GMHC Treatment Issues; Volume 4 no. 1 January 29, 1990
Karen Dennis

Background

Naltrexone (Trexan R, DuPont), at dosages of 50 mg/day, is used in the treatment of narcotic addiction. It is believed to work by blocking opiate receptors in the brain. A growing body of evidence suggests that immune system regulation is linked to endorphins, which are neurotransmitters that have receptors in the brain. These hormones are the body's "natural painkillers". They are produced by the brain in response to acute stress and work by attaching to opiate receptors on cell surfaces. Endorphins have also been linked to the regulation of movement, mood and behavior. Interaction between endorphins and the immune system suggesets a potential role for opiate antagonists in the treatment of AIDS-related conditions. Therapeutic doses for immunosuppressed patients would be much lower than 50 mg/day, a dose that blocks opiate receptors. A lower dose may increase endorphin production without causing blockage.

Naltrexone also has a suppressive effect on alpha interferon levels. Elevated levels of alpha interferon in PWAs may suppress endorphin production in the brain (1). However, the clinical significance of elevated levels is still a matter of debate.

Acid-Labile vs. Acid-Stable Alpha Interferon

Alpha interferon that remains stable in acid has been shown to be therapeutic. This substance has been reproduced in large quantities through DNA technology and is used as a treatment for Kaposi's sarcoma. It is also being investigated as an antiviral treatment for HIV. (For more information on alpha interferon, see Treatment Issues vol. 3 no. 7). Yet a subclass of alpha interferon which is destroyed by acid ("acid-labile" alpha interferon) has been shown to be produced at high levels by macrophages and monocytes (white blood cells) which are infected with HIV (2). It is acid-labile alpha interferon which is implicated as a predictor of AIDS and is associated with a greater likelihood of developing opportunistic infections (3).

Clinical Experience in AIDS

A research team headed by Dr. Bernard Bihari of Kings County Addictive Disease Hospital in Brooklyn (and currently Executive Director of the Community Research Initiative) investigated the use of low-dose naltrexone (1.75 mg/day) in the treatment of people with AIDS, using a double-blind, placebo-controlled protocol. The trial began in July 1985 and ran until January 1986, with subsequent follow-up of the surviving participants to date. Originally, there were 56 PWAs enrolled in the study, of whom 18 dropped out in the first three months. Of the 38 remaining, 29 had a diagnosis of KS, 6 had a major opportunistic infection (OI) associated with AIDS and 3 had both.

The control (placebo) period of the trial was designed to last only for the initial 12 weeks, because of the researchers' reluctance to offer placebo to PWAs for a longer period. An independent statistician assigned each subject to naltrexone (22 of 38) or placebo (16 of 38). Both groups were monitored bi-weekly and later monthly. At the end of this time, the pharmacist who administered the drug was instructed to provide naltrexone to all participants in the study.

Analysis of test results for the first three months of the trial showed that alpha interferon levels dropped significantly in those subjects receiving naltrexone, while the control group showed no change. After the placebo group was switched to drug, 25 of the 38 participants exhibited declines in alpha interferon.

As of December 1986, 21 of the 25 who experienced this drop in alpha interferon had survived, while all of those who had shown no such drop had died (within nine months of the start of the trial). At 39 months of follow-up, 10 of the 25 still survived; of these, only one had experienced a major OI, and the others were symptom-free (4).

Subjects who had received naltrexone from the start of the study had significantly fewer OIs throughout the trial, with only eight cases as compared to 19 for the control group. Of these eight episodes, four were mild cases of PCP (5). The remaining four episodes, however, as with all 19 of those in the control group, were life threatening (and mostly fatal).

No change was noted in p24 antigen levels for any of the trial subjects. But those patients on drug maintained an immuno-logic response to CMV, while those on placebo had a decrease in this response. Patients who responded to naltrexone therapy sustained this immunologic response to CMV for up to 18 months (6). No subjects who began the trial with positive blood culture tests for HIV became negative, and none with negative initial results had changed to positive by 39 months (7).

Summary

Since the initial study, Dr. Bihari's group has used naltrexone at 3.0 mg/day. The drug is sold in 50 mg and 100 mg tablets, but pharmacists can prepare lower doses in solution. Naltrexone has the significant advantage of being orally administered and is relatively inexpensive. Since the FDA has approved the drug (for treatment of narcotic addiction), physicians may prescribe it for other uses. Some doctors are offering naltrexone to their patients as part of their treatment regimen. Some promising results have been reported: one physician reports noticeable remission of symptoms and absence of OIs in newly diagnosed PWARCs (6). It should be noted that, in the latter study, recipients of the drug reported difficulty in sleeping during the early weeks of use. Insomnia, mild depression and irritability are common symptoms in narcotic addicts being treated at the higher doses that block opiate receptors (7).

Neither the CRI nor the AIDS Treatment Registry (ATR) has any information on current trials of naltrexone, and DuPont is not planning any such trials for the drug. A large-scale clinical study tracking naltrexone's efficacy as an adjunctive therapy for people with AIDS and ARC may not take place in the near future, although only such a trial would help clarify the drug's utility in AIDS treatment and its limitations. In the meantime, many people who are HIV infected consider naltrexone a harmless gamble that might or might not be helping them. Once again, an experimental reatment remains in limbo because there is not sufficient financial or political interest in the drug to investigate its potential aggressively. All that can be concluded at this time is that naltrexone shows some promise in warding off major OIs associated with AIDS, possibly by "re-setting" the controls of the endorphin system and suppressing levels of acid-labile alpha interferon.

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