Current Perspectives on Pain in AIDS

July 1, 2002

The article by Dr. William Breitbart and Lucia DiBiase offers an excellent in-depth review of our current knowledge of the epidemiology, pharmacologic, and nonpharmacologic interventions in the field of pain management in patients with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS).

The article by Dr. William Breitbart and Lucia DiBiaseoffers an excellent in-depth review of our current knowledge of theepidemiology, pharmacologic, and nonpharmacologic interventions in the field ofpain management in patients with human immunodeficiency virus (HIV) and acquiredimmunodeficiency syndrome (AIDS).

Epidemiologic surveys suggest that pain is highly prevalent and frequentlyundertreated in both cancer and HIV/AIDS patients.[1-3] Studies have stronglyindicated, however, that the problem of pain undertreatment is far worse in theHIV/AIDS population. Pain management needs to be a fundamental priority in theprovision of care and relief of suffering for these patients. In order toaddress this priority, health-care providers should familiarize themselves withthe pain syndromes prevalent in HIV/AIDS and principles of pain management.

Adjuvant Analgesics

Many different adjuvant analgesics are used to treat pain in the HIV/AIDSpopulation. Neuropathic pain syndromes associated with disease progression ortreatment-related side effects are the most prevalent pain complications inHIV/AIDS patients, and they pose a daunting challenge for management. Inclinical practice, unsuccessful trials are frequently attributed to theincomplete duration of the trial, inadequate dose titration, overly rapidtitration producing dose-limiting side effects, issues of nonadherence, and/orunrealistic expectations held by patient or clinician.

The authors have presented an extensive list of drugs that have potentialbenefit in the treatment of neuropathic pain. In light of the extensive numberof adjuvant medications, it is recommended that felbamate (Felbatol) use beavoided because of the possibility of aplastic anemia and hepatic failure.[4]

Opioid Pharmacology

Breitbart and DiBiase provide an excellent, comprehensive guide to opioidselection for the management of pain in patients with HIV/AIDS. It would havebeen worthwhile, however, to devote an additional paragraph to the use ofmethadone for pain management. It appears that the recent increase in the use ofmethadone for pain management may be related to its low cost and efficacy inpatients for whom opioid trials have been inadequate. Despite the paucity ofefficacy studies, an opioid rotation to methadone is recommended for patientswho experience dose-limiting side-effects on other opioids.

The half-life of methadone ranges from about 12 hours to more than150 hours. This variability among individuals implies that a steady state—achievedafter about four half-lives—may be reached in as little as several days or aslong as weeks. Aggressive titration before maximal efficacy is observed witheach single dose may result in toxic blood levels, even weeks after doseadjustment has been completed. Moreover, methadone tends to be more potent thanit would appear based on equianalgesic dosing. For this reason, it isrecommended that, when switching from another opioid to methadone, the doseshould be reduced by 75% to 90% to avoid methadone-induced toxicity. Awarenessof these peculiarities of the pharmacokinetics of methadone may help thepractitioner plan for frequent assessments during initiation of treatment ordose adjustment. Although patients on methadone maintenance receive the drugonce a day, the use of methadone for pain management requires different dosescheduling. The frequency of dosing varies from once or twice daily (in aminority of patients) to four or five times a day.[5]

Pain and Chemical Dependency

As the authors correctly point out, pain management in HIV/AIDS patients witha comorbidity of chemical dependency presents a therapeutic challenge. Methadonehas been shown to be very valuable for managing pain in patients alreadyreceiving the drug for opioid replacement. If the patient is on methadonemaintenance, it is recommended that he or she continue taking the maintenancedose in the morning. In addition, an extra amount of methadone divided in threeor four daily doses can be prescribed for pain control. In the United States, ageneral practitioner cannot prescribe methadone for opioid replacement ormaintenance therapy but can prescribe it for pain control. Effective managementof pain requires fluid communication between the clinician responsible for painmanagement and the methadone maintenance treatment program, in order tocoordinate the writing of prescriptions and to ensure appropriate assessment.

