Headache associated with illicit drug use

Shuu-Jiun Wang MD

Headache & Pain

Updated 04.08.2024
Released 01.21.1994
Expires For CME 04.08.2027

Headache associated with illicit drug use

Author: Shuu-Jiun Wang MD

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Headache associated with illicit drug use

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Introduction

Overview

In general, most physicians are not familiar with headache syndromes induced by the use of illicit drugs such as cocaine, marijuana, and opioids. Some patients may develop thunderclap headache and reversible cerebral vasoconstriction syndrome. In this article, the author provides an update on the underlying pathophysiology and reviews the clinical aspects of headache syndromes induced by illicit drugs in light of the criteria presented in the International Classification of Headache Disorders, 3rd edition (ICHD-3), published in January 2018. Patients with cluster headache tend to use illicit drugs; in contrast, patients with migraine are less likely to use them (46). Greco and colleagues suggest that the endocannabinoids and related lipids may be candidates for migraine treatment (24).

Key points

	• Illicit drugs, including cocaine, methamphetamine cannabis, and opioids, can induce headache. However, acute withdrawal of opioids can also induce headache.
	• The diagnostic criteria of headache induced by illicit drugs are provided in the third edition of The International Headache Classification (ICHD-3), which was published in January 2018.
	• Reversible cerebral vasoconstriction syndrome manifesting as thunderclap headache was reported as a complication of the use of illicit drugs such as cannabis.
	• Cocaine- and amphetamine-induced acute severe headache may be related to a sympathomimetic effect.
	• Modulation of the metabolic pathways of the endocannabinoid system may be a basis for new migraine treatment.
	• Compared with the normal population, patients with migraine are less likely to use illicit drugs, but patients with cluster headache were more likely to use illicit drugs.

Historical note and terminology

Although the use of opium and its derivatives dates back to the 3rd century BC, headache caused by illicit drugs appears to be a relatively recent phenomenon, with the earliest reports dating from the mid-1980s (31; 20; 40). El-Mallakh described the appearance of migraine headaches after the abrupt discontinuation of long-term marijuana use. Satel, Gawin, Lipton and colleagues have described migraine-like headaches as also being associated with cocaine use. Neurologic complications, including headache, are rarely reported in association with ecstasy (3,4-methylenedioxymethylamphetamine, MDMA) use (05; 04).

The third edition of the International Classification of the Headache Disorders (ICHD-3) defines four headache syndromes related to illicit drug use; they include cocaine-induced headache, cannabis-induced headache, opioid-overuse headache, and opioid-withdrawal headache (27).

Clinical manifestations

Presentation and course

Several different headache syndromes have been associated with illicit drug use. A diffuse, continuous, long-lasting headache, which resembles tension-type headache, follows the intake of certain types of heroin. A frontotemporal, pulsating, long-lasting, migraine-like headache is associated with opioid withdrawal (16). However, a study done in China on 90 heroin-dependent female women showed that 74 experienced headache attacks within two hours of heroin use, which subsided within 72 hours of discontinuation (32). Of note, heroin-induced headaches were similar to migraine attacks. With cocaine use, several headache patterns can be observed: (1) a bitemporal, pulsating, short-duration headache appearing within minutes of cocaine use; (2) a frontal, throbbing headache accompanied by nausea, occurring during "binge" cocaine use; and (3) chronic daily headaches associated with depression, often with suicidal ideation, related to cocaine withdrawal (33; 17). A syndrome resembling hemiplegic migraine has also been reported following cocaine use (33). Cannabis-induced headache is usually bilateral with a stabbing or pulsating quality or feeling of pressure in the head. It is associated with dryness of the mouth, paresthesias, feelings of warmth, and suffusion of the conjunctivae (26). A French study reported 62 patients who developed thunderclap headache and reversible cerebral vasoconstriction syndrome (19). Thirty-two of these patients used cannabis, cocaine, or both. Thunderclap headache describes an unanticipated, severe headache reaching peak intensity within one minute. Some of these patients experienced complications of cortical subarachnoid hemorrhage or ischemic episodes. Although it is considered that many kinds of illicit drugs are related to reversible cerebral vasoconstriction syndrome, a systemic review found the strongest evidence for cannabis, but a relative lack of evidence to support other drugs, particularly as individual precipitating factors (43). In contrast, about 65% of marijuana-addicted headache sufferers experienced pain relief when they smoked the drug at the onset of the headache attack (02). Nevertheless, it has been reported that 22% of patients with suspected acute opioid overdose developed headaches with naloxone treatment (10). One report showed that a 43-year-old woman developed severe headache due to reversible cerebral vasoconstriction syndrome and complicated with watershed zone infarction after ingestion of 4-bromo-2,5-dimethoxyphenethylamine (2C-B) (01). This is a “designer” drug variant of ecstasy, and its recreational use has increased significantly in Europe and the United States over the last 10 years.

