Clinical manifestations

Presentation and course

Headaches occur in all stages of HIV-1 infection, and the characteristic progressive immune decompensation modifies the determinants and, consequently, the clinical spectrum of headache. Table 1 provides a framework for organizing the causes and understanding the clinical spectrum of headache in this population.

Table 1. HIV-Related Headaches

Primary HIV-related headaches
	• Acute illness associated with HIV-1 seroconversion • Acute, recurrent, or chronic "aseptic" meningitis • Late stage HIV-headache without pleocytosis
Secondary HIV-related headaches
	• Opportunistic infections and opportunistic tumors • Medications used in HIV-1 infection • Immune restoration inflammatory syndrome

Headache attributed to human immunodeficiency virus (HIV) infection. (Current nomenclature as appears in the International Classification of Headache Disorders, 3rd edition; 43). Headaches are often part of the acute mononucleosis-like illness experienced as part of the primary infection with HIV-1 (11; 57; 48). This acute illness, which occurs in 53% to 93% of individuals, develops 2 to 4 weeks after HIV-1 exposure and lasts 1 to 2 weeks. The headaches these individuals develop range from a febrile headache associated with the systemic viral infection to headaches associated with retro-orbital pain, photophobia, and meningeal signs, reflecting acute viral lymphocytic meningitis (26). The acute aseptic meningitis has been estimated to occur in 1% to 2% of all primary HIV-1 infections (40). However, headache due to primary infection with HIV is less common (24). Other neurologic complications that may accompany the primary infection with HIV-1 include Bell palsy, acute encephalitis, acute demyelinating polyneuropathy, and brachial neuritis (57). Aseptic meningitis is often self-limited but can recur at any time following the primary infection.

Tambussi and colleagues found a strong correlation between neurologic symptoms during primary HIV infection and cerebrospinal fluid viral load (55). The authors reported that CSF viral load was significantly higher for patients who had neurologic manifestations, ranging from severe and persistent headache to clinical meningitis, compared with those without neurologic symptoms. Another study of patients with primary HIV infection demonstrated that those with headache had greater than 200-fold higher plasma viral loads at the time of seroconversion than did asymptomatic patients (34).

At any stage of the disease following initial infection, an acute or chronic headache can develop in the presence of an unexplained lymphocytic pleocytosis (63). The acute headache resembles meningitis associated with the primary infection and is associated with fever, meningeal signs, and cranial nerve palsies. The cerebrospinal fluid lymphocytic pleocytosis ranges from 20 cells/mm³ to 300 cells/mm³ and is often associated with an elevated cerebrospinal fluid protein (18). Hollander and Stringari studied 14 patients who demonstrated a cerebrospinal fluid pleocytosis without a definable etiology. Half of their patients developed an acute-onset illness with headache, fever, and nausea that usually resolved within 10 days. Three of their 7 patients had meningeal signs (28).

HIV-infected individuals can also suffer from chronic headaches. In a study, 3 of 7 patients presented with chronic headaches lasting months (28). Chronic headaches may resemble primary headache semiologies, including chronic tension-type headache or chronic migraine. Patients may also have an unexplained cerebrospinal fluid lymphocytosis, but the increase, which is rarely above 40 cells/mm³, is not as dramatic as in those patients with the acute aseptic meningitis. This finding is not specific for headache; a mild lymphocytic pleocytosis and an elevated cerebrospinal fluid protein can also be seen in asymptomatic HIV-infected individuals without headaches.

Patients in late stages of the disease may also present with new-onset headache without an identifiable etiology (07). Patients usually complain of holocephalic pain and frequently experience photophobia. A defining feature of the headache is the absence of CSF pleocytosis and may represent "aseptic" meningitis in a lymphocyte-depleted patient. Due to the availability of highly active antiretroviral therapy, only a minority of HIV patients have headache attributable to opportunistic infections presently.

