Anticonvulsant therapy such as gabapentinoids (gabapentin and pregabalin) are widely used neuropathic agents. One small study on HIV-DSP demonstrated significant pain reduction and improved sleep with the use of gabapentin.14 Pregabalin, however failed to show a benefit when compared to placebo in two large multicenter trials, predominantly due to the high placebo response.15,16 Lamotrigine, another anticonvulsant, has shown benefit in conditions including trigeminal neuralgia, diabetic polyneuropathy, and complex-regional pain syndrome.17 However because of its complex titration schedule and concern of potentially serious adverse effects including Steven Johnson syndrome, it is not commonly used in neuropathic pain.
Opiate use in non-cancer related pain has been a controversial issue because of the risk of serious adverse effects and dependency. However, in severe, refractory pain, opiates may be an effective treatment both in neuropathic and nociceptive pain. Precautionary measures should include starting with immediate release formulations at the lowest effective dose, regularly assessing the risks and benefit, and discontinuing therapy once the risks outweigh the benefits. Many opiates have interactions with anti-retroviral agents, which should be considered when planning a treatment regimen (Table).
Another agent, high dose topical capsaicin, derived from chili peppers, has demonstrated significant pain reduction in HIV neuropathy up to 12 weeks post application.18,19 However, treatment availability and pain with application has limited its use. Cannabinoids have also emerged as a potential therapy for chronic neuropathic pain, with several studies that demonstrated pain reduction in HIV-DSP.20,21
Given the complexity of treating HIV-related neuropathic pain and limited evidence for most of the agents, combination therapy using agents with different mechanisms of action is often used. Furthermore, non-pharmacologic therapies, such as physical activity, cognitive behavioral therapy, and acupuncture should also be considered.
HIV-associated neurocognitive disorder
HIV-associated neurocognitive disorder (HAND) has historically been a significant cause of disability in HIV, estimated to affect up to 50% of patients.22 Presentation is often insidious. Common symptoms include cognitive slowing, impaired concentration and memory, and behavioral changes. Motor disturbances such as psychomotor slowing, gait impairment, clumsiness, and even movement disorders (eg, parkinsonian features, chorea) have also been described.
In mild cases, bedside neurological exam may be normal. Cortical findings such as aphasia is less commonly seen, suggesting predominantly subcortical involvement. MRI studies typically reveal cerebral atrophy, especially in the hippocampus and basal ganglia, often with associated bilateral and symmetrical white matter abnormalities.
Although good viral control is protective against the development of HAND early on, this condition appears to re-emerge late in the disease course in older populations. Risk factors include advanced age, low CD4 count, longer duration of HIV illness, AIDS-defining illnesses and high viral load. Medical and lifestyle (such as substance abuse) comorbidities also likely play a role.
The pathophysiology of HAND is not well understood although it is possibly multifactorial. A few contributors likely include direct cerebral toxicity from the HIV virus, chronic inflammation in the setting of HIV, elaboration of HIV-associated neurotoxins, and associated metabolic changes that increase the risk of cerebrovascular disease and amyloidosis.
Primary headache. Headaches may occur in up to 60% of HIV-infected individuals and have a wide range of potential etiologies.23 Migraine and tension-type headaches are most common.24 Lower CD4 count is associated with higher frequency and severity of these conditions.23
Migraines are treated similarly in HIV as in the general population, with a few exceptions. For example, ergots (such as dihydroergotamine) are contraindicated in patients taking protease inhibitors and non-nucleoside reverse transcriptase inhibitors because of the risk of psychosis, seizures, and gangrene, and are therefore are not typically used in the HIV population. Steroids, which are occasionally used for abortive therapy, should be used with caution because of the risk of additional immunosuppression.
Secondary headaches. CNS manifestations of HIV can occur at any point in the disease progression because of the high viral permeability through the blood brain barrier. A dull, bilateral headache can occur in patients during the prodromal stage, 2 to 4 weeks after exposure. Aseptic meningitis, manifesting with fever, meningismus, and cranial neuropathies, can also occur at any point in the disease course and are typically self-limited.
