Management of Pain in End-Stage HIV Disease

The International Society for the Study of Pain has defined pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" -- a definition that emphasizes the highly subjective nature of pain. There are no readily available, reliable, objective criteria for measuring pain, and as a result many patients who suffer severe pain are undertreated or even untreated. For patients with a terminal disease such as AIDS, proper and adequate control of pain is perhaps the single most important factor in helping those patients maintain their dignity and self-sufficiency, especially in the last stages of the disease. Moreover, effective control of pain may be the most important determinant of quality of life for such patients.

Because pain cannot be assessed by purely objective criteria, the patient's subjective assessment is essential to accurate diagnosis and effective management. Social and cultural factors play major roles in the self-assessment of pain, and behavioral patterning, set down in early childhood, influences the patient's pain experience. While sensation threshold does not differ from culture to culture or among members of different communities, the translation of sensation into pain does differ widely from patient to patient.

"Pain secondary to HIV infection should be thought of, and treated, like the pain associated with malignant disease. Like cancer pain, AIDS-related pain can be caused by many factors, including nociceptive and neuropathic etiologies."

In clinical practice, pain is generally classified on the basis of the duration of symptoms (Table 1). This temporal classification assigns patients to one of five categories of pain: acute, subacute, recurrent acute, ongoing acute, and chronic benign. Unsurprisingly, both the etiology and treatment of these entities differ considerably. For example, the causes of acute pain are usually self-limited, and therefore this category of pain is easier to manage than the others . By contrast, chronic benign pain -- often referred to as Chronic Intractable Benign Pain Syndrome (CIBPS) or Chronic Pain Syndrome (CPS) -- is extremely difficult to treat, especially when it is coupled with poor coping mechanisms. While acute pain can usually be managed by a single physician, CIBPS/CPS will often require a multimodal approach, one that should include psychological evaluation and treatment as well as medication.

Pain secondary to HIV infection should be thought of, and treated, like the pain associated with malignant disease. Like cancer pain, AIDS-related pain can be caused by many factors, including nociceptive and neuropathic etiologies.

Over the past three decades basic science has elucidated much of the pain transmission system. Many of the neurotransmitters, modulators, and receptors of pain have been identified throughout the system, from peripheral nociceptors to the cerebral cortex itself. Drugs have been developed that can interfere with, or augment, aspects of this transmission and modulation system, thus diminishing the input of pain impulses into the cortex.

The available medications to treat pain include conventional narcotic analgesics and non-steroidal anti-inflammatory drugs as well as neuroactive and psychoactive agents. Each has its place in the pharmacological management of one or more of these pain syndromes (see the PULL OUT AND SAVE feature in this issue, "A Guide to Pain Management in HIV-Infected Patients").

Medication is mandatory in AIDS patients with pain, but drugs are not the only means of alleviating pain. Alternative or adjuvant modalities include transcutaneous electrical nerve stimulation, hypnosis, biofeedback, nerve blocks, and physical therapy. These non-pharmacological alternatives are beyond the scope of this article, but clinicians should be aware of their existence and their potential utility.

TABLE 1: Pain Classification by Duration of Symptoms

1: ACUTE 0-7 days duration Mild to severe Etiology known or unknown, usaually a single, "fixable" event Input from nociceptors (peripheral pain receptors) Treatment of causes and pain reduction: often an emergency Analgesics: Narcotic and non narcotic Mild psychological contribution 2: SUBACUTE 7 days to 6 months duration Mild to severe Etiology same as acute pain Input from nociceptors Treatment of causes and pain reduction: usually not an emergency Mild psychological contribution 3: ONGOING ACUTE Any duration of time Usually severe Due to ongoing tissue damage from neoplasms Input from nociceptors Treatment of causes and pain reduction Analgesics: Narcotic and non-narcotic Depression and anxiety common

4: RECURRENT ACUTE Any duration of time Mild to severe Due to chronic organic non-malignant pathology Input from nociceptors Treatment of causes and pain reduction Analgesics: Non-narcotic and co-analgesics as first line Narcotics sometimes indicated Depression and anxiety common 5: CHRONIC BENIGN Greater than 6 months duration Mild to severe Etiology unknown No known nociceptor input Treatment aimed at pain reduction Non-narcotic and co-analgesics are primary medications Usually no indication for narcotics Psychological factors very important, psychotherapy indicated Patient may or may not have adequate coping mechanisms

Effective management of pain

The clinical management of all pain syndromes should begin with an attempt to identify and treat the underlying cause of the pain. On occasion -- especially in patients with well advanced HIV disease who suffer from concurrent infections and/or neoplasms -- the underlying cause of a patient's pain cannot be identified or cannot be treated. Fortunately, this situation does not pre'mpt effective pain management; it simply shifts the focus of treatment from the cause to the pain itself.