Opportunistic infections and tumors. Two studies analyzed headache characteristics and associated symptomatology in HIV-infected patients presenting with an opportunistic infection or tumor (21; 38). Headaches secondary to an opportunistic infection causing meningitis were constant, gradual in onset, and associated with fever, nausea, vomiting, and photophobia. Headaches secondary to mass lesions were variable in onset and quality and associated with focal neurologic deficits and confusion. However, considerable variability occurs, and a fulminant opportunistic disease can arise in patients with mild or no symptoms, including the absence of headache.

Headaches due to medications used in HIV-1 infection. Medications used to treat either HIV-1 disease or its complications can cause headaches. In a double-blind, placebo-controlled trial of zidovudine in patients with AIDS, the incidence of headache was not significantly different between groups (approximately 40%), but more patients reported moderate or severe headache on zidovudine (43%) than placebo (24%) (47). Singer and colleagues found that 16% of their pain patients suffered from zidovudine-induced headaches, but most of their patients’ headaches gradually subsided over a period of weeks to months after starting the medication (54). Headache occurs in greater than 5% of patients receiving other nucleoside/nucleotide reverse transcriptase inhibitors, such as abacavir, stavudine, or tenofovir (25; Cheer and Goa 2002; 17). Neurologic symptoms, including headache, appear to be the most common adverse events reported with efavirenz, a non-nucleoside reverse transcriptase inhibitor (Adkins and Noble 1998). Headache was reported in less than 5% of patients receiving nelfinavir-containing regimens (29).

Headache was among the most frequent adverse events associated with some protease inhibitors, such as amprenavir (01) and lopinavir/ritonavir (12). However, use of lopinavir/ritonavir in 6 double-blind trials noted an adverse event of headache between 0.06% to 7% (42). Headache was related to 6 of 80 patients (7.5%) taking efavirenz (14). In several non-nucleoside reverse transcriptase inhibitor-based combination therapies, headache was the most common side effect (11.5%) (19). Baldwin and Ceraldi described drug interaction between protease inhibitors and ergot alkaloid agents leading to ergotism, a rare condition of acute vasospasm, and central nervous system manifestations, including seizure (03). Castagna and colleagues found fewer constitutional symptoms, including headache, in patients taking enfuvirtide, a class of medication known as fusion inhibitors, compared with a control group (09). Furthermore, 1 of the most common side effects of HIV integrase strand transfer inhibitor, raltegravir, is headache. Table 2 lists current medications used to treat HIV.

Table 2. Individual Medications Used to Treat HIV

Multiclass combination products
Brand name	Generic name
Atripla Complera Delstrigo Dovato Evotaz Prezcobix Stribild	efavirenz, emtricitabine, tenofovir disoproxil fumarate emtricitabine, rilpivirine, tenofovir disoproxil fumarate doravirine, lamivudine, tenofovir disoproxil fumarate dolutegravir, lamivudine atazanavir sulfate, cobicistat cobicistat, darunavir ethanolate elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate
Nucleoside reverse transcriptase inhibitors
Brand name	Generic name
Combivir Emtriva Epivir Epzicom Hivid Retrovir Trizivir Truvada Videx Videx EC Viread Zerit Ziagen	lamivudine, zidovudine emtricitabine, FTC lamivudine, 3TC abacavir, lamivudine zalcitabine, dideoxycytidine, ddC (no longer marketed) zidovudine, azidothymidine, AZT, ZDV abacavir, zidovudine, lamivudine tenofovir disoproxil fumarate, emtricitabine didanosine, dideoxyinosine, ddI enteric coated didanosine, ddI EC tenofovir disoproxil fumarate, TDF stavudine, d4T abacavir sulfate, ABC
Nonnucleoside reverse transcriptase inhibitors
Brand name	Generic name
Edurant Intelence Pifeltro Rescriptor Sustiva Viramune (immediate release) Viramune XR (extended release)	rilpivirine etravirine doravirine delavirdine, DLV efavirenz, EFV nevirapine, NVP nevirapine, NVP
Protease inhibitors
Brand name	Generic name
Agenerase Aptivus Crixivan Fortovase Invirase Kaletra Lexiva Norvir Prezista Reyataz Viracept	amprenavir, APV (no longer marketed) tipranavir, TPV indinavir, IDV saquinavir (no longer marketed) saquinavir mesylate, SQV lopinavir, ritonavir, LPV/RTV fosamprenavir calcium, FOS-APV ritonavir, RTV darunavir atazanavir sulfate, ATV nelfinavir mesylate, NFV
Fusion inhibitors
Brand name	Generic name
Fuzeon	enfuvirtide, T-20
Entry inhibitors - CCR5 co-receptor antagonist
Brand name	Generic name
Selzentry	maraviroc
HIV integrase strand transfer inhibitors
Brand name	Generic name
Isentress Tivicay Vitekta	raltegravir dolutegravir elvitegravir

