Pain Syndrome and Peripheral Neuropathy

Background

The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage." Pain is subjective, it is whatever the patient says it is, and it exists whenever the patient says it does. Pain is a common symptom in people with HIV infection, especially those with advanced disease. It occurs in 30-60% of HIV/AIDS patients and can diminish their quality of life significantly. Like cancer patients, HIV patients experience an average of 2.5 to 3 types of pain at once. Pain in HIV-infected patients may have many causes (as discussed below).

Pain is significantly undertreated, especially among 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.

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 of <200 cells/µL), to medication toxicity (e.g., from certain nucleoside analogues such as stavudine or didanosine), or to the effects of chronic illnesses (e.g., 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 also may be affected. Patients may develop difficulty walking because of discomfort, or because they have difficulty feeling their feet on the ground. Factors associated with increased risk of peripheral neuropathy include the following:

  • Previous peripheral neuropathy
  • Low CD4 count (<200 cells/µL)
  • Previous AIDS-defining opportunistic infection or neoplasm
  • Vitamin B12 deficiency
  • Exposure to stavudine or didanosine
  • Use of other drugs associated with peripheral neuropathy (e.g., isoniazid, dapsone, metronidazole, hydroxyurea, thalidomide, linezolid, ribavirin, vincristine)
  • Use of other neurotoxic agents (e.g., alcohol)
  • Diabetes mellitus

Patients should be assessed carefully before the introduction of a potentially neurotoxic medication (including stavudine or didanosine), and the use of these medications for patients at high risk of developing peripheral neuropathy should be avoided.

S: Subjective

Self-report is the most reliable method to assess pain.

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 (e.g., burning, sharp, dull)
  • Intensity
  • Severity (using the 0-10 scale; see Figure 1)
  • Neurologic symptoms (e.g., weakness, cranial nerve abnormalities, bowel or bladder abnormalities)
  • Exacerbating or relieving factors
  • Response to current or past pain management strategies
  • Past medical history (e.g., AIDS, diabetes mellitus)
  • Psychosocial history
  • Substance abuse and alcohol use history (amount, duration)
  • Medications, current and recent (particularly zalcitabine, didanosine, stavudine, and isoniazid)
  • Nutrition (vitamin deficiencies)
  • Meaning of the pain to the patient

Measuring the severity of the pain: Have the patient rate the pain severity on a numeric scale of 0-10 (0 = no pain; 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.

Figure 1. Faces Pain Rating Scale (0-10)

Faces Scale from 1-10

Figure 1. Faces Pain Rating Scale (0-10)

Faces Scale from 1-10

Quick screen for peripheral neuropathy: Ask about distal numbness and check Achilles tendon reflexes. Screening for numbness and delayed or absent ankle reflexes has the highest sensitivity and specificity among the clinical evaluation tools for primary care providers. For a validated screening tool, use the ACTG Brief Peripheral Neuropathy Scale (BPNS) to scale and track the degree of peripheral neuropathy (see www.hiv.va.gov/provider/manual-primary-care/peripheral-neuropathy.asp#S4.2X).

O: Objective

Measure vital signs (increases in blood pressure, respiratory rate, and heart rate can correlate with pain). Perform a symptom-directed physical examination, including a thorough neurologic and musculoskeletal 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.

To evaluate peripheral neuropathy: Check ankle Achilles tendon reflexes and look for delayed or absent reflexes as signs of peripheral neuropathy. Distal sensory loss often starts with loss of vibratory sensation, followed by loss of temperature sensation, followed by onset of pain. Findings are usually bilateral and symmetric.

A: Assessment

Pain assessment includes determining the type of pain, for example, nociceptive, neuropathic, or muscle spasm pain.

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. It 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. It is associated with decreased sensation and hypersensitivity.

Muscle spasm pain can accompany spinal or joint injuries, surgeries, and bedbound patients. It is described as tight, cramping, pulling, and squeezing sensations.

Although pain in HIV-infected patients can result from 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 (e.g., owing to growth hormone, granulocyte colony-stimulating factor)
  • Medication-induced peripheral neuropathy (e.g., owing to didanosine, stavudine, isoniazid, vincristine)
  • Other causes of peripheral neuropathy: diabetes, hypothyroidism, B12 deficiency, syphilis, cryoglobulinemia (especially in patients with hepatitis C coinfection)
  • Mycobacterium avium complex
  • Myopathy
  • Pancreatitis
  • Pelvic inflammatory disease
  • Toxoplasmosis

P: Plan

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

Treatment

Figure 2. Pharmacologic Approaches to Pain Management: WHO Three-Step Ladder

3 step pain ladder showing treatments for ascending levels of pain

Adapted from World Health Organization. Cancer Pain Relief and Palliative Care, Report of a WHO Expert Committee. Geneva: World Health Organization; 1990.

Note: "Adjuvants" refers either to medications that are coadministered to manage an adverse effect of an opioid or to so-called adjuvant analgesics that are added to enhance analgesia.

