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PostPosted: Fri May 04, 2018 7:39 am 
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Found this recent article on Dr. Andrew Byrne's blog. Seems recent research indicated that we do absorb some naloxone via the sublingual route:

https://www.ncbi.nlm.nih.gov/pubmed/29433352

http://methadone-research.blogspot.com.au/2018/03/buprenorphine-alone-or-with-naloxone.html

Quote:
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 ..


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PostPosted: Fri May 04, 2018 10:35 am 
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I have not read the full publication, but to me there seem to be an obvious risk of bias here. If the buprenorphine mono product is more commonly prescribed to low risk patients (which is not totally unlikely, since doctors would probably be more comfortable prescribing this to stable patients who are unlikely to divert or inject), this could explain why the combination product appears to be connected with worse outcomes.

The problem with naturalistic observational studies is that it is difficult to draw conclusions on causality. There is a reason for that randomised, prospective studies is the golden standard...


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PostPosted: Sat May 05, 2018 11:34 pm 
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The information you presented is mostly about the effects of the addiction of naloxone on the injection of the drug. There is a referral to naloxone and up-regulation of receptors, but the reference is not provided (it says Kelty et al., but the list of references is not included in the blog post, that I can find).

The blog posts contains a part of an opinion piece by Kelty, in which he cites himself on naloxone absorption. I don't know if he is citing comments, or citing clinical findings-- and if so, the nature of those findings. He says that a portion of naloxone is absorbed, and then says 'this is known to up-regulate receptors'.

We KNOW that 3% of naloxone is absorbed, and people argue on whether that's significant or not. I am in the 'not significant' camp because of the short half-life of naloxone. Kelty is suggesting (I think- but I don't know what he is citing so I can't find it and find out what he is suggesting for sure) that the naloxone in the combination product results in up regulation of opioid receptors. We know that naloxone cause up-regulation in tissue cultures under constant infusion of the drug. But it is a big stretch to say that may happen after 20-minutes of exposure of mu receptors to naloxone in humans. This is hard to explain-- but Kelty takes two known, correct statements to imply something else when he first says 'naloxone is absorbed' and then says 'this is known to up-regulate...'.

I could probably express this thought more clearly with a bit more effort.... but that's all I can muster for now!


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PostPosted: Sun May 06, 2018 2:56 am 
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I for one think that the naloxone in buprenorphine products is totally unnecessary and useless. It has been proven time and time again that buprenorphine will out compete Naloxone even when the patient IV's the drug (if anyone has any studies that refute this please share!) I knew four people in my in patient rehab that IV'ed the combination product and never went through precipitated antagonist withdrawal.


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PostPosted: Wed May 09, 2018 11:33 am 
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Trent, that is the anecdotal response that we have heard as well. I believe that pharmaceutical profit was the only reason Reckitt Benckiser made the combination product. They then went on an all out campaign to convince the FDA and doctors that there was an important purpose to adding the naloxone and that addicts couldn't be trusted with the mono-product of buprenorphine alone. It is extremely unfortunate for opioid addicts that profits were placed over reality.

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PostPosted: Wed May 16, 2018 1:14 pm 
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I’m the “prior authorization person” in a doctors office and am in the middle of a fight between a patient and her new insurance company over the with-or-without-naxolone question :(

The patient has taken generic buprenorphine for four years, but the new company has denied coverage, saying plain bupe is only covered for induction. They WILL cover Suboxone, but the patient is adamant about not taking it....because “everyone will think I’m an ADDICT.” (I guess she doesn’t realize that her diagnosis in our chart and on everything we’ve ever submitted to her insurance company is “opioid dependency disorder.”)

Anyway. She wants to appeal, but it’s been sitting on my desk for days because I can’t find a reason for her to not have naloxone. She has significant chronic pain that is under control with buprenorphine and OTC meds, but of course pain is a no-go. She does have Addison’s, but I haven’t found anything there that is affected by naloxone.

Unfortunately, Dr. Byrnes’ paper didn’t help me out with this dilemma, but I’m very glad I found this blog and the forums! Your experiences (with insurance and otherwise) offer a lot of insight, and I will definitely pass the url on to the patients in our MAT program.


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PostPosted: Wed May 16, 2018 2:05 pm 
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Hello sun67girl,

Welcome to the talkzone!


So, I just have a couple questions because I need to get a prior authorization done by June 23rd so that I have another year of my medication (Suboxone) covered. I have Molina healthcare & I'm from Michigan. But I want to do EVERYTHING I possibly can to make sure that I'm covered for another year, I'm very serious about recovery. I've never had a dirty drug screen, I did however smoke weed but it was never a problem with my doctor. I was told to quit smoking so that my insurance company won't have a reason to deny me. I've also started counseling, but I wasn't comfortable with my counselor. So I've decided to seek a psychiatrist instead. I've also been at 8 mgs for over a year & didn't really plan on tapering yet, as I'm scared to & really have no desire to do so. But if tapering down a bit will get me another year covered, so be it. I guess what I wanna know is how can I make sure that I get approved? I've been worried about this & want to do everything in my power to show Molina that I'm extremely serious about recovery. I understand if you wish not to respond, but I would also greatly appreciate it if you did :)


Ash

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