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.


       

Infection Disease Docs - Treating Addiction

There was a very interesting commentary in this week's New England Journal of Medicine.  In it the authors describe a case from their infection disease practice of a young man with infectious complications of intravenous heroin use ( Staph. aureus tricuspid valve endocarditis, septic arthritis, and empyema).  He had a history of doing well on buprenorphine maintenance in the past and was offered that treatment again by the Infectious Disease (ID) team as he was leaving inpatient hospital.  They completed the induction phase on the afternoon of discharge and he was discharged on buprenorphine-naloxone (Suboxone).  The ID  faculty at Beth Israel Deaconess Medical Center, a large tertiary care hospital in Boston have all been certified as buprenorphine prescribers and present this as an option to all of their patients with infectious complications of  intravenous substance use.  In addition to the buprenorphine they also provide rescue naloxone to treat acute opioid overdoses, discussions about harm reduction, injection practices, and cravings.  In the case that was presented, there was a discussion of the relapse risk and risk of recurrent infection or death from an accidental overdose.

This group of physicians has provided an outstanding example of what can be done when you are working with a highly motivated group who seizes the opportunity to make a significant difference. Part of their discussion is in terms of expanding their practice outside of the traditional role and expecting some pushback on that.   As I read their report, I thought about how this process might occur within the usual hospital setting.  A psychiatric consultation would be placed.  In tertiary centers a psychiatrist would see the patient, make a detailed assessment and recommend outpatient care somewhere.  That psychiatrist may or may not have a buprenorphine license.  Depending on location, there may not be a buprenorphine provider to refer the patient to.  In the case of intravenous heroin use that practically guarantees a relapse to heroin at the time of discharge with the attendant mortality and morbidity.  In this case the patient is familiar with the same treatment team that discusses the issue with him and gets him on Suboxone prior to discharge.  In today's world of rationed medical care - I cannot think of a more perfect intervention for high risk patients from an addiction standpoint.

The use of buprenorphine to treat opioids use disorders is not a perfect solution but it helps a large number of patients remain abstinent in general treatment populations.  The patient described in this paper was perhaps more highly motivated than most due to his complicated illnesses.  The authors experience reflects the fact that they clearly know the treatment process is complicated but view what they are doing as a bridge to long term care for opioid use disorders.  I agree with them completely.

There are a few considerations that they did not touch on that I think are important.  The personal characteristics of the physicians in this group is a major factor.   They discuss the history of their specialty as one that values social justice and public health.  They suggest this was a primary factor in allowing them to not get caught up in the stigma of treating addicts and the associated lack of resources.  I witnessed this first hand in the 1980s and 1990s when ID physicians and clinic staff were dealing with the HIV epidemic.  That went on for years before there was adequate treatment and the death toll was high.  Many ID clinics provided critical support to patient and their families during that  time.  I don't think that they ever got any recognition for that role.  Treating addiction above all else takes emotional neutrality and that was a characteristic I observed first hand in HIV clinics.        

I certainly hope that this group gets the credit for innovation and hard work that goes with this approach.  They mention a couple of other groups who have picked up on this approach.  At the same time I have concerns about how other groups may view this article.  The billing and coding system and clinic structures are generally not setup to allocate enough time to deal with two very complicated problems.  In the outpatient setting, sober homes set up to deal with the substance use and medical complications are extremely rare.  In some cases, sober homes and halfway houses refuse to accept patients taking Suboxone or other potentially addictive drugs.  It takes dedicated social work or case management staff to negotiate those problems.  It also takes some level of administrative support to know that discharging a patient as soon as possible when they are in opioid withdrawal makes little sense.

Time and burnout are also relevant factors.  The primitive state of productivity based medical administration needs to be able to accommodate this level of complex care and allot physicians enough time to provide both medical and addiction services.  I have over 20 years of experience in providing both medical and psychiatric services on inpatient settings.  Even though I enjoyed doing it - there was a tremendous time penalty associated with the additional work and that can easily lead to burnout.  If addiction care expands among specialists and generalists - they need the additional times and reimbursement to provide this level of care.

None of these considerations detracts from the accomplishment of this department of infectious disease doctors.  Taking on this additional role is especially striking in an era where patients are told that they can only discuss one problem per clinic visit with their doctors.  This approach is a shining example of the highest level of medical professionalism and my hat is off to them.


George Dawson, MD, DFAPA

1: Rapoport AB, Rowley CF. Stretching the Scope - Becoming Frontline Addiction-Medicine Providers. N Engl J Med. 2017 Aug 24;377(8):705-707. doi: 10.1056/NEJMp1706492. PubMed PMID: 28834479. (free full text).