Figure 2. Pharmacologic Approaches to Pain Management: WHO Three-Step Ladder

3 step pain ladder showing treatments for ascending levels of pain

Adapted from World Health Organization. Cancer Pain Relief and Palliative Care, Report of a WHO Expert Committee. Geneva: World Health Organization; 1990.

Note: "Adjuvants" refers either to medications that are coadministered to manage an adverse effect of an opioid or to so-called adjuvant analgesics that are added to enhance analgesia.

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 (not necessarily zero pain) with minimal medication adverse effects. Use the three-step pain analgesic ladder originally devised by the World Health Organization (WHO); see Figure 2.

Nonpharmacologic interventions

The following interventions can be used at any step in the treatment plan:

  • A therapeutic provider-patient relationship
  • Physical therapy
  • Exercise
  • Relaxation techniques
  • Guided imagery
  • Massage
  • Biofeedback
  • Reflexology
  • Acupuncture
  • Thermal modalities (hot and cold compresses or baths)
  • Transcutaneous electrical nerve stimulation (TENS)
  • Spiritual exploration
  • Prayer
  • Deep breathing
  • Meditation
  • Enhancement of coping skills
  • Self-hypnosis
  • Humor
  • Distraction
  • Hobbies

Pharmacologic interventions

Principles of pharmacologic pain treatment

  • The dosage of the analgesic is adjusted to give the patient adequate pain control.
  • The interval between doses is adjusted so that the pain control is uninterrupted. It can take 4-5 half-lives before the maximum effect of an analgesic is realized.
  • 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. When using opiates for both scheduled analgesia and breakthrough pain, a good rule of thumb is to use 10% of the total daily dosage of opiates as the "as needed" opiate dose for breakthrough pain.
  • Oral administration has an onset of analgesia of about 20-60 minutes, tends to produce more stable blood levels, and is cheaper.
  • Beware of the risk of prolonged analgesic half-lives in patients with renal or hepatic dysfunction.
  • Caution when using combination analgesics that are coformulated with ingredients such as acetaminophen, aspirin, or ibuprofen. Determine the maximum daily dosage of all agents.

The following three steps are adapted from the WHO analgesic ladder. Agents on higher steps are progressively stronger pain relievers but tend to have more adverse effects.

Step 1: Nonopiates for mild pain (pain scale 1-3)

  • The most common agents in this step include acetaminophen (650-1,000 mg PO Q6H as needed) and nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen 600-800 mg PO TID with food, and cyclooxygenase-2 (COX-2) inhibitors such as celecoxib and rofecoxib.
  • A proton-pump inhibitor (such as omeprazole) can decrease the risk of gastrointestinal bleeding when using NSAIDs.
  • Acetaminophen has no effect on platelets and no antiinflammatory properties; avoid use in patients with hepatic insufficiency, and in general limit to 4 g per day in acute use (or 2 g per day for patients with liver disease). Monitor liver function tests in chronic use.
  • NSAIDs and acetaminophen can be used together for synergism.
  • Note that COX-2 inhibitors have been associated with an increased risk of cardiovascular events and should be used with caution.

Step 2: Mild opiates with or without nonopiates for moderate pain (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. Codeine can be dosed as codeine sulfate, separately from acetaminophen. Beware of acetaminophen toxicity in these combination drugs.
  • Other agents include buprenorphine (partial opiate agonist).
  • Tramadol (Ultram) is a centrally acting nonopiate that can be combined with NSAIDs. As with opiates, it is prone to abuse. Tramadol lowers the seizure threshold; avoid use for patients with a seizure history. Avoid coadministration with selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) because of the risk of serotonin syndrome.

Step 3: Opioid agonist drugs for severe pain (pain scale 7-10)

  • Morphine is the drug of choice in this step. Start with short-acting morphine and titrate the dosage to adequate pain control, then divide the 24-hour total in half to determine the dosing for the sustained-release morphine, given Q12H. When converting from IV to PO morphine, PO dosage is about two to three times the parenteral dosage.
  • Other agents 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, sustained-release PO dosing will achieve optimum pain relief.
  • Patients unable to take PO therapy may use transdermal fentanyl patches or do rectal administration of sustained-release tablets such as long-acting morphine. Note that the onset of analgesia with fentanyl patches can take more than 12 hours, and the analgesic effect can last more than 18 hours after the patch is removed.
  • Anticipate and treat complications and adverse effects of opioid therapy, such as nausea, vomiting, and constipation. Constipation often leads to nausea and can be prevented with prophylactic stool softeners (such as docusate) and stimulant laxatives (such as senna).

Adjunctive treatments

The addition of antidepressant medications can improve pain management, especially for chronic pain syndromes. These agents, and anticonvulsants, usually are used to treat neuropathic pain (discussed in more detail below), but should be considered for treatment of 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. For patients on stavudine or didanosine, in particular, switch to another nucleoside analogue if suitable alternatives exist, or at least consider dosage reduction of stavudine to 30 mg BID (consult with an HIV expert). For patients on isoniazid, ensure that they are taking vitamin B6 (pyridoxine) regularly to avoid isoniazid-related neuropathy.

