6 April 2013

Old study on withdrawals induced by sublingual naloxone.

Effects of sublingually given naloxone in opioid-dependent human volunteers. Preston KL, Bigelow GE, Liebson IE. Drug Alcohol Dependence 1990 25:27-34

Dear Colleagues,

This old study was sent to me recently in response to a discussion about the use of naloxone in combination with other opioids in an effort to prevent or deter injecting.

In this small but well constructed study sublingual (SL) naloxone precipitated withdrawal in two of six heroin users and in all three methadone subjects who were given graduated doses of naloxone sublingually. This occurred about 30 minutes after administration, about twice as long as when used intramuscularly.  The authors concluded that ‘naloxone doses up to 1-2mg can be administered sublingually to opioid abusers/addicts without precipitating withdrawal’.  Yet up to 32mg buprenorphine with 8mg naloxone is routinely used in practice.  The conventional wisdom from many quarters is that naloxone is not absorbed sublingually in clinically significant amounts.  This study, by prominent authors, showed quite the reverse over 20 years ago. 

The induction of withdrawals by naloxone (SL or injected) would seem to be academic since buprenorphine alone will precipitate withdrawal in those using heroin, methadone or other pure agonists regularly. For those who already have buprenorphine in the body, neither additional buprenorphine nor naloxone will cause withdrawals if injected. This is because buprenorphine already had the strongest known affinity for the mu receptor. This raises the question of why naloxone would be needed at all (see below). In addition, since naloxone is indeed absorbed, could repeated exposure be harmful? It appears that the regulators did not require evidence on this issue, perhaps believing the misconception that sub-lingual absorption was negligible.

In the 1970s naloxone was combined with methadone yet these early attempts were soon abandoned. Early combinations with buprenorphine around 1990 did not eliminate abuse and the drugs were withdrawn in some countries (Robinson 1993). Yet the attractive sounding concept reappeared around 2003 for a number of reasons, not the least that it ‘sounded attractive’. The pure form was also about to come off patent.

The original abstract (see below) does not indicate, as in the full text, that only 4mg was used in a third of the heroin subjects because that level already caused unpleasant withdrawals and 8mg was not considered acceptable, even in paid volunteers. The authors also use the imprecise expression “up to 1-2mg”, perhaps hoping to give some ‘flexibility’ to their findings. The study was partly funded by Reckitt and Coleman, the company which invented and marketed buprenorphine in that era.

Notes by Andrew Byrne ..

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/2323306