Why Has Suboxone Turned Into A Problem?

The short answer is that it is like very other drug and there was always the potential for a problem.  Any practicing physician realizes that when a drug is approved by the FDA for general release to the public there are all kinds of unintended consequences that are possible.  That is the basis of post marketing surveillance by the FDA.  There is invariably a lot of hype associated with the release of a drug, but as I have previously pointed out the FDAs approval process is not in place to guarantee a drug that is safe for everyone.  It is focused on a releasing a drug that is a potential tool for responsible practitioners.  That means any drug can potentially cause a small number of serious unexpected reactions (liver failure, cardiac arrhythmia)  that even the most experienced practitioners will not be able to predict.  There is also an implicit understanding that the practitioners prescribing the drug have a thorough understanding of its pharmacology, indications and contraindications.  Many practitioners advise against trying out a product that has just been released but that advice is tempered by the severity of individual circumstances and the hope of relief and also the general bias that new drugs are somehow better than the old ones.  That bias has been repeatedly disproven.

Suboxone prescribers have to take a special course in order to get a prescriber number in addition to their usual DEA number.  I took the Suboxone prescriber course about 7 years ago.  It was a total of 8 hours of lectures given in a convention center room in a hotel.  It was jointly sponsored by state medical association.  The morning sessions were largely a review of the pharmacology of the drug and the scope of the opioid addiction problem at the time.  The afternoon session focused on vignettes of patients with addictions of varying complexities and the exercise was to determine of Suboxone should be prescribed to that person and how the induction would be done.  That was the first suggestion that something was problematic.  There apparently were no contraindications to Suboxone.  The clear message was that it should be given to anyone with an opioid addiction no matter what their social circumstances or comorbid psychiatric diagnoses and addictions.  There was a definite implication that this was a drug that would revolutionize the treatment of opioid addiction.

 
Suboxone is a combination of buprenorphine and naloxone.  Buprenorphine is the active ingredient in terms of treating addiction.  In this post I will use Suboxone and buprenorphine interchangeably.  The pharmacological properties of buprenorphine that were interesting in terms of potential use for addiction included the fact that it was a opioid mu receptor partial agonist and antagonist at the kappa receptor.  The partial agonist effects relevant for addiction such as euphoria and sedation occur at the lower doses and the antagonist effects occur at higher doses.  The antagonist effects like preventing respiratory depression were thought to put a ceiling effect on this side effects and make it safer than pure mu receptor agonists that would produce dose related toxicities.  In the Suboxone course the mixed agonist/antagonist effects were described as producing less toxicity and less risk of abuse.  The naloxone component of Suboxone is a pure mu receptor antagonist.  In the course I took, the explanation for the combination of buprenorphine and naloxone was that it reduced the risk of intravenous drug use and that this had occurred in Europe and it resulted in several deaths.  The company also sold Subutex which was buprenorphine only and indicated for use in pregnant women.

The pharmacodynamics and pharmacokinetics in real life can differ quite a bit from the idealized cases that the initial marketing and advertising was based upon.  Like many medications it can be a life changing drug.  People can recover and break the cycle of addiction, recovery and relapse and go on to productive lives.  It is the outliers that physicians need to be most concerned about.  In real life there are always going to be people who get significant side effects even at low doses and cannot tolerate the drug.  There are also people who tolerate the drug at high doses and do not experience the ceiling effect of mu receptor antagonism.  The people are probably very low in number but they are significant because they are not protected by the ceiling effect that is supposed to be there from the drug.  Drug addiction always attracts or produces a significant number of people who become amateur pharmacologists and use the drug to facilitate their addiction.  The word gets out and suddenly buprenorphine has street value (about $1,000 for a 1 month prescription) and opioid addicts can use it when they run out of heroin or oxycodone.  In a few people it is their preferred opioid because it has a longer half life.

The politics of Suboxone are as complicated as you will find in the pharmaceutical industry.  There are plenty of conflicts of interest in terms of how the drug was initially marketed and plenty of crossover between regulators and the company who developed, marketed and sold it - Reckitt-Benckiser.  According to a New York Times article last fall, the company was granted a period of exclusive sales that ended in 2009.  After that they went on the offensive to suggest that their new product - a Suboxone film was superior to the generic tablets especially in the area of child safety.  They stopped selling the Suboxone tablets at that point.  Insurance companies can work any controversy to their advantage and people on buprenorphine maintenance have been cut off based solely on the amount of time they have been taking the drug.  There are no scientific guidelines for how long a person should take buprenorphine and like most drugs used for maintenance therapy there will never be a study that looks at that question due to the expense.  Most experts would agree that if you have a severe addiction and have recovered based on buprenorphine there is no reason why you would be cut off.  In fact discontinuing buprenorphine seems to present a more significant problem as dose is tapered to 2 mg and  lower.   We also have a familiar political theme in the issue of opioids with the government seeming to create the problems in the first place and now saying: "Trust us we have the solution."  That may have explained the desperation in the descriptions of how public health officials were trying to increase Suboxone prescribers to address a public health opioid epidemic that was a likely result of government initiatives to improve the treatment of pain.

