Chapter 48. Pain in HIV and AIDS

In the era of highly active antiretroviral therapy, HIV-infected patients live longer and healthier lives, which makes relief of pain associated with the complications of HIV infection an important factor in improving the quality of life. Relief of acute pain is important not only because pain relief affects the quality of life of caregivers as well as the individual suffering pain, but also because unrelieved pain can become chronic pain, which is much more difficult to manage because a vicious cycle that sustains pain develops.1,2

Acute pain may be classified in various ways, but is usually more or less directly related to some pathologic condition, although the intensity of the pain experienced may be out of proportion to the physiologic cause. When unrelieved acute pain has become chronic pain (often called “benign” when it is not associated with malignancy), special management considerations not found in acute pain become important.

A variety of studies have found the prevalence of pain in patients with HIV disease to vary from 40% to 60%, with even higher rates of pain found in inpatient settings and in patients near the end of life.3–5 Although different risk groups (eg, men who have sex with men, intravenous drug users, women) have different degrees of unrelieved pain, in general pain in HIV-infected individuals is underdiagnosed and undertreated. In one survey, only 7.3% of 110 patients with AIDS who reported “severe” pain received a strong opioid according to treatment guidelines, whereas 11.8% received no analgesic and 39.1% received a nonsteroidal anti-inflammatory drug.6

A French study7 found that doctors underestimated pain severity in more than half (52%) of AIDS patients and that only a fifth (21%) received a strong opioid, whereas 57% received no analgesic treatment. This is somewhat higher than a recent estimate based on a meta-analysis of 15 studies that found a median point prevalence of chronic pain of 15% (range 2% to 40%) in adults.8

Many studies show that the intensity of pain in HIV disease is comparable to that experienced by cancer patients. However, a patient with AIDS often experiences several painful syndromes simultaneously. Table 48-1 lists some causes of HIV-related pain.

Painful syndromes may be nociceptive, neuropathic, or idiopathic. Nociceptive (somatic or visceral) pain, which is mediated by pain receptors, accounts for the majority of painful syndromes reported by ambulatory AIDS patients. Nociceptive pain is usually effectively relieved by conventional analgesics. Although non-opioid analgesics may be enough in many situations, a strong opioid may be necessary to effectively manage some severe nociceptive pain syndromes. Neuropathic pain, which is due to damage within the nervous system, may occur in a quarter of patients with HIV disease, who may also be experiencing nociceptive pain. Often neuropathic pain is poorly localized and described as a sensation other than pain, for example, burning, shooting, tingling, itching, or crawling. Adjuvant analgesics, often with conventional analgesics given concurrently, are the treatment of choice for neuropathic pain.

Studies have shown that pain is dramatically undertreated in patients with HIV disease and that opioids in particular are underprescribed.9

In a recently published study of 199 ambulatory AIDS patients in New York City, pain management was inadequate in 83% (165/199).9 This sample included a high proportion of women (only 36% were men), of African-Americans and Hispanics (only 27% were white), and drug users (only 15% were homosexuals).9Table 48-2 lists the most frequently patient-endorsed barriers to pain management, which focus on potential addiction and, to a lesser extent, on side effects. Effective pain management should address such patient-related barriers as well as those related to clinicians and the health care system.9

The most well-established principles for pain relief have been developed for the management of pain in patients with cancer10–12 and, more recently, patients with chronic pain.13 However, patients with HIV disease are typically younger and less psychologically prepared for the consequences of devastating illness and chronic pain than cancer patients and older patients with chronic pain due to arthritis. In addition, patients with HIV disease are often taking a variety of medications that are metabolized by the cytochrome P450 system and are likely to cause drug interactions. In patients with HIV disease, diarrhea, either associated with various opportunistic infections or with antiretroviral drug therapy, can complicate use of sustained-release oral analgesic formulations. Finally, concomitant drug abuse is common in patients with HIV disease, which presents a significant barrier to effective pain relief. The general principles of pain management are largely derived from experience with pain associated with cancer (Table 48-3).

The WHO three-step analgesic ladder suggests initial treatment with a non-opioid, typically acetaminophen, aspirin, or a nonsteroidal anti-inflammatory drug (NSAID) for mild to moderate pain.10 These agents are all associated with a “ceiling effect,” that is, higher doses do not increase analgesia but do increase toxicity, which is increasingly recognized as quite significant, especially to the gastrointestinal (GI) system.