Hagigat (capsules of 200 mg cathinone, an amphetamine-like sympathomimetic amine) has been marketed in several countries as a natural stimulant but is considered illicit in the United States. An Israeli study showed headache was common (50%) in 34 subjects (aged 16 to 54 years old) who used Hagigat (one half to six capsules) (08). Prolonged headache lasting up to 7 days was reported by 11 patients (32.4%). Three major complications were myocardial ischemia (n=3), pulmonary edema (n=2), and intracerebral hemorrhage (n=1), all in young subjects.

Methamphetamine abuse is increasing (14). A review on the clinical toxicology of methamphetamine reports that headache is one of the most common complications and many patients develop vasculopathy at the same time (41). A poison-control center in the United States reported that the most frequent symptom in those with exposure to methamphetamine labs was headache (17%) followed by nausea or vomiting (14%), respiratory difficulty (8%), and eye irritation (7%) (44). Healthcare facility utilization was highest for law enforcement personnel (93%) and persons involved in methamphetamine production, or “cooks” (90%). An Italian study surveyed headache profile in a group of chronic cocaine users (23). The authors found, of the 80 enrolled subjects, 72 (90%) reported current headaches, in most cases migraine or probable migraine without aura. Of these 72, 29 (40.3%) had a headache history, whereas 43 (59.7%) reported de novo headache after beginning to use cocaine. Most subjects reported that headaches worsened when they used cocaine.

In contrast, a retrospective study on medical marijuana use in 121 migraine patients with at least one follow-up visit between January 2010 and September 2014 in two Colorado private clinics reported that migraine headache frequency was markedly decreased in frequency from 10.4 to 4.6 days per month. Of note, to interpret the study, one should be cautious due to its retrospective design and a high rate of loss to follow-up (141 out of 262 patients: 54%) (38). One review done by Greco and colleagues proposed that modulation of the metabolic pathways of the endocannabinoid system may be a basis for migraine treatment (24). Multiple molecules related to the system or to allosteric modulation of cannabinoid-1 receptors have emerged as potential targets for migraine treatment.

Prognosis and complications

There are no published data on the prognosis of patients with headaches associated with illicit drug use.

Clinical vignette

Brain edema presenting as severe headache followed by consciousness change or coma was reported in a 23-year-old woman after she used ecstasy, benzylpiperazine, and consumed a large volume of fluids (05). The patient died of tonsillar herniation. Hyponatremia was considered to be related and has been reported in several other cases after ecstasy use and consumption of a large volume of fluids (05; 11).

Biological basis

Etiology and pathogenesis

Headache from illicit drug use can occur with CNS stimulants (amphetamines, cocaine, cathinone, and designer drugs), barbiturates and sedatives, cannabis, or opioids. The headaches may be associated with acute use or "binge" use, or occur during withdrawal from these substances.

Cocaine- and amphetamine-induced headaches begin immediately after drug ingestion. The cocaine surge leads to a rapid block of presynaptic norepinephrine reuptake with potent sympathomimetic effects and acute constriction of vascular smooth muscle. Derangements of norepinephrine and vasomotor control have also been proposed as important factors in the genesis of migraine (17). Other causes, such as metabolic alterations, including abnormal cerebral glucose metabolism (48) and reduced levels of dopamine D2 receptors (47), have also been reported.

Prolonged cocaine use may lead to a secondary presynaptic serotonin depletion, accounting for the increased severity of the headaches. A local anesthetic effect of nasal cocaine on the sphenopalatine ganglion may also contribute to the headaches (17).

Withdrawal headaches result from physical dependence after the use of CNS depressants, opioids, or stimulants (cocaine, amphetamines). The withdrawal symptoms associated with many of these classes of agents are generally characterized by rebound effects in those physiologic systems that were initially modified by the drug (29). Therefore, withdrawing opioids or CNS depressants will cause increased pain sensitivity and anxiety. Cocaine withdrawal headaches may result from disruptions in serotonin metabolism (48).

