Opioid detoxification with buprenorphine, clonidine, or methadone in hospitalized heroin-dependent patients with HIV infection

Abstract

With the growing role of intravenous drug use in the transmission of HIV infection, HIV-infected patients frequently present with comorbid opioid dependence. Yet, few empirical evaluations of the efficacy and consequences of opioid detoxification medications in medically ill HIV-infected patients have been reported. In a randomized, double-blind clinical trial, we evaluated the impact of three medications on the signs and symptoms of withdrawal and on the pain severity in heroin-dependent HIV-infected patients (N=55) hospitalized for medical reasons on an inpatient AIDS service. Patients received a 3-day pharmacologic taper with intramuscular buprenorphine (n=21), oral clonidine (n=16), or oral methadone (n=18), followed by a clonidine transdermal patch on the fourth day. Observed and self-reported measures of opioid withdrawal and pain were taken 1–3 times daily for up to 4 days. Opiate administration used as medically indicated for pain was also recorded. Observer- and subject-rated opiate withdrawal scores decreased significantly following the first dose of medication and overall during treatment. Among all 55 subjects, self-reported and observer-reported pain decreased after treatment (on average observer-rated opioid withdrawal scale (OOWS) scores declined 5.6 units and short opioid withdrawal scale (SOWS) declined 4.8 units, P<0.001, for both) with no indication of increased pain during medication taper. There were no significant differences of pain decline and other measures of withdrawal between the three treatment groups. During the intervention period, supplemental opiates were administered as medically indicated for pain to 45% of the patients; only 34% of men versus 62% of women received morphine (P<0.05). These findings suggest buprenorphine, clonidine, and methadone regimens each decrease opioid withdrawal in medically ill HIV-infected patients.

Introduction

Hospitalization of opioid-dependent individuals for acute (as well as chronic) illness often interrupts their heroin use and can result in withdrawal. Untreated opioid withdrawal, aside from being very unpleasant, can confound medical assessment and increase patients' anxiety towards necessary medical procedures, resulting in conflicts with the healthcare team or in premature discharges against medical advice (with potentially harmful consequences). Although pharmacological treatments have been shown to minimize opioid withdrawal intensity in medically stable patients, their effects on withdrawal have not been evaluated in drug users hospitalized for an acute illness.

Of particular interest are hospitalized drug users infected with HIV, as injection drug use is a major cause of HIV transmission in the United States (Center for Disease Control, 1997, Karon et al., 2001). When HIV-infected drug users are hospitalized, they are brought in contact with healthcare professionals who could alleviate drug use withdrawal discomfort and possibly intervene in the cycle of drug use. Besides withdrawal-related discomfort during hospitalization, HIV-infected opioid users may experience additional pain from their underlying HIV-related illnesses (Breitbart et al., 1996, Breitbart et al., 1997, Rosenfeld et al., 1996). Neurologic changes associated with HIV progression may affect the response to opioid detoxification and perhaps even exacerbate pain from withdrawal-related conditions. For example, animal research has demonstrated that neuromediator changes underlying neuropathic pain are similar to those observed in opioid tolerance (Mao et al., 1995). This finding raises the question of whether intensity of HIV-related pain could be increased by opioid withdrawal and, thus, promote relapse to heroin use upon discharge. It is, therefore, important to assess the potential impact of opioid detoxification on pain syndromes and to develop standards of care that minimize suffering.

This study was designed to evaluate responses to three different opioid detoxification medications (clonidine, methadone, and buprenorphine) on withdrawal and pain measures while HIV-infected patients received treatment for their acute medical condition. Clonidine, an α₂-noradrenergic agent, is a presynaptic inhibitor of norepinephrine release in the locus coeruleus with weak analgesic activity at the spinal level (Aghajanian, 1978, Gold et al., 1978, Gold et al., 1980, Guthrie, 1990, Striebel et al., 1993, Bischoff and Kochs, 1993), though the importance of this activity in opioid-dependent human is not known. Methadone, a μ-opioid agonist with pharmacological properties qualitatively similar to those of morphine, has been recommended for managing opioid dependence in the hospital setting (Perkins, 1970, Stimmel, 1997). Buprenorphine is a partial μ-opioid agonist analgesic that is 25–50 times more potent than morphine (Jaffe and Martin, 1990, Jasinski et al., 1978). All three medications have been tested in clinical trials for opioid detoxification and shown to be effective in suppressing opioid withdrawal in healthy opioid-dependent volunteers seeking treatment (Umbricht et al., 1999, Jasinski et al., 1985, Agren, 1986, Buccafusco, 1992, Cheskin et al., 1994, Nigam et al., 1993, O'Connor et al., 1997, Bearn et al., 1998, Bickel et al., 1988).

The outcome of opioid detoxification in HIV-infected individuals hospitalized for an acute medical condition has not been evaluated. We hypothesized that, while all three regimens would be effective among hospitalized HIV-infected persons, buprenorphine would be superior to clonidine and methadone because it has high receptor affinity, a long duration of action, and low intensity of withdrawal symptoms following abrupt discontinuation (Jasinski et al., 1978). Because of its partial agonist activity, buprenorphine causes little or no cardio-respiratory depression in opioid-tolerant individuals, even at high doses (Walsh et al., 1994, Preston et al., 2001) and, thus, may be the safest in medically compromised patients.

The objectives of this study were to compare the effectiveness of these three opioid detoxification methods on withdrawal and pain scores in HIV/AIDS patients during hospitalization for an acute medical condition. A subsidiary objective was to evaluate patterns of medical indication for opiate (morphine) administration during the detoxification and associated treatment outcome.