November 30, 1999
The advent of highly active antiretroviral treatment has not diminished the need for palliative care for people living with HIV/AIDS. In fact, because of new treatments, fewer patients are dying from HIV/AIDS in the U.S. and the total number of people living with HIV/AIDS is increasing. New treatments, particularly HAART, are also responsible for additional symptoms and complications, including pain that must be understood and managed. Additionally, as the epidemiology of the AIDS epidemic changes in the United States, the challenge of managing pain in AIDS patients who have a history of substance abuse is a growing issue.
Several studies have documented that pain in individuals with HIV infection or AIDS is:1-12
Moreover, pain has a profound negative impact both on physical and psychological functioning and overall quality of life.7, 11 It is important, therefore, that pain management be more integrated into the total care of patients with HIV disease.13 This chapter describes the types and prevalence of pain syndromes encountered in patients with HIV disease and reviews the psychological and functional impact of pain as well as the barriers to adequate pain treatment in this population. Finally, the chapter outlines the principles of pain management.
Pain is classified in two major categories, nociceptive and neuropathic pain (see Table 4-1).14 Nociceptive pain derives from the stimulation of intact 'nociceptors' or pain receptors in afferent nerves and is further subdivided into somatic pain (involving skin, soft tissue, muscle and bone) and visceral pain (involving internal organs and hollow viscera). Nociceptive pain may be well-localized (common in somatic pain) or more diffuse (common in visceral pain), and may be sharp, dull, aching, gnawing, throbbing, constant, or spasmodic, with varying intensity. Neuropathic pain involves stimulation of damaged or compromised nerve tissue, and may be burning, tingling, stabbing, shooting, with a sensation of electric shock, or allodynia (the sensation of pain or discomfort produced by a minimal stimulus such as light touch to the skin). The differentiation of pain into one of these subtypes (particularly nociceptive vs. neuropathic) can help in determining appropriate therapy, as further discussed.
Summary of Pain Syndromes in HIV/AIDS
Pain syndromes encountered in AIDS are diverse in nature and etiology (see Table 4-2). The most common pain syndromes reported in studies to date include painful sensory peripheral neuropathy, pain due to extensive Kaposi's sarcoma, headache, oral and pharyngeal pain, abdominal pain, chest pain, arthralgias and myalgias, and painful dermatologic conditions.4, 6, 8, 10, 12, 15-18
Hewitt and colleagues in 1997 demonstrated that while pains of a neuropathic nature (e.g., polyneuropathies, radiculopathies) certainly comprise a large proportion of pain syndromes encountered in AIDS patients, pains of a somatic and/or visceral nature are also extremely common clinical problems.6
The etiology of pain syndromes seen in HIV disease can be categorized into three types: those directly related to HIV infection or consequences of immunosuppression; those due to AIDS therapies; and those unrelated to AIDS or AIDS therapies (see Table 4-3).
In studies to date, approximately 45% of pain syndromes encountered are directly related to HIV infection or consequences of immunosuppression; 15% to 30% are due to therapies for HIV- or AIDS-related conditions and to diagnostic procedures; and the remaining 25% to 40% are unrelated to HIV or its therapies.2, 6
Pain in Women With HIV/AIDS
One study has suggested that women with HIV disease experience pain more frequently than men with HIV disease and report somewhat higher levels of pain intensity.6, 19 This may in part reflect the fact that women with AIDS-related pain are twice as likely as men to be undertreated for their pain.3 Women with HIV disease have unique pain syndromes of a gynecologic nature specifically related to opportunistic infectious processes and cancers of the pelvis and genitourinary tract, and in one survey women with AIDS were significantly more likely to be diagnosed with radiculopathy and headache.6, 20
Pain in Children With HIV/AIDS
Children with HIV infection also experience pain.21 HIV-related conditions in children that are observed to cause pain include:
For more information on HIV palliative care in children, see Chapter 12: The Care of Children and Adolescents.
Specific Pain Syndromes in Patients With HIV Disease
The following section reviews, in detail, the various painful manifestations of HIV disease. The author acknowledges the important review by O'Neill and Sherrard that formed the basis of this section on specific pain syndromes in HIV disease.10
Gastrointestinal Pain Syndromes
Many of the opportunistic infections and HIV-associated neoplasms as well as side effects of some commonly used antiretroviral medications may present as pain referable to the gastrointestinal tract. Generally the pain will be alleviated by specific treatment of the causative diseases or by changing treatments. Adequate analgesia should be provided during diagnostic assessment.10
For more information, see Chapter 7: Gastrointestinal Symptoms.
Oral cavity and throat pain is very common, accounting for approximately 20% of the pain syndromes encountered in one study.8 Common sources of oral cavity pain are candidiasis; necrotizing gingivitis; and dental abscesses and ulcerations caused by herpes simplex virus (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), atypical and typical mycobacterial infection, cryptococcal infection, or histoplasmosis. Frequently no infectious agent can be identified and these painful recurrent aphthous ulcers (RAU) are a clinically challenging problem.10 RAU can be controlled with topical steroids (mixed with Orabase), systemic steroids, and/or thalidomide. Up to 75% of patients with cutaneous Kaposi's sarcoma (KS) also have intraoral lesions, most commonly on the palate, although these seldom cause pain.10 Finally, zalcitabine (ddC) can cause a painful stomatitis. For more information, see Chapter 8: Oral Problems.
Many HIV/AIDS patients experience dysphagia or odynophagia, most commonly caused by esophageal candidiasis. Ulcerative esophagitis, which can be quite painful, is usually a result of CMV infection but can be idiopathic. Thalidomide has been used successfully in this case.
Infectious causes of esophagitis include: HIV itself, papovavirus, herpes simplex, Epstein-Barr virus, mycobacteria, Cryptosporidium and Pneumocystis carinii. Kaposi's sarcoma and lymphoma both have been reported to invade the esophagus resulting in dysphagia, pain and ulceration.10 Zidovudine and zalcitibine (ddC) have been implicated in esophagitis as have been non-steroidal medications.