If the pain persists or increases, the second step is a weak opioid, often in the form of a combination product that includes a weak opioid and acetaminophen, aspirin, or ibuprofen. The pain relief available from weak opioids is limited, especially if they are combined with an agent that has a ceiling effect. Because hepatic disease is common in patients with HIV disease, acetaminophen-containing formulations should be avoided because of potential hepatotoxicity.

For moderate to severe pain or for mild to moderate pain that is uncontrolled by a step 1 or step 2 agent, a strong opioid is indicated. For chronic pain, patients should receive adequate doses of a long-acting agent around the clock with a short-acting agent available for breakthrough pain as needed. Long-acting opioid treatments currently available are oral formulations of morphine and oxycodone and transdermal fentanyl. The short-acting agent for breakthrough pain does not have to be the same chemical entity as the long-acting agent. Often, the short-acting opioid is used before instituting treatment with a long-acting opioid. The amount of the rescue medication is used to adjust the dose of the long-acting medication.

The general strategies to control pain in patients with HIV disease are similar to those for cancer pain but also include considerations specific to HIV disease such as the observation that patients often experience several painful syndromes simultaneously (Table 48-4 and Table 48-5).

Since self-report is the primary source of information about pain and pain relief, consistent use of one of the validated intensity/severity rating systems (eg, numerical, visual analog, happy/sad faces) is very helpful. Systematically monitor and record information about side effects and quality of life.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are effective for a variety of mild to moderate painful syndromes, especially when the pain is due to inflammation. These drugs, alone or in combination with weak opioids, are limited by a ceiling effect. Although there are many different NSAIDs, toxicity, especially GI toxicity, is common to all of them. NSAIDs can also damage renal function. Acetaminophen, particularly, is associated with liver toxicity. These highly protein-bound drugs can interact with other highly protein-bound medications, including HIV protease inhibitors. Masking fever may delay diagnosis of certain opportunistic infections.

Opioids are effective against many types of pain, especially nociceptive pain. There is no ceiling effect for the pure agonist opioids such as morphine, hydromorphone, and fentanyl. Also, opioid therapy has not been associated with major organ toxicity even in long-term use. Patient response to opioids varies, and some patients require sequential trials of several different opioids before an effective and well-tolerated regimen is identified.14

Opioid dose can be increased until pain is relieved or until side effects limit therapy. Constipation, sedation, and nausea are the most common side effects. Opioid side effects are usually manageable. Many practitioners manage these side effects preemptively. The prevalence of diarrhea is high among patients with HIV disease, so constipation is usually not a problem. Antiemetics to control nausea may also cause sedation. Use of caffeine or psychostimulants (dextroamphetamine, methylphenidate, or pemoline) may be helpful. In most cases, pain management with opioids, such as methadone maintenance, is fully compatible with normal function. Instructions to limit driving or other activities is not given unless overt impairment is observed.15

Although respiratory depression may occur and can be life-threatening, it is rare in patients who have been receiving long-term opioid therapy, even at high doses. Opioid antagonists (ie, naloxone) should be available for patients initiating opioid therapy.

Weak opioids are often used when stronger opioids are necessary, which results in inadequate pain relief. A patient with moderate to severe pain should receive a strong opioid initially, with the dose increased until effective pain relief is achieved. Dose titration is limited by the customary formulations, combining a weak opioid and aspirin, acetaminophen, or ibuprofen. Codeine is relatively emetogenic and constipating, relative to its analgesic potency. Dihydroxycodone and hydrocodone are stronger than codeine but not as strong as oxycodone. Tramadol, a nonopioid with dual-analgesic action (modest affinity for the opioid μ-receptor and inhibition of uptake of norepinephrine and serotonin) is generally considered equivalent in analgesic power to codeine.16,17

Morphine is the prototypical strong opioid and is available in a wide variety of short-acting,immediate-release formulations. Onset of analgesia begins within 30 minutes of oral administration and usually persists for 3 to 4 hours. Maintaining effective levels of morphine with these formulations requires frequent administration, and these formulations are best used to initiate analgesia and to treat breakthrough pain in patients maintained on a long-acting, sustained-release opioid formulation. The usual initial oral dose of morphine for adults and children weighing more than 50 kg (110 lb) is 30 mg every 3 to 4 hours around the clock, which is three times the parenteral dose. Oxycodone, which is 1.5 to 2 times as potent as morphine, should be classed as a strong opioid along with morphine and hydromorphone. The usual initial oral dose of oxycodone is 5 to 10 mg every 3 to 4 hours. Both morphine and oxycodone are available in long-acting formulations.