We do not completely understand the underlying mechanism responsible for the lack of efficacy, or even headache exacerbation, related to opioid usage in patients with intractable headache. Biondi proposed an interesting concept that chronic daily headache can be viewed as a form of neuropathic pain syndrome because of the neural plasticity in the context of neuropathic pain states, the physiologic basis for opioid tolerance, and opioid-induced hyperalgesia (09). Therefore, if patients with intractable headache are not carefully monitored, their risk of opioid overuse headache is high (39).

Epidemiology

Because studies of substance abuse headaches have come from specialized drug abuse treatment programs, the epidemiology of this disorder in the general population is largely unknown. A survey of students from a university in Colombia showed that the students who were psychoactive drug users (marijuana or crack-like [basuco] substance) were more likely to have migraine-type headaches (41% vs. 25%) than were nonusers (03). A study done in a substance abuse rehabilitation center in Turkey showed 27% of 1015 hospitalized patients reported having headache. Eighteen percent of patients reported having headache attributed to a substance or its withdrawal and 1.4% had unclassified headache. The most commonly used substances were cannabis (80.5%), alcohol (74.6%), methylamphetamine (18.7%), benzodiazepine (10.4%), volatile solvent (5.8%), cocaine (4.4%), heroin (2.1%), opioids (0.5%), and other substances (1.7%). Fifteen patients reported that onset of headache occurred prior to onset of substance use, whereas 94.5% had headaches after substance abuse (07). Nevertheless, the causal relationship between headaches and marijuana or basuco usage could not be completely delineated. El-Mallakh and colleagues reported a significant increase in the prevalence of headaches in persons who used cocaine or marijuana but not in persons who used alcohol exclusively (21). They also found no associations between specific substances and headache type. Their data do not support the hypothesis that self-medication for migraine headaches plays a significant role in the genesis or maintenance of marijuana or cocaine use.

Among cocaine users, as many as 60% to 75% report severe headaches that they relate to use of the drug (17). Law enforcement workers have developed headaches as a result of inhaling methamphetamine in clandestine drug laboratories (12). One review showed that headache is one of the most common acute subjective effects experienced by subjects who used MDMA, ranging from 3% to 60% (06). Khat leaves (mainly cathinone and cathine) have been chewed for centuries as stimulants. Hagigat (capsules of 200 mg cathinone) has been marketed in several countries. Headache was reported in as high as 50% in those who used Hagigat (08).

A study done in two emergency departments at San Diego showed that among 1298 patients who took energy drinks that contained caffeine, 68 patients (5%) reported headache. Other common adverse events included feeling "shaky/jittery" (22%), insomnia (10%), palpitations (12%), gastrointestinal upset (6%), and seizures (0.5%). Of note, some patients reported purposely taking energy drinks with illicit drugs, mostly cocaine and methamphetamine (35).

Diagnostic workup

The key to the diagnosis of illicit drug-related headache is a careful history of drug use, specifying the amount, route of administration, and dosing frequency of any illicit drugs. Urine drug screens can occasionally help to determine illicit drug use. High-dose riboflavin used for migraine prophylaxis may interfere with urine drug screen immunoassays that employ fluorescein-labeled antibody (30). Because illicit drug users have a significant risk of intracranial hemorrhage, ischemic stroke, endocarditis, brain abscess, or brain edema, illicit drug users who have acute headache should probably undergo neuroimaging. Patients who abuse ecstasy should have serum sodium levels checked to rule out hyponatremia.

The ICHD-3 defines four headache syndromes related to illicit drug use under group 8, Headache attributed to a substance or its withdrawal. These include cocaine-induced headache (coded as 8.1.6), opioid-overuse headache (8.2.4), and opioid-withdrawal headache (8.3.2) (27). Their diagnostic criteria follow:

