Pain Syndrome and Peripheral Neuropathy

Pain from HIV-associated peripheral neuropathy is particularly common, and may be debilitating. Peripheral neuropathy is clinically present in approximately 30% of HIV-infected individuals and typically presents as distal sensory polyneuropathy (DSP). It may be related to HIV itself (especially at CD4 counts <200 cells/µL), to medication toxicity (eg, from certain nucleoside analogues such as didanosine or stavudine), or to the effects of chronic illnesses (eg, diabetes mellitus). Patients with peripheral neuropathy may complain of numbness or burning, a pins-and-needles sensation, shooting or lancinating pain, and a sensation that their shoes are too tight or their feet are swollen. These symptoms typically begin in the feet and progress upward; the hands may be affected. Patients may develop difficulty walking because of discomfort. Factors associated with increased risk of peripheral neuropathy include the following:

	Previous peripheral neuropathy
	Low CD4 count (<100 cells/µL)
	Prior AIDS-defining opportunistic infection or neoplasm
	Vitamin B12 deficiency
	Concomitant use of other drugs associated with peripheral neuropathy (eg, isoniazid)
	Use of neurotoxic agents (eg, alcohol)

Patients should be assessed carefully before the introduction of a potentially neurotoxic nucleoside analogue (eg, didanosine, stavudine) to avoid the use of these medications in patients at greatest risk of developing peripheral neuropathy.

Pain is significantly undertreated, especially in HIV-infected women, because of factors ranging from providers' lack of knowledge about the diagnosis and treatment of pain to patients' fear of addiction to analgesic medications. Pain, as the so-called fifth vital sign, should be assessed at every patient visit.

The patient complains of pain. The site and character of the pain will vary with the underlying cause. Ascertain the following from the patient:

Duration, onset, progression Distribution, symmetry Character or quality (eg, burning, sharp, dull) Intensity Severity (see below) Neurologic symptoms (eg, weakness, cranial nerve abnormalities, bowel or bladder abnormalities) Exacerbating or relieving factors Response to current or past treatments Past medical history (eg, AIDS, diabetes mellitus) Alcohol intake (amount, duration) Medications, current and recent (particularly zalcitabine, didanosine, stavudine, and isoniazid) Nutrition (vitamin deficiencies) Meaning of the pain to the patient

Measure vital signs (an increase in blood pressure, respiratory rate, and heart rate can correlate with pain). Perform a symptom-directed physical examination, including a thorough neurologic examination. Look for masses, lesions, and localizing signs. Pay special attention to sensory deficits (check for focality, symmetry, and distribution [such as "stocking-glove"]), muscular weakness, reflexes, and gait. Patients with significant motor weakness or paralysis, especially if progressive over days to weeks, should be evaluated emergently.

Pain assessment includes determining the type of pain: nociceptive or neuropathic. Nociceptive pain occurs as a result of tissue injury (somatic) or activation of nociceptors resulting from stretching, distention, or inflammation of the internal organs of the body. Nociceptive pain usually is well localized; may be described as sharp, dull, aching, throbbing, or gnawing in nature; and typically involves bones, joints, and soft tissue. Neuropathic pain occurs from injury to peripheral nerves or central nervous system structures. Neuropathic pain may be described as burning, shooting, tingling, stabbing, or like a vise or electric shock; it involves the brain, central nervous system, nerve plexuses, nerve roots, or peripheral nerves.

Assess the severity of the pain. Have the patient rate the pain severity on a numeric scale of 0-10 (0 = no pain and 10 = worst imaginable pain), a verbal scale (none, small, mild, moderate, or severe), or a pediatric faces pain scale (when verbal or language abilities are absent). Note that pain ratings >3 usually indicate pain that interferes with daily activities. Use the same scale for evaluation of treatment response.