Hydromorphone is a strong opioid that can be used instead of morphine for patients who do not tolerate morphine or if extremely high doses are needed. The usual initial oral dose of hydromorphone is 7.5 mg every 3 to 4 hours. No sustained-release formulation of hydromorphone is available.

A number of opioid analgesics are not appropriate for chronic pain relief. Meperidine is not suitable for long-term administration because of the accumulation of toxic metabolites associated with central nervous system excitation and seizures. Combination agonist-antagonist opioids such as buprenorphine, butorphanol, and nalbuphine may interfere with the effects of pure agonist opioids and are not recommended for treatment of chronic pain.

The development of long-acting opioids, including transdermal fentanyl, has simplified treatment of acute pain that requires strong opioids for more than a few days and chronic painful syndromes. In addition, the less frequent dosing and flatter and lower peak drug levels are associated with less risk of drug abuse.

Long-Acting Oral Opioids

Long-acting morphine, which is indicated for use for patients who will require repeated administration of a strong opioid for more than a few days, is available in two oral formulations, MS Contin and Oramorph. A long-acting formulation of oxycodone, OxyContin, is now available. These formulations are tablets that must be swallowed whole; tablets must not be broken in half, crushed, or chewed. The usual dosing interval is 12 hours. The orally administered sustained-release morphine results in higher peak levels and lower trough levels than more frequent administration of immediate-release morphine. The release of morphine from these controlled-release tablets is not continuous over the dosing interval.

Patients are typically initially treated with immediate-release morphine and then converted to sustained-release formulations. If opioid-related side effects occur early in the dosing interval, the dose should be reduced. If breakthrough pain occurs near the end of the dosing interval, the dosing interval should be shortened. To avoid acute toxicity from overdosing, the dosing interval should never be longer than every 12 hours.

Transdermal Fentanyl

Fentanyl is a potent opioid analgesic whose pharmacologic properties are particularly suitable to transdermal administration.18 Fentanyl is short-acting when administered intravenously, but the transdermal system (Duragesic) provides a long duration and overall smoothing of the plasma concentration curve (reduction in height of peaks and depth of troughs). Most patients change patches every 3 days (72 hours) (Fig. 48-1 and Fig. 48-2).

A depot of drug concentrates in the viable epidermis under the transdermal fentanyl patch, and this depot is slowly introduced into the systemic circulation in the subdermal tissue through the cutaneous microcirculation in the dermis (Fig. 48-3).

In patients with fever, not uncommon in patients with HIV disease, fentanyl release may be faster since there is increased cutaneous circulation. Therefore, lower dose patches may need to be applied more frequently. Dosing at 2- or 3-day intervals simplifies the pain-relief regimen, reducing mediation errors and increasing compliance, especially in patients with cognitive impairment.

Because of the slow onset, analgesia using the short-acting opioid prescribed for breakthrough pain should be provided during the first 12 to 24 hours after application of the first transdermal fentanyl patch. The short-acting breakthough medication can be any strong opioid. The maximum level is typically sustained for 48 hours. After a transdermal patch is removed, plasma fentanyl levels decline with a half-life of approximately 17 hours (range 13 to 22 hours).

Transdermal administration, which is convenient in most patients, is particularly desirable in those patients with GI problems such as nausea, vomiting, or diarrhea, where malabsorption of oral medications is likely. Many patients with HIV have periods during which swallowing is difficult because of opportunistic complications of HIV infection. Transdermal fentanyl is particularly useful in such patients, but it is beneficial and effective in all patients with pain. The choice of analgesic and route of administration depends on the pain syndrome, the patient, and the physician’s judgment.

The patch must be applied to an area of intact normal skin. Significant dermatolgoic or allergic reactions are rare, but some patients experience erythema at the site of application.

In opioid-naive patients the initial dose is typically 25 μg/hour, supplemented with a short-acting opioid. Based on use of breakthrough medication, the dose and dosing interval can be adjusted over 1 to 2 weeks to achieve consistent pain relief with minimal use of breakthrough medication.

Sustained-release morphine and transdermal fentanyl were compared in a randomized, open-label, crossover study of 202 cancer patients requiring strong opioid analgesia at 38 palliative care centers in the United Kingdom.21 Patients received one treatment for 15 days, followed immediately by the other treatment. Immediate-release morphine was used freely to titrate patient’s pain control at the start of the study, at the crossover, and for breakthrough pain. Pain relief as recorded by patients was comparable; however, of those who felt able to express an opinion, transdermal fentanyl was preferred by 54% compared with 36% who preferred sustained-release morphine tablets, P = .037.

