Gaurav Mathur MD
Peter A. Selwyn MD, MPH
Essentials of Diagnosis
Review of HIV/AIDS
An estimated 38 million people are infected with HIV worldwide. More than 20 million people have died of HIV or AIDS since it was first identified in 1981. The rate of infection continues to climb at a staggering pace. In 2003, five million people were newly infected. Public health workers struggle to control the epidemic while clinicians struggle to manage its devastating consequences for patients and their families: preventing and treating opportunistic infections, maintaining quality of life through increasingly sophisticated but complicated medications, and ensuring adequate social support. The task is even more daunting in HIV-infected patients who suffer from substance abuse, psychiatric illness, and marginalization due to race, gender, and poverty.
Pain is one of the most common symptoms in persons with HIV and AIDS. Pain affects up to 90% of all HIV-infected patients and is often severe. It is disappointingly undertreated, and many patients never receive effective pain management. There are many obstacles to the effective assessment and treatment of HIV pain. Unlike illnesses that cause pain in a single identifiable pattern, HIV produces a multitude of pain syndromes from a variety of causes. Patients with HIV experience pain caused directly by opportunistic infections, by the virus itself, and by antiretroviral treatment.
HIV-infected patients are susceptible to a variety of opportunistic infections and malignancies, and many of these illnesses are painful. Most of these illnesses are uncommon in the general population; moreover, opportunistic illnesses may present in different ways in different patients, fooling even the most skilled of clinicians.
Even in the absence of opportunistic infection, the HIV virus itself can cause pain and painful sequelae. HIV can cause painful arthritis and avascular necrosis of certain joints. HIV also directly infects the nervous system and causes painful neuropathies. Neurologic findings can be subtle; repeated assessments may be necessary to pinpoint the cause.
Unfortunately, antiretroviral treatments for HIV can also induce pain. Specifically, stavudine, didanosine, and zalcitabine (the latter now rarely used) have all been found to cause a painful distal symmetric polyneuropathy. Many of the antiretrovirals can induce potentially painful syndromes such as hepatitis and pancreatitis, making the treatment of HIV even more difficult.
Pain in HIV-Infected Women
HIV-infected women are at greater risk for gynecologic illnesses than non HIV-infected women. Human papillo-mavirus can cause cervical dysplasia and cervical cancer, and HIV-infected women are more at risk for human papillomavirus infection and its sequelae. Pelvic inflammatory disease and many sexually transmitted diseases are also more common in HIV-infected women. Many of these illnesses are very painful. The clinician should make every effort to evaluate the patient for gynecologic illness in the pain assessment.
HIV Pain & Substance Abuse
Injection drug use has become one of the highest exposure risk categories for HIV transmission in recent years.
Patients who have a history of substance abuse are often the most challenging patients to treat. The clinician must balance the critical need for effective pain management against the consequences of substance abuse, especially when deciding whether to prescribe opioids. There are numerous issues that cause concern, such as the risk of drug diversion by the patient, the fear that patients will use prescribed opioids to get high, and the fear that patients are lying about their pain to obtain opioids simply to feed their addiction. In addition, patients who are tolerant to large doses of opioids generally require much higher doses than opioid-naive patients.
Furthermore, clinicians may be concerned about law enforcement agencies targeting well-intentioned clinicians for prescribing opioids that were eventually diverted without the knowledge of the prescriber. It is not surprising, therefore, that pain in HIV-infected patients with current or past substance abuse is woefully undertreated. In order to effectively treat these patients, clinicians should use a variety of strategies (Table 20-1), keeping in mind the principles of sound prescribing, knowledge of legal issues in prescribing, and a commitment to reduce suffering in all patients.
Table 20-1. Approach to Pain Management in Substance Abusers with HIV Disease.
Palliative Care for AIDS%
Patients with AIDS can benefit greatly from palliative care. The recognition that the illness is beyond cure allows clinicians to focus on quality of life and thereby ease suffering. Relief of pain, dyspnea, nausea, diarrhea, and depression are examples of ways in which suffering can be improved. Antiretroviral therapy can have a great impact on health early in the course of the illness; however, as HIV infection progresses to AIDS, the side effects of highly active antiretroviral therapy (eg, diarrhea or pancreatitis), can become very troublesome. In many cases, discussing whether to discontinue antiretroviral therapy may be worthwhile, especially if a multidrug-resistant virus is suspected. Other medications can also be discontinued if burdens of treatment outweigh the benefits. At the very end of life, patients with AIDS may resemble those with cancer. Cachexia and wasting are common, and patients become severely debilitated. Oral intake is limited, consciousness declines, and breathing becomes labored and distressed. Patients may experience great pain and agitation. Just as in patients with cancer, clinicians should make every effort to keep patients with AIDS as comfortable as possible while making sure that dignity is preserved.
Clinicians should discuss goals of care with their patients, including such issues as whether or not to resuscitate in the event of death, who the patient's health care agent should be in case the patient is incapacitated, and whether or not the patient would desire artificial nutrition and hydration. It is not possible to prepare for every medical scenario, but with some clear guidelines and communication, most patients can make their wishes known. A clear and honest description of prognosis is essential to this discussion. It is also important to have these discussions early; do not wait until the patient is seriously ill to discuss how to treat serious illness.
Principles of Pain Management in HIV
The principles of pain management in HIV/AIDS are similar to those of every patient. Often, the most difficult task is simply the recognition of how severe HIV-related pain can be. Evidence demonstrates that clinicians usually underestimate and, consequently, undertreat pain.
Many patients whose pain is initially mild experience worsening of pain with disease progression. Clinicians must be empathic to their illness and use a multimodality strategy, including pharmacotherapy, interventional procedures, psychological treatment, and complementary/alternative treatment when appropriate. Most importantly, clinicians should advise patients that pain in HIV is common, but effective pain control is possible in the vast majority of cases.