Although pain in HIV-infected patients is often due to opportunistic infections, neoplasms, or medication-related neuropathy, it is important to include non-HIV-related causes of pain in a differential diagnosis. Some of these other causes may be more frequent in HIV-infected individuals. A partial list for the differential diagnosis includes:

	Anorectal carcinoma
	Aphthous ulcers
	Appendicitis
	Arthritis, myalgias
	Candidiasis, oral or esophageal
	Cholecystitis
	Cryptococcal disease
	Cytomegalovirus colitis
	Dental abscesses
	Gastroesophageal reflux disease (GERD)
	Ectopic pregnancy
	Herpes simplex
	Herpes zoster
	Kaposi sarcoma
	Lymphoma
	Medication-induced pain syndromes (eg, due to growth hormone, granulocyte colony-stimulating factor)
	Medication-induced peripheral neuropathy (eg, due to didanosine, stavudine, isoniazid, vincristine)
	Mycobacterium avium complex
	Myopathy
	Other neuropathy
	Pancreatitis
	Pelvic inflammatory disease
	Toxoplasmosis

Perform a diagnostic evaluation based on the suspected causes of pain.

Treatment

Treatment should be aimed at eliminating the source of pain, if possible. If symptomatic treatment of pain is needed, begin treatment based on the patient's pain rating scale, using the least invasive route. The goal is to achieve optimal patient comfort and functioning with minimal medication adverse effects. Use the 3-step pain analgesic ladder originally devised by the World Health Organization (WHO). Nonpharmacologic Interventions Interventions such as relaxation techniques, guided imagery, massage, reflexology, acupuncture, thermal modalities, prayer, deep breathing, and meditation can be used as adjunctive therapy at any step in the treatment plan. Pharmacologic interventions The following 3 steps are adapted from the WHO analgesic ladder. Step 1: Nonopiates for mild pain (scale 1-3) The most common agents in this step include acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) inhibitors. Acetaminophen has no effect on platelets and no antiinflammatory properties; avoid use in patients with hepatic insufficiency. Note that COX-2 inhibitors have been associated with an increased risk of cardiovascular events and should be used with caution. Tramadol (Ultram) is a centrally acting nonopiate that can be combined with NSAIDs. Avoid coadministration with selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) because of serotonin syndrome; also avoid in patients with a seizure history. Step 2: Mild opiates with or without nonopiates for moderate pain (scale 4-6) Most agents used to treat moderate pain are combinations of opioids and Step 1 agents. The most common agents are acetaminophen combined with codeine, oxycodone, or hydrocodone. Meperidine (Demerol) should be avoided because its active metabolite, normeperidine, has activating properties that may cause delirium and seizures. Chronic pain is more likely to be controlled when analgesics are dosed on a continuous schedule rather than "as needed." Sustained-release formulations of opioids should be used whenever possible. For breakthrough pain, use "as needed" medications in addition to scheduled-dosage analgesics. Step 3: Opioid agonist drugs for severe pain (scale 7-10) Morphine is the drug of choice in this step. Others used are oxycodone, hydromorphone, fentanyl, levorphanol, methadone, codeine, hydrocodone, oxymorphone, and buprenorphine. Avoid meperidine because of the increased risk of delirium and seizures. Around-the-clock, oral, sustained-release dosing will achieve optimum pain relief. Patients unable to take oral therapy may use transdermal fentanyl patches or rectal administration of sustained-release tablets. Anticipate and treat complications and adverse effects of opioid therapy, such as nausea, vomiting, and constipation. Adjunctive Treatments The addition of antidepressant medications can improve pain management, especially for chronic pain syndromes. These agents, and anticonvulsants, are usually used to treat neuropathic pain (discussed in more detail below), but should be considered for other chronic pain syndromes as well. Treatment of Neuropathic Pain Assess the underlying etiology, as discussed above, and treat the cause as appropriate. Review the patient's medication list for medications that can cause neuropathic pain. Discontinue the offending agents, if possible. Consider dosage reductions of stavudine to reduce peripheral neuropathy (consult with an HIV expert). For isoniazid regimens, ensure that patients are taking vitamin B6 (pyridoxine) regularly to avoid isoniazid-related neuropathy. Nonpharmacologic interventions for neuropathic pain The nonpharmacologic interventions