneously, 15 to 30 minutes; and orally, 30 minutes.

In clinical use for more than 30 years as a rapid-acting general anesthetic, ketamine can be administered intravenously, intramuscularly, subcutaneously, orally, rectally, nasally, transdermally, epidurally, or intrathecally, and appears to be most effective for nociceptive and/or neuropathic pain.

Dr. Strand reviewed studies using ketamine in varying dosages. Clinical experience has shown that anxious and apprehensive patients are more likely to have psychomimetic side effects, which may be prevented if they are pretreated with a benzodiazepine. Contraindications to ketamine are summarized in the Table.

Table. Contraindications to Ketamine

 Pregnancy (placental transfer)
 Substance abuse
 Glaucoma
 Thyrotoxicosis
 Significant psychiatric comorbidities including bipolar disorder and schizophrenia
 Active post-traumatic stress syndrome
 Uncontrolled hypertension or hypotension
 Cardiac failure
 Renal failure
 Liver failure
 Prolonged QT syndrome
 Neurogenic bladder or urinary retention
 Known elevated CSF
 Methadone usage
 Daily opioid dose > a morphine equivalent of 120 mg
 History of stroke unless cleared by cardiology and neurology
 Significant cognitive dysfunction


Due to the duration of ketamine, patients should be educated to avoid driving a car, operating hazardous machinery, or engaging in hazardous activities for a minimum of 24 hours after administration. They should also contact their clinician if they experience severe confusion, hallucinations, unusual thoughts, extreme fear, dream-like feeling, double vision, jerky muscle movements, dizziness, drowsiness, nausea, vomiting, loss of appetite, or insomnia.

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