Pain in Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome

S. Jane Marshall

Sarah Cox

Andrew S. C. Rice

I esteem it… to be clearly the office of a physician not only to restore health, but also to mitigate the pains and torments of diseases.

—Francis Bacon, “The Advancement of Learning,” 1605, IV ii, in The Works of Francis Bacon, James Spedding, Robert Leslie Ellis, and Douglas Denton Heath, eds. 15 vols, London: Longman and Co, 1860–1864;4:387

I. INTRODUCTION

Between 40% and 88% of individuals infected with human immunodeficiency virus (HIV) experience pain. This pain may occur as a consequence of the following:

HIV-induced tissue damage (e.g., myalgia and neuropathy)
HIV-related infection or malignancy (e.g., herpes virus infections and headache from cerebral lymphoma)
Immunologic repair as a consequence of HIV treatment (e.g., increased risk of herpes zoster after starting antiretroviral treatment)
Side effects of HIV treatment (e.g., nucleoside reverse transcriptase inhibitor-induced peripheral neuropathy; indinavir-induced ureteric calculi)
Causes unrelated to HIV

In general, the principles of pain management in the context of HIV differ little from those of pain management in other scenarios. However, painful peripheral neuropathy is common in HIV and requires particular attention, as does the potential for serious drug interactions with HIV therapy.

II. UPDATE ON HUMAN IMMUNODEFICIENCY VIRUS

HIV, an RNA virus, causes a predominantly cell-mediated immunodeficiency. Humans are susceptible to infection by two types of HIV: HIV-1 and HIV-2. Worldwide, HIV-1 is the most common virus associated with progressive disease, whereas HIV-2 is found predominantly in West Africa, is less infectious, and causes immunodeficiency more slowly than HIV-1.

HIV infection is a pandemic that has exceeded the projections of 10 years ago and now represents one of the ten major causes of death worldwide. The Joint United Nations Programme on HIV/AIDS reports that at the end of 2003, there were approximately 40 million people worldwide living with HIV or acquired immunodeficiency syndrome (AIDS). During the same year, there were three million deaths related to HIV. In developed countries, the prevalence of HIV continues to rise, largely owing to life-prolonging antiretroviral therapy and new infections related to high-risk behavior.

HIV infection generally occurs after transfer of infected bodily fluids. Seroconversion occurs some weeks after acute infection and 75% of individuals recall an associated influenzalike illness.

The clinical consequences of HIV infection largely correlate with the degree of immunosuppression, as reflected in the CD4 T-cell count, which, together with the HIV viral load, is used as a disease marker for monitoring disease activity/progression and the response to therapy. In untreated HIV, the viral load rises and is followed by a falling CD4 count. With effective treatment, the viral load becomes undetectable in the laboratory and the CD4 count may rise, provided immune system damage has not become irreversible. With more advanced immunologic damage, as the CD4 T-cell count falls below 500 × 10⁶ per L, patients experience increased susceptibility to opportunistic infections, diseases of the central nervous system (CNS) and malignancies, some of which are AIDS-defining illnesses, including candidiasis, cytomegalovirus disease, Kaposi sarcoma (KS), lymphoma, and Pneumocystis carinii pneumonia. If the CD4 T-cell count falls below 200 × 10⁶ per L, prophylaxis against infection with P. carinii pneumonia should be prescribed. At this level of immune dysfunction, patients are also at risk from cerebral toxoplasmosis, progressive multifocal leukoencephalopathy, dementia, and wasting disease. Cytomegalovirus infection causing retinitis and colitis and disseminated nontuberculous mycobacterial infection occur at CD4 T-cell counts less than 50 × 10⁶ per L.

Preventing the immunologic consequences of HIV infection, using complex regimens of antiretroviral drugs [highly active antiretroviral therapy (HAART)], is the most effective way of improving quality of life as well as prognosis. These drugs are administered in combination to reduce the potential for viral mutations that result in the evolution of resistant strains of HIV. The complexity of these treatment regimens dictates that therapeutic decisions must be made by HIV specialists.

Antiretroviral drugs are susceptible to drug interactions and great care should be taken when introducing other drugs to people being treated for HIV. Drug interactions have the potential
to compromise the efficacy of antiretroviral drugs, with consequential failure to suppress the viral load and the development of drug resistance (see Table 1).

III. COMMON PAIN SYNDROMES ASSOCIATED WITH HUMAN IMMUNODEFICIENCY VIRUS

1. Painful Peripheral Neuropathies in Human Immunodeficiency Virus

Peripheral neuropathy is commonly associated with HIV and can occur at any stage of HIV disease because of HIV itself, opportunistic infections, or malignancies, or as a consequence of treatment (see Table 2). A proportion of these neuropathies are associated with neuropathic pain, and particularly notable in this regard are AIDS-associated distal sensory neuropathy (AADSN), antiretroviral toxic neuropathy (ATN), and herpes zoster-associated pain.

(i) Acquired Immunodeficiency Virus–associated Distal Sensory Neuropathy (AADSN)

AADSN has an incidence of approximately 35% in subjects with moderate to severe immunosuppression. AADSN has the features of a distal axonal sensorimotor polyneuropathy, predominantly affecting small fibers. Sensory loss, paresthesias, dysesthesias, burning pain, and lancinating pain are frequent features. Large-fiber symptoms such as motor weakness of the intrinsic muscles of the feet can complicate advanced AADSN.

