25 March 2018

Buprenorphine alone or with naloxone: Which is safer? Subutex versus Suboxone

Buprenorphine alone or with naloxone:  Which is safer?  Kelty E, Cumming C, Troeung L, Hulse G. Journal of Psychopharmacology (2018) in press. 1-9
Dear Colleagues,
After a ten year chronological comparison of 3500 patients prescribed either pure buprenorphine or the combination product with naloxone these authors found few differences in hospital admissions or death rates while in treatment.  However there was a significant increase in mortality post-treatment in those who were prescribed the combination product (odds ratio 1.59).  There were also higher all-cause hospital admission rates in those prescribed the combination product but slightly lower rates for those with skin infection diagnosis.  These extended to the post treatment period and the authors conclude that: “The addition of naloxone does not appear to improve the safety profile of buprenorphine”. 
These Western Australian researchers had access to Health Department prescribing records which were then compared with hospital admission rates and mortality over a ten year period, month by month, in 3500 patients starting in 2001.  The combination product was introduced in the middle of the study period and it quickly became about 90% of the market, allowing a useful comparison.  The 90% transition rate was partly because in WA take-away doses of the pure drug were banned coercively.  There may have been an exemption for pregnant women for whom the pure drug remains the recommended product. 
So here finally we have a study comparing pure buprenorphine with the combination product, although not a randomised controlled trial.  To my knowledge, despite the claims for benefit, there has been little rigorous comparative research before widespread replacement of the pure product with the combination.  The opioid antagonist naloxone was added to an existing sub-lingual product with the intention that it would be safer by being less attractive to inject.  As with other approved medicines, there is no obligation to do comparative research before TGA/FDA approval.  Indeed, all of the early research was on the pure product including the MOTHER study in 2009.  The only real support for the combination product meantime has been some indication that it was marginally less desirable on the black market, attracting a slightly lower reported price.  Yet it would seem self evident that a pure drug would be more desirable to drug seekers than a combination, regardless of the constituents.  Two studies indicated the need for higher doses when the combination drug was used (Fudala and Bell). 
In a small pilot study Bell and colleagues found that after transitioning to the combination product most seemed to do quite well on a number of indices.  However, they also found that subjects appeared to require substantially higher doses (>50% on average) when naloxone was added.  Fudala et al. found substantially more cravings in a large multi-centre RCT in the combination group using fixed doses.  There have been no confirmatory studies to my best knowledge. 
Western Australia has always been a good location for serious D&A research, Perth being a wealthy metropolis with good public health facilities in a relatively isolated position.  And with earnest, experienced and one-time well funded researchers. 
Kelty et al. point out that significant amounts of naloxone are in fact absorbed and that this is known to up-regulate the opioid receptors, possibly making some patients more vulnerable to overdose even after ceasing treatment.  It is also possible that this was the cause of the Sydney patients seemingly requiring higher doses in Bell’s old study. 
A good investigative journalist might make a good story over the profit motive, drug ‘evergreening’ and such, but I leave all this to others.  Suffice it to say that currently our government through the PBS is paying high prices whereas in France the pure product has been used since 1994 and is sold to the government suppliers as a cheap generic (and by an Australian company I believe!). 
Notes by Andrew Byrne ..
Bell J, Byron G, Gibson A, Morris A. A pilot study of buprenorphine-naloxone combination tablet (Suboxone®) in treatment of opioid dependence. Drug Alcohol Rev 2004 23;3:311-318
Fudala PJ, Bridge TP, Herbert S, Williford WO, Chiang CN, Jones K, Collins J, Raisch D, Casadonte P, Goldsmith RJ, Ling W, Malkerneker U, McNicholas L, Renner J, Stine S, Tusel D. Office-Based Treatment of Opiate Addiction with a Sublingual-Tablet Formulation of Buprenorphine and Naloxone. NEJM (2003) 349:949-958