(U.S. Food and Drug Administration 2019)

Over the years, the terminology for combinations of medication has changed. An initial popular term for combination therapy was HAART (highly active antiretroviral therapy). In efforts to communicate more effectively that these medications could be used in patient’s normal lives, the term was changed to cART (combination antiretroviral therapy). However, due to single pills that could now combine multiple medications, the use of the word “combination” was not needed. Hence, treatment is now often called ART (antiretroviral therapy).

Several investigators examined the tolerability of antiretroviral post-exposure prophylaxis in health care workers following occupational injuries in the workplace. Headache was among the significant toxicities encountered in 1 report (35). One study showed that headache occurs in 18% of health care workers while on post-exposure prophylaxis (61), and it was a reason for early drug discontinuation in 4% of health care workers on post-exposure prophylaxis in another study (50).

Other medications frequently used in the HIV population and associated with headaches include trimethoprim-sulfamethoxazole, fluoxetine, rifampin, ethambutol, methotrexate, and acyclovir (46).

Immune restoration inflammatory syndrome. Treatment with potent antiretroviral regimens can cause immune restoration inflammatory syndrome. This is likely due to restored immune function against previously identified or subclinical infections. The symptoms of this syndrome may be indistinguishable from the initial infection or relapse of the virus (39). It typically begins within the first 2 months after therapy initiation and resolves within several weeks (15).

Prognosis and complications

The prognosis depends on the underlying cause of the headache and if the patient is on appropriate treatment. Acute meningitis associated with the primary infection is usually a self-limited condition lasting less than 2 weeks. Adequate outcome data are lacking on the more indolent headache associated solely with a lymphocytic pleocytosis. Since the development of ART, secondary headaches are less frequent due to the decreased incidence of opportunistic infections and tumors. Studies comparing prognosis pre-ART era with current-day treatment found significant decreases in incidence of AIDS-defining events, such as toxoplasmosis, cytomegalovirus disease, progressive multifocal leukoencephalopathy, AIDS dementia, necrotizing herpes simplex, and non-Hodgkin lymphoma. For instance, a study by Brodt noted a decrease in AIDS-defining events by more than 70% from 1992 to 1996 (08). Patients with more advanced disease, but not HIV duration nor number of antiretroviral combinations, were more likely to have headaches; have more frequent, severe, disabling headaches; and have more migrainous versus tension-type headache presentations (33).

Without effective ART, however, survival is more tenuous. The median survival of patients surviving the first episode of toxoplasmosis encephalitis or cryptococcal meningitis is approximately 9 months (45; 62). Baumgartner and colleagues found a median survival of 4 months in AIDS patients with primary central nervous system lymphoma (04). The predicted median survivals for progressive multifocal leukoencephalopathy and cytomegalovirus encephalitis are shorter: 8 weeks and 4.6 weeks, respectively (31; 27).