"Regardless of cause, the objective of pain treatment is threefold: to reduce the patient's discomfort, decreased his anxiety, and return him to his previous level of function. There are no easy formulas to achieve these objectives. Treatment must always be individualized, because patients exhibit a remarkably wide range of pain tolerance and an equally wide range of responsiveness to pharmacotherapy."

Regardless of cause, the objective of treatment is threefold: to reduce the patient's discomfort, decreased his anxiety, and return him to his previous level of function. There are no easy formulas to achieve these objectives. Treatment must always be individualized, because patients exhibit a remarkably wide range of pain tolerance and an equally wide range of responsiveness to pharmacotherapy.

The vast majority of all complaints of pain arise from acute and subacute causes. Here the underlying problem is usually tissue injury, either from intrinsic or extrinsic causes. For these forms of pain, the essence of effective clinical management is to provide good analgesic support while the body has time to repair itself.

Chronic malignant and non-malignant pain with ongoing tissue injury is categorized as ongoing or recurrent acute pain. Pain in AIDS is often a combination of the two. For these patients it is imperative to follow the pain analgesic ladder that the World Health Organization developed for cancer patients in 1990. Each step in the ladder represents a further step in the pharmacologic management of the patient's pain, steps necessitated by progression of disease or progression of symptoms (Figure).

The WHO analgesic ladder does not take into account neuropathic pain, from which many AIDS patients suffer, either as a direct result of some disease process or as an indirect result of antiretroviral therapy . Therefore medications that reduce the pain associated with neuropathies should be used in all affected patients.

"The ideal way to use narcotics is to titrate them to the desired level of efficacy, on a case-by-case basis. The major limiting factor in increasing narcotic doses is the escalation of undesirable side effects (such as constipation, sedation, respiratory suppression, and confusion). When narcotics are used for the treatment of pain, it is unlikely that habituation will become a factor."

At the first rung of the WHO ladder are non-steroidal anti-inflammatory drugs and aspirin (Table 2). NSAIDs reduce pain by decreasing prostaglandin synthesis, relieving mild to moderate inflammation, and exerting an antipyretic effect. Aspirin, because of its long history of safety and effectiveness, has been the prototype against which all NSAIDs have been judged. These agents have a ceiling effect, a dose above which there is no additional benefit, but they also have no tolerance limits or addiction potential. These drugs have roughly the same activity when given in equipotent doses. The major limiting factors are adverse reactions and convenience of dosage schedules.

Acetaminophen, which is marketed under many trade names, is not a NSAID. Although it is an antipyretic agent, it has no peripheral anti-inflammatory or prostaglandin inhibitory activity. It does, however, have analgesic properties, probably through CNS activity. The usual dose is 650-1000 mg every 4-6 hours by mouth or per rectum, with a maximum daily dosage of 6-8 grams. It can be given in conjunction with NSAIDs and narcotic analgesics (whose activity it can potentiate).

Management of mild-to-moderate pain

Many narcotic analgesics can be used to treat mild-to-moderate AIDS-related pain (Table 3). In outpatient situations, the most convenient route of administration is via the GI tract (oral or rectal). This route has the added benefit of preventing abrupt swings in serum levels, providing a slow onset and slow decay. Care must be taken when giving parenteral narcotics that adequate time is allowed for gastrointestinal absorption -- which can take up to 90 minutes. Repeat doses should be given well before serum drug concentrations drop to subtherapeutic levels.

"The therapeutic goal of any analgesic regimen sis to achieve an adequate serum level, one sufficiently high to assure pain relief in the resting state, with additional medication readily available to provide analgesia for breakthrough pain. Doses should be spaced well within the drug's serum half-life, to maintain effective serum levels. This is most easily accomplished by providing medication on a fixed schedule for background analgesia."

The ideal way to use narcotics is to titrate them to the desired level of efficacy, on a case-by-case basis. With the important exceptions of meperidine, propoxyphene and pentazocine, there are no peak doses for narcotics, as there are with NSAIDs. The major limiting factor in increasing narcotic doses is the escalation of undesirable side effects (such as constipation, sedation, respiratory suppression, and confusion). When narcotics are used for the treatment of pain, it is unlikely that habituation will become a factor. In any case, the spectre of addiction should not be a consideration in the use of these analgesics if they are deemed necessary for the management of pain in late-stage HIV disease.

The therapeutic goal of any analgesic regimen sis to achieve an adequate serum level, one sufficiently high to assure pain relief in the resting state, with additional medication readily available to provide analgesia for breakthrough pain. Doses should be spaced well within the drug's serum half-life, to maintain effective serum levels. This is most easily accomplished by providing medication on a fixed schedule for background analgesia. Additionally, some rapid-onset medication should be available for breakthrough pain on an "as needed" basis.