Nonpharmacologic interventions for neuropathic pain

The nonpharmacologic interventions described above 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. As with antidepressant effects, optimum analgesic effects may not be achieved until several weeks after starting therapy.

  • Tricyclic antidepressants (TCAs): Note that ritonavir and other protease inhibitors, and the pharmacokinetic booster cobicistat, may increase the level of TCAs, so start at the lowest dosage and titrate up slowly. Dosages may be titrated upward every 3-5 days, as tolerated. In general, TCAs are best avoided in elderly patients.
    • Nortriptyline (Pamelor): Starting dosage is 10-25 mg QHS. Usual maintenance dosage is 20-150 mg QHS.
    • Desipramine (Norpramin): Starting dosage is 25 mg QHS. Usual maintenance dosage is 25-250 mg QHS.
    • Imipramine: Starting dosage is 25 mg QHS. Usual maintenance dosage is 25-300 mg QHS.
    • Amitriptyline (Elavil): Starting dosage is 10-25 mg QHS. Usual maintenance dosage is 25-150 mg QHS. Amitriptyline has the highest rate of adverse effects among the TCAs, so other agents typically are preferred.

Adverse effects include sedation, anticholinergic effects (e.g., dry mouth, urinary retention), altered mental status, QT prolongation, arrhythmias, and orthostatic hypotension. Monitor TCA levels and EKG at higher dosage levels. There is a significant risk of overdose if taken in excess.

  • SSRIs: See chapter Major Depression and Other Depressive Disorders 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). Note that there are limited data on using venlafaxine for patients with HIV infection.
  • Duloxetine (Cymbalta): Starting dosage is 30-60 mg daily. Dosages of >60 mg per day are rarely more effective for either depression or pain treatment. Note that there are limited data on using duloxetine for patients with HIV infection.

Anticonvulsants

The following agents may be effective for neuropathic pain:

  • Gabapentin (Neurontin): Considered first-line for HIV sensory neuropathy for its tolerability. Starting dosage is 100-300 mg QHS; may be increased every 3-5 days to BID or TID to achieve symptom relief. Monitor response and increase the dosage every 1-2 weeks by 300-600 mg/day. Usual maintenance dosage is 1,200-3,600 mg/day in divided doses. Adverse effects include somnolence, dizziness, fatigue, weight gain, and nausea. To discontinue, taper over the course of 7 or more days.
  • Pregabalin (Lyrica): Starting dosage is 25-50 mg TID; may be increased by 25-50 mg per dose every 3-5 days as tolerated to achieve symptom relief. Maximum dosage is 200 mg TID. Adverse effects are similar to those of gabapentin. To discontinue, taper over the course of 7 or more days.
  • Lamotrigine (Lamictal): Starting dosage is 25 mg QOD; titrate slowly to 200 mg BID over the course of 6-8 weeks to reduce the risk of rash (including Stevens-Johnson syndrome). Adverse effects include sedation, dizziness, ataxia, confusion, nausea, blurred vision, and rash. Note that lopinavir/ritonavir (Kaletra) may decrease lamotrigine levels; higher dosages may be needed. To discontinue, taper over the course of 7 or more days.
  • 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 with HIV-infected patients is limited. Topiramate and valproic acid have been used for migraine prophylaxis and anecdotally may be useful for treating peripheral neuropathy, but have not been well-studied in HIV-related neuropathies.

Topical therapy

  • Capsaicin cream (0.075%, 0.1%): Capsaicin inhibits the secretion of substance P and has been found to be effective for the management of pain associated with arthritis and neuropathy. It may be applied BID or TID. Patients must be instructed to wash their hands well after applying to avoid spreading the residual cream to sensitive areas such as the nose or eyes. It may cause burning.

Treatment of Muscle Spasm Pain

Stretching, heat, and massage may help the pain of muscle spasm. This pain also can respond to muscle relaxants such as baclofen, cyclobenzaprine, tizanidine, benzodiazepines, as well as intraspinal infusion of local anesthetics for spinal injuries.

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 addiction 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 (e.g., one 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.

Patient Education

  • Pain management is part of HIV treatment, and patients should give feedback to allow the best treatment decisions. If pain persists for more than 24 hours at a level that interferes with daily life, patients should inform their health care provider so that the plan can be changed and additional measures, if needed, can be tried.
  • Patients should not expect full pain relief in most cases, but enough relief that they can perform their daily activities.
  • "Mild" pain medications (e.g., NSAIDs, aspirin, acetaminophen) usually are continued even after "stronger" medications are started because their mechanism of action is different from that of opiates. This combination of pain medication has additive effects, so that pain may be controllable with a lower narcotic dosage.
  • Patients taking "around-the-clock" medications should take them on schedule. Those taking "as needed" medications should take them between doses only if they have breakthrough pain.
  • Patients who are prescribed opiates should be advised to take no more than the prescribed dosages. Misuse or inappropriate use can result in overdose.
  • Opiates may cause severe constipation. Patients must remain hydrated and will likely need stool softeners, laxatives, or other measures. They should contact their health care provider promptly if constipation occurs.
  • Patients taking opiates should avoid driving and operating machinery.

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