The treatment of HIV-related pain must include primary therapy as well as direct pain management. Primary therapy refers to treatment of HIV disease and HIV-related complications, notably painful opportunistic infections and malignancies (eg, amphotericin B for cryptococcal infection, radiotherapy for Kaposi sarcoma.) Many opportunistic illnesses improve and pain management may be temporary; other illnesses, such as peripheral neuropathy, generally persist and pain management will be ongoing. Effective primary therapy usually substantially reduces the accompanying pain. Clinicians should be mindful that antiretrovirals-the primary therapy for HIV disease-may cause painful conditions.
In addition, direct pain management with opioids and other therapies should be thoughtfully applied to treat the pain that accompanies the primary illness. An “analgesic ladder” has been developed by the World Health Organization for the treatment of pain (see Figure 3-1). This set of guidelines suggests the initial use of nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen for mild pain and strongly supports the role of opioids in the treatment of moderate to severe pain (see Chapter 3).
For both pain and other symptoms commonly seen in palliative care, it is also important to recognize the unique possibilities for drug-drug interactions between medications used for pain and palliative care and those used for HIV-specific and related anti-infective therapy. For example, several of the nonnucleoside reverse transcriptase inhibitors (eg, nevirapine, efavirenz) as well as the rifamycins, which are used to treat mycobacterial infections, are potent inhibitors of the cytochrome P-450 enzyme system in the liver. Several of the protease inhibitors (eg, ritonavir, indivanir, saquinavir) are inhibitors of the P-450 enzyme system or its subunits to varying degrees. These pharmacologic properties may affect the metabolism of certain opioids (eg, methadone), antidepressants (eg, tricyclic antidepressants), anticonvulsants (eg, phenytoin), or other drugs when these are used together with the HIV-related medications. It is not possible to keep track of all the individual interactions, but it is important to be aware that these must be considered when providing both palliative and disease-specific care to patients with HIV/AIDS. Clinicians are strongly urged to use available print and Internet-based resources to check for drug-drug interactions in this setting (see below).
Montessori V et al. Adverse effects of antiretroviral therapy for HIV infection. CMAJ. 2004; 170:229. [PMID: 14734438]
O'Neill JF, Selwyn PA, Schietinger H, eds. A Clinical Guide to Palliative and Supportive Care for HIV/AIDS. Rockville, MD: Health Resources and Services Administration, 2003.
Piscitelli SC et al. Interactions among drugs for HIV and opportunistic infections. N Engl J Med. 2001;344:984. [PMID: 11274626]
Yeni PG et al. Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA Panel. JAMA. 2004;292:251. [PMID: 15249575]
World Health Organization. Cancer Pain Relief. Geneva: WHO, 1986. AIDS info http://www.aidsinfo.nih.gov Web-based resource for up-to-date HIV treatment consensus guidelines as well as information about drug-drug interactions and links to other resources.
Pain Syndromes in HIV
Organ systems that are often affected by pain syndromes include neurologic, musculoskeletal, gastrointestinal, and dermatologic. Often several painful processes may coexist, making assessment more complex. Clinicians who make a skillful and comprehensive assessment can relieve much of the pain associated with HIV.
Neurologically Related Pain Syndromes
Virtually all HIV-infected patients have some degree of involvement of the central nervous system or peripheral nervous system, or both, and most will have some neurologic illness during the course of the disease. Patients may be affected by pain caused directly by the effects of the virus or pain due to opportunistic infections and malignancies that affect the nervous system. Medications and treatments can also cause neurologic pain.
Headache is commonly seen in patients with HIV/AIDS (Table 20-2). Headache can signify a wide spectrum of illnesses, from benign causes, such as tension headache, to severe and life-threatening illness, such as toxoplasmosis. The clinician must include a wide differential diagnosis. It is important to recognize that several etiologies may coexist to cause headache. Some causes of headache in immunocompetent persons may present more frequently in HIV-infected persons.
Diagnosing the cause of headache can be challenging. Benign illness, such as migraine, can present with severe headache, while the headache from a dangerous illness, such as cryptococcal infection, may be mild. The quality and characteristics of the pain can sometimes be helpful, but they cannot be consistently relied upon for accurate diagnosis.
Diagnostic studies that are likely to be helpful include lumbar puncture, computed tomography (CT) scanning,
and magnetic resonance imaging (MRI). Clinical judgment is crucial in assessing which of these tests are necessary, keeping in mind that headache in the immunocompromised may need etiologic investigation even when mild.
Table 20-2. Selected Causes of Headache in HIV Disease.
HIV and cytomegalovirus can cause a subacute encephalitis that may progress over months. Headache, confusion, memory loss, seizures, and progressive dementia may develop in patients weeks to months preceding death. Cerebrospinal fluid examination findings are non-specific but may include pleocytosis and elevated protein. CT or MRI may reveal cortical atrophy.
Aseptic meningitis is a common illness that may present in any but the late stages of HIV, suggesting that it may be an immune-mediated disease. It commonly presents during primary HIV infection. Symptoms include headache, photophobia, and lymphocytic pleocytosis on cerebrospinal fluid examination.
Opportunistic cancers include primary B-cell (non-Hodgkins) lymphoma and systemic lymphoma with central nervous system involvement. Primary central nervous system lymphomas are much more commonly seen in HIV patients than in immunocompetent persons. The lymphoma causes a mass effect and consequent increased intracranial pressure. Presenting symptoms include focal neurologic deficits, including cranial nerve findings, headache, and seizure; papilledema may also be seen. In severe cases, herniation may occur with devastating consequences. Corticosteroids are helpful to reduce the mass effect. Radiation and chemotherapy can also be helpful. Systemic lymphoma may involve the central nervous system, most commonly, the leptomeninges, in about 20% of patients. Pain and other focal neurologic deficits may be alleviated by radiation. Rarely, Kaposi sarcoma involves the central nervous system.