described above also can be useful in treating neuropathic pain. Pharmacologic interventions for neuropathic pain Follow the WHO ladder of pain management described above. If Step 1 medications are ineffective, consider adding antidepressants, anticonvulsants, or both before moving on to opioid treatments. Antidepressants Antidepressant medications often exert analgesic effects at dosages that are lower than those required for antidepressant effects. However, as with antidepressant effects, optimum analgesic effects may not be achieved until several weeks of therapy. Tricyclic antidepressants (TCAs): Doses may be titrated upward every 3-5 days, as tolerated. Amitriptyline (Elavil): Starting dose is 10-25 mg at bedtime. Usual maintenance dosage is 25-150 mg at bedtime. Desipramine (Norpramin): Starting dose is 25 mg at bedtime. Usual maintenance dosage is 25-250 mg at bedtime. Nortriptyline (Pamelor): Starting dose is 10 mg at bedtime. Usual maintenance dosage is 20-150 mg at bedtime. Adverse effects include sedation, anticholinergic effects (eg, dry mouth, urinary retention), and orthostatic hypotension. There is a risk of overdose if taken in excess. SSRIs: See chapter Depression for dosing, side effects, and drug interactions associated with this class of agents. SSRIs are less effective than TCAs in treating chronic pain. Venlafaxine (Effexor): Starting dosage is 37.5 mg daily. Usual maintenance dosage is 75-300 mg daily in divided doses or by extended-release formulation (Effexor XR). Anticonvulsants The following may be effective for neuropathic pain. Gabapentin (Neurontin): Starting dosage is 100-300 mg 2 or 3 times daily. Usual maintenance dosage is 1,200-3,600 mg/day in divided doses. Monitor response and increase the dosage every 1-2 weeks by 300-600 mg/day. Adverse effects include somnolence, dizziness, fatigue, and nausea. Lamotrigine (Lamictal): Starting dosage is 25 mg twice daily. Usual maintenance dosage is 50-300 mg/day in divided doses. Adverse effects include sedation, dizziness, ataxia, confusion, nausea, blurred vision, and rash. Valproic acid (Depakote): Starting dosage is 500 mg twice daily. Usual maintenance dosage is 500-1,500 mg 2 or 3 times daily. Monitor valproic acid serum levels. Adverse effects include weight gain, sedation, ataxia, nausea, and diarrhea. Although phenytoin and carbamazepine have some effectiveness in treating neuropathy, they have significant drug interactions with protease inhibitors and nonnucleoside reverse transcriptase inhibitors, and their use in HIV-infected patients is limited. Substance Abuse, HIV, and Pain Some health care providers hesitate to treat pain in patients with current or past substance abuse because of concern about worsening these patients' dependence on opioids or suspicion that such patients are seeking pain medications for illicit purposes. However, the following points should be considered: Many patients with current or past substance abuse do experience pain, and this pain should be evaluated by care providers and treated appropriately. Failure to distinguish among addiction, tolerance, and dependence can lead to undertreatment of chronic pain by health care providers. Addiction (substance abuse) is a complex behavioral syndrome characterized by compulsive drug use for the secondary gain of euphoria. Pharmacologic tolerance refers to the reduction of effectiveness, over time, of a given dosage of medication. Physical dependence is the consequence of neurophysiologic changes that take place in the presence of exogenous opioids. Aberrant use of pain medications, if it develops, is best managed by an interdisciplinary team of providers from HIV clinical care, psychiatry, psychology, pharmacy, social services, and drug addition management. Drug-drug interactions between certain antiretroviral medications and methadone can decrease methadone serum concentrations (see chapter Drug-Drug Interactions with HIV-Related Medications). If this occurs, methadone dosages may need to be increased to prevent opiate withdrawal. As part of chronic pain management in patients with substance abuse, consider establishing a written pain-management contract to be signed by the clinician and the patient. The contract should: Clearly state limits and expectations for both the patient and provider Identify a single clinician responsible for managing the pain regimen Tell the patient what to do if the pain regimen is not working Describe the procedure for providing prescriptions (eg, 1 prescription given to the patient, in person, for a limited period of time, such as 1 month). List the rules for dealing with lost medications or prescriptions