The abdomen is the primary site of pain in 12-25% of patients with HIV disease.6, 8, 22 Infectious causes of abdominal pain predominate, and include: cryptosporidiosis, shigella, salmonella and Campylobacter enteritis, CMV ileitis and mycobacterial infection (MAI).
Perforation of the small and large intestine secondary to CMV infection has been described.22 Repeated intussusception of the small intestine has been seen in association with Campylobacter infection.23 Lymphoma in the gastrointestinal (GI) tract can present with abdominal pain and intestinal obstruction.10, 24 Other causes of abdominal pain in HIV positive patients10 include ileus, organomegaly, spontaneous aseptic peritonitis, toxic shock, herpes zoster, and Fitzhugh-Curtis syndrome (perihepatitis in association with tubal gonococcal or chlamydia infection).
Many antiretroviral agents are responsible for GI symptoms but lactic acidosis, a rare but serious complication of some HAART regimens, can present with abdominal pain. Didanosine (ddI), zalcitabine (ddC) and stavudine (d4T) can cause pancreatitis (see below) and patients taking indinavir are at increased risk for nephrolithiasis.
Biliary Tract and Pancreatic Pain
Cholecystitis is a painful condition that may occur in HIV-infected patients as a result of opportunistic infection, with CMV and cryptosporidiosis being the most common infectious agents. Pain from extrahepatic biliary tract obstruction secondary to KS or MAI infection has been reported.10 Sclerosing cholangitis (CMV, cryptosporidiosis) can cause right upper quadrant or epigastric pain, and opportunistic liver infections (CMV, MAI, fungal infections) as well as drug-induced hepatic toxicities (ddI, pentamidine, ritonavir and nevirapine) are sources of hepatitis and abdominal or right upper quadrant pain.25 Viral hepatitis (especially hepatitis B or C) is an increasingly common coinfection and cause of hepatic pain.
Pancreatitis, an extremely painful condition, is often related to adverse effects of HIV-related therapies, in particular didanosine (ddI), stavudine (d4T) and dideoxycytidine (ddC). Intravenous pentamidine is also associated with pancreatitis. Other causes of pancreatitis include CMV infection, MAI infection, cryptococcal lymphoma and KS.
Painful anorectal diseases are often caused by perirectal abscesses, CMV proctitis, fissure-in-ano, and HPV and HSV infection.
Chest Pain Syndromes
Chest pain is a common complaint in patients with HIV disease, comprising approximately 13% of the pain syndromes encountered in a sample of ambulatory AIDS patients.6 Sources of chest pain in patients with HIV disease are similar to those encountered in the general population, i.e., cardiac, esophageal, lung and pleura, and chest wall. However, the etiologies may be somewhat unique, i.e., opportunistic infections and cancers. The index of suspicion for coronary artery disease, even in young patients with no other risk factors, must be high if the patient is being treated with HAART.
In immunosuppressed patients, infectious causes of chest pain should be considered, particularly in the presence of fever and some localizing sign such as dysphagia, dyspnea, or cough. Infectious causes of chest pain include the following:
Opportunistic cancers (KS, lymphoma) invading the esophagus, pericardium, chest wall, lung and pleura may also be sources of chest pain. Rarely, pulmonary embolus or bacterial endocarditis may be the cause of chest pain.
For more information, see Chapter 6: Pulmonary Symptoms.
Neurological Pain Syndromes
Pain syndromes originating in the nervous system include headache, painful peripheral neuropathies, radiculopathies, and myelopathies.
The HIV virus is highly neurotropic, invading central and peripheral nervous system structures early in the course of HIV disease. Consequently, many complications of HIV/AIDS and opportunistic infections result in neurological pain, and many commonly used HIV/AIDS medications can also be implicated in neurological pain.
Rarely, cerebrovascular events (e.g., thalamic stroke) occurring in hypercoagulable states can result in central pain syndromes.
Headache is extremely common in the HIV/AIDS patient and can pose a diagnostic dilemma for providers in that the underlying cause may range from benign stress and tension to life-threatening central nervous system infection.10 The differential diagnosis of headache in patients with HIV disease includes: 26
Toxoplasmosis and cryptococcal meningitis are the two most commonly encountered opportunistic infections of the central nervous system that cause headaches in patients with HIV disease. Other opportunistic infections of the central nervous system that can present as headache in the AIDS patient include:
One of the most common causes of headache without focal findings is sinusitis. Opportunistic cancers of the central nervous system include central nervous system lymphoma, metastatic systemic lymphoma, and metastatic intracranial KS. These can present, particularly in the immunocompromised patient with HIV disease, with signs of increased intracranial pressure with or without focal neurological signs, as well as fever and meningismus.
More benign causes of headache in the patient with HIV disease include AZT-induced headache; tension headache; migraine with or without aura; and unclassifiable or idiopathic headache. Evers and colleagues in 1999 concluded that the progressing immunological deficiency of HIV-infected patients seems to influence the pain processing of headache in different ways.27 During that natural course of infection, the migraine frequency significantly decreased, while the frequency of tension type headaches increased.27
Neuropathic pain occurs in about 40% of AIDS patients.6 While several types of peripheral neuropathy have been described in patients with HIV/AIDS (see Table 4-4, PDF), the most common painful neuropathy encountered is the predominantly sensory neuropathy (PSN) of AIDS. Other potentially painful neuropathies in HIV/AIDS patients, however, can be caused by the following:
Several antiretroviral drugs can cause painful toxic neuropathy, including the following:
Predominantly Sensory Neuropathy (PSN) of AIDS
The most frequently encountered neuropathy is a symmetrical predominantly sensory painful peripheral neuropathy. This is typically a late manifestation, occurring most often in patients with an AIDS-defining illness.30 The prevalence of this neuropathy in hospice populations ranges from 19% to 26%.17, 31, 32
The predominant symptom in about 60% of patients is pain in the soles of the feet. Paraesthesia is frequent and usually involves the dorsum of the feet and soles. Most patients have signs of peripheral neuropathy (most commonly, absent or reduced ankle jerks and elevated thresholds to pain and vibration sense); and, while the signs progress, the symptoms often remain confined to the feet.30, 33, 34 Although the patients' complaints are predominantly sensory, electrophysiological studies demonstrate both sensory and motor involvement.