Opportunistic infections are a common cause of headache and can be life threatening. Toxoplasmosis and cryptococcal meningitis are the two most common opportunistic causes of headache in the HIV-infected patient. Toxoplasmosis gondii accounts for 38% of all secondary central nervous system infections in AIDS patients and 28% of first seizures. The organism is a protozoan parasite, and infection occurs through ingestion of cat feces or undercooked meat, which should be avoided by immunocompromised patients and pregnant women because the illness is also dangerous to the fetus. Disease in HIV/AIDS patients is more often due to reactivation of a preexisting latent infection than to newly acquired infection. Generalized CNS symptoms, including headache, visual disturbance, cranial nerve palsies, motor or sensory disturbance, and seizures may develop. Mental status may be altered, with progression to coma and, if untreated, death. Serology is used in immunocompetent persons but is not helpful in AIDS patients. Instead, the cerebrospinal fluid may demonstrate lymphocytic pleocytosis and elevated protein levels. Contrast CT or MRI scans will demonstrate dense rounded lesions with characteristic ring enhancement.
Cryptococcus neoformans is a yeast-like fungus and is the leading cause of meningitis in HIV patients. Fever, nausea, vomiting, headache, altered mental status, and meningeal signs are common; seizures and focal neurologic deficits are not. Symptoms are thought to be due to generalized brain edema. Patients may have subacute disease for weeks or months before diagnosis. Culturing the cerebrospinal fluid, blood, or urine can help make the diagnosis; a cerebrospinal fluid latex agglutination test can provide a more rapid diagnosis. Pulmonary manifestations and systemic illness can also be present.
Syphilis is caused by Treponema pallidum, a spirochete bacteria with primary, secondary, and tertiary stages of infection. There are diverse clinical manifestations and the course may be accelerated in the presence of HIV. Neurosyphilis is generally diagnosed during the second or third stage of infection; presenting symptoms and signs include acute meningitis, deafness, stroke, or retinitis. Acute syphilitic meningitis may present with headache, neck stiffness, and cranial nerve lesions with occasional papilledema.
Tuberculosis is caused by Mycobacterium tuberculosis; transmission generally occurs through inhalation of aerosolized droplets. Although tuberculosis most commonly causes pneumonia, extrapulmonary manifestations are also common in HIV, including tuberculosis meningitis and brain abscesses. Like other forms of meningitis, tuberculosis meningitis is characterized by fever, stiff neck, and stupor that if untreated progresses to coma and death. Tubercle bacilli can form an abscess in the brain parenchyma that can also be very dangerous. Diagnosis is made by cerebrospinal fluid examination, but organisms may not be seen on smear or even culture. A low cerebrospinal fluid glucose, elevated cerebrospinal fluid protein, and lymphocytosis is suggestive. Polymerase chain reaction examination of cerebrospinal fluid is most helpful.
Antiretroviral therapy for HIV and AIDS, most notably zidovudine, can also cause headache. A history of headache that coincides with medication initiation may help guide the diagnosis. Headache is usually temporary and resolves with time, but some patients may have persistent pain. Other benign causes of headache include migraine, tension-type headache, and sinusitis; evidence suggests that migraine frequency may decrease and tension headache frequency may increase as HIV infection progresses.
Post lumbar puncture headache is typically described as a dull occipital discomfort that may radiate
to the frontal head or to the shoulders. Nausea and dizziness are common, and in severe cases may be accompanied by vomiting and diaphoresis. In some patients, supine position may help alleviate the pain. Pain usually develops hours to several days after the procedure, and is believed to be related to a reduction in cerebrospinal fluid volume due to leakage through the dura. This complication can be reduced by using a small gauge spinal needle with a non cutting rounded tip and a lateral opening. If headache is persistent, an epidural “blood patch” may be used; several milliliters of autologous blood are obtained and sterilely injected into the epidural space at the site of the lumbar puncture.
Treatment of headache should include primary therapy of the underlying illness as well as effective pain management. As in most illnesses, opioids are the mainstay of treatment, and patient-controlled analgesia is optimal in allowing the patient to participate in effective pain relief. In chronic headache, many adjuvants are available, including antidepressants, anticonvulsants, migraine-specific medications, and others (see Chapter 12). If HIV therapy is the cause of pain, the clinician should consider the benefits of changing therapies versus continuing the pain-producing medication and treating the headache.
Pain can be described as nociceptive or neuropathic. Nociceptive pain is thought to be maintained by ongoing tissue injury. In contrast, neuropathic pain is sustained by abnormal somatosensory processing due to damage to nerve tissue. It is typically characterized by the descriptions of burning and electric-type pain and is often accompanied by paresthesias and dysesthesias. On physical examination, the presence of allodynia (pain induced by nonpainful stimuli) and hyperalgesia (increased perception of painful stimuli) further suggests this diagnosis. Electrophysiologic nerve studies may reveal decreased conduction velocity, which is suggestive of demyelination, or decreased conduction amplitude, which is suggestive of axonopathy.
In HIV, neuropathic pain can be caused by a variety of illnesses (Table 20-3). In general, several different neuropathic syndromes tend to present at various times during the progression of HIV to AIDS. The syndromes can be polyneuropathies that affect many nerves in generally symmetric distributions (eg, stocking-glove pattern) or mononeuropathies that affect many nerves in patchy distributions, such as radiculopathies, plexopathies, and specific mononeuropathies. Depending on the type of nerve injury, patients may experience sensory changes, motor disturbances, or both. Pain is common in the distribution of the affected nerve(s); muscle tenderness and swelling may also be present.
Table 20-3. Causes of Neuropathic Illness in HIV and AIDS.
In the acute seroconversion stage of HIV infection, some patients acquire an acute inflammatory demyelinating polyneuropathy, which is characterized by progressive distal weakness extending proximally in a pattern similar to Guillain-Barré syndrome (Table 20-4). Patients become areflexic, but there are minimal sensory changes. This illness is thought to be autoimmune mediated and is generally self-limited; however, in severe cases, treatment with plasmapheresis, intravenous immunoglobulin, and even corticosteroids may be required. Acute and chronic demyelinating polyneuropathies may continue to occur during the clinically latent phase of infection.
