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Efficacy of Stimulants in Migraineurs with Comorbidities

Stimulants may be beneficial for chronic migraine patients presenting with various comorbidities such as attention deficit hyperactivity disorder (ADHD), depression and fatigue.
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Amphetamines have been shown to possess intrinsic analgesic properties, primarily through brain catecholamine activity. They also intensify the analgesic effects of certain opioids.1 When prescribed for headache patients, stimulants may be beneficial for various comorbidities such as attention deficit hyperactivity disorder (ADHD), depression and fatigue. In addition, stimulants do not cause the weight gain that is seen with a number of other current headache preventives.

This article reviews our experience with stimulants in chronic migraine patients over a period of six years.


Study Design

This retrospective study was conducted at a single U.S. headache clinic. Data was collected via chart review, patient diary and patient interview. Patients who had been prescribed stimulants during the six year period of 2002-2007 were assessed.

Patients kept a headache diary and used a 10-point visual analog scale to measure the severity of the pain.

Patient Characteristics: Seventy-three patients (57F, 16M) were evaluated. The patients had been diag-nosed previously as having chronic migraine. With a few exceptions, the stimulants were prescribed primarily for the associated comorbidities. The comorbidities (some patients had more than one) included: ADHD (n=28), unipolar depression (n=28), fatigue/sleepiness (n=17), bipolar depression (n=14), and narcolepsy (n=3).

Inclusion Criteria: Long-time patients at the treating headache clinic with the diagnosis of chronic migraine were included. Chronic migraine was defined according to the International Headache Society criteria.2 All patients had been prescribed stimulants, including amphetamine/ dextroamphetamine, dextroamphetamine, and methylphenidate.

Primary Outcome Measure: The primary outcome measure was efficacy of the stimulant with regards to headache. Efficacy was determined to be positive if the patient continued on the stimulant for at least nine months and consistently reported a 30% or more improvement in headache frequency and/ or severity over a three-month baseline.


Efficacy: Of the 73 patients, 55 (75%) continued on the stimulant for at least nine months. Of the 55 patients, 26 (47%) met the standard of efficacy of at least a 30% decrease in headache frequency and/or severity. Of the original 73 patients, 34% remained on the stimulant and reported positive headache efficacy.

Efficacy in Relation to Comorbidity: The positive headache response allocated by comorbidity is presented in Table 1.

Adverse Events: 30/73(41%) of the patients experienced at least one side effect. The side effects are presented in Table 2 (note that some patients reported multiple side effects).

Abuse or Addiction: Two patients (3%) abused the stimulant.


Psychopharmacology of Stimulants: Common stimulants include nicotine, caffeine, amphetamine and amphetamine derivatives. As a group, central nervous system (CNS) stimulants cause excitement and euphoria, decrease feelings of fatigue and increase motor activity.3 Caffeine, the most widely consumed stimulant in the world, is believed to act by several mechanisms of action in the pre-frontal cortex and other areas of the brain. These include translocation of extracellular calcium, inhibition of phosphodiesterase and adenosine receptor antagonism, resulting in decreased fatigue and increased mental alertness.3

Nicotine, the active ingredient in tobacco, specifically stimulates nicotinic receptors in the autonomic ganglia, resulting in euphoria, arousal, relaxation, improved attention, learning, problem solving and reaction time.3 However, in very high doses, nicotine causes blockade of autonomic ganglia, resulting in respiratory depression and severe hypotension.

Table 1. Efficacy in Relation to Comorbidity
Comorbidity No. of patients with comorbidity No. of patients with positive efficacy % of patients with positive efficacy
ADHD 28 7 25%
Unipolar depression 28 8 29%
Fatigue/sleepiness 17 6 35%
Bipolar depression 14 3 21%
Narcolepsy 3 2 66%

Cocaine acts to stimulate the CNS in a more indirect manner by blocking re-uptake of nor-epinephrine, serotonin and dopamine into the presynaptic terminal from which they are released.3 This reuptake antagonism serves to potentiate and prolong the CNS and peripheral nervous system (PNS) effects of these catecholamines. In the CNS, this results in intense euphoria, acutely increased mental awareness and increased motor activity. At high doses, these effects manifest as hallucinations, delusions, paranoia, tremors and convulsions. Peripherally, the effects of cocaine include tachycardia, hypertension, pupillary dilation and peripheral vasoconstriction.3

Amphetamine and its derivatives, such as methylphenidate, demonstrate indirect CNS and PNS effects similar to cocaine. Like cocaine, they initially increase levels of catecholamines. However, amphetamines do this by a different mechanism of action. They accomplish this effect by causing the release of intracellular stores of catecholamines and inhibiting monamine oxidase (MAO).3 The major cause of the behavioral effects of amphetamines is thought to be due more to release of dopamine rather than norepinephrine.3 This ultimately results in increased alertness, decreased fatigue, decreased appetite and insomnia, as well as the usual “fight or flight” response characteristic of adrenergic stimulation in the PNS.

Stimulants and Headache: Our study assess-ed 73 chronic migraineurs who had been prescribed stimulants in addition to their other medications. While the stimulants were primarily prescribed for certain co-morbidities, their effect on headaches was also assessed. Seventy-five percent of the patients placed on the stimulants remained on them for at least nine months. Thirty-four percent of the 73 patients both remained on the stimulants and reported positive efficacy with regard to headache. Forty-one percent of the patients suffered at least one adverse event, while only two patients abused the stimulant.

Last updated on: January 28, 2012
First published on: September 1, 2009