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 (47) and reduced levels of dopamine D2 receptors (46), 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 (47).

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).

Prevention

Illicit-drug-induced headache can be prevented by eliminating illicit drug use. Chronic headaches preceded drug abuse in most studies, but data do not support the hypothesis that self-medication for chronic headaches played a significant role in the genesis or maintenance of marijuana or cocaine use (22). Law enforcement personnel should be advised to use personal protective masks when they investigate clandestine drug laboratories.

Differential diagnosis

The acute onset of headaches in cocaine users or parenteral drug abusers can signal intracranial hemorrhage, ischemic stroke, endocarditis, brain abscess, or other psychiatric or medical illness (17). An 18-year-old young man developed a subarachnoid hemorrhage after his first usage of ecstasy and a 20-year-old woman developed a subarachnoid hemorrhage after using MDMA and common cold medications (04; 28). Both patients developed a severe headache five hours after using the illicit drugs. A 29-year-old woman developed bilateral angle closure glaucoma with the presentation of blurred vision and severe headaches after she consumed ecstasy and marijuana (45). A 19-year-old woman experienced delayed cerebral infarction with severe headache following a methamphetamine injection (36). In addition, cannabis usage should be considered if patients develop thunderclap headache and reversible cerebral vasoconstriction syndrome (19).

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

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.

Management

The cornerstone of managing headaches associated with illicit drug use is discontinuing the offending drug. Managing the drug abusing patient can be difficult and usually requires a drug dependence unit for detoxification. Abrupt discontinuation of opioids and cocaine can precipitate withdrawal headaches. Nimodipine can be considered if patients develop reversible cerebral vasoconstriction syndrome after using cannabis (13; 19).

Special considerations

Pregnancy

There are no data on headache associated with illicit drug use in pregnancy. None of the illicit drugs are considered safe for use during pregnancy; every effort should be made to prevent this problem during pregnancy.

Anesthesia

No data are available about headache associated with illicit drug use and anesthesia. Because opiates, barbiturates, and sedatives can affect the metabolism of anesthetic drugs, a careful history of drug use is critical in patients undergoing anesthesia. Withdrawal headaches from opioids, cocaine, and sedatives may complicate postoperative management.