If the methadone dose has to be increased to achieve better pain relief, thepractitioner should discuss these changes in advance with both the patient andthe methadone clinic case manager. It is important to be aware that an increasein the methadone maintenance dose may be perceived by the patient as a sign ofmistrust, because the maintenance dose of methadone is often increased toprevent further opioid abuse. Patients should be reassured that their methadoneis being adjusted for pain relief.

In circumstances of documented abuse or aberrant use of opioid medications,additional strategies are recommended. These may include occasional pill counts;unscheduled urine toxicology screens; a written contract or agreement thatclearly spell out expectations and assurances signed by both the practitionerand patient; and frequent follow-up visits. Such strategies are intended toprovide structure and facilitate the development of a therapeutic alliance.

Future Directions

Nausea, vomiting, constipation, pruritus, respiratory depression, and thedevelopment of tolerance are commonly observed with opioid therapy. Strategiesthat decrease opioid requirements may decrease the incidence of these sideeffects. In animal studies, blockade of excitatory receptors preventedhyperalgesia and the development of tolerance. Tolerance is defined as a shiftto the right of the dose-response curve. Indeed, pretreatment withdextromethorphan (N-methyl-d-aspartate [NMDA] antagonist) resulted in theprevention of tolerance and a decrease in opioid requirements for paincontrol.[6] Clinical studies, however, have shown only modest benefit. Thecombination of NMDA antagonists and morphine in the right proportion seem to bemore effective.[7]

Independently, low-dose opioid antagonists have been proposed to prevent thedevelopment of tolerance and potentiate opioid-mediated analgesia in animalmodels.[8-10] One clinical study has shown a sparing effect of morphine withconcomitant naloxone administration.[11] Additional studies are currently inprogress. Whether the combination of NMDA antagonist and low-dose opioidantagonists results in a more significant opioid-sparing effect, remains to bedemonstrated.

References:

1. Cleeland CS, Gonin R, Hatfield AK, et al: Pain and its treatment inoutpatients with metastatic cancer. N Engl J Med 330:592-596, 1994.

2. Lebovits AH, Lefkowitz M, McCarthy D, et al: The prevalence and managementof pain in patients with AIDS: A review of 134 cases. Clin J Pain 5:245-248,1989.

3. Breitbart W, McDonald MV, Rosenfeld B, et al: Pain in ambulatory AIDSpatients. I: Pain characteristics and medical correlates. Pain 68:315-321, 1996.

4. Kaufman DW, Kelly JP, Anderson T, et al: Evaluation of case reports ofaplastic anemia among patients treated with felbamate. Epilepsia 12:1261-1264,1997.

5. Portenoy RK: Contemporary Diagnosis and Management of Pain in Oncologicand AIDS Patients. Newton, Pa, Handbooks in Health Care Co, 2000.

6. Trujillo KA, Akil H: Inhibition of morphine tolerance and dependence bythe NMDA receptor antagonists MK-801. Science 251:85-87, 1991.

7. Cleeland E: Morphine with dextromethorphan: Conversion from other opioidanalgesics. J Pain Symptom Manage 19:S42-S49, 2000.

8. Crain SM, Shen K-F: Opioids can evoke direct receptor-mediated excitatoryeffects on sensory neurons. Trends Pharmacol Sci 11:77-81, 1990.

9. Crain SM, Shen K-F: Antagonists of excitatory opioid receptor functionsenhance morphine’s analgesic potency and attenuate opioid tolerance/dependenceliability. Pain 84:121-131, 2000.

10. Cruciani RA, Pasternak GW: Blockade of hyperalgesia by antisenseoligodeoxynucleotide to Gsa (abstract). Program and abstracts of the 31stInternational Narcotic Research Conference, July 15-20, 2000, Seattle, p 59.

11. Gan TJ, Ginsberg B, Glass PSA, et al: Opioid sparing effects of alow-dose infusion of naloxone in patient-administered morphine sulfate.Anesthesiology 87:1075-1081, 1997.