As the patient enters the transition phase to immunodeficiency, susceptibility develops to zoster (shingles), a painful sensory neuritis caused by reactivation of latent herpes zoster virus, often in the distribution of a
single dermatome. A vesicular eruption develops in a dermatomal pattern several days after the onset of pain. Although the infection is self-limited, treatment with antivirals can shorten the duration of pain. Postherpetic neuralgia is a feared complication of the neuritis and is often described as an intense burning pain that may persist long after the acute infection has healed. Opioids, tricyclic antidepressants, gabapentin, and topical lidocaine have been shown to be beneficial. Topical capsaicin may be of benefit but its side effect of burning limits its tolerability.
Table 20-4. Overview of Neuropathic Pain Syndromes in HIV and AIDS.
Mononeuropathy multiplex occurs in a patchy multifocal pattern, affecting the peripheral nervous tissue apparently in a random pattern. Demyelination is the underlying disorder in a subset of patients with mononeuropathy multiplex and is thought to be autoimmune mediated, (like the demyelinating neuropathies described above), and treatment is similar. A vasculitis of the vasa vasorum is responsible for the neuropathy in many of the remainder of patients with mononeuropathy multiplex; the underlying disorder may be polyarteritis nodosa or one of the connective tissue diseases.
The late phase of HIV is characterized by immunodeficiency and the progression to AIDS. Cytomegalovirus infection of the nerve roots may develop and result in cytomegalovirus polyradiculopathy, which can cause severe pain in lumbar and sacral nerve root distributions. The illness may progress to involve the cauda equina. Ganciclovir can help arrest the disorder.
Distal sensory polyneuropathy is the most commonly seen neuropathic pain syndrome in patients with HIV or AIDS. It usually occurs relatively late in the course of the illness. Patients generally report onset of a tingling, prickly sensation on the soles of the feet or the tips of the toes. As illness progresses, sensation is lost in an ascending fashion, first throughout the foot, and motor deficits may follow. Ankle jerk reflex is generally lost, and by the time sensory disturbances reach the upper shin, similar dysesthesias may be noted in the fingertips. This distribution is a result of axonal destruction and is directly related to the length of the axon. In severe cases, disease may progress so proximally that ventilatory function may be impaired.
The treatment of neuropathic pain in HIV is similar to treatment of neuropathic pain in immunocompetent patients. Many adjuvant medications exist for the treatment of neuropathic pain in conjunction with opioids
(see Chapter 10). An anticonvulsant (such as lamotrigine, gabapentin, carbamazepine) or, less commonly, one of the tricyclic antidepressants can usually be used with moderate to good results. Selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), corticosteroids, and N-methyl-D-aspartate (NMDA) receptor agonists can also be used in the treatment of neuropathic pain (see Chapter 10). Experimental studies with recombinant nerve growth factor suggested possible efficacy, but this product is not in commercial development at this time. Recent preliminary studies have suggested possible benefit from a trans-dermal capsaicin patch in the treatment of chronic neuropathic pain in AIDS.
Primary therapy with antiretrovirals may halt the progression of neurologic damage and arrest the worsening neuropathic pain. However, in some cases, antiretrovirals may be the cause of the neuropathy and may need to be discontinued. In the case of neuropathy caused by viral or other infectious illness, primary treatment of the infection will often help improve the pain.
Belman AL. HIV-1 infection and AIDS. Neurol Clin. 2002;20:983. [PMID: 12616678]
Keswani SC et al. Incidence of and risk factors for HIV-associated distal sensory polyneuropathy. Neurology. 2003;61:279. [PMID: 12874429]
Musculoskeletal Pain Syndromes
Patients with HIV infection are at risk for painful illnesses arising in the musculoskeletal system (Tables 20-5 and 20-6). Presentations vary according to risk factors and stage of HIV infection. Pain may arise due to direct injury from HIV virus, from opportunistic illness, or from primary antiretroviral therapy. Familiarity with these pain syndromes can allow a skilled clinician to treat the underlying source of pain effectively. Note that while NSAIDs are often used to treat the inflammatory component of illness, they may not be efficacious for pain management. Opioids should be used whenever necessary to treat moderate to severe pain.
Polymyositis, also known as idiopathic inflammatory myositis, is characterized by weakness in the proximal muscles, usually in the shoulder girdle and hips. It generally occurs in the early stages of HIV disease. Insidious
muscle weakness, fatigue, and aching pain in the affected muscles develop first, although pain is commonly absent. Muscle tenderness and wasting can be found on physical examination, and erythrocyte sedimentation rate and creatine phosphokinase may be elevated. Presently, the etiology is unclear; however, evidence suggests that the illness may be due to either direct infection of muscle cells by HIV and subsequent cell death or by an autoimmune response to muscle cells harboring HIV; further studies are needed. MRI, electromyography, and muscle biopsy are generally helpful in making the diagnosis. Treatment usually includes anti-inflammatories or corticosteroids, or both. Zidovudine commonly causes a similar myopathy, possibly due to mitochondrial effects, and it may be difficult to distinguish zidovudine-induced myopathy from polymyositis; laboratory test results may also be similar. If suspected, a muscle biopsy can be helpful in distinguishing the illness. Cessation of zidovudine generally reverses the clinical findings.
Table 20-5. Painful HIV-Related Muscular Illnesses.
Table 20-6. Painful HIV-Related Skeletal Illness.
Pyomyositis is an infection of skeletal muscle tissue. Until recently, it was only commonly found in sub-Saharan Africa but is now emerging in incidence in HIV-infected persons in the United States. It tends to occur relatively late in HIV illness, often after the development of AIDS, and is usually caused by Staphylococcus aureus, although other bacteria and mycobacteria have been implicated. Large muscle groups in the lower extremities are more commonly infected, especially the quadriceps. Usually, a cramp-like muscle pain, muscle stiffness, and low-grade fevers develop first. As infection progresses, high-grade fever develops and an abscess may develop within the muscle. The muscle then begins to necrose and sepsis ensues; septic shock and death may occur if left untreated. Early diagnosis is crucial; MRI and CT scanning can be helpful. Treatment consists of antibiotics and surgical drainage.
