What Are The Implications Of The Suboxone Versus Vivitrol Study For Treating Opioid Use Disorder?

A major study came out in the Lancet last week that was a head-to-head comparison of  Suboxone (buprenorphine-naloxone or BUP-NX) and Vivitrol (extended-release naltrexone or XR-NTX).  I am beginning with the product names here because they were the actual medications used in the study and nobody uses the generic names at this point other than physicians.  This is an important study for a couple or reasons.  The first is that oral naltrexone tablets have already been tried for the treatment of opioid use disorder (OUD) and that approach failed.  XR-NTX used in this study is a long acting intramuscular injection that is given every 28 days.  The second is that many people with OUD do not want to take BUP-NX for many reasons.  They may be philosophically opposed.  They may have the experience that they know they will relapse on it, using heroin and then covering heroin withdrawal with BUP-NX.  They may not be able to tolerate the medication either because of side effects or the possibility of cognitive side effects.  The cognitive set of the patient is also important in the decision.  It is common to find patients who benefit from XR-NTX because using the medication makes heroin ineffective and therefore using it is a waste of money.

The study design is relatively straightforward.  This is a 24 week open-label randomized trial comparing BUP-NX to XR-NTX.  There is no placebo arm and I hope that at this point there are no human subjects committees suggesting that there should be.  OUD is just too dangerous to be considering a placebo group.  The protocols for starting treatment with either medication make blinding impossible. Eight study sites of the National Drug Abuse Clinical Trials Network (CTN) were used.  One of the non-uniform aspects of this trial was that the detox protocols varied by site:

1:  Two sites used no opioids, but used clonidine or "comfort meds" a term that I really don't like to see. Other comfort meds typically include an NSAID like naproxen for muscle and joint pain, hydroxyzine for anxiety and insomnia, methocarbamol for muscle spasm, and dicyclomine for abdominal cramping.

2:  Four sites used 3-5 day methadone tapers.

3:  Two sites used 3-14 day buprenorphine tapers. 

If a subject was going on to the XR-NTX group they had to be off all opioids for three days, have negative toxicology for the presence of opioids, and have a negative naloxone challenge test.  The authors don't explicitly state this but all of these detox protocols favor BUP-NX in the induction phase or initial dosing toward maintenance.  That is basically because most moderate to heavy users of heroin will be experiencing withdrawal symptoms at the end of these protocols.

Random assignment of 283 subjects to the XR-NTX group and 287 subjects to the BUP-NX group occurred.  Early termination occurred for a number of reasons in 78 of the XR-NTX group and 62 of the BUP-NX group.  A total of 283 and 287 subjects respectively were assigned in the final intent to treat analysis.

The primary outcome variable was time to relapse.  Relapse was defined as self report of use and either provided positive urine toxicology for any non-study opioid or failed to provide a urine sample.  The subjects were seen weekly for monitoring of cravings, self reported use, reports of adverse events and report of other substance use.  Standard physician or nurse led office based medication management was described as happening at these visits.  It is not clear to me what that is but they described a standard medication focused visit.  Psychosocial counseling was recommended and available but it was not a variable for this research. 

Secondary outcome variables included portion of subjects getting through the induction phase and into the active study, adverse events (including overdoses), frequency of non-opioid study use, and opioid cravings (rated on a 0-100 visual analogue scale).

In terms of results, they were broken down across several variables.  The intent-to-treat analysis showed that relapse-free survival was 8.4 weeks in the XR-NTX group and 14.4 weeks in the BUP-NX group but 20.4 weeks in the XR-NTX group and 15.2 weeks in the BUP-NX group when the protocol group rather than treatment intent was used.  The difference in these results was due to induction (starting of either medication at the end of detox) failures in the XR-NTX group.  The rates of successful XR-NTX induction varied site from 95% at an extended stay opioid free program to 52% at the methadone detox programs.  Self reported opioid abstinent parallels these results.  The graphical representations of these data (survival curves) show essentially parallel curves after an initial drop due to differences in the induction protocol.  The authors conclude that the drugs are equally safe and effective in preventing opioid relapse.

A separate interesting survival curve was the rating of opioid cravings over time.  The authors interpretation of these curves was that that the BUP-NTX group had fewer cravings initially but that by 24 weeks the ratings converged.  There may be some additional data in that graph showing that the low point in cravings was reached about 5 weeks earlier in the BUP-NX group and therefore it persistent longer.

The other important secondary outcome measure was the number of overdose deaths.  If analyzed just by the protocol there were 10 overdose events in the XR-NTX group and 9 overdose events in the BUP-NX group.  Including the failed induction subjects in the intent-to-treat analysis increases these number to 18 and 10 respectively.  There were 2 fatal overdoses in the XR-NTX group and 3 fatal overdoses in the BUP-NX group. The fatal overdose group was due to failed induction and premature termination of treatment.

