Safety And Efficacy
              

Practical Considerations For The Clinical use of Buprenorphine

Hendree E. Jones Ph.D.
John Hopkins University School of Medicine
Baltimore, Maryland 

Research On Safety And Efficacy

Initial research showed that buprenorphine produced signs and symptoms similar to those of morphine use (for example, constricted pupils, sleepiness, and itchy skin), yet, unlike morphine, it produced little physical dependence or respiratory depression and only mild withdrawal symptoms, even when withdrawn abruptly (Fudala et al., 1990; Jasinski, Pevnick, and Griffith, 1978). In early efficacy studies, chronic buprenorphine-treated subjects did not self administer heroin to the same extent as placebo-treated subjects (Mello and Mendelson, 1980; Mello, Mendelson, and Kuehnle, 1982). Given its positive psychoactive effects, buprenorphine seemed likely to be accepted by patients (Mello and Mendelson, 1995), while its improved safety profile (Jasinski and Preston, 1995) would provide treatment practitioners with a unique medication for treating opioid dependence.

Subsequently, numerous studies examined the safety and efficacy of buprenorphine maintenance treatment (Ahmadi, 2002; Amass, Kamien, and Mikulich, 2000; Fischer et al., 1999; Fudala and Johnson, 1995; Fudala et al., 2003; Johnson, Jaffe, and Fudala, 1992; Johnson et al., 1995a, 1995b, 2000; Kosten et al., 1993; Ling et al., 1996; Mattick et al., 2003; Pani et al., 2000; Perez de los Cobos et al., 2000; Petitjean et al., 2001; Schottenfeld et al., 1997, 2000; Strain et al., 1994; Uehlinger et al., 1998). The only study to compare buprenorphine, LAAM, and high-dose methadone found that all three produced similar reductions in illicit opioid use and were superior to low dose methadone (Johnson et al., 2000).  
Many of the randomized controlled clinical trials conducted with buprenorphine have limitations.

 Most of the trials were conducted with men only, in monitored outpatient settings as opposed to office settings, over periods of less than a year, and with fixed doses (whereas flexible doses would be expected to produce better outcomes). Most studies used the liquid form of buprenorphine, so a dose conversion from liquid to tablet is necessary for proper interpretation   of   the   results.  In  addition,  most   studies   with tablets used Subutex, whereas Suboxone is the intended first-line form of buprenorphine.

Some studies have reported similar patient retention rates for buprenorphine and methadone (Johnson, Jaffe, and Fudala,1992; Johnson et al., 2000; Pani et al., 2000; Strain et al., 1994). Where differences in  retention  were  observed, buprenorphine treatment
was associated with greater dropout rates. Although the reason for this difference is not known, it is possible that:

The buprenorphine induction was too slow (Fischer et al., 1999; Mattick et al., 2003; Petitjean et al., 2001);
The maximum buprenorphine dose was too low (Fischer et al., 1999; Kosten et al., 1993; Ling et al., 1996; Mattick et al., 2003; Petitjean et al., 2001; Schottenfeld et al., 1997); or
Patients were able to terminate buprenorphine treatment more comfortably than methadone treatment because of buprenorphine’s milder withdrawal effects (Mattick et al., 2003).

Despite its limitations, this research, in sum, demonstrates that buprenorphine has efficacy similar to methadone over a broad dose range. Trials that used larger maintenance doses of the medications produced greater decreases in illicit opioid use, a dose-response relationship that confirms the medication’s causal contributions to the desired outcome. There is a great deal of variation in individuals’ responses to medication; consequently, patients should receive dosage tailored to their individual responses.
 
Though buprenorphine and methadone have shown similar efficacy in controlled trials, the comparative mildness of buprenorphine’s positive psychoactive effects has raised questions about its effectiveness for highly dependent patients. (Walsh et. al., 1994). Although there are reports of effective treatment of highly dependent patients  with  Subutex doses higher than 32mg  (personal  communication,  Rolley  E. Johnson, Reckitt Benckiser Pharmaceuticals, Inc., September 6, 2003), buprenorphine's limitations in this population of patients warrant further study.   

The effectiveness of high dose methadone, (80-120mg) compared with high-dose buprenorphine (16-32mg) was not examined (RCGP, 2004).  Various studies come to a similar conclusion and call for further research to determine if buprenorphine is more effective than methadone in particular settings or in particular subgroups of patients (Barnett et al, 2001; Giacomuzzi et al, 2003).   

Gowing et al (2005) looked at buprenorphine for the management of opioid withdrawal, or detoxification and concluded...

     For groups treated with buprenorphine, withdrawal severity
     was  less than  that  in  groups  treated  with clonidine;  peak
     severity  was  similar  to those treated with methadone,  but
     withdrawal   symptoms   may   resolve   more  quickly  with
     buprenorphine.   The  authors  conclude  on  the  basis of the
     meta-analysis  that  buprenorphine  is  more   effective  than
     clonidine  for the management of opioid withdrawal.  There
     appears  to  be  no significant  difference between buprenor-
     phine  and methadone  in terms of completion of treatment, 
     but withdrawal  symptoms  may resolve more quickly with 
     buprenorphine.
   

Just as with methadone (Ernst et al., 2002), a number of overdose deaths have been reported with intravenous use or very high doses of the combination of buprenorphine and benzodiazepines (Kintz, 2002; Reynaud et al., 1998; Singh et al., 1992). The interaction mechanism is unclear, but it appears not to be related to the drugs’ absorption, distribution, metabolism, or elimination from the body (Kilicarslan and Sellers, 2000). The interaction potential of sublingual buprenorphine and oral benzodiazepines is unclear. In controlled clinical trials in the United States, one death has been reported of a patient using oral benzodiazepine in conjunction with buprenorphine.

Suboxone, the buprenorphine-naloxone combination, has been shown to effectively treat opioid dependence or block the effects of illicit opioids without noticeable negative effects of naloxone (Amass, Kamien, and Mikulich, 2000, 2001; Comer and Collins, 2002; Harris et al., 2000; Strain et al., 2000, 2002). Given buprenorphine’s (particularly Suboxone’s) lower potential for abuse and strong safety profile— its plateau of subjective effects with increasing doses and the fact that it causes little respiratory depression— it is considered a first-line medication option for beginning opioid-dependence treatment (Fudala et al., 2003; Ling and Compton, 1997).

References: 1. Science Practice Perspectives Vol. 2 No. 2  August 2004
                   2. Buprenorphine; Critical Questions Answered;  Annette Verster & Ernst Buning; Euro-Methwork, 2005

Editor: Deborah Shrira                                      Date: September 2008