Acute Guillain-Barré syndrome has been described in association with seroconversion (group-I infection) but may occur at any time. Both acute and chronic inflammatory demyelinating polyneuropathies are predominantly motor-related, and sensory abnormalities are rare.35 Mononeuritis multiplex presents with sensory or motor deficits in the distribution of multiple spinal, cranial or peripheral nerves and may progress into a chronic inflammatory demyelinating polyneuropathy.35, 36
Polyradiculopathies (associated with CMV infection) often present with radicular pain and follow a distinct course.37 The onset is usually subacute and the deficit initially confined to sacral and lumbar nerve roots. Both sensory and motor functions are involved, and there is usually early involvement of sphincters. Progression is relentless.35
Harrison and colleagues identified three variables related to herpes zoster pain: extent of lesion healing; extension of lesion crusting; and the number of new vesicles.38 According to their study, the significance of baseline pain due to herpes zoster was a predictor of return to daily life functioning. Furthermore, the significance of pain at presentation and at one month was a significant predictor of chronic pain.38
Painful Neuropathies According to Stage of HIV Infection
In general, the type of neuropathy varies with the stage of infection,29 as follows:
Rheumatological Pain Syndromes
In studies conducted by the Memorial Sloan-Kettering group, over 50% of pain syndromes were classified as rheumatologic in nature including various forms of arthritis, arthropathy, arthralgia, myopathy, myositis and myalgias.6
Arthritis and Arthropathies
The most frequently reported arthritis is a reactive arthritis or Reiter's syndrome.40, 41, 43 Acute HIV infection may present with a polyarthralgia in association with a mononucleosis-like illness. There is also a syndrome of acute severe and intermittent articular pain, often referred to as HIV-associated painful articular syndrome, which commonly affects the large joints of the lower limbs and shoulders. Psoriasis and psoriatic arthritis have been reported in patients with HIV infection.40, 44 The arthritis is typically seen in conjunction with the skin changes of psoriasis, and authors O'Neill and Sherrard suggest it may follow a disease course that proves refractory to conventional therapy.10 An HIV-associated arthritis also was described by Rynes, et al., which typically presents as an oligoarthritis affecting the joints of the lower limbs.44 Septic arthritis has been reported in patients with HIV disease, including arthritis due to bacterial infections and infections with Cryptococcus neoformans and Sporothrix schenckii.40, 41
Myopathy and Myositis
Muscle pain is very common in patients with HIV disease. Several types of myopathy and myositis have been described, including: 45-51
Polymyositis may occur at any stage of HIV infection; it is thought to be the result of direct viral infection of muscle cells40 and may present with a sub-acute onset of proximal muscle weakness and myalgia.45 Electromyographic evidence of myopathy, a raised serum creatinine kinase, and biopsy evidence of polymyositis are common in symptomatic patients. Drugs used in the treatment of HIV disease may also be associated with the development of myalgia26 and myositis.46, 52 Zidovudine has been particularly implicated; symptoms frequently improve following discontinuation of zidovudine therapy.10
Overview of Pain Management in HIV/AIDS
Optimal management of pain requires a multidisciplinary approach. The initial assessment should shed light on etiology and contributing factors as well as establish a baseline from which to monitor the impact of therapy. Pain assessment tools for noting the intensity of pain, time, dose, and impact of medications are discussed below. Clear communication between provider and patient/family is important to monitor the impact of any intervention (see Chapter 21: Patient-Clinician Communication).
WHO Pain Ladder
Choice of analgesic agents should follow the World Health Organization's pain ladder (see Figure 4-1, PDF):
It is important that providers be comfortable with the use of one or two medications in each analgesic step (see Tables 4-6, 4-7 and 4-8; PDFs), including management of side effects; conversion from one step, or level, to another; drug interactions (see Chapter 27: Pharmacologic Interactions of Clinical Significance); and dosing schedules.
Adjuvant treatments are important components of the pain ladder and have key roles in AIDS, particularly in management of neuropathic pain.
Dame Cicely Saunders introduced the concept of total pain in the early years of the hospice movement in the United Kingdom.53 This approach emphasizes the need to keep in mind psychological, social, and spiritual aspects as well as physical aspects when approaching a patient in pain. Therefore, a close collaboration of the entire health care team is optimal when attempting to adequately manage pain in the AIDS patient.
The initial step in pain management is a comprehensive assessment of pain symptoms. A health professional in the AIDS setting must have a working knowledge of the etiology and treatment of pain in AIDS, including an understanding of the different types of AIDS pain syndromes discussed as well as a familiarity with the parameters of appropriate pharmacologic treatment.