Table 1. Diagnostic Criteria for Headache Associated With Illicit Drug Use

Headache code: 8.1.5 Cocaine-induced headache
Diagnostic criteria:
	(A) Any headache fulfilling criterion C (B) Cocaine has been administered by any route (C) Evidence of causation demonstrated by all of the following:
		1. headache has developed within 1 hour of cocaine administration 2. headache has resolved within 72 hours after cocaine administration 3. headache has at least one of the following four characteristics:
			a. bilateral b. mild to moderate intensity c. pulsating quality d. aggravated by physical activity
	(D) Not better accounted for by another ICHD-3 diagnosis
Headache code: 8.2.4 Opioid-overuse headache
Diagnostic criteria:
	(A) Headache fulfilling criteria for 8.2 Medication-overuse headache (B) Regular intake of one or more opioids on ≥10 days per month for >3 months
Headache code: 8.3.2. Opioid-withdrawal headache
Diagnostic criteria:
	(A) Headache fulfilling criterion C (B) Opioid intake daily for >3 months, which has been interrupted (C) Evidence of causation demonstrated by both of the following:
		1. headache has developed within 24 hours after last opioid intake 2. headache has resolved within 7 days after total opioid withdrawal
	(D) Not better accounted for by another ICHD-3 diagnosis

Studies have disclosed that narcotics or some illicit drugs might play a role in headache prevention. Saper and colleagues reported that daily scheduled opioids offered some benefit for a highly selected group of patients with intractable headache (39).

Dextroamphetamine might also be effective in decreasing headache frequency in patients with chronic tension-type headache or migraine (25). An interesting study showed that psilocybin or lysergic acid diethylamide (LSD) could be used to treat cluster headache as both acute and preventive agents (42). In his review, McGeeney suggests that hallucinogens are used more and more frequently in patients with cluster headache (34). However, their efficacy is not certain because no randomized control trials were performed. Of note, an Italian online study showed some patients with cluster headache (N=54) who were unsatisfied with the current treatment and ended up using illicit drugs for acute (ie, cannabinoids, cocaine, heroin) or prophylactic (LSD, lysergic acid amide, psilocybin) treatment (18). These patients obtained the information from the Internet, and they seemed to underestimate the judicial consequences and were overconfident in the safety of their treatment. de Coo and colleagues reported higher illicit drug use in patients with cluster headache than in the general population (31.7% vs. 23.8%; p< 0.01) in the Netherlands (15). In addition, Ponte and colleagues reported a series of seven cases with cluster headache who frequently used illicit drugs (37). They estimated a cluster headache prevalence of 0.9% in their patients with drug addiction as compared with 0.1% in the general population. This coexistence suggests a possible common neurobiological pathway, which would include the hypothalamus. In contrast, a Dutch study showed that patients with migraine are less likely to use illicit drugs, smoke, or drink in comparison with the general population (46).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Shuu-Jiun Wang MD

Dr. Wang of National Yang-Ming University and Taipei Veterans General Hospital has no relevant financial relationships to disclose.
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Former Authors

Glen D Solomon MD
Li-Chi Hsu

Patient Profile

Age range of presentation: 6 to 65+ years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Drug withdrawal syndrome or symptoms: 292.0

Headache: 784.0
ICD-10: Drug-induced headache, not elsewhere classified: G44.4 + F1x.3

Headaches associated with psychoactive substances (dependence-producing): G44.83 + F1x.3

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Headache associated with illicit drug use

Associated Disorders

Depression
Drug addiction
Migraine
Suicidal ideation
Tension-type headache

Differential Diagnosis

intracranial hemorrhage
ischemic stroke
endocarditis
brain abscess
other psychiatric or medical illness
- subarachnoid hemorrhage
- bilateral angle closure glaucoma
- cerebral infarction
- aneurysmal rupture
- thunderclap headache and reversible cerebral vasoconstriction syndrome

Also Relevant

Headache associated with acute substance use
Illicit drug use: neurologic complications
Medication overuse headache
Medications and substances causing headache
Migraine
- Reversible cerebral vasoconstriction syndromes
- Stroke associated with drug abuse
- Stroke in young adults
- Tension-type headache

Headache associated with illicit drug use

Headache associated with illicit drug use

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Table 1. Diagnostic Criteria for Headache Associated With Illicit Drug Use

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Primary headache associated with sexual activity

Primary cough headache

Medications and substances causing headache

Headache in children: overview and treatment approaches

Alternating hemiplegia of childhood

Late-life migrainous accompaniments

Complex regional pain syndrome

Headache associated with intracranial neoplasms

Headache associated with illicit drug use

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Table 1. Diagnostic Criteria for Headache Associated With Illicit Drug Use

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Primary headache associated with sexual activity

Primary cough headache

Medications and substances causing headache

Headache in children: overview and treatment approaches

Alternating hemiplegia of childhood

Late-life migrainous accompaniments

Complex regional pain syndrome

Headache associated with intracranial neoplasms

This is an article preview.
Start a Free Account
to access the full version.