Risk factors for the development of AADSN include increasing age, high viral load (a viral load of >10,000 copies per mL is associated with a 2.3-fold greater risk for the development of AADSN than a viral load of <500 copies per mL), and reduced CD4 count (CD4 <750 × 10⁶ per L increases the risk of AADSN >100-fold, but the association is weaker than with viral load).

The underlying pathologic mechanism of AADSN is unknown, although an hypothesis currently receiving much attention is a HIV glycoprotein 120 (GP120)-induced toxicity of primary sensory neurones, possibly by GP120 acting as a co-ligand for chemokine receptors expressed by dorsal ganglion cells.

(ii) Antiretroviral Toxic Neuropathy

Some of the nucleoside reverse transcriptase inhibitors (NRTIs) used to treat HIV infection have been associated with a distal axonal sensorimotor polyneuropathy, which is possibly a mitochondrial neuropathy. ATN is often clinically indistinguishable from AADSN and the conditions may, of course, overlap. Sometimes, ATN can be deduced from the temporal relation to NRTI use and cessation. Stavudine (d4T), didanosine (ddI), and zalcitabine (ddC) have all been implicated. In individuals receiving ddC, painful peripheral neuropathy has been reported in 15% to 25% of patients. Combining dideoxy-nucleoside analogs has an additive or even synergistic effect on ATN development. Other risk factors include elevated viral load, dose or cumulative dose of NRTI, increased age, preexisting neuropathy, advanced disease, coprescription with other drugs causing neuropathies, for example, thalidomide, isoniazid, or vincristine, or coprescription of hydroxyurea as part of a salvage regime.

Table 1. Examples of drug interactions between antiretroviral drugs and drugs used in pain management

Class of Drug	Example	Comment
Analgesics	Fentanyl Methadone	Fentanyl clearance decreased by ritonavir Methadone withdrawal reported with nevirapine and efavirenz
Antacids		Reduced absorption of delavirdine and protease inhibitors
Antibiotics	Rifampicin Metronidazole Isoniazid	Rifampicin clearance reduced by protease inhibitors Antabuse reaction with alcohol in oral solution of amprenavir and Kaletra Additive toxicity with drugs causing peripheral neuropathy, for example, d4T
Anticonvulsants	Phenytoin Carbamazepine	Avoid with all NNRTIs and protease inhibitors, will lead to reduced levels and potentially loss of efficacy of antiretrovirals As for phenytoin
Antidepressants	Trazadone Amitriptyline	Ritonavir inhibits metabolism of these antidepressants leading to increased effects
Antihistamines	Terfenadine Pimozide	Avoid with efavirenz as risk of arrhythmias Avoid with protease inhibitors because of reduced metabolism of pimozide
Antipsychotics	Haloperidol Olanzapine Risperidone	Caution with ritonavir as metabolism of antipsychotics is reduced
Oral contraceptives		Reduced efficacy with efevirenz, nevirapine, and most protease inhibitors
Sedatives	Diazepam Triazolam Alprazolam Midazolam	Caution with ritonavir, which enhanced sedative effect Caution with protease inhibitors, enhanced sedative effect
NNRTI, nonnucleoside reverse transcriptase inhibitors. From Davies E. Drugs. In: Gazzard B, ed. AIDS care handbook. London, UK: Mediscript, 2002, with permission.

Table 2. Examples of peripheral neuropathies associated with human immunodeficiency virus

Early stages (immune dysregulation)
–Acute inflammatory demyelinating polyradiculopathy
–Chronic inflammatory demyelinating polyradiculopathy
–Vasculitic neuropathy
–Brachial plexopathy
–Cranial mononeuropathy
–Multiple mononeuropathies
Mid and late stages (HIV-1 replication driven)
–AIDS-associated distal sensory neuropathy (AADSN)
–Autonomic neuropathy
Late stages (opportunistic infection and malignancy)
–CMV polyradiculopathy
–CMV mononeuritis multiplex
–Acute herpes zoster/postherpetic neuralgia
–Syphilitic radiculopathy
–Tuberculosis polyradiculomyelitis
–Lymphomatous polyradiculopathy
–AIDS cachexia neuropathy
All stages
–Antiretroviral toxic neuropathy (ATN)
–Nucleoside reverse transcriptase inhibitors (e.g., ddI, DDC, D4t)
–Other drugs (e.g., vincristine, ethambutol, thalidomide)
Other causes, for example,
–Nutritional (B₁₂, B₆)
–Alcohol, diabetes, etc.

HIV, human immunodeficiency virus; CMV, cytomegalovirus; AIDS, acquired immunodeficiency syndrome.
From Verma A. Epidemiology and clinical features of HIV-1 associated neuropathies. J Peripher Nerv Syst 2001;6:8–13, with permission.

Discontinuing or reducing implicated NRTIs may lead to symptomatic improvement but will reduce therapeutic options for virologic control. Decisions regarding antiretroviral therapy are complex and must be made by a specialist in HIV disease.

After a decision to terminate therapy with a NRTI there can be a “coasting period” of 4 to 8 weeks, when symptoms may even worsen. Signs and symptoms may be more easily reversed with early diagnosis; hence the need to assess those on dideoxy-NRTIs appropriately.

(iii) Pain Management in Peripheral Neuropathy

Because ATN and AADSN present with similar clinical pictures, and no specific disease-altering therapies are currently available, pain management in these conditions will be discussed as a single entity.

Peripheral neuropathies in the context of HIV infection must be appropriately investigated and other neuropathies, both HIV-related and coincidental neuropathies, excluded. This especially applies to other distal axonal sensorimotor polyneuropathies with

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