HIV arthralgia is a very common manifestation of HIV and can occur at almost any stage of the disease, commonly occurring at the time of primary infection. Most patients experience mild to moderate pain in one or several joints that can be persistent or migratory. The etiology is unclear but is believed not to be truly inflammatory in nature. Some patients may have an acute painful arthralgia that lasts less than 24 hours, most commonly in the knee. Although symptoms may mimic septic arthritis, examination, aspiration, and radiography of the knee are generally normal. The illness is generally self-limited. HIV arthritis has been described as a self-limited sub-acute oligoarthritis that may persist from 1 week up to 6 months. Patients experience acute onset of joint pain, generally in the knees or the ankles. Synovial biopsy demonstrates a chronic mononuclear cell infiltrate; there is debate as to whether the illness is caused by direct HIV infection of the synovial tissue or by reactive immune complexes within the synovium. Primary therapy may consist of intra-articular corticosteroid injection or NSAIDs; opioids may be needed for pain control.
Acute symmetric polyarthritis bears resemblance to rheumatoid arthritis. Physical examination reveals ulnar deviation and swan neck deformities of the hands, and radiography demonstrates joint space narrowing and periarticular osteopenia. However, unlike rheumatoid arthritis, onset is generally acute and radiologic findings are seen rapidly; rheumatoid factor is generally negative.
Reactive arthritis, or Reiter syndrome, is much more common in HIV-infected persons than in immunocompetent persons, with a prevalence of 5 to 10% of the HIV-infected population. Although the etiology is not well understood, there appears to be an association with the HLA-B27 antigen, while additional evidence points to a link to some bacterial infections such as Yersinia, Campylobacter, and Shigella.
Reiter syndrome consists of a triad of arthritis, conjunctivitis, and urethritis, but the full triad is not often seen. Most patients have involvement of the feet and ankles, but the hands and other large joints can also be involved. Some patients have a mild course that resolves on its own; in others, severe arthritis may develop at multiple sites and fever may also be present. Other connective tissue sites may be involved as well, including tendons and fascia. Patients may experience tendinitis of the Achilles, rotator cuff tendinitis, and de Quervain tenosynovitis. A symptom termed “AIDS foot” may develop in some patients and is a particularly severe consequence consisting of involvement of the Achilles tendon, the anterior and posterior tibial tendons, extensor tendons, and plantar fascia. These patients may have a wide gait and ankle stiffness in order to reduce painful load on the heel. Other patients may have uveitis, oral ulcers, involvement of the glans penis, and scattered hyperkeratotic skin lesions. NSAIDs are generally helpful for primary therapy; opioids may be necessary for pain control.
It may be difficult to distinguish reactive arthritis from psoriatic arthritis, a clinically similar illness found in 2 to 3% of HIV-infected patients. Psoriatic arthritis often, but not always, presents with skin manifestations of psoriasis, including confluent circumscribed, discrete reddish, silvery-scaled maculopapules, predominantly on the elbows, knees, scalp, and trunk. Pitting of the nails is often present as well. Treatment is similar to that of reactive arthritis.
Hypertrophic osteoarthropathy is characterized by severe pain in the lower extremity, often with clubbing of the digits, nonpitting edema, and joint pain. Skin over affected areas may demonstrate edema, warmth, and a shiny appearance. Radiography reveals periosteal and subperiosteal changes in the long bones of the affected
areas. It appears to be associated with pulmonary infections, most commonly Pneumocystis jiroveci pneumonia. The condition usually resolves with treatment of the opportunistic illness.
Septic arthritis refers to the acute bacterial infection of a joint space and is very common in HIV-infected patients. Risk factors include hemophilia, injection drug use, and male homosexual sex. Patients generally complain of monoarticular pain and fever; physical examination findings are consistent with septic arthritis, and joint aspirate is helpful in diagnosis. The most common pathogen is S aureus, but many others have been implicated. The hip and knees are most commonly affected; however, HIV-infected patients can be affected in unusual locations, such as the sternoclavicular joint. Septic bursitis refers to the infection of the bursa surrounding the joint space, and commonly involved sites include the olecranon and prepatellar bursae. Plain films and MRI are helpful in making the diagnosis. Treatment of these conditions is with antibiotics, surgical debridement, and drainage.
Osteomyelitis refers to the progressive infection of bone and is commonly seen in HIV-infected patients, usually late in the disease course. Patients usually seek medical attention complaining of sudden onset of high fever, chills, and pain and tenderness of the involved bony area. Commonly involved bones include the spine and long bones. Additional riskfactors include injection drug use and vascular insufficiency. Erythrocyte sedimentation rate is elevated. Blood cultures are essential, and bone aspirate can help reveal the causative organism. Plain films are generally normal in early disease, but early findings may include periarticular demineralization of bone; bony erosion and periosteal reaction may be seen 2 weeks later. MRI is the most sensitive test, especially when soft-tissue involvement is a concern. Nuclear medicine studies may detect multifocal sites of infection. The most common pathogen is S. aureus, but many organisms have been found to cause osteomyelitis, including M. tuberculosis infection. Tuberculosis osteomyelitis can be particularly dangerous and this diagnosis should be considered in all HIV-infected patients with osteomyelitis. Treatment for osteomyelitis is very difficult, consisting of appropriate long-term antibiotic therapy (often parenteral) and surgical drainage.