Potential for Abuse of Long-Acting Opioids

Although it is possible to abuse almost any psychoactive drug, it is quite uncommon for patients, even those with a history of intravenous drug use, to abuse transdermal fentanyl or other long-acting opioids. The steady blood levels of analgesic provided by these formulations provide effective pain relief but little euphoria, which is associated with the peak levels that occur with frequent dosing of short-acting opioids. Appropriate treatment of moderate to severe pain with opioids, especially long-acting opioids, in my clinical experience rarely results in substance abuse or addiction.

Adjuvant analgesics, that is, agents that are not primarily considered analgesics such as antidepressants and anticonvulsants, may be added to any of the previously described regimens if indicated. The most common complication treated with adjuvant analgesics is peripheral neuropathy, which can arise from a variety of causes (Table 48-6). As a general rule, any medications associated with peripheral neuropathy should be promptly discontinued and alternatives substituted for patients who develop peripheral neuropathy. The incidence of peripheral neuropathy has decreased because, currently, patients are treated typically earlier in the course of the disease with lower doses than in the past. A recent review estimates that approximately 10% of patients receiving stavudine or zalcitabine will discontinue due to peripheral neuropathy with didanosine. The discontinuation rate specifically attributable to peripheral neuropathy is only 1% to 2%.22

Progressive polyradiculopathy should be considered when treating patients with CMV infection and they should be treated immediately with anti-CMV drugs.

Neuropathic pain is generally considered to respond relatively poorly to opioid analgesics. There is a potential for a favorable response in any individual patients, so the diagnosis of a neuropathic cause for pain does not justify withholding opioids on the presumption of inefficacy.15 For example, in a prospective open-label study of transdermal fentanyl for treatment on noncancer neuropathic pain, 35% (17/48) reported satisfactory pain relief with acceptable side effects after 12 weeks. For unexplained reasons, neuropathic pain did not recur in 4 of the 17 patients when transdermal fentanyl was discontinued. Of the other 13 patients who had responded to transdermal fentanyl treatment for neuropathic pain, 8 still reported satisfactory pain relief after 2 years of treatment.23

The tricyclic antidepressants amitriptyline, nortriptyline, imipramine, or doxepin are frequently used for painful peripheral neuropathy. When they are used as a single nighttime dose, they usually improve sleep with little effect on daytime activities. Two surveys of controlled clinical trials24,25 found that tricyclic antidepressants were effective analgesics in about one half the patients treated. The anticonvulsants carbamazepine, phenytoin, valproic acid and, more recently, gabapentin have been used successfully for treatment of sharp, shooting (lancinating) pain. In patients whose pain is not controlled with adjuvant analgesic, use of long-acting opioids is a reasonable option. For some patients with debilitating peripheral neuropathy that does not respond to pharmacotherapy, regional anesthetic blockade may be necessary.

Patients with HIV infection take large amounts of a wide variety of medications to control HIV infection and to treat or prevent opportunistic infections. A comprehensive medication history of all current drugs, including over-the-counter drugs and herbal medications, and dosage regimens is essential.

The HIV protease inhibitors, which are a component of most highly active antiretroviral regimens,26 interact with the cytochrome p450 enzyme system, especially the isoenzyme, which is responsible for more than half of the drugs that are metabolized.27–29Table 48-7 lists commonly used medications that are substrates of, or interact with, the p450 3A4 isoenzyme.29–30 Concurrent administration either of an inducer or an inhibitor and a substrate should be approached with caution. Another isoenzyme 2D6 is responsible for metabolism of another 30% of drugs, including codeine and many psychotherapeutic agents.28,30 These drug interactions may be complex and unpredictable.

Ritonavir is the most potent inhibitor and is associated with the most drug interactions including increased levels (usually measured by total drug exposure or AUC, area under the time-concentration curve) of, for example, saquinavir and rifabutin. Indinavir and nelfinavir are more modest inhibitors of p450, and saquinavir is a weak inhibitor.27

Many drugs metabolized by the liver are likely to be affected by concurrent administration of any of the HIV protease inhibitors and there are many drugs not recommended for concurrent use. The prescribing information of the relevant HIV protease inhibitor should be consulted as well as the most recent National Institutes of Health guidelines for antiretroviral therapy.26 Of particular note, the anticonvulsants phenytoin, phenobarbital, and carbamazepine are enzyme inducers and would be anticipated to reduce levels of HIV protease inhibitors.32