As a physician involved in the treatment of OUD the implications here are:

1.  BUP-NX and XR-NTX are equivalent treatments and should be recognized as such - there has been some press about XR-NTX not being an "evidence-based" treatment despite the fact that it has been in use for some time.  Those articles either ignore the fact that it had the FDA approved indication or they ridicule the study used to get that approval. Here is the additional evidence.

2.  There is a need for standardized opioid detox protocols that are optimized for patient safety and efficacy for treating withdrawal symptoms - the three options used in the treatment center in these trials are representative of what is available in the community.  One of the goals of detox is to optimize  the transition to medication assisted treatment (MAT) to prevent relapse to opioid use.  As the authors point out the lack of a smooth transition to XR-NTX was the main reason for treatment failures and poorer outcomes in that group in the intent-to-treat  analysis.

3.  Besides the detoxification protocol other resources to facilitate the transition from detox to MAT maintenance are unknown -  It is clear that transitioning the patient from detox to MAT is a critical step in the treatment process. That not only involves the medication but the structure of the program and individual patient support at that time.  People leave treatment for sustained and untreated withdrawal symptoms and that include severe psychiatric comorbidity including severe anxiety +/- panic attacks, insomnia that often involves days of no sleep and drenching night sweats, and depression.  There is often a lot of confusion over which symptoms are due to an associated psychiatric disorder and which symptoms are due to withdrawal.  The confusion can be heightened if the patient comes in being treated for anxiety, insomnia, or depression with a maintenance medication.  The current paper does not describe an optimal path for treating those patient characteristics (psychiatric disorders and other substance use disorders were an exclusion criteria).   

4.  Optimal patient selection for the BUP-NX versus XR-NTX are unknown - In additional to significant psychiatric symptoms there are a number of other factors that will influence patient selection not the least of which are cost and logistics.  In many parts of the country it is still extremely difficult to find a BUP-NX provider.  Even when a physician is found, many do not accept insurance and the out of pocket cost for patients for both the visits and associated lab tests is prohibitive.  XR-NTX is a very expensive injection that may not be covered by insurance companies or patient assistance programs.  This study may increase the likelihood of coverage despite the fact that XR-NTX has had an FDA approved indication for "the prevention of relapse to opioid dependence, following opioid detoxification" since 2010. 

5.  Clinicians should use this information to discuss realistic treatment with their patients - as I have previously pointed out BUP-NX is no panacea and neither is XR-NTX.  Contrary to the idea that antagonist therapy prevents overdoses, there was no significant differences in overdose deaths in this study.  That should lead to a very serious informed consent based discussion about these medications with patients.  The idea of how long the medication should be taken or whether it should be taken indefinitely should not be part of that initial discussion.  The focus needs to be on completing detox and transitioning onto one of these medications.  The patient's capacity to make a realistic decision and what their preferences are with regard to these medications are all part of that process.  Life is not a randomized clinical trial.  Part of the skill set of the physician is the ability to have these discussions. It takes more than the ability to prescribe these medications.

That's my take on the head-to-head comparison of Vivitrol (XR-NTX) and Suboxone (BUP-NX).  Even with effective treatments to prevent relapse to opioid use - many more elements need to be in place.  The practical issue most frequently discussed is the availability of prescribers. Nobody seems to be talking about the fact that some treatment programs offer neither option.  There is also very little discussion about the fact that some treatment programs lack the atmosphere or expertise to provide patients with a shot at being successful and getting off opioids. 

We have come a long way with agents to treat OUD  compared to the days when I would see hospitalized heroin addicts who wanted to stop but had no realistic options.  I could only offer the 3 days methadone detox, continuing their methadone maintenance dose, or covering the sympathetic symptoms of withdrawal with clonidine. I could tell them where the closest methadone maintenance program was but that did not assure them an appointment or a place in that program.  Federal Law at the time prohibited the active treatment of OUD unless you happened to be in a licensed methadone maintenance program. Now that the legal and regulatory landscape has improved - it is up to treatment programs everywhere to get up to speed and offer state of the art care.  It is up to state licensing agencies to not allow treatment centers to take care of these patients if they don't.


George Dawson, MD, DFAPA



References:


1:  Joshua D Lee, Edward V Nunes Jr, Patricia Novo, Ken Bachrach, Genie L Bailey, Snehal Bhatt, Sarah Farkas, Marc Fishman, Phoebe Gauthier, Candace C Hodgkins, Jacquie King, Robert Lindblad, David Liu, Abigail G Matthews, Jeanine May, K Michelle Peavy, Stephen Ross, Dagmar Salazar, Paul Schkolnik, Dikla Shmueli-Blumberg, Don Stablein, Geetha Subramaniam, John Rotrosen.  Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial.  The Lancet
Published: November 14, 2017.