A comprehensive assessment includes the following:
Pain intensity (current, average, at best, at worst) should be assessed to determine the need for weak versus potent analgesics and as a means to serially evaluate the effectiveness of ongoing treatment. Pain descriptors (e.g., burning, shooting, dull or sharp) will help determine the mechanism of pain (somatic, nociceptive, visceral nociceptive, or neuropathic) and may suggest the likelihood of patient response to various classes of traditional and adjuvant analgesics (nonsteroidal anti-inflammatory drugs, opioids, antidepressants, anticonvulsants, oral local anesthetics, corticosteroids, etc.).58-60
Additionally, detailed medical, neurological and psychosocial assessments (including a history of substance use or abuse) must be conducted. Where possible, family members or partners should be interviewed and included in the pain management treatment plan. During the assessment phase, pain should be aggressively treated while pain complaints and psychosocial issues are subject to an ongoing process of re-evaluation.56
Pain Measurement/Assessment Tools
Pain assessment is continuous and needs to be repeated over the course of pain treatment. Readily available, simple and clinically validated pain self-report measures or tools can make pain assessment easier and more reliable. There are essentially four aspects of pain experience in AIDS that require -- and can be aided by -- ongoing assessment and evaluation:
Many pain assessment tools rely on visual analog testing. Three commonly used self-report pain intensity assessment tools, illustrated in Figure 4-2, are a simple descriptive pain intensity scale, a 0-10 numeric pain intensity scale, and a Visual Analog Scale (VAS) for pain intensity. The Pain Faces scale, shown in Figure 4-3, can be used with children, patients who do not share a common language with the provider, or illiterate patients. The Memorial Pain Assessment Card (MPAC) may also be used, since it is a helpful clinical tool that allows patients to report their pain experience.61 The MPAC consists of visual analog scales that measure pain intensity, pain relief and mood (see Figure 4-4).
The Brief Pain Inventory (BPI) is another pain assessment tool (Figure 4-5) that has been widely used in cancer and AIDS pain research and clinical settings.62 The BPI has a useful Pain Interference Subscale that assesses pain's interference in seven domains of quality of life and function.
For more information or to download the BPI, go to the Pain Research Group website at www.mdanderson.org/departments/prg.
JCAHO Pain Standards
Effective January 1, 2001, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) established new pain management standards for accreditation.63 These standards include the following statements:
Some key concepts of the JCAHO standards are listed in Table 4-5 (PDF). The complete standards are available at www.jcrinc.com/subscribers/perspectives.asp?durki=3243&site=10&return=2897. The pain assessment tools and measures described above can help organizations and practitioners comply with these standards. The general principles of pain assessment and management described in this chapter may also be helpful.
Other sources of help in meeting the pain standards include Building an Institutional Commitment to Pain Management: The Mayday Resource Manual for Improvement, an excellent compilation of resource material to promote institutional support of pain management; all of the sample resource tools are available on a disc. Available from Wisconsin Cancer Pain Initiative, 3675 Medical Sciences Center, Univ. of Wisconsin Medical School, 1300 University Avenue, Madison, WI 53706; 608-262-0278, FAX 608-265-4014; E-mail firstname.lastname@example.org or www.aacpi.org.
Federal guidelines developed by the Agency for Health Care Policy and Research (AHCPR) for the management of cancer pain also address the issue of pain management in AIDS. The guidelines state, the principles of pain assessment and treatment in the patient with HIV/AIDS are not fundamentally different from those in the patient with cancer and should be followed for patients with HIV/AIDS.58 In contrast to pain in cancer, pain in HIV disease more commonly may have an underlying treatable cause.10
Optimal management of pain in AIDS is multimodal and requires pharmacologic, psychotherapeutic, cognitive-behavioral, anesthetic, neurosurgical and rehabilitative approaches. A multidimensional model of AIDS pain that recognizes the interaction of cognitive, emotional, socioenvironmental and nociceptive aspects of pain suggests a model for multimodal intervention.
Pharmacologic Interventions for Pain
The World Health Organization has devised guidelines for analgesic management of cancer pain which the AHCPR has endorsed for the management of pain related to cancer or AIDS.58, 59 These guidelines, also known widely as the WHO Analgesic Ladder (Figure 4-1), have been well validated.65 This approach advocates selection of analgesics based on the severity of pain as well as the type of pain (i.e., neuropathic vs. non-neuropathic pain). For pain that is mild to moderate in severity, non-opioid analgesics such as NSAIDs (non-steroidal anti-inflammatory drugs) and acetaminophen are recommended. For pain that is persistent and moderate to severe in intensity, opioid analgesics of increasing potency (such as morphine) should be utilized.
Adjuvant agents, such as laxatives and psychostimulants, are useful in preventing as well as treating opioid side effects such as constipation or sedation respectively. Adjuvant analgesic drugs, such as the antidepressant analgesics, are suggested for considered use, along with opioids and NSAIDs, in all stages of the analgesic ladder (mild, moderate or severe pain), but have their most important clinical application in the management of neuropathic pain.
The WHO approach, while not yet validated in AIDS, has been recommended by the AHCPR and clinical authorities in the fields of pain management and AIDS.8, 10, 12, 17, 29, 58, 66 In addition, clinical reports have appeared in recent literature describing successful application of the WHO Analgesic Ladder principles to pain management in AIDS, with particular emphasis on the use of opioids.9, 17, 67-71
The non-opioid analgesics are prescribed principally for mild-to-moderate pain or to augment the analgesic effects of opioid analgesics in the treatment of severe pain (see Table 4-6). The use of NSAIDs in patients with AIDS must be accompanied by heightened awareness of toxicity and adverse effects. NSAIDs are highly protein-bound, and the free fraction of available drug is increased in AIDS patients who are cachectic, wasted and hypoalbuminic, often resulting in toxicities and adverse effects. Patients with AIDS are frequently hypovolemic, on concurrent nephrotoxic drugs, and experiencing HIV nephropathy, and so are at increased risk for renal toxicity related to NSAIDs. The antipyretic effects of the NSAIDs may also interfere with early detection of infection in patients with AIDS.
Major adverse effects associated with NSAIDs include the following:
The nonacetylated salicylates, such as salsalate, sodium salicylate, and choline magnesium salicylate, theoretically have fewer gastrointestinal (GI) side effects and might be considered in cases where GI distress is an issue. Prophylaxis for NSAID-associated GI symptoms includes H2 antagonist drugs (cimetidine 300 mg tid-qid or ranitidine 150mg bid); misoprostal 200 mg qid.; omeprazole 20 mg qd; or an antacid.