Osteonecrosis, also called avascular necrosis, is the pathologic destruction of bone tissue as a result of vascular compromise. Osteonecrosis appears to be more common in the HIV-infected population, with an estimated prevalence of 4 to 5%. The precise etiology of the vascular compromise resulting in HIV osteonecrosis is unclear. In recent years, the use of protease inhibitors has been associated with an increased risk for osteonecrosis of the femoral head, through a mechanism that is not yet clear. Patients with osteonecrosis most commonly have an intermittent deep throbbing pain. The pain may begin suddenly or insidiously and is often associated with weight bearing and physical activity. However, pain can occur at rest in advance disease, while some patients with osteonecrosis never experience pain until much later in the illness. It occurs most commonly in the hip, and other sites may include the knee, shoulder, ankle, and wrists; multiple joints are frequently involved in the same patient. Radiographs, CT, and nuclear medicine studies can all be helpful, but MRI is the most sensitive test. In its early stages, management consists of reducing weight bearing on the affected joint in order to slow progression. As illness progresses, surgical intervention may be needed to revascularize, stabilize, or replace the joint. Pain may greatly intensify as the illness progresses; aggressive pain control is invaluable.
Plate AM et al. Musculoskeletal manifestations of HIV infection. AIDS Read. 2003; 13:62. [PMID: 12645490]
Tehranzadeh J et al. Musculoskeletal disorders associated with HIV infection and AIDS. Part I: infectious musculoskeletal conditions. Skeletal Radiol.2004;33:249. [PMID: 15034682]
Tehranzadeh J et al. Musculoskeletal disorders associated with HIV infection and AIDS. Part II: non-infectious musculoskeletal conditions. Skeletal Radiol.2004;33:311. [PMID: 15127244]
Gastrointestinal Pain Syndromes
HIV-infected patients are susceptible to a wide range of illnesses involving the entire gastrointestinal tract, including the oral mucosa, esophagus, stomach, pancreas, hepatobiliary tract, small and large bowel, and anorectum (Table 20-7). As with other pain manifestations in HIV, clinicians should pay heed to the diagnosis and treatment of the pain-producing illness as well as the management of the pain itself. Painful opportunistic illnesses are frequent in the gastrointestinal tract. Pain may also be caused by illnesses that are found in the non-HIV-infected persons, such as peptic ulcer disease. Antiretroviral therapy for HIV can cause painful illness as well. In addition, patients may experience pain caused by more than one etiology.
Diagnosis of gastrointestinal disorders in HIV-infected persons, such as candidiasis, may occasionally be apparent by accurate history taking and findings on physical examination. Laboratory data is usually helpful, and the skilled use of radiologic tests is generally of great value. However, additional diagnostic data is often required and may necessitate consultation with a gastroenterologist for such procedures as endoscopy and biopsy.
Disturbances in motility, absorption, and oral intolerance can result in the patient being unable to take oral medications. This is a challenge to effective pain management. The clinician should be astute to these needs and be prepared to prescribe medications that can be taken
via the transmucosal, transdermal, rectal, and parenteral routes.
Table 20-7. Selected Painful Gastrointestinal Disorders in HIV.
Treatment of the underlying illness can be complex and is essential for relief of suffering. Many illnesses respond to treatment, and the need for pain management will diminish. In addition, as HIV illness progresses, other gastrointestinal symptoms, such as nausea, vomiting, diarrhea, and constipation, may cause suffering that is no less intense. These symptoms may coexist with pain; indeed, patients may have difficulty distinguishing the cause of the intense discomfort. As illness progresses, palliative management of these symptoms must intensify as well. Fortunately, therapy is often successful even when the underlying etiology is not identified.
Odynophagia is often described as a sharp substernal pain that occurs predominantly on swallowing and can be distinguished from pyrosis, or “heartburn,” which is retrosternal wavelike pain associated with gastroesophageal reflux. Such pain deserves investigation, especially in immunocompromised persons. Causes of esophageal pain include viral, bacterial, fungal, or parasitic infection; pill esophagitis; and opportunistic malignancies. In general, endoscopy is the procedure of choice for diagnosis, and endoscopic brush biopsy can be very helpful. Other radiologic studies, such as barium swallows, are less helpful.
There are numerous infectious causes of esophagitis. Candidiasis is one of the most common causes; characteristic white plaques on the esophageal mucosa can be visualized by endoscopy. Dysphagia (difficulty in swallowing) is common, and odynophagia, while less common, can still occur. The presence or absence of oral thrush is not a reliable indicator of esophageal candidiasis. If candidiasis is suspected in an otherwise stable patient, the clinician may decide to empirically start antifungal therapy. However, if there has been no response for several days, the patient should be reassessed.
Viral etiologies of esophagitis include cytomegalovirus, herpes simplex virus, varicella-zoster virus, and a self-limited HIV esophagitis. Cytomegalovirus, the most common viral esophagitis, causes odynophagia more commonly than dysphagia. It occurs in patients who are profoundly immunodeficient and often manifests concurrently with symptomatic infection at other sites in the body, such as the retina. Cytomegalovirus esophageal ulcers are often very large and can be visualized on endoscopy, which is the procedure of choice. Primary therapy with antivirals is crucial for treatment.
Herpes simplex virus uncommonly causes a viral esophagitis with a similar presentation. Endoscopic biopsies reveal diffuse erosive esophagitis or multiple shallow ulcerations. Treatment is with antivirals.
Idiopathic esophageal ulceration can also cause odynophagia and dysphagia and is usually associated with severe immunodeficiency. Endoscopy reveals multiple ulcerations of varying depth. While the appearance may mimic other types of viral esophagitis, biopsy will demonstrate only HIV virus. Treatment includes corticosteroids, which is generally accompanied by antifungal therapy to decrease the likelihood of infection with candidiasis. Other infections that have been reported to involve the esophagus include Cryptosporidia, Pneumocystis jiroveci, Mycobacterium sp., Nocardia, and Actinomyces sp.
Opportunistic malignancies that cause esophagitis include Kaposi sarcoma and Non-Hodgkin's lymphoma. These should also be included in the differential diagnosis. In some cases, swallowed pills can cause pill esophagitis; zidovudine, zalcitabine, doxycycline, tetracycline, and clindamycin have been reported as causative agents. Pill esophagitis can be prevented by swallowing while in the upright position and following with plenty of water.