Clinical vignette

A 29-year-old HIV-1-infected man presented with a 3-week history of a constant, pressure-like, bifrontal headache. He had a CD4+ count of 780 cells/mm³. He had started taking zidovudine approximately 6 weeks prior to presentation. He denied fever, neck stiffness, photophobia, or nausea. He had no history of migraine. He took approximately 5 acetaminophen tablets each week for the constant headaches. On examination, he had a supple neck. His neurologic and neuropathologic examinations were unremarkable. His serum cryptococcal antigen titer was nonreactive.

He was diagnosed with zidovudine-induced headaches, and the medication was discontinued. His headaches continued, however, and 4 weeks later, 7 weeks after the onset of his symptoms, he had a head CT with contrast and a lumbar puncture. The CT was unremarkable, and CSF analysis revealed a mildly elevated total protein and a slight CSF mononuclear pleocytosis (11 cells). All CSF cultures and serologies were negative. Headache attributed to human immunodeficiency virus (HIV) infection was the likely diagnosis, although tension-type headache and new daily persistent headache remained as possible diagnoses. He was started on low-dose (25 mg) nightly amitriptyline and demonstrated an excellent response, with near resolution of his head discomfort.

Biological basis

Etiology and pathogenesis

Tables 3 and 4 list the most common headaches in HIV-infected individuals based on early or late stages of the disease. Early and late HIV infection is distinguished, in part, by greater immunosuppression in the latter, which, in turn, is accompanied by a greater susceptibility for opportunistic infections and tumors. The tables below list headaches unique to the HIV-infected population as well as other headache syndromes that enter into the differential diagnosis, such as migraine, tension-type headache, headache associated with substance abuse or withdrawal, post-lumbar puncture headache, and headache due to inflammation of the cranial nerves.

Table 3. Causes of Headache in Early or Latent HIV-1 Disease

• Acute meningitis associated with HIV-1 seroconversion • Acute, recurrent, or chronic "aseptic" meningitis • Syphilitic meningitis • Drug-induced headache • Medication overuse headache or withdrawal headache • Tension-type headache • Migraine • Depression or other psychiatric illnesses • Inflammation of the cranial nerves (eg, herpes zoster)

Table 4. Causes of Headache in Late HIV-1 Disease

Opportunistic infections and tumors
Meningitides
	• Cryptococcal meningitis • Tuberculous meningitis • Syphilitic meningitis • Lymphomatous meningitis • Acute, recurrent, or chronic "aseptic" meningitis
Focal brain lesions
	• Toxoplasmosis encephalitis • Primary central nervous system lymphoma • Progressive multifocal leukoencephalopathy • Cryptococcoma • Candida abscess
Diffuse brain lesions
	• Cytomegalovirus encephalitis • Herpes simplex virus encephalitis • Toxoplasmosis encephalitis • HIV-associated dementia
Drug-induced headache
	• Zidovudine • Analgesics • Recreational drugs • Medication overuse headache
Primary and other types of headaches
	• Tension-type headache • Migraine • Depression • Post lumbar puncture headache • Inflammation of the cranial nerves (eg, herpes zoster)

In the setting of immunosuppression, opportunistic infections and tumors enter into the differential diagnosis of patients presenting with headache. The most common opportunistic infections include toxoplasmosis encephalitis, cryptococcal meningitis, cytomegalovirus encephalitis, progressive multifocal leukoencephalopathy, and neurosyphilis. The most important opportunistic tumor is primary central nervous system lymphoma. In these patients, the headache is often secondary, as the associated symptomatology, including fever, mental status changes, and focal deficits, dominate the clinical picture. Table 5 lists, by diagnosis, the percentage of patients with complaints of headache.