Patients should be informed about these side effects, issued guaiac cards with reagent, and taught to check their stool weekly.
NSAIDs affect kidney function and should be used with caution. NSAIDs can cause decrease in glomerular filtration, acute and chronic renal failure, interstitial nephritis, papillary necrosis, and hyperkalemia.72 Especially in patients with renal impairment, NSAIDs should be used with caution, since many (e.g., ketoprofen, feroprofen, naproxen and carpofen) are highly dependent on renal function for clearance. The risk of renal dysfunction is greatest in patients with advanced age, preexisting renal impairment, hypovolemia, concomitant therapy with nephrotoxic drugs and heart failure. Prostaglandins modulate vascular tone and their inhibition by the NSAIDs can cause hypertension as well as interference with the pharmacologic control of hypertension.73
Caution should also be used with patients receiving B-adrenergic antagonists, diuretics, or angiotensin-converting enzyme inhibitors. Several studies have suggested that there is substantial biliary excretion of several NSAIDs, including indomethacin and sulindac. In patients with hepatic dysfunction, these drugs should be used with caution. NSAIDs, with the exception of the nonacetylated salicylates (e.g., sodium salicylate, cholinemagnesium trisalicylate), produce inhibition of platelet aggregation (usually reversible, but irreversible with aspirin). NSAIDs should be used with extreme caution, or avoided, in patients who are thrombocytopenic or who have clotting impairment.
Opioid analgesics are the mainstay of pharmacotherapy for moderate-to-severe intensity pain in the patient with HIV disease (see Table 4-7, PDF).
Principles of Opioid Pharmacotherapy
It is important that the provider have a systematic approach to the use of opiates to provide around-the-clock pain coverage. (Other than as backup for breakthrough pain, PR.N. dosing should never be used for treatment of chronic pain.) If a patient has no prior experience with opiates, adequate relief may be achieved with weaker opiates such as codeine or hydrocodone. More severe pain or pain in a non-naive patient may require starting with morphine, hydromorphone, or other potent agents. If a patient needs more than two or three pills every four hours to control pain, the provider should switch to a stronger agent.
In order to switch from one opiate to another, use a simple calculation to estimate the relative potency of regimes: convert both the current medication and the new medication to oral morphine equivalents (see Table 4-7). Then, estimate the number of oral morphine equivalents needed to control pain for a 24-hour period based on the current regimen. A dosing schedule and dose that will provide the same number of morphine equivalents can then be determined based on the pharmacological properties of the new drug choice.
The optimal regimen is one that will keep the patient comfortable and maintain his or her quality of life. The regimen should prevent breakthrough pain from occurring, and should minimize iatrogenic complications and cost. Provision for breakthrough pain or incident (usually movement-related) pain should be provided, usually 50% to 100% of the around-the-clock dose. Careful records of the breakthrough doses should be maintained so that appropriate increases in the around-the-clock regimen can be calculated. Increases in the around-the-clock dose should, in general, never be less than 25% of the base dose.
Classes of Opioids
Opioid analgesics are divided into two classes, the agonists and the agonist-antagonists, based on their affinity to opioid receptors. Opioid analgesics with mixed agonist-antagonist properties include pentazocine, butorphanol, and nalbuphine. These drugs can reverse opioid effects and precipitate an opioid withdrawal syndrome in a patient who is opioid-tolerant or dependent. They are of limited use in managing chronic pain in AIDS. Oxycodone (in combination with either aspirin or acetaminophen), hydrocodone, and codeine are the so-called weaker opioid analgesics and are indicated for use in step two of the WHO ladder for mild-to-moderate intensity pain. More severe pain is best managed with morphine or another of the stronger opioid analgesics, such as hydromorphone, methadone, levorphanol, or fentanyl. Oxycodone, as a single agent without aspirin or acetaminophen, is available in immediate and sustained-release forms and is considered a stronger opioid in these forms.
Routes of Administration
The oral route has often been described as the preferred route of administration of opioid analgesics from the perspectives of convenience and cost. However, the transdermal route of administration has gained rapid acceptance by clinicians and patients since patients are often taking many oral medications.
Patients with HIV infection are burdened with taking anywhere from 20 to 40 tablets of medication per day and often need to follow complicated regimens where medication has to be taken on an empty stomach, etc. In a study on patient-related barriers to pain management in AIDS patients, the vast majority of AIDS patients endorsed a preference to utilize a pain intervention that required a minimal number of additional pills (e.g., sustained-release preparations of oral opioids) or interventions that did not require taking pills at all (e.g., transdermal opioid system).74
Immediate-release oral morphine or hydromorphone drug preparations must be taken every three to four hours. Longer-acting, sustained-release oral morphine preparations and oxycodone preparations are available that provide up to 8 to 12 hours or more of analgesia, minimizing the number of daily doses required to control persistent pain. Rescue doses of immediate-release, short-acting opioid are often necessary to supplement the use of sustained-release morphine or oxycodone, particularly during periods of titration or pain escalation.
The transdermal fentanyl patch system (Duragesic) has useful applications in the management of severe pain in AIDS.67, 69 Each transdermal fentanyl patch contains a 48- to 72-hour supply of fentanyl, which is absorbed from a depot in the skin. Levels in the plasma rise slowly over 12 to 18 hours after patch placement so dosage forms are available. As with sustained-release morphine preparations, all patients should be provided with oral or parenteral rapidly acting short duration opioids to manage breakthrough pain. The transdermal system is convenient and can minimize the reminders of pain associated with repeated oral dosing of analgesics. In AIDS patients, it should be noted that the absorption of transdermal fentanyl could be increased with fever, resulting in increased plasma levels and shorter duration of analgesia from the patch.