In HIV-infected patients, gastric disorders are frequently not related to HIV disease and may, in fact, be illnesses found in the general population, such as Helicobacter pylori infection. However, opportunistic disorders can cause gastric illness, especially in advanced HIV disease. Gastrointestinal illnesses can manifest with abdominal pain, nausea, vomiting, anorexia, early satiety, or hematemesis.
Cytomegalovirus can cause inflammation or ulceration of the gastric mucosa, which is best evaluated by endoscopy. Epigastric pain may be severe, but infections are often asymptomatic. Other infectious etiologies of gastritis have been reported but are less common. Kaposi sarcoma is the most common opportunistic malignancy to involve the stomach, and cutaneous illness is usually present. Patients may be asymptomatic, but pain can be severe, and hemorrhage may be present. Diagnosis is confirmed with endoscopy.
HIV-infected patients are at risk for numerous intestinal infections as well as several opportunistic malignancies. Small bowel disease may produce cramplike pain associated with nausea, vomiting, and diarrhea, which may be explosive and occur in large volumes. Malabsorption and weight loss may be present. Colitis often produces lower abdominal pain and cramping associated with urgency and tenesmus. However, there is considerable overlap in disease presentation, and it may be quite difficult to distinguish between small and large bowel illness.
Table 20-8. Common Infectious Illness in the Small and Large Intestines in HIV-Infected Patients.
Numerous bacterial, viral, and parasitic organisms can infect the small and large bowel, often causing significant pain in the process (Table 20-8). Typically, the workup begins with an extensive history and physical examination, including assessment of risk factors for exposure to enteric pathogens (eg, recent travel). This is followed by culture of the stool for enteric pathogens as well as stool examination for leukocytes, ova and parasites, and Clostridium difficiletoxin. If the cause remains unclear, upper endoscopy or colonoscopy should be considered, depending on the nature of the patient's symptoms and the presumed location of illness. In as many as 50% of cases, no cause is found. Some of these patients have AIDS enteropathy, the pathology of which is still not fully understood but thought to be caused by the HIV virus itself.
Kaposi sarcoma can involve multiple areas of the gastrointestinal tract including the colon. Patients often have cutaneous manifestations of the illness. Although colonic lesions are often clinically silent, patients may present with bleeding or abdominal pain. The lesions can become quite large and can obstruct and even perforate the bowel. NonHodgkins lymphoma and colonic adenocarcinoma can also involve the bowel. Diagnosis can usually be made by colonoscopic biopsy.
In addition to the causes of pancreatitis in the general population (eg, trauma, alcohol, gallstones), HIV-infected patients are susceptible to pancreatitis caused by opportunistic infections, including cryptosporidiosis, cytomegalovirus, Mycobacterium avium complex, and tuberculosis. Patients may also be at risk for drug-induced pancreatitis; some predisposing medications include didanosine, zalcitabine, stavudine, lamivudine, ritonavir, and pentamidine. Typically, patients feel a deep boring pain in the epigastrium that radiates to the back, accompanied by nausea and vomiting. CT scanning of the abdomen and pelvis is the best imaging technique to visualize the pancreas and differentiate fluid collections, abscesses, and other infectious etiologies. If necessary, CT-guided biopsy can be performed. Gallstones can be best visualized or excluded by ultrasonography. Endoscopic retrograde cholangiopancreatography (ERCP) can be both diagnostic and therapeutic in visualizing gallstones and removing them. Treatment of pancreatitis consists of aggressive pain control and primary therapy, including treatment of infection. Any offending drug should be discontinued.
Many opportunistic infections can cause hepatitis and patients may experience fever, abdominal pain, nausea, and vomiting, in addition to other symptoms. Jaundice may also be present. Fungal infections such as cryptococcosis, coccidiosis, histoplasmosis, and candidiasis can cause hepatocellular damage and consequent inflammatory response. Extrapulmonary tuberculosis can cause abscesses in the liver, and M avium is the most common pathogen to infect the liver, often at the later stages of the disease. Parasitic infections can also occur.
Viral infections include cytomegalovirus, Epstein-Barr virus, herpes simplex virus, and adenovirus. While not technically opportunistic infections, hepatitis B and hepatitis C viruses may coinfect many HIV-infected injection drug users. The coexistence of HIV may increase the likelihood of hepatitis B virus infection to become chronic and may accelerate the course of hepatitis C virus disease.
Opportunistic malignancies include Kaposi sarcoma, which can cause hepatomegaly and abdominal pain, and less commonly non-Hodgkins lymphoma. Hepatocellular carcinoma may be present in patients with cirrhosis.
Many medications are toxic to the liver and must be carefully assessed. Acetaminophen produces fulminant hepatic necrosis if taken in large quantities through the depletion of glutathione, which normally detoxifies the drug. Clinicians must be very careful with antiretrovirals; many of them can cause elevated transaminase levels, hepatic steatosis, and lactic acidosis, which can be very dangerous. Zidovudine, nevirapine and ritonavir have been shown to be particularly hepatotoxic. Periodic
monitoring of transaminase levels may be prudent. Other drugs can cause hepatocellular necrosis through different mechanisms, including isoniazid, methyldopa, mono-amine oxidase inhibitors, indomethacin, propylthiouracil, phenytoin, diclofenac, and halothane. Isoniazid toxicity is enhanced by coadministration of rifampin. Some of these medications can cause a persistent hepatitis that may appear clinically similar to viral hepatitis. Pain is not always present; indeed liver toxicity may remain subclinical. If medication toxicity is suspected, stopping the offending medication is the first step in pain control.
HIV-infected patients are at risk for opportunistic infections of the biliary tree and gallbladder. Fever, abdominal pain, and tenderness in the right upper quadrant are typically the presenting symptoms. Laboratory studies show elevated alkaline phosphatase levels. Gallstones lead to cholecystitis in many patients, but a substantial number have an infectious acalculous cholecystitis. Cytomegalovirus, Cryptosporidium, and microsporidians account for many of these cases, and other pathogens are not uncommon. These pathogens also commonly cause AIDS-associated cholangiopathy, or infection of the biliary tree, and symptoms may be similar. Ultrasonography, radionuclide hepatobiliary scintigraphy, and CT scanning are all diagnostic tests that can be helpful. ERCP can be diagnostic and therapeutic.