Table 5. Frequency of Headache Based on Neurologic Diagnosis in the HIV-infected Individual

Diagnosis	Percentage with headache
Cryptococcal meningitis Neurosyphilis Tuberculous meningitis Toxoplasmosis encephalitis Cytomegalovirus encephalitis Progressive multifocal leukoencephalopathy HIV-associated dementia	88% (44) 88% (32) 59% (05) 55% (45) 30% (27) 23% (31) 14% (41)

Many mechanisms have been proposed to explain the pathogenesis of HIV-associated neurologic disease, including the secretion of soluble toxins, autoimmunity, deficiency states, and undisclosed opportunistic infections (16; 49). However, these theories have been concerned with the dementia, myelopathy, and neuropathy associated with HIV-1 and do not specifically address the pathogenesis of headache. HIV-1 is nonetheless considered to be a neurotrophic virus, and HIV-1 can be found in multinucleated giant cells, microglia, mononuclear cells, and capillary endothelial cells. It has been suggested that infiltration of mononuclear cells triggers release of cytokines that activate latent infected astrocytes and express the virus. Infected macrophages and glial cells can cause toxicity by cytokine release such as TNF-α and IL-1β, which can then release arachidonic acid metabolites from astrocytes (30). Furthermore, viral proteins such as Tat and gp120 have been implicated in neurotoxicity primarily by increased production of glutamate, an excitatory amino acid associated in migraine pathophysiology (37). HIV-1 infection also causes histamine release from mast cells primarily due to viral-mediated cell death (56). As mast cells release calcitonin gene-related peptide (CGRP), a neuropeptide also implicated in migraine pathophysiology, mast cell death may also play a role in primary HIV-related headaches.

Implicating HIV-1 as a cause for primary HIV-related headaches is based on at least 3 observations in affected patients: (1) HIV-1 can be isolated from their cerebrospinal fluid (26; 36), (2) their cerebrospinal fluid contains a lymphocytic pleocytosis with or without an elevated protein, and (3) no other cause is found. These data only provide indirect evidence that HIV-1 causes headache because many neurologically asymptomatic patients have a cerebrospinal fluid lymphocytic pleocytosis with or without an elevated cerebrospinal fluid protein (28; 63). In a study of 74 Kenyan women with acute HIV-1, there was a correlation of elevated plasma viral load with a constellation of symptoms including headache, fever, vomiting, and arthralgia (34). Non-HIV-related causes, such as new-onset migraine and headache as a manifestation of depression or other neuropsychiatric illnesses, should be entertained as well.

Epidemiology

An estimated 36.9 million people currently live with HIV. Fewer than 1 million people die each year from AIDS-related illnesses, thanks to sustained access to antiretroviral therapy. Furthermore, 3 out of 4 people living with HIV now know their status and 21.7 million people are on treatment, which is a net increase of 2.3 million people since the end of 2016 (UNAIDS 2018). Approximately 1% to 2% of recently infected persons develop the acute aseptic meningitis associated with the primary infection (40). Singer and colleagues studied 191 HIV-infected individuals who were recruited by advertisements and through local sources over a 1- to 2-year period. Of those asymptomatic patients at entry, 11% complained of headaches compared with 39% with AIDS-related complex or AIDS.

Headaches are 1 of the most common medical complaints among HIV patients, with 38% to 61% suffering from headache complaints (33). In ambulatory HIV-infected persons without severe immunosuppression, the appearance of a new headache is most likely not due to an opportunistic infection or tumor (54).

Utilizing International Classification of Headache Disorders (ICHD)-II criteria, a study of 200 HIV/AIDS patients (49% female, 74% African American) determined that 21% of patients suffered from episodic migraine and an additional 11% had probable migraine. Fifty-three percent of patients fulfilled criteria for chronic migraine and another 12% could be classified as tension-type headache. Lower CD4 counts also correlated with increased headache severity and frequency and disability (33). Cerebrospinal fluid lymphocytic pleocytosis was not assessed in this study.

Prevention

Other than preventing HIV-1 infection itself through modification of high-risk behaviors as well as safety in blood products, barrier products, and medical equipment, there are no known strategies to prevent the development of HIV-related headaches. However, efforts exist to develop new HIV vaccines as well as microbicides.