It is important to note that opioids can be administered through a variety of routes: oral, rectal, transdermal, intravenous, subcutaneous, intraspinal and even intraventricular.69 There are advantages and disadvantages, as well as indications for use of these various routes. Further discussion of alternative delivery routes appears in the Agency for Health Care Policy and Research Clinical Practice Guideline #9: Management of Cancer Pain, available free of charge by calling 1-800-4-CANCER.58
Side Effects of Opioids
The opioids are extremely effective analgesics. Their side effects are common but when anticipated can be minimized. Sedation is a common CNS side effect, especially during the initiation of treatment. Sedation usually resolves after the patient has been maintained on a steady dosage. Persistent sedation can be alleviated with a psychostimulant, such as dextroamphetamine, pemoline or methylphenidate, which are all prescribed in divided doses in early morning and at noon. Additionally, psychostimulants can improve depressed mood and enhance analgesia.75, 76
Delirium, either agitated or somnolent, can also occur while a patient is on opioid analgesics. Delirium is usually accompanied by attentional deficits, disorientation, and perceptual disturbances (visual hallucinations and more commonly illusions). Myoclonus and asterixis are often early signs of neurotoxicity that accompany the course of opioid-induced delirium. Meperidine (Demerol), when administered chronically in patients with renal impairment can lead to a delirium due to accumulation of the neuro excitatory metabolite normeperidine.77
Three strategies may alleviate opioid-induced delirium:
The strategy of using high potency neuroleptics is especially useful for agitation, and clears the sensorium.78 For agitated states, intravenous haloperidol in doses starting at between 1 mg and 2 mg is useful, with rapid escalation of dose if no effect is noted.
Gastrointestinal side effects of opioid analgesics are common. The most prevalent are nausea, vomiting, and constipation.60 Concomitant therapy with prochlorperazine for nausea is sometimes effective. Since not all opioid analgesics are tolerated in the same manner, switching to another narcotic can be helpful if an anti-emetic regimen fails to control nausea. Constipation caused by narcotic effects on gut receptors is a frequently encountered problem that tends to be responsive to the regular use of senna derivatives. A careful review of medications is imperative, since anticholinergic drugs such as the tricyclic antidepressants can worsen opioid-induced constipation and cause bowel obstruction.
Respiratory depression is a worrisome but rare side effect of the opioid analgesics. Respiratory difficulties can almost always be avoided by adhering to two general principles:
Adjuvant analgesics are the third class of medications frequently prescribed for the treatment of chronic pain and have important applications in the management of pain in AIDS (see Table 4-8). Adjuvant analgesic drugs are used to enhance the analgesic efficacy of opioids, treat concurrent symptoms that exacerbate pain, and provide independent analgesia. They may be used in all stages of the WHO analgesic ladder. Commonly used adjuvant drugs include antidepressants, neuroleptics, psychostimulants, anticonvulsants, corticosteroids and oral anesthetics.56, 58, 76
The current literature supports the use of antidepressants as adjuvant analgesic agents in the management of a wide variety of chronic pain syndromes, including cancer pain, postherpetic neuralgia, diabetic neuropathy, fibromyalgia, headache and low back pain.79-84 The antidepressants are analgesic through a number of mechanisms that include antidepressant activity,80 potentiation or enhancement of opioid analgesia, 85-87 and direct analgesic effects.88
The leading hypothesis suggests that both serotonergic and noradrenergic properties of the antidepressants are important, and that variations among individuals in pain (as to the status of their own neurotransmitter systems) are an important variable.54 Other possible mechanisms of antidepressant analgesic activity that have been proposed include adrenergic and serotonin receptor effects, adenosinergic effects, anti-histaminic effects, and direct neuronal effects, such as inhibition of paroxysmal neuronal discharge and decreasing sensitivity of adrenergic receptors on injured nerve sprouts.86, 89, 90, 91
There is substantial evidence that the tricyclic antidepressants in particular are analgesic and useful in the management of chronic neuropathic and non-neuropathic pain syndromes. Amitriptyline is the tricyclic antidepressant most studied and has been proven effective as an analgesic in a large number of clinical trials addressing a wide variety of chronic pain syndromes, including neuropathy, cancer pain, fibromyalgia and others.54, 80, 81, 92-94 Other tricyclics that have been shown to have efficacy as analgesics include imipramine, desipramine, nortriptyline, clomipramine,100 and doxepin.55, 95-99, 101
The heterocyclic and non-cyclic antidepressant drugs may be useful as adjuvant analgesics for chronic pain syndromes.54, 81, 88, 96, 97, 102-107 These drugs include trazodone, mianserin, maprotiline and the newer serotonin-specific reuptake inhibitors (SSRIs), fluoxetine and paroxetine.
Fluoxetine, a potent antidepressant with specific serotonin reuptake inhibition activity, has been shown to have analgesic properties in experimental animal pain models but failed to show analgesic effects in a clinical trial for neuropathy.97, 106, 107 Several case reports suggest fluoxetine may be a useful adjuvant analgesic in the management of headache and fibrositis.108-109
Paroxetine, a newer SSRI, is the first antidepressant of this class shown to be a highly effective analgesic in a controlled trial for the treatment of diabetic neuropathy.96 Newer antidepressants such as sertraline, venlafaxine, and nefazodone may also eventually prove to be clinically useful as adjuvant analgesics. For instance, nefazodone has been demonstrated to potentiate opioid analgesics in an animal model.110
Given the diversity of clinical syndromes in which the antidepressants have been demonstrated to be analgesic, trials of these drugs can be justified in the treatment of virtually every type of chronic pain.111 The established benefit of several of the antidepressants in patients with neuropathic pains, however, suggests these drugs may be particularly useful with cancer and AIDS patients, where an underlying neuropathic component to the pain(s) often exists.96, 97, 111 While studies of the analgesic efficacy of these drugs in HIV-related painful neuropathies have not yet been conducted, the drugs are widely applied clinically using the model of diabetic and post-herpetic neuropathies.