The longer-acting narcotic analgesics are the logical choice for background analgesia because they achieve extremely stable serum narcotic levels with only a few doses per day. The same effect can be attained with the shorter-acting narcotics, but they require frequent dosing. These shorter-acting narcotics do provide good coverage for breakthrough pain, however.

"In the clinical management of intractable long-standing pain , there is no specific dose of opiate, and no ceiling above which further dosing is inadvisable. Therefore, the opiate dose should be pushed to whatever level it takes to make the patient comfortable -- especially at the end of life."

Management of moderate-to-severe pain

Narcotic analgesics are rarely used for mild pain, but they are frequently used in cases of moderate to severe pain. Pharmacologically, they are of two classes: pure opiate-receptor agonists, and mixed agonist-antagonists that have some properties of naloxone (an opiate-receptor antagonist) mixed with the direct agonist properties. The prototype pure receptor agonist is morphine, although there are many drugs in this class (see the PULL OUT AND SAVE feature). The mixed agonist-antagonist analgesics have been slow to achieve popularity for several reasons: a ceiling effect for analgesia, reversal of analgesia in patients who are also taking pure agonists, and the unavailability of oral preparations.

For the sustained pain from which many patients with end-stage AIDS suffer, it is most appropriate to use a sustained-release narcotic analgesic. The specific agent chosen is less important than the principal that maintaining a therapeutic blood level of opiate is the most appropriate treatment for long-standing pain. In order to avoid overdosing, the sustained-release opiate should be dosed for analgesia with the patient at rest. Incident or breakthrough pain can then be treated with small doses of immediate-release short-acting opiates.

In this context it is important for the care-provider to remember that opiates should be given in escalating doses until the desired effect is achieved. Side effects are the only limiting factor. In the clinical management of intractable long-standing pain , there is no specific dose of opiate, and no ceiling above which further dosing is inadvisable. Therefore, the opiate dose should be pushed to whatever level it takes to make the patient comfortable -- especially at the end of life.

"For the sustained pain from which many patients with end-stage AIDS suffer, it is most appropriate to use a sustained-release narcotic analgesic. The specific agent chosen is less important than the principal that maintaining a therapeutic blood level of opiate is the most appropriate treatment for long-standing pain. In order to avoid overdosing, the sustained-release opiate should be dosed for analgesia with the patient at rest."

Neuropathic pain may be resistant to opiate dosing alone. For severe neuropathies, the dose of opiate should be titrated upwards, but adjuvant drugs should be used concomitantly. Neuropathic pain syndromes are managed first with a tricyclic antidepressant (TCA) given once daily, usually at bedtime (Table 4). It is important for AIDS patients to lead as normal a day/night cycle as possible, and these drugs not only help manage neuropathic pain, they are for the most part sufficiently sedating to be used as a sleep aid as well.

Although amitriptyline as generally regarded as the first-line TCA, the anticholinergic side effects and excess sedation of this and the other first-generation TCAs, doxepin and imipramine, limit their usefulness. Most patients find nortriptyline or desipramine to be as effective as the first generation TCAs in controlling neuropathic pain, and they usually experience fewer deleterious side effects. This increases compliance and, with it, effectiveness.

In many cases of AIDS-related neuropathic pain, a TCA alone proves inadequate, and additional agents must be started (Table 5). Antiseizure drugs such as carbamazepine and phenytoin can be helpful, but both have significant side effects and toxicities which can make their use inadvisable, especially at very sick patients. A newer antiseizure agent, gabapentin, holds great promise of diminishing neuropathic pain with a minimum of side effects. Clonazepam, a benzodiazepine antiseizure drug, can be very potent, especially when used in combination with gabapentin.

"It is within the ability of current clinical practice to deliver a high degree of pain control to most patients with end-stage HIV disease -- without sacrificing their sense of self and their ability to think and function. In the vast majority of cases, carefully considered titration of medication can result in a satisfactory outcome, one that ablates the patient's pain and maintains his dignity and comfort."

Conclusion

It is within the ability of current clinical practice to deliver a high degree of pain control to most patients with end-stage HIV disease -- without sacrificing their sense of self and their ability to think and function. In some patients, more invasive techniques may be needed, including spinal narcotics and destructive nerve-block procedures. However, these patients are the exceptions to the rule. In the vast majority of cases, carefully considered titration of medication can result in a satisfactory outcome, one that ablates the patient's pain and maintains his dignity and comfort.

Howard L. Rosner, M.D., is Associate Professor of Clinical Anesthesiology at Cornell University Medical College and Director of Pain Management Service at The New York Hospital.