Getting us hooked on Suboxone

We at KFx Towers like a good pharmaceutical success story as much as the next person. So the news that Schering Plough received an EU-wide licence for Suboxone before Christmas must have been good news for the good people at said company. Indeed, so happy were they at their success, that they decided to make their new medicine available at knock-down prices, so that more people could start on this new treatment. We understand in some areas that Suboxone is being made available more cheaply than Subutex, which shows how much they care about the little people....

Only the truly and despicably cynical would think anything else, but we've had several emails about Suboxone so we thought an article would be in order.

Suboxone is a 'cocktail' of Buprenorphine (Subutex (r)) and Naloxone. The idea is that Naloxone is badly absorbed sublingually, but the amount reaching the brain is very high if the drug is taken intranasally or injected. 100% bioavailability is achieved if Naloxone is injected, and levels as high as 100% are claimed for snorting, but this may not be the same in street settings.

If a patient takes their suboxone sublingually, as directed, they should only get the subutex. But if they are tempted to snort or inject the tablets, then they will get the subutex, but also a dose of Naloxone. This should, the theory goes, act as an opiate blocker, making it ineffective to inject it.

The very pretty Suboxone website explains it thus:

"The naloxone component in SUBOXONE is included to help discourage diversion and misuse. Naloxone has very limited bioavailability when administered sublingually, as intended. However, if SUBOXONE is crushed and injected, the naloxone will precipitate opioid withdrawal. In the absence of an opioid, the antagonist has no effect."

But if we pause for attention and recap some important facts, the situation is less clear.

The NIDA took a leading role in the development of Suboxone: they reported
"the medication buprenorphine/naloxone (marketed as Suboxone), developed by NIDA in collaboration with the pharmaceutical industry for the treatment of opioid addiction..."1
1)

The US department of Justice goes further, explaining "In fact, Suboxone was designed specifically to meet FDA requirements for a more diversion-proof drug for use in opiate addiction therapy."2

But ironically the NDIC reports ongoing abuse of Suboxone, saying
"Suboxone also can be diverted and abused; however, it is more likely to be abused by individuals who are addicted to low doses of opiates since it can precipitate withdrawal symptoms in high doses. The naloxone in Suboxone guards against abuse by causing withdrawal symptoms in abusers who crush and either inject or snort the drug; however, law enforcement and pharmacist reporting indicates that Suboxone is being abused successfully when snorted.

Using buprenorphine and heroin in combination does not produce increased effects, but if buprenorphine and methadone are abused together, the effects of both drugs are enhanced. Consequently, diverted buprenorphine may be attractive to patients currently using methadone for opiate addiction therapy."3

All this talk of precipitating withdrawals can get confusing. So what's really going on?

1) the ratio of buprenorphine to Naloxone is 4:1 - a very low level of Naloxone.

2) Buprenorphine is a partial opiate antagonist - it will block heroin from reaching opiate receptors reasonably well. But it is a less effective antagonist than, for example, Naloxone

3) Buprenorphine can and does cause respiratory suppression; especially when injected in large doses, and especially if mixed with benzodiazepines.

4) If a user has heroin in their system, and they use a dose of buprenorphine, this may produce withdrawal symptoms. The severity of these symptoms will depend on the levels of heroin in the system, the amount of buprenorphine used and the quantity of buprenorphine used.

5) but if a person has no opiates in their system (i.e. in withdrawal) and they take buprenorphine, they will get the opiate agonist effects of the buprenorphine, as in relief from withdrawal and mild opiate effects.

6) Naloxone is less effective at blocking or reversing buprenorphine than it is heroin. The literature says that a higher dose of Naloxone will be required, and attention given to maintaining breathing as Naloxone alone might be inadequate.

7) the amount of buprenorphine reaching the brain via snorting is around 49% compared with 29% sublingually, meaning that if someone were titrated and tolerant to a sublingual dose, they would be getting almost a 1/5th more drug by snorting. The time to reach peak levels would also drop from around 200 mins sublingually, to 30mins nasally, according to sources at Schering Plough.

So let's put all these pieces together.

If crushed and snorted, the subutex in suboxone is reportedly still effective. It is possible that the low doses of Naloxone, combined with the higher effective dose of burprenorphine and the relative poor blockading of Naloxone against burprenorphine make snorting the drug effective.

Schering Plough say "Currently no studies have been carried out looking at the effects of nasal snorting of Suboxone tablets." So it would be curious for them to claim that it cannot be effectively snorted.

If injected then all the subutex and all the Naloxone reaches the brain. If the user has heroin still in the system this will precipitate rapid and marked withdrawal symptoms. In fairness, this is likely to have happened even if the naloxone was not present, as the buprenorphine alone would have precipitated withdrawal.

But if the user has no other opiates in their system and inject crushed suboxone, what happens? Well it won't precipitate withdrawal if there's no opiates in place, that's for sure. So for someone not dependent or already in withdrawal, there won't be a sudden reversal into unpleasant symptoms.

It may be that nothing will happen - the naltrexone component will block the buprenorphine from working.

What could also happen is that the nNaloxone partially blocks the subutex - but not wholly. And so by taking a large dose of suboxone by injection, the person could still overdose, as the low dose of Naloxone would be a poor antagonist in such an overdose.7

The risk of buprenorphine-induced overdose would go up if use were taking place alongside benzo use.

So suboxone appears to be of limited value in preventing snorting, and of questionable benefit in preventing injecting. It will still be good for preventing use on top - but then if used properly no better than Subutex alone.

In which case why the big sell on Suboxone? If it isn't being driven by its clinical superiority, what's the appeal?

Firstly, this drug was developed to meet the demands of the US drug treatment and enforcement bodies. By complying with their demands, Schering Plough have a drugs which is the only one to receive federal approval for the treatment of heroin addiction - which is a huge cash-cow however you look at it;

But it should also be noted that away from the US, the patent period for Subutex has expired 4 leaving the way open for cheaper competitors.

To get an idea of the impact of this, the NHS pricing tariffs demonstrate the difference in costs between generic methadone, generic buprenorphine, and branded Subutex:

buprenorphine: 50x 20mg sublingual tablets £5.33
subutex 7 x 2mg £6.72
methadone 1 x 50mls 75p
5

Given these price differences it would be imperative that Schering Plough get a newer Patented product on the market and quickly - and the advent of Suboxone appears to meet that need.

Thanks to EU wide approval 6
Suboxone is now in a privileged position to become the prescribed drug of choice, regardless of cost or relative effectiveness. And by providing subsidised early "trials" which won't be randomised or controlled, Schering Plough can accrue claims to effectiveness which wouldn't survive rigorous academic scrutiny.

So on balance, and until we have independent and rigorous evidence to the contrary, Suboxone is more expensive than generic buprenorphine, can still be snorted, and won't induce withdrawal when injected unless the person already has opiates in their system. Further, it will still leave people at risk of overdose when injected, as the Naloxone won't effectively or fully reverse the buprenorphine.

Now why exactly is your rep pushing your patients on to Suboxone???
Don't you think you should ask?
Let us know what they say.


KFx 2007
[thanks to Kate for getting me started on this one]