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Clinical Management of Opioid Dependence in HIV

Here we present a case vignette highlighting a common clinical problem. Various options for management are then presented, followed by the author's clinical recommendations.

CK is a 52-year-old woman with AIDS who has been followed since 1990. She has a history of heroin addiction and acquired her HIV infection through intravenous drug use. She has painful peripheral neuropathy (caused by prolonged exposure to ddI and d4T) that has been unresponsive to trials of myriad non-opioid medications. On a regimen of tenofovir/3TC + lopinavir/ritonavir, her viral load is undetectable, and her CD4 count is 225 cells/mm³. She says that because of her unrelenting pain, she has been self-medicating with heroin. What are her treatment options?

THE CLINICAL PROBLEM

An estimated 800,000 to 1 million individuals in the U.S. are addicted to heroin, and in 2008, another 4.7 million were reported to have abused prescription pain medications. Many in this latter group will eventually move on to injecting heroin, because it is less expensive than prescription drugs and is readily available. Injection-drug use accounts for up to half of all new HIV infections in the U.S., as a consequence either of sharing syringes or being a sexual partner of an injection-drug user. Unfortunately, syringe-exchange and drug-treatment programs, both of which have been scientifically documented to prevent HIV acquisition, are not readily available in many parts of the country. Meanwhile, drug-overdose deaths have risen markedly in the U.S. during the past 10 years, almost entirely because of opioid misuse.

Globally, about 16 million people are injection-drug users, and such drug use accounts for 30% of new infections outside sub-Saharan Africa. In Russia, Eastern Europe, and parts of Southeast Asia, injection-drug use is the predominant mode of HIV acquisition, accounting for up to 80% of new infections. Unfortunately, in most countries in these regions, little or no treatment is available for drug addiction, and the predominant response has been through the criminal justice system.

MANAGEMENT STRATEGIES

Treatment for opioid dependence includes abstinence-based therapy as well as pharmacotherapy.

Abstinence-Based Therapy
Abstinence-based therapy relies on residential treatment programs, addiction counseling, and self-help groups, such as Narcotics Anonymous. Unfortunately, research shows that up to 85% of patients with opioid dependence will relapse within the first year of such a program if they do not also receive pharmacotherapy. At present, three FDA-approved medications are available to treat opioid dependence: methadone, naltrexone, and buprenorphine.

Methadone
Methadone has been used to treat opioid dependence since the 1950s. As a full opioid agonist, it not only prevents the recipient from achieving euphoria from opioids, but it also blocks craving and eliminates withdrawal symptoms. In the U.S., it is regulated by the government and is legally available only through approved methadone maintenance programs. Such programs have been shown to decrease participants' illicit opioid use, criminal activity, and risk for HIV acquisition. Furthermore, for HIV-infected individuals, these programs can improve adherence to antiretroviral therapy. Side effects of methadone include constipation, excessive sweating, central hypogonadism, and prolonged QTc syndrome, with increased risk for torsades de pointes. Notably, methadone is metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme and, thus, HIV providers must be aware of potential drug interactions when their patients enter methadone treatment programs.

Naltrexone
Naltrexone, an opioid antagonist, is available in two formulations: oral and intramuscular extended release. The drug binds tightly to the opioid receptor, thus preventing the euphoric effects of opioid use. However, it does not block drug craving or withdrawal symptoms. Thus, the oral formulation, which is taken daily, requires a tremendous amount of willpower and consequently has a low success rate, except in highly motivated individuals, such as impaired physicians at risk of losing their medical license. The intramuscular formulation addresses this limitation because it is administered in the clinic once a month, but it is currently approved by the FDA only for the treatment of alcoholism.

Buprenorphine
Buprenorphine was approved by the FDA in 2002 for the treatment of opioid dependence. It is available as a sublingual tablet, either alone (Subutex) or coformulated with the antagonist naloxone (Suboxone). Buprenorphine is well absorbed sublingually, while naloxone is not. When buprenorphine/naloxone is taken sublingually as directed, the major effect is from the partial agonist buprenorphine. If patients attempt to abuse the medication by crushing and injecting the tablet, they will primarily feel the effect of the antagonist naloxone.

Buprenorphine is the first opioid agonist approved for treating addiction in an office-based setting. The prescriber must be a physician with a full medical license and at least 8 hours of training in the use of this medication. Addiction counseling must be available, either on site or by referral. At present, prescribers are initially limited to treating 30 patients at any one time but, after 1 year, may apply for a waiver to treat up to 100.

Buprenorphine has several attractive properties:

• It is a partial opioid agonist with a ceiling effect at approximately 30% of receptor activation, so overdose is exceedingly unlikely.
  
• It has a higher affinity for the opioid receptor than heroin and thus blocks euphoria if heroin or other opioids are used.
  
• It has a half-life of 24 to 48 hours and thus can be dosed once daily.
  