While antidepressant drugs are analgesic in both neuropathic and non-neuropathic pain models, they are most commonly used clinically in combination with opioid drugs, particularly for moderateto-severe pain. Antidepressant adjuvant analgesics have their most broad application as co-analgesics, potentiating the analgesic effects of opioid drugs.58 The opioid sparing effects of antidepressant analgesics have been demonstrated in a number of trials, especially in cancer populations with neuropathic as well as non-neuropathic pain syndromes.84, 87 The dose and time course of onset of analgesia for antidepressants when used as analgesics appears to be similar to their use as antidepressants.
There is compelling evidence that the therapeutic analgesic effects of amitriptyline are correlated with serum levels, as are the antidepressant effects, and that analgesic treatment failure is due to low serum levels.93, 97 A high dose regimen of up to 150 mg of amitriptyline or higher is suggested.93 The proper analgesic dose for paroxetine is likely in the 40 to 60 mg range, with the major analgesic trial utilizing a fixed dose of 40 mg.96
Anecdotal evidence suggests that in cases of depression or pain, the debilitated medically ill (cancer and AIDS patients) often respond to lower doses of antidepressant than are usually required in the physically healthy, probably because of impaired metabolism of these drugs103 As to the time course of onset of analgesia, a biphasic process appears to occur. Immediate or early analgesic effects occur within hours or days, and probably mediated through inhibition of synaptic reuptake of catecholamines. In addition, there are later, longer analgesic effects that peak over a two to four week period that are probably due to receptor effects of the antidepressants.92, 93, 97
Neuroleptics and Benzodiazepines
Neuroleptic drugs, such as methotrimeprazine, fluphenazine, haloperidol and pimozide, may play a role as adjuvant analgesics101, 112-114 in AIDS patients with pain; however, their use must be weighed against what appears to be an increased sensitivity to the extrapyramidal side effects of these drugs in AIDS patients with neurological complications.115 Anxiolytics, such as alprazolam and clonazepam, may also be useful as adjuvant analgesics, particularly in the management of neuropathic pains.116-118
Psychostimulants such as dextroamphetamine, methylphenidate, pemoline and modafinil may be useful antidepressants in patients with HIV infection or AIDS who are cognitively impaired.116, 119 Psychostimulants also enhance the analgesic effects of the opioid drugs,75 are useful in diminishing sedation secondary to narcotic analgesics, and are potent adjuvant analgesics. Bruera, et al., demonstrated that a regimen of 10 mg methylphenidate with breakfast and 5 mg with lunch significantly decreased sedation and potentiated the effect of narcotics in patients with cancer pain.119 Methylphenidate has also been demonstrated to improve patient functioning on a number of neuropsychological tests, including tests of memory, speed and concentration, in patients receiving continuous infusions of opioids for cancer pain.119 Dextroamphetamine has been reported to have additive analgesic effects when used with morphine in postoperative pain.120 In relatively low doses, psychostimulants stimulate appetite, promote a sense of well being, and decrease feelings of weakness and fatigue in cancer patients.
Pemoline is a unique alternative psychostimulant that is chemically unrelated to amphetamine but may have similar usefulness as an antidepressant and adjuvant analgesic in AIDS patients.76 Advantages of pemoline as a psychostimulant in AIDS pain patients include the following:
Clinically, pemoline is as effective as methylphenidate or dextroamphetamine in the treatment of depressive symptoms and in countering the sedating effects of opioid analgesics. There are no studies of pemoline's capacity to potentiate the analgesic properties of opioids. Pemoline should be used with caution in patients with liver impairment, and liver function tests should be monitored periodically with longer-term treatment. The Food and Drug Administration (FDA) suggests that when pemoline is prescribed, patients sign an informed consent document that outlines the potential liver toxicities of pemoline.
Modafinil, a novel psychostimulant that has shown efficacy in treating excessive daytime sleepiness associated with narcolepsy, has recently demonstrated potential for the treatment of depression and fatigue.121 Although modafinil needs further study, it appears to be a promising alternative to other psychostimulants in patients who cannot tolerate or have contraindications to the use of other stimulants. Modafinil has minimal cardiovascular effects, does not cause tolerance or dependence, has a low abuse potential, and does not require a special triplicate prescription.
Selected anticonvulsant drugs appear to be analgesic for the lancinating dysesthesias that characterize diverse types of neuropathic pain.111 Clinical experience also supports the use of these agents in patients with paroxysmal neuropathic pains that may not be lancinating and, to a far lesser extent, in those with neuropathic pains characterized solely by continuous dysesthesias. Although most practitioners prefer to begin with carbamazepine because of the extraordinarily good response rate observed in trigeminal neuralgia, this drug must be used cautiously in AIDS patients with thrombocytopenia, those at risk for marrow failure, and those whose blood counts must be monitored to determine disease status. If carbamazepine is used, a complete blood count should be obtained prior to the start of therapy, after two and four weeks, and then every three to four months thereafter. A leukocyte count below 4000 is usually considered to be a contraindication to treatment, and a decline to less than 3000 or an absolute neutrophil count of less than 1500 during therapy should prompt discontinuation of the drug. Other anticonvulsant drugs may be useful for managing neuropathic pain in AIDS patients, including phenytoin, clonazepam, valproate and gabapentin.111
Several newer anticonvulsants have been used in the treatment of neuropathic pain, particularly with patients who have reflex sympathetic dystrophy. These drugs include gabapentin, lamotrigine, tiagabine, and felbamate. Of these newer anticonvulsants, experience has been most favorable with gabapentin, now being widely used by pain specialists to treat neuropathic pain of various types. Gabapentin has a relatively high degree of safety, with no known drug-drug interactions and a lack of hepatic metabolism.111 Treatment with gabapentin is usually initiated at a dose of 300 mg/day and then gradually increased to a dose range of 900-3200 mg/day in three divided doses.