Differential diagnosis

Table 6 lists the other diagnoses to consider when evaluating an HIV-infected individual for headaches in addition to the HIV-related headaches listed in Table 1.

Table 6. Differential Diagnosis of Headache in the HIV-infected Individual

• Migraine headache • Tension-type headache • Depression • Medication overuse headache • Postlumbar puncture headache • Inflammation of the cranial nerves (eg, herpes zoster) • Sinusitis

Use of and withdrawal from many recreational drugs may cause headache as well. Establishing a headache diagnosis requires sorting out the contributions from these competing possibilities.

HIV-infected individuals often undergo diagnostic lumbar punctures and are, therefore, susceptible to post-lumbar puncture headaches. In addition, facial pain can herald the onset of cranial herpes zoster and can be present in postherpetic neuralgia.

Diagnostic workup

No formal criteria exist for the workup of HIV-1 infected patients with a new headache or change in frequency or intensity of a preexisting headache disorder. The main effort is to identify signs and symptoms indicating a serious underlying cause of the headache. These "red flags" (first and worst headache; subacute headache and getting worse; headache associated with fever, nausea, and vomiting; headache associated with neurologic findings; and thunderclap headache [abrupt headache escalation within 5 minutes]) should prompt urgent neuroimaging followed by a lumbar puncture. A CT without contrast will sufficiently detect life-threatening hemorrhage, mass, or edema. It will also anticipate the lumbar puncture. An MRI with and without contrast should be performed following the CT if needed for further evaluation (22).

All HIV patients presenting with headache without neurologic findings or other complications should have recent CD4+ counts. HIV RNA level as well as exposures to Toxoplasma gondii, Treponema pallidum, and Cryptococcus neoformans should also be considered during the clinical evaluation. If exposure to syphilis is documented, even if treated in the past, brain imaging is performed followed by a lumbar puncture. Patients should also be screened for depression, effects from recently administered medications, and drug abuse, if indicated. Beyond these routine considerations, further workup is governed by the patient's degree of immunosuppression.

Tuite states that HIV patients presenting with headache and a CD4+ cell count of less than 500 cells/mm³ should be considered for brain imaging followed by a lumbar puncture (58). Other studies have looked at predictors to identify HIV-infected patients complaining of headache who do or do not need immediate imaging of the head (23; 20). Graham states that if CD4+ counts are equal to or greater than 200 cells/mm³, then patients with headaches uncomplicated by altered mental status, focal neurologic signs, or seizure are unlikely to have intracranial mass lesions; such patients may be treated with analgesics and monitored clinically. However, all patients with CD4+ counts less than 200 cells/mm³ should undergo head CT or MRI because of the high prevalence of positive imaging at this stage of HIV disease. MRI is preferred over CT because of its superior sensitivity in detecting abnormalities in this population. If imaging is noncontributory, a lumbar puncture is recommended to rule out infection (22). Routine cerebrospinal fluid analyses should include routine chemistry, microscopy, cytologic analyses, and culture and stains for bacteria, Mycobacterium, viruses, and fungi, as well as cryptococcal antigen titers, toxoplasmosis antibody titers, and cerebrospinal fluid VDRL titers.

In individuals who have not yet been diagnosed with HIV-1 infection, certain headache syndromes (aseptic meningitis, cranial herpes zoster, facial pain associated with Bell palsy, and subacute or chronic progressive headache) should prompt a detailed query for risk behaviors and, if present, HIV-1 antibody testing.

If the original HIV-1 antibody test is negative, testing should be repeated in 6 months because of the possible delay in the development of detectable serum antibodies.