• It effectively blocks craving and withdrawal, but it has fewer side effects and causes less sedation than methadone.
  
• It has analgesic properties, although the sublingual formulation is not FDA approved for use as an analgesic.
  

Buprenorphine is a mild CYP3A4 inhibitor and is also metabolized by this enzyme. No significant interactions have been reported thus far with NRTIs or NNRTIs. With respect to PIs, one case series described three patients who had increased sedation from buprenorphine after starting an antiretroviral regimen that contained ritonavir-boosted atazanavir. In addition, a recent pharmacokinetic study in HIV-uninfected individuals demonstrated reduced tipranavir levels in patients given ritonavir-boosted tipranavir while receiving buprenorphine/naloxone.

Studies have shown that buprenorphine yields results similar to those of methadone maintenance therapy in decreasing illicit opioid use. In addition, treating the addiction improves adherence to HIV medications and increases the likelihood of retention in care. Providing buprenorphine in the primary care setting helps to destigmatize as well as to medicalize the treatment of addiction.

RECOMMENDATIONS AND CONCLUSIONS

Detoxification seems unlikely to be effective for the patient presented in the vignette, because she will still be in pain after it is complete. Methadone maintenance is a possibility, but she is reluctant because of the stigma, and once-daily methadone often leaves patients in pain toward the end of the day. A prescription for buprenorphine/naloxone from her trusted HIV provider can be an effective way to treat her pain and addiction and keep her on track with her HIV care.

In the 1980s and early 1990s, HIV providers became adept at hospice and palliative care. In the following decade, they developed mastery of lipid management and preventive care. The next frontier is the management of drug addiction. The work is challenging and the stakes are enormous, but when the outcomes are successful, the rewards are like those I experienced when my first patient returned from near death after receiving potent antiretroviral therapy in 1996.

FURTHER READINGS AND RESOURCES

U.S. Department of Health and Human Services. Center for Substance Abuse Treatment (CSAT) Buprenorphine Information Center. (http://buprenorphine.samhsa.gov)

Barry DT et al. Patient satisfaction with primary care office-based buprenorphine/naloxone treatment. J Gen Intern Med 2007 Feb; 22:242.

Bruce RD and Altice FL. Three case reports of a clinical pharmacokinetic interaction with buprenorphine and atazanavir plus ritonavir. AIDS 2006 Mar 21; 20:783.

Bruce RD et al. Pharmacokinetic drug interactions between opioid agonist therapy and antiretroviral medications: Implications and management for clinical practice. J Acquir Immune Defic Syndr 2006 Apr 15; 41:563.

Bruce RD et al. Pharmacokinetic interactions between buprenorphine/naloxone and tipranavir/ritonavir in HIV-negative subjects chronically receiving buprenorphine/naloxone. Drug Alcohol Depend 2009 Aug 31; [e-pub ahead of print].

Cunningham CO et al. Barriers to obtaining waivers to prescribe buprenorphine for opioid addiction treatment among HIV physicians. J Gen Intern Med 2007 Sep; 22:1325.

Fudala PJ et al. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med 2003 Sep 4; 349:949.

Khalsa J et al. Buprenorphine and HIV primary care: New opportunities for integrated treatment. Clin Infect Dis 2006 Dec 15; 43:S169.

Malinoff HL et al. Sublingual buprenorphine is effective in the treatment of chronic pain syndrome. Am J Ther 2005 Sep/Oct; 12:379.

Mattick RP et al. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev 2008; 2:CD002207. (http://dx.doi.org/10.1002/14651858.CD002207.pub3)

Mintzer IL et al. Treating opioid addiction with buprenorphine-naloxone in community-based primary care settings. Ann Fam Med 2007 Mar/Apr; 5:146.

Sullivan LE and Fiellin DA. Narrative review: Buprenorphine for opioid-dependent patients in office practice. Ann Intern Med 2008 May 6; 148:662.

— Mark Eisenberg, MD

Dr. Eisenberg is Assistant Professor of Medicine, Harvard Medical School, and Unit Chief, Adult Medicine, MGH-Charlestown HealthCare Center. He declares no conflicts of interest.

Published in AIDS Clinical Care October 5, 2009

Reader Remarks:

Read all Reader Remarks on this article

• Clinical Management of Opioid Dependence
  G Florentin-Lee, 7 Oct 2009 12:43 PM EST
  The progress made over the last 50 years in pain management can best be described as no progress at all.... [more]
• Too little, too late
  Alan Wartenberg, MD, 13 Oct 2009 12:50 PM EST
  I am pleased to see the management of a patient's opioid dependency take center stage, and even called the "next... [more]
• Too Little, Too Late
  mark eisenberg, 19 Oct 2009 2:49 PM EST
  I can't agree more. I was amazed when the new HIVMA clinical guidelines for managing patients with HIV were released... [more]