Suboxone has become a problem for the same reason that every other drug becomes a problem - unrealistic expectations, conflicts of interest, and a knowledge deficit on the part of the practitioners.  The title of the New York Times article illustrates how the press can look at the dual nature of drugs and imply that there is a larger problem.  I don't know of two many drugs that do not have a "Dark Side".  The negative trends in buprenorphine use can be reversed but it will take more than the suggested strategy in the NY Times article.  Here are a few ideas:

1.  The CDC needs to get involved and look at Suboxone/buprenorphine related deaths and study it in the same manner that they studied methadone.  It would be very instructive to see exactly where Suboxone/buprenorphine falls on the spectrum of deaths/100 kg MME (milligram morphine equivalents).  The expectation of some in the article is that it is much safer, I would prefer to see the numbers.  Only the CDC has access to the detailed data to look at this issue.  I would take it a step farther and suggest that the CDC recalculate this table on an annual basis as a key metric in reversing the significant public health problem of accidental opioid overdose deaths.

2.  The physicians prescribing the buprenorphine need to be highly motivated and well versed in prescribing medications to individuals with addictions.  The NY Times article suggests that there are many who take an entrepreneurial approach to the prescription of buprenorphine with cash only practices that vary from $100 - $250 a visit.  I have no problem with cash only practices if there is a quality approach.  By definition that involves a lot more than handing someone a prescription in 5 minutes.  The problem is the rest of what happens during that time is poorly defined.  The original prescribing information said that the physician needed to refer the patient to counseling services.  In many presentations of research that I have seen there is a clear movement to illustrate that - counseling adds little to nothing to outcomes when buprenorphine is prescribed.  There are problems drawing that conclusion about this research given the modest outcomes of the buprenorphine treatment.

3.  At least part of the interview of any patient recovering from the severe addiction that occurs with opioids is assessing their functional capacity.  What are they doing on a day to day basis and is that routine consistent with both recovery and a lack of cognitive side effects from the buprenorphine?  Being able to corroborate that improvement with a third party makes it even more reliable.

4.  A big part of the unconscious aspects of addiction is the behaviors that are present to continue the addiction despite the best conscious efforts of the person affected.  Good examples include craving, lying, and hiding use from others.  That requires prescribing physicians to engage their patients at this level and not develop a law enforcement transference.  A lot of physicians don't know how to respond to an accusation of: "You don't trust me!" when there is a question of the need for a toxicology screen or a discussion of a positive toxicology.  The interpersonal aspect of treatment is very important and it received no attention in the standard Suboxone prescribing course.

5.  Continued work on a model of treatment looking at all of the potential positive factors is needed.  There is nothing worse in medicine than to treat a scientific topic like a political one and not have a rational approach to the person with the problem.  Like the original course I took, there are  people out there who say that buprenorphine prescribed out of a physicians office is all that is needed.  Is that the case when you have a person who takes two to three times the prescribed amount to get high?  Or the person who is crushing it and snorting or injecting it?  Or the person who is selling it on the street to get purchase heroin?  Or the person who can't function due to cognitive problems at 2 mg a day?  Or the person who is hospitalized for recurrent bowel obstructions due to severe constipation?  As the prescribing physician - are  you confident that you can accurately screen for these problems?  What about competing approaches like the long acting mu antagonist naltrexone injections?  Where does 12-step recovery like Narcotics Anonymous fit in?  Where do sober housing and residential treatment fit in?  And finally - where can a person get detoxified and should anyone be forced to go through acute opioid withdrawal when they are incarcerated?

All of these questions are currently unanswered.  But like most treatments in medicine, the solution is typically a lot more than a pill.  Drugs with addictive potential always add the complication of significant financial gain from a captive audience.        

George Dawson, MD, DFAPA

Deborah Sontag.  Addiction Treatment With A Dark Side.  New York Times. November 16, 2013.

SAMHSA.  Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction.  A Treatment Improvement Protocol.  TIP 40.

NICE.  Naltrexone for the management of opioid dependence. 2010.

NICE.  Methadone and buprenorphine for the management of opioid dependence.  2010.