Effectiveness of Buprenorphine Treatment

Buprenorphine can be used for either longterm maintenance or for medically supervised withdrawal (detoxification) from opioids. The preponderance of research evidence and clinical experience, however, indicates that opioid maintenance treatments have a much higher likelihood of long-term success than do any forms of withdrawal treatment. In any event, the immediate goals in starting buprenorphine should be stabilization of the patient and abstinence from illicit opioids, rather than any arbitrary or predetermined schedule of withdrawal from the prescribed medication.

                       Maintenance Treatment   

A number of clinical trials have established the effectiveness of buprenorphine for the maintenance treatment of opioid addiction. These have included studies that compared buprenorphine to placebo. (Johnson et al. 1995; Ling et al 1998; Fudala et al. 2003), as well as comparisons to methadone (e.g., Johnson et al. 1992; Ling et al. 1996; Pani et al.   2000; Petitjean et al. 2001; Schottenfield et al. 1997; Strain et al. 1994a, 1994b) and to methadone and levo-alpha-acetyl-methadol  (LAAM) (Johnson et al. 2000).  Results from these studies suggest that buprenorphine in a dose range of 8-16mg a day sublingually is as clinically effective as approximately 60mg a day of oral methadone, although it is unlikely to be as effective as full therapeutic doses of methadone (e.g., 120mg per day) in patients requiring higher levels of full agonist activity for effective treatment. 

A meta-analysis comparing buprenorphine was more effective than 20-35 mg of methadone but did not have as robust an effect as 50-80 mg methadone much the same effects as the individual studies have concluded.

Buprenorphine's partial mu agonist properties make it mildly reinforcing, thus encouraging patient compliance with regular administration. This is in contrast to medications such as naltrexone, which also blocks the effects of opioid agonists but lacks any agonist effects. Because a medication such as naltrexone is not reinforcing, adherence in therapeutic use is poor. Naltrexone also may increase the risk for overdose death in the event of relapse following its discontinuation.

Medically Supervised Withdrawal

Although  controlled clinical studies of the use of buprenorphine as an agent for treating opioid withdrawal (detoxification) are scarce, some clinical research on its use for this indication has been conducted (Parran et al. 1994). In general, buprenorphine has been used in three ways for withdrawal from opioids: long-period withdrawal (>30 days), usually on an outpatient basis; moderate -period withdrawal (>3 days but <30 days), again on an outpatient basis; and short -period withdrawal (<3 days), which often has been conducted on an inpatient basis. The available evidence from buprenorphine and methadone research suggests that long-period buprenorphine withdrawal probably would be more effective than moderate or short-period withdrawals but that all forms of withdrawal are less effective compared with ongoing opioid maintenance (Amass et al. 1994a ,b; Sees et al. 2000).

Long-Period Withdrawal

Although few data are available on the use of buprenorphine for gradual withdrawal over a period of months, the literature on opioid withdrawal can be used to guide recommendations in this regard. This literature suggests that using buprenorphine for gradual detoxification is more effective than its use for rapid detoxification in terms of patient compliance and relapse to opioid use. These findings are analogous to those seen with methadone which show that patients undergoing a 10 -week methadone dose reduction (i.e., 10 percent per week) had a higher rate of opioid-positive urine samples than those receiving a 30-week dose reduction (i.e., 3 percent per week) and asked for more schedule interruptions (Senay et al. 1977).

Moderate-Period Withdrawal

Few studies of withdrawal from illicit opioids have been conducted using buprenorphine for moderate periods (>3 days, but <30 days). Moderate-period withdrawal using buprenorphine suppresses signs and symptoms of withdrawal, is tolerated by patients, and is safe. For example, a study comparing 10 days of buprenorphine versus clonidine for the inpatient treatment of opioid withdrawal found buprenorphine superior to clonidine in relieving withdrawal signs and symptoms (Nigam et al. 1993). Outcomes with moderate-period withdrawal, however, are unlikely to be as positive as those seen with long-period withdrawal (Amass et al. 1994a ,b).

 Short-Period Withdrawal

The liquid form of buprenorphine has been studied for the withdrawal from opioids over short periods (e.g., 3 days) (Armenian et al. 1999). In these studies, the doses of buprenorphine administered were low (compared to maintenance doses) and typically were administered two or three times per day, either by injection or by having the patient hold the liquid under his or her tongue. (Note that this off -label use of the liquid form of buprenorphine is unlawful outside an approved study setting and is now unnecessary due to the FDA approval of Subutex and Suboxone.)