Corticosteroid drugs have analgesic potential in a variety of chronic pain syndromes, including neuropathic pains and pain syndromes resulting from inflammatory processes.111 Like other adjuvant analgesics, corticosteroids are usually added to an opioid regimen. In patients with advanced disease, these drugs may also improve appetite, decrease nausea and malaise, and improve the overall quality of life. Adverse effects include neuropsychiatric syndromes, gastrointestinal disturbances and immunosuppression.
Baclofen is a GABA-agonist that has proven efficacy in the treatment of trigeminal neuralgia.122 On this basis, a trial of this drug is commonly employed in the management of paroxysmal neuropathic pains of any type. Dosing is generally undertaken in a manner similar to the use of the drug for its primary indication, spasticity. A starting dose of 5 mg two to three times per day is gradually escalated to 30-90 mg per day, and sometimes higher if side effects do not occur. The most common adverse effects are sedation and confusion.
Oral Local Anesthetics
Local anesthetic drugs may be useful in the management of neuropathic pains characterized by either continuous or lancinating dysesthesias. Controlled trials have demonstrated the efficacy of tocainide and mexiletine and clinical evidence suggests similar effects from flecainide and subcutaneous lidocaine.123-126 It is reasonable to undertake a trial with oral local anesthetic in patients with continuous dysesthesias who fail to respond adequately to, or who cannot tolerate, the tricyclic antidepressants, and with patients with lancinating pains refractory to trials of anticonvulsant drugs and baclofen.
Mexiletine is preferred in the U.S.111 Paice and colleagues in 2000 studied twenty-six subjects in order to test the efficacy of topical capsaicin in the management of HIV-associated pain.127 Results suggest that capsaicin was ineffective in relieving pain with HIV-associated distal symmetrical peripheral neuropathy (DSPN). However capsaicin has been shown to be effective in relieving pain associated with other neuropathic pain syndromes.127
Drug Interactions: Analgesics and Anti-HIV Drug Therapies
Many of the available anti-HIV drugs have the potential to interact with other medications prescribed for pain, depression, anxiety or other medical conditions. These drug interactions can be dangerous, resulting in drug toxicities due to elevated levels of medication, or drug ineffectiveness due to lower drug levels in the serum. Opioid analgesics can interact with certain anti-HIV drug therapies and these interactions should be kept in mind when prescribing opioids.
The protease inhibitor ritonavir (Norvir) can increase the levels of several opioid drugs including codeine, hydrocodone, oxycodone, methadone, and fentanyl. Patients on ritonavir should not be prescribed meperidine or propoxyphene because of increased risk of serious toxicity. Antidepressant and anticonvulsant analgesics can also interact primarily with ritonavir. Ritonavir can increase the serum levels of bupropion (Wellbutrin, Zyban), fluoxetine, trazodone, and desipramine, resulting in increased drug toxicities (e.g., seizures with bupropion). Both ritonavir and saquinavir (Invirase) may increase levels of anticonvulsants such as phenobarbital, phenytoin, carbamazepine and clonazepam.
Physical interventions, psychological therapies and neurosurgical procedures may also prove useful in the management of HIV-related pain (see Table 4-9, PDF).
Physical interventions range from bed rest and simple exercise programs to the application of cold packs or heat to affected sites. Other non-pharmacologic interventions include whirlpool baths, massage, the application of ultrasound and transcutaneous electrical nerve stimulation (TENS). Increasing numbers of AIDS patients have resorted to acupuncture to relieve their pain, with anecdotal reports of efficacy.
Several psychological interventions have demonstrated potential efficacy in alleviating HIV-related pain, including hypnosis, relaxation and distraction techniques such as biofeedback and imagery, and cognitive behavioral techniques.
See Tables 4-10 (PDF) and 4-11 (PDF) for sample relaxation and distraction exercises. Where non-pharmacologic and standard pharmacologic treatments fail, anesthetic and even neurosurgical procedures (such as nerve block, cordotomy, and epidural delivery of analgesics) are additional options available to the patient who appreciates the risks and limitations of these procedures.
Additional points: Very likely some of the things you think of in answer to these questions can be recorded for you, such as your favorite music or a prayer. Then, you can listen to the tape whenever you wish. Or, if your memory is strong, you may simply close your eyes and recall the events or words. Source: Adapted from McCaffery M, Beebe A. Pain: Clinical Manual for Nursing Practice. St. Louis: RV Mosby Co, 1989.
Barriers to Pain Management in HIV/AIDS
A number of different factors have been identified as potential influences on the widespread undertreatment of pain in AIDS, including patient-, clinician-, and health care system-related barriers.3, 74, 128, 129 Sociodemographic factors that have been reported to be associated with undertreatment of pain in AIDS patients include gender, education level, and substance abuse history.4 Women, less educated patients, minorities, and patients who reported injection drug use as their HIV risk transmission factor are significantly more likely to receive inadequate analgesic therapy for HIV-related pain.
In a 1999 survey of approximately 500 AIDS care providers, clinicians (primarily physicians and nurses) rated the barriers to AIDS pain management they perceived to be the most important in the care of AIDS patients (see Table 4-12, PDF).129
Managing pain in AIDS patients with a history of substance use is a particularly challenging problem that HIV providers will face with increasing frequency. Table 4-13 (PDF) identifies basic interventions for pain management in substance users. For more information, see Chapter 11: Substance Use Problems.
Pain in AIDS, even in this era of protease inhibitors and decreased AIDS death rates, is a clinically significant problem contributing greatly to psychological and functional morbidity. Pain can be adequately treated and so must be a focus of palliative care of the person living with HIV/AIDS.
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