Management

No effective therapy is known for the acute aseptic meningitis associated with HIV-1 infection. However, this condition is self-limited and can be treated symptomatically with antipyretics and analgesics. Recommendations for the treatment of chronic headache associated with a cerebrospinal fluid lymphocytic pleocytosis are based on anecdotal experience. Some clinicians have found that a 2-week course of oral prednisone, starting at 60 mg a day followed by a taper reduces the headache severity in many of these patients. No adverse events, such as worsening immunosuppression, have been noted with the use of steroids. Moreover, prednisone has been used with tolerable side effects in other HIV-associated diseases, such as HIV-associated myopathy and pneumocystis pneumonia. Alternative treatments exist, however, and low-dose amitriptyline, starting at 10 mg each evening, may be effective in ameliorating these chronic headaches. With few exceptions, many preventative and rescue medications that would otherwise be used for migraine treatment may also benefit HIV-infected individuals.

The treatment of migraine and tension-type headache is similar to that for the general medical population, and comprehensive reviews of headache management are available elsewhere (53). The same principles of education, modifying risk factors, abortive treatment, prophylactic treatment, and developing a treatment plan agreeable to both patient and physician apply. Several factors influence the choice of treatment, including the severity of headache, the frequency of headache, the presence of comorbid medical and psychiatric conditions, patient preferences, and access to care, including insurance coverage. Recognizing and referring or treating patients with concurrent mood and anxiety disorders may be the most important aspect in the management of many of these patients.

Because many medications used to treat tension-type and migraine headache have comparable efficacy, the governing principle of prioritizing therapy is based on managing comorbid conditions with as few medications as possible, in addition to evaluating side effect profiles. For example, antidepressants such as amitriptyline, with its sedative properties, may not be appropriate for patients with fatigue and low energy levels; selective serotonergic antidepressants, such as fluoxetine, sertraline, and paroxetine, which have less sedating properties, would likely serve these patients better. However, data demonstrating headache improvement with selective serotonergic antidepressants are limited. These serotonergic antidepressants, with their associated side effects of gastrointestinal distress and diarrhea, would also prove less useful for patients suffering from chronic diarrhea.

The physician must guard against medication abuse and avoid precipitating analgesic-overuse syndromes by instructing patients to limit caffeine consumption, limiting the use of commonly prescribed analgesics, and restricting the use of butalbital and analgesic-containing mixtures. Narcotics and butalbital-containing medications should remain a “last resort” alternative in medical management in all cases. Patients with chronic daily headache from polysubstance abuse may require inpatient withdrawal if outpatient therapy seems unrealistic. A coordinated and detailed treatment plan through a drug rehabilitation unit is essential for long-term success in treating headaches secondary to illicit substances. Comprehensive headache care may also be needed and can be achieved in dedicated headache centers.

Interactions occur between drugs used to treat HIV-associated diseases and drugs used to treat headaches (Sanford et al 1993). Although the clinical significance of most offensive interactions is unknown, it may be prudent to avoid these combinations given the number of alternative headache medications available. The most common interaction is between zidovudine and acetaminophen. Because acetaminophen decreases blood levels of zidovudine, aspirin or nonsteroidal anti-inflammatory agents should be encouraged for chronic headache treatment. Ratonavir has several significant drug interactions, including increasing the plasma concentrations of analgesics, antidepressants, calcium channel blockers, and ergotamine derivatives (13). Table 7 lists common drug interactions.

Table 7. Potential Drug Interactions Between HIV-Related Medications and Headache Medications

HIV-related medication	Headache medication	Interaction
Zidovudine Zidovudine Zidovudine Isoniazid Rifampin Ethambutol Ritonavir	Acetaminophen Indomethacin Valproic Acid Acetaminophen B-blockers Verapamil Hydrocodone, oxycodone, methadone, fentanyl, calcium channel blockers, antidepressants, ergotamine derivatives	Decreases zidovudine blood levels Decreases zidovudine blood levels Increases zidovudine blood levels Decreases metabolism of acetaminophen Decreases effect of B-blockers Decreases levels of verapamil Increases the levels of all headache medications listed

Special considerations

Pregnancy

The pharmacological principles of treating headache in pregnant women were reviewed, and they also apply in the setting of HIV-1 infection (52).