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).

Enhancing The Volkow-Collins Approach To The Opioid Epidemic

Nora Volkow, MD - Director of the National Institute on Drug Abuse and Francis S. Collins, MD, PhD - Director of the National Institutes of Health co-authored a paper on the role of science in the current opioid crisis.  Full text of the article is available free online from the New England Journal of Medicine at the reference given below.  In the article the authors review the scientific interventions at three levels of care in treating opioid addiction and use, treating and preventing overdoses, and the treatment of chronic pain.  The treatment of chronic non-cancer pain (CNCP) with opioids can be realistically viewed as the precipitant of this epidemic.  The brief 4 page review is a good rapid review of the science behind these interventions.  The level of cooperation between NIDA and NIH with private industry may surprise a few people but as the authors point out -  the level of mortality with the current epidemic needs to be approached with urgency at all levels.

At the level of opioid overdose prevention and reversal - more potent and long lasting opioid antagonists are being developed to counter exposure to fentanyl and carfentanil appearing at an increasing rate on the street.  Narcan Nasal Spray is probably the most effective and practical outcome of the industry-NIDA partnership.  A wearable device that can detect signals of an impending overdose and administer a μ-opioid receptor antagonist is mentioned.  At the level of addiction treatment methadone, buprenorphine, and extended-release naltrexone are all mentioned as current treatments for opioid use disorder.  Access to providers is discussed as a limiting factor.  vaccines and novel receptor approaches are discussed as potentially new pharmacological approaches to the problem.  New approaches to chronic pain are discussed in greater detail.  Cooperation between the NIH and industry is emphasized again in terms of getting these approaches to market and clinical use.  In the concluding section - the emphasis on NIH-industry partnerships is a central theme.  The argument makes imminent sense, but after two decades of rancorous debate about the effects of pharmaceutical company pizza on prescribing - this level of access to the highest level of taxpayer funded research is somewhat stunning.

But what else might be immediately useful?  I can concentrate just on buprenorphine and come up with a couple.  Anyone working with this compound and people who are addicted to opioids routinely encounters problems with its use.  It is common to treat people who still have withdrawal symptoms and cravings on the  recommended doses and remain at high risk for relapse even after being treated with what is described as one of the best current therapies.  Taking a look at the recommended dose range from the package insert:

The upper limit of the recommended dose is 24mg/6mg buprenorphine/naloxone per day for SUBOXONE. The reported lack of significant increase in brain mu‐receptor occupancy between doses of 16 mg and 32 mg implies that there should be little difference in clinical effectiveness at doses between 16 mg and 24 mg in most patients. When a patient expresses a need for a higher dose, consider the possible causes (e.g., environmental stressors or psychosocial issues that increase cravings or possible drug interactions). Before increasing the patient’s dose, explore other alternatives. Also consider the possibility that the patient may be exaggerating symptoms to obtain additional medication for diversion. (p 34-35).

And:

The recommended target dose is 16 mg buprenorphine/4 mg naloxone per day. Clinical studies have shown that this is a clinically effective dose. Although lower doses may be effective in some patients, for most patients, a 16 mg dose should alleviate withdrawal symptoms and block or attenuate the effects of other opioid agonists for at least 24 hours. (p. 34)

In clinical practice there is a wide range of effects to buprenorphine doses.  The FDA approved considerations show the subjectivity involved in adjusting the dose.  But that is even an understatement.  There needs to be a much greater investigation of the causes of continued craving and withdrawal symptoms when the patient is taking a recommended dose of buprenorphine.  This may be a genetically determined phenomenon either at the pharmacokinetic or pharmacodynamic level.  That is only partially accounted for by drug interactions.

Investigation of withdrawal symptoms and continued craving is more than just a passing concern.  It potentially determines who will be able to remain on maintenance therapy and stay off of heroin.  It is important because a significant number of these patients are being actively treated for psychiatric disorders with antidepressants, anxiolytics, atypical  antipsychotics and mood stabilizers.  How much of that medication use is due to inadequate treatment with buprenorphine and the common symptoms of insomnia, anxiety, and depression associated with opioid withdrawal.  These are all very complex clinical situations.  Many of these patients have a life long history of stress intolerance and there can be a reluctance on the part of clinicians especially if they have no mental health training to explore and treat those problems.  Once the patient has been indoctrinated into the idea that a maintenance medication is going to help them stay off heroin - it is a difficult transition to now say that all of these other factors are now important and need to be addressed.  That is especially true when some of the existing buprenorphine studies minimize counseling or are publicly presented as "counseling adds nothing to the results obtained with buprenorphine."  Finally, there is a large social media movement of people who want to stop buprenorphine and are warning others about it.  What is behind this widespread dissatisfaction and what needs to be done to resolve it?  The overall impression that all of the issues in this paragraph leaves is that buprenorphine is another heavily hyped medication that does not live up to the claims.  All of these areas could use much clearer input from NIDA through additional scientific investigation.

Additional studies on drug interactions with buprenorphine are critically needed.  I use a standard commercially available drug interaction software package.  Any time I enter a psychiatric medication I get a warning to consider to modify therapy and a list of 230 potential drug-drug pharmacodynamic interactions at the CNS level.  Since there is a high prevalence of patients on maintenance psychiatric medications this represents a deterrent to some physicians, especially if they are not psychiatrists and they are in a state with an unfavorable malpractice environment.