Hemorrhoidal disease is the most common anorectal disorder in both the general and HIV-infected populations, and pain can be severe. Fistulas and anal fissures can also be quite painful. Dietary modifications and stool softeners can be used to reduce hard painful stools. Patients with diarrhea may experience painful irritation of lesions, and antimotility agents may be helpful. Topical therapies may be helpful for hemorrhoids.
Homosexual men who engage in receptive anal intercourse are at risk for sexually transmitted diseases in the anorectum, including syphilis, gonorrhea, chlamydia, herpes simplex virus, and human papillomavirus. Manifestations include condyloma lesions, proctitis, and abscesses. Many of these can be very painful, and primary therapy should be directed at the infection, including antibiotics, drainage and, if necessary, surgical intervention.
Slaven EM et al. The AIDS patient with abdominal pain: a new challenge for the emergency physician. Emerg Med Clin North Am. 2003;21:987. [PMID: 14708816]
Wallace MR et al. Gastrointestinal manifestations of HIV infection. Curr Gastroenterol Rep. 2000;2:283. [PMID: 10981025]
Dermatologic Pain Syndromes
Kaposi sarcoma is caused by disregulation of vascular cell growth, and evidence points to a causative role in human herpesvirus 8. Due to transmission of the virus, the lesion has typically been seen most in homosexual men; however, Kaposi sarcoma can also develop in women who have sex with bisexual men. Lesions may occur in virtually any organ, and commonly occur on the skin, oropharyngeal mucosa, lymphatic tissue, lungs, and gastrointestinal tract. Cutaneous lesions generally present as firm macular reddish or purple colored rashes, often resembling a bruise. This is due to the vascular nature of the lesion. Cutaneous lesions are generally not painful, but lesions involving the oropharyngeal mucosa are more likely to cause pain and bleeding. Lesions involving lymphatic structures can cause painful distal lymphedema. Gastrointestinal Kaposi sarcoma can cause severe bleeding but is rarely painful. Treatments include radiation therapy, cryotherapy, and chemotherapy. Kaposi sarcoma is rarely the cause of death in AIDS patients; however, it remains a considerable source of morbidity.
HIV-infected patients are at risk for bacterial skin infections, such as S aureus as well as others. Infections can progress from localized folliculitis to frank cellulitis, furuncles, carbuncles, and abscess (Table 20-9). Secondary impetigo can superinfect other lesions, such as eczema, scabies, herpetic lesions, and Kaposi sarcoma. Bacterial infections can become very painful and, if severe, life-threatening. Treatment generally consists of topical or systemic antibiotics (or both) and when appropriate, surgical drainage.
Aphthous stomatitis are generally small (<1 cm) white circular lesions surrounded by an erythematous margin and are often disproportionately painful. They occur on soft mucosal surfaces like the inner lips, bucca, tongue, soft palate, and pharynx. The pain usually persists for 4 to 5 days, after which the ulcer heals. Though there is no clear infectious etiology, HIV patients are at risk for the progression of these lesions, and they frequently enlarge and become chronic, causing great pain, often limiting oral intake and increasing suffering. Laser ablation or intralesional corticosteroids can be used to treat the ulcers. Pain can be controlled with topical corticosteroids, topical tetracycline, and viscous topical lidocaine.
Herpes simplex virus (types 1 and 2) causes genital and oral herpes. Lesions are highly painful and are more troublesome in immunocompromised persons than in immunocompetent persons. Primary infection consists of fever and the distinctive vesicles, which burst and
form painful ulcerations; these then crust and usually heal completely. Like aphthous stomatitis, pain may greatly limit oral intake. Pain typically lasts 10 to 14 days, and the virus then recedes to the sensory ganglion where it remains latent. It can, however, be reactivated by stress or immunodeficiency, resulting in secondary infection or reactivation. Patients typically feel a prodromal tingling or burning in the affected area, followed by the development of the lesions, which last 4 to 5 days. Both systemic and topical antiherpetic therapies are available and should be used as soon as the patient feels the prodromal sensation, as duration of symptoms can be modestly reduced.
Table 20-9. Selected Painful Dermatologic Conditions in HIV and AIDS.
Herpes zoster (shingles) is caused by varicella-zoster virus. The primary manifestation of this virus is chickenpox, an illness that usually occurs in childhood. Like herpes simplex virus, the virus remains latent in sensory nerve ganglia and may be reactivated by immunodeficiency. Patients usually experience pain at the involved site 2 to 3 days before the onset of the characteristic rash; vesicles develop on an erythematous base in the distribution of a sensory dermatome. Pain may be severe. If ophthalmic involvement is suspected, an ophthalmologist should be consulted immediately in order to prevent eye involvement and vision loss. Topical remedies such as wet compresses may be helpful, and systemic treatment may consist of intravenous acyclovir, famciclovir, or valacyclovir.
Postherpetic neuralgia occurs after some cases of zoster; see the section on Neurologically Related Pain Syndromes.
Sulfonamide drugs, such as sulfamethoxazole and sulfadiazine, can cause a severe skin reaction called toxic epidermal necrolysis, which is believed to exist on a continuum of symptoms from erythema multiforme to
Stevens-Johnson syndrome. Localized painful erythema and blisters that may peel off develop; this may be accompanied by fevers, malaise, and chills. The illness can be life-threatening, and patients must be hospitalized for treatment. Some other medications that have been associated with painful rash include nevirapine, delavirdine, efavirenz, amprenavir, and fosamprenavir. Any suspected offending agent should be discontinued, and the patient should be treated immediately.
Garman ME et al. The cutaneous manifestations of HIV infection. Dermatol Clin. 2002;20:193. [PMID: 12120434]