Nucleoside analogues have more limited potential for drug interactions compared with other antiretroviral drugs.32 Zidovudine, like morphine, is glucuronidated to a significant extent, but there is no documented drug interaction between zidovudine and morphine based on this similar metabolic pathway. Interestingly, induction of p450 also induces the glucuronyl transferases that add glucuronide to increase water solubility and facilitate renal excretion.27

Of the nonnucleoside reverse transcriptase inhibitors, nevirapine induces cytochrome p450 enzyme and delavirdine inhibits them. Efavirenz is a mixed inducer/inhibitor of cytochrome p450 3A4 isoenzymes, and concentrations of concomitant drugs may be increased or decreased, depending on the specific enzyme pathway involved.26

Substance abuse is an important risk factor for HIV infection. The prevalence and intensity of pain experienced by substance abusers is not different from that reported in persons who do not use substances. However, substance abusers are more likely to be undertreated for pain. Physicians are usually reluctant to prescribe opioids for patients using other substances, whereas patients in recovery may be reluctant to accept appropriate opioid therapy.

Pain was compared in a sample of AIDS patients that included 270 who reported intravenous drug use as their HIV transmission risk factor and 246 individuals who did not report a history of intravenous drug use (IVDU).33 Pain was similar in the two groups, whereas pain relief differed between the two groups (Table 48-8). The percentage of IVDUs receiving adequate pain relief was less than half that of non-IVDUs, but pain relief was very poor with 80% to 90% of these patients receiving inadequate pain relief.

Management of such patients can be challenging. A thorough and accurate substance abuse history is essential. Concerns are very different in active users than in patients in recovery (either abstinent or receiving methadone maintenance therapy). Individualization of therapy must include the pattern of past or current substance use. Objective assessment of the cause and probably severity of the pain in a patient with HIV disease and substance abuse is critical, but the patient’s report of pain and pain relief is the ultimate guide. The physician must accept and respect the report of pain in spite of the possibility of being misled. Realistic treatment goals and conditions for opioid therapy must be set. Clear limits and predetermined consequences for drug abuse behaviors must be established by a single prescriber who is experienced in recognizing drug abuse behaviors (Table 48-9). Major aberrant behavior may be managed by very frequent weekly or even daily supply of opioid or discontinuation (weaning). Minor aberrant behaviors may be managed by reassessing medication (dose may be too low) and expectations (complete pain relief all the time may not be possible), consider changing to another drug, or reducing time interval between supply of opioid. Minor aberrant behaviors may be evidence of unrelieved pain or patient self-knowledge about what analgesics work and do not work for him or her.

It is critical to distinguish between tolerance and physical dependence, which are pharmacologic properties of opioids, and addiction or drug abuse, which is a complex psychological phenomenon involving drug craving, compulsive use despite physical, psychological, or social harm to the user, and various aberrant drug-related behaviors. Interestingly, in patients receiving opioids for pain relief over long periods, the opioid dose typically stabilizes and dose increases are associated with a worsening physical lesion or a change in psychological status.15

In my clinical experience, it is possible to use opioids for pain relief in patients with a history of substance abuse. Short-acting opioids are more problematic than long-acting opioids, which have a much lower abuse potential since the peak levels are much flatter and lower than those with short-acting opioids. Transdermal fentanyl patches replaced every 2 to 3 days are much less subject to abuse than two Percocet tablets taken every 3 to 4 hours.

Chronic pain is underrecognized and undertreated in patients with HIV infection. Patients receiving effective antiretroviral therapy may live for long periods with HIV infection and often experience HIV-related pain. Once the underlying medical complication(s) signaled by pain have been diagnosed and treatment initiated, the pain should be relieved, since unrelieved pain contributes greatly to psychological and functional morbidity in patients living with HIV infection. Although a multidisciplinary approach is optimal and may be necessary, especially in patients with a history of past or current substance use, many of the painful syndromes associated with HIV disease can be readily managed by the primary care practitioner. It is important to give pain a high priority in patients at all stages of HIV disease. Documenting pain and its management, including its efficacy and side effects, clearly in the patient’s chart will allow prescription of strong analgesics in appropriate doses to effectively relieve AIDS-related pain and suffering without fear of regulatory action. Table 48-10 outlines an approach to managing pain in patients with HIV disease. Some patients with an AIDS diagnosis receiving multiple-drug antiretroviral therapy and appropriate prophylaxis for opportunistic infections may be able to work if they are not suffering from unrelieved pain. Other patients should receive effective pain relief as part of palliative terminal care.