Reports have indicated that buprenorphine is well accepted by patients for short-period withdrawal and that opioid withdrawal signs and symptoms are suppressed (DiPaula et al. 2002; Bickel et al. 1988a ). When compared with clonidine for the treatment of short-period withdrawal, buprenorphine is better accepted by patients and more effective in relieving withdrawal symptoms (Cheskin et al. 1994). Long-term outcomes from short-period opioid withdrawal using buprenorphine have not been reported, however, and studies of other withdrawal modalities have shown that brief withdrawal periods do not produce measurable long-term benefits (Simpson and Sells 1989); patients usually relapse to opioid use.

Buprenorphine/Naloxone Combination

There have been reports from several countries of abuse of buprenorphine   by injection. Because of this buprenorphine abuse, a sublingual tablet form containing naloxone has been developed for the U.S. market to decrease the potential for abuse of the combination product via the injection route. Sublingual naloxone has relatively low bioavailability (Preston et al. 1990), while sublingual buprenorphine has good bioavailability. (Both naloxone and buprenorphine have poor GI bioavailability.) Thus, if a tablet containing buprenorphine plus naloxone is taken as directed sublingually the patient will experience a predominant buprenorphine effect.

 However, if an opioid-dependent individual dissolves and injects the combination tablet, then the antagonistic effect of naloxone predominates because of its high parenteral bioavailability (Stoller et al. 2001). Under such circumstances, the individual should experience a precipitated withdrawal syndrome. This should decrease the likelihood of misuse and abuse of the combination tablet by the injection route.

The safety and efficacy profile of sublingual buprenorphine/naloxone appears to be equivalent to that of buprenorphine alone (Harris et al. 2000). Currently, no special safety or side-effect considerations exist for the combination formulation, but it is not recommended for use in pregnant women. If buprenorphine treatment is elected for a pregnant woman, the monotherapy product should be used.

Diversion and Misuse  of  Either Buprenorphine Alone or  Buprenorphine/Naloxone Combination Product

As with any prescription opioid, physicians prescribing or dispensing buprenorphine or the buprenorphine/naloxone combination should monitor patients for diversion of these medications. As noted above, naloxone is combined with buprenorphine to decrease the potential for abuse of the combination via injection. Four types of individuals might attempt to abuse buprenorphine or buprenorphine/naloxone tablets parenterally:

Those using diverted tablets who are physically dependent on illicit opioids (e.g., heroin). Parenteral use of the combination buprenorphine/naloxone tablet by these individuals would result in precipitated withdrawal more reliably than injection of buprenorphine alone.

Those using diverted tablets who are taking therapeutic full agonist opioids (e.g., oxycodone, methadone). Parenteral use of the combination buprenorphine/naloxone tablet by these individuals also would result in a precipitated withdrawal syndrome more reliably than injection of buprenorphine alone.

Those receiving prescription buprenorphine or buprenorphine/naloxone tablets who dissolve and inject their own medication. This population would experience an agonist effect from buprenorphine but no antagonist effect from naloxone, as large doses of opioid antagonists are needed to precipitate withdrawal in buprenorphine -maintained subjects (Eissenberg et al. 1996). Although some of the agonist effects of buprenorphine may be attenuated by the simultaneous injection of naloxone, acute agonist effects will still be experienced whether the combination or the monotherapy product is injected.

Those who abuse opioids but who are not physically dependent on them. In this group, neither naloxone nor buprenorphine will produce precipitated withdrawal. Sublingual or injected use of either buprenorphine product will produce opioid agonist effects; however, the euphoric effects would be mild.

An understanding of both the general pharmacology of opioids and the specific pharmacological properties of buprenorphine is essential for physicians who intend to treat opioid addiction with buprenorphine. Buprenorphine has unique qualities that make it an effective and safe addition to the available pharmacological treatments for opioid addiction. The combination of buprenorphine with the opioid antagonist naloxone further increases its safety and decreases but does not eliminate the likelihood of diversion and misuse.

Are you ready to get the monkey off your back?

Reference:  Clinical Guidelines For The Use of Buprenorphine In The Treatment Of Opioid Addiction (TIP 40) Chapter 2 Pharmacology

Compiled And Edited By: Deborah Shrira
Updated: 11 March 20
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