Opportunistic infections must always be considered when assessing new-onset headaches in an HIV patient and therefore warrants careful evaluation, especially in those with low CD4 count. Toxoplasmosis and progressive multifocal leukoencephalopathy are the most common focal, CNS infections associated with HIV.25
Toxoplasmosis, a parasitic infection caused by Toxoplasma gondii, can present as focal granulomas, abscesses or leptomeningitis especially in patients with CD4 count of less than 100. progressive multifocal leukoencephalopathy, caused by the John Cunningham (JC) virus, consists of patchy or confluent lesions within the white matter. Focal neurologic deficits are commonly seen in these conditions although indolent headaches can also be the primary presenting feature. Cryptococcus is another frequently seen agent, often presenting with indolent headache and confusion with or without overt signs of meningismus. CMV, seen in advanced AIDS (CD4 <50), typically causes diffuse meningoencephalitis.
Opportunistic intracranial malignancies are also potential causes of headaches and focal neurological symptoms. Primary CNS lymphoma is the most common, although systemic lymphoma with CNS metastases and intracranial Kaposi sarcoma can also occur.
Treatment of secondary headaches is centered on treating the underlying condition. However many of the abortive therapies used in treatment of primary headaches may also be used for severe or refractory pain. Opiates, which are not recommended in primary headaches, can be used with caution for severe pain in those with secondary headaches.
1. Zhou L, Kitch DW, Evans SR, et al. Correlates of epidermal nerve fiber densities in HIV-associated distal sensory polyneuropathy. Neurology. 2007;68:2113-2119.
2. Lyons J, Venna N, Cho TA. Atypical nervous system manifestations of HIV. Semin Neurol. 2011;31:254-265.
3. Moulin DE, Hagen N, Feasby TE, et al. Pain in Guillain-Barré syndrome. Neurology. 1997;48:328-331.
4. Robinson-Papp J, Simpson DM. Neuromuscular diseases associated with HIV-1 infection. Muscle Nerve. 2009;40:1043-1053.
5. Douaihy AB, Stowell KR, Kohnen S, et al. Psychiatric aspects of comorbid HIV/AIDS and pain: part 1. AIDS Read. 2007;17:310-314.
6. Frich LM, Borgbjerg FM. Pain and pain treatment in AIDS patients: a longitudinal study. J Pain Symptom Man. 2000;19:339-347.
7. Kirsh KL, Whitcomb LA, Donaghy K, Passik SD. Abuse and addiction issues in medically ill patients with pain: attempts at clarification of terms and empirical study. Clin J Pain. 2002;18(4 Suppl):S52-60.
8. Kieburtz K, Simpson D, Yiannoutsos C, et al. A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection: AIDS Clinical Trial Group 242 Protocol Team. Neurology. 1998;51:1682-1688.
9. Shlay JC, Chaloner K, Max MB, et al. Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy: a randomized controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS. JAMA. 1998;280:1590-1595.
10. Krashin DL, Merrill JO, Trescot AM. Opioids in the management of HIV-related pain. Pain Phys. 2012;15(3 Suppl):ES157-168.
11. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014;1:CD007115.
12. Aiyer R, Barkin RL, Bhatia A. Treatment of neuropathic pain with venlafaxine: a systematic review. Pain Med. 2016;18:1999-2012.
13. Ozyalcin SN, Talu GK, Kiziltan E, et al. The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache. 2005;45:144-152.
14. Hahn K, Arendt G, Braun JS, et al. A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies. J Neurol. 2004;251:1260-1266.
17. McCleane GJ. Lamotrigine in the management of neuropathic pain: a review of the literature. Clin J Pain. 2000;16:321-326.
18. Simpson DM, Brown S, Tobias J, Group, N-CS. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy. Neurology. 2008;70: 2305-2313.
19. Brown S, Simpson DM, Moyle G, et al. NGX-4010, a capsaicin 8% patch, for the treatment of painful HIV-associated distal sensory polyneuropathy: integrated analysis of two phase III, randomized, controlled trials. AIDS Res Ther. 2013;10:5.
20. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacol. 2009;34: 672-680.
21. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68:515-521.
22. Smail RC, Brew BJ. HIV- associated neurocognitive disorder. Handbk Clin Neurol. 2018;152:75-97.
23. Kirkland KE, Kirkland K, Many WJ, Smitherman TA. Headache among patients with HIV disease: prevalence, characteristics, and associations. Headache. 2012;52:455-466.
24. Evers S, Wibbeke B, Reichelt D, et al. The impact of HIV infection on primary headache. Unexpected findings from retrospective, cross-sectional, and prospective analyses. Pain. 2000;85:191-200.
25. Brew B., Miller J. Human immunodeficiency virus-related headache. Neurology. 1993;43:1098-1100.