The next issue is determining who is susceptible to opioid overuse and dependence.  In my mind the phenotype is very clear.  The person who takes the first opioid tells me that they either "fall in love with it" or they experienced an intense euphoric and almost hypomanic effect.  They felt transformed by the medication into a person that they had always wanted to be.  Side effects are modestly effective deterrents, but I have been told that side effects and a complete lack of analgesia are acceptable in order to get the intense, euphoric high.  How can these people be identified?  The authors discuss biomarkers for pain and pain relief - but the single-most important biomarker would identify this high risk group of patients for addiction.  There are currently commercial databases out there that poll their members on various traits and symptoms.  Can NIH or NIDA design the polling questions and look for markers in these existing databases?

Even before that marker is identified, is there a simple strategy that could be used in clinical practice? Could a clinician tell a patient to self monitor for the intense euphoria and report back to the physician as soon as possible if it occurs?  Could the patient be told to just dispose of the pills by bringing them in to the pharmacy if euphoria and thoughts of dose escalation occur?

These are some thoughts that come to mind that might be immediately useful.  They would address both the limitations of medication assisted treatment and identifying the at-risk population for primary prevention of opioid use problems.                
    

     
George Dawson, MD, DFAPA

1: Volkow ND, Collins FS. The Role of Science in Addressing the Opioid Crisis. N Engl J Med. 2017 May 31. doi: 10.1056/NEJMsr1706626. [Epub ahead of print] PubMed PMID: 28564549.

Why Buprenorphine Is No Panacea for Opioid Addiction - An Insider View

That's right - I am an insider in the current opioid epidemic.  I only treat people with addictions.  I am licensed to prescribe buprenorphine and have been for 10 years, but in my current position my role is to do independent psychiatric assessments and treat associated psychiatric comorbidity.  Opioid detox is done by addictionologists and the maintenance decision is made by a multidisciplinary committee.  In that capacity I see a wide variety of people who end up addicted to opioids and eligible for opioid maintenance treatment.  I see them in various stages of detoxification/withdrawal and maintenance.  I know what works and what does not work.  Forget what you read about from all of the politicians and administrators - buprenorphine containing products (Suboxone, Subutex, etc) are not a panacea for opioid addiction.  It takes more than a pill to stop an addiction to opioids and more importantly assist in long term recovery.  Forget what you hear about how cravings to use a substance not predicting future use.  I can predict who will be able to remain abstinent from a drug with a high degree of certainty.  Anybody who suggests that is not possible does not know what they are talking about.

What follows is a discussion of some of the factors that limit the utility of buprenorphine based products in the treatment of opioid addiction and the reasons for these limitations.  Before getting into it it I want to clarify that I do support the use of buprenorphine for the treatment of opioid addiction.  People on medication assisted treatment with buprenorphine are about twice as likely to remain off opioids as people without this treatment.  They are more likely to remain in treatment and are less likely to develop Hepatitis C seroconversion.  But there are a lot of factors that are not discussed along the way when politicians talk about widespread use of buprenorphine as the best way to address the current opioid epidemic.  I had thought about including a comprehensive table on results to look at the limitations but decided against it - due to complexity.  If you would like to see what that table looks like - let me know and I will finish it.  For now here are a few of the issues as I see it.

1.  Indefinite maintenance:  Nobody wants to be on indefinite maintenance medication - even people with known chronic medical conditions like hypertension and asthma much less opioid addiction.  The first consideration is that the person with an opioid addiction needs to view it as a chronic medical problem and most addicts do not.  That is especially true for addicts in their 20s who may have started using as early as their teenage years.  Their general attitude is that they will quit some day, but not before they have acquired enough time getting high.  That is nothing particularly unique in terms of the rationalizations that accompany addictions, but at this point in time mapped onto this demographic it may be a unique problem.  It certainly is not conducive to realizing the need to take a maintenance medication every day.  It is common in clinical practice to see a number of patients who stay on buprenorphine for a few months at a time and "go back to using heroin for a while."  The attitude about prescribing buprenorphine seems to be just to keep prescribing it and at some point a stable maintenance situation will result.  I don't think there is any evidence that will happen.  Since opioid addiction is generally a chronic condition going on and off maintenance would seem to be more likely than indefinite maintenance.  There is confusion among some prescribing physicians whether or not repeated relapses is a relative contraindication to future opioid buprenorphine use or it it means referral to a methadone maintenance clinic.  The real life problem is the patient who cannot tolerate withdrawal symptoms, may have a history of buprenorphine diversion, and has no easy access to a methadone program.    

2. Buprenorphine has definite street value:  Every opioid user knows this to be true.  Buprenorphine can generally be sold and the proceeds will result in being able to purchase 3 - 4 times the equivalent amount of heroin.  The other option is just to resume heroin and use the buprenorphine to cover heroin withdrawal when the drug is in short supply or there are not any reliable street sources.  As previously indicated this sort of diversion is a contraindication if the patient is using it as a consistent way to cover withdrawal from other opioids or to acquire other opioids. 

3. There are a small but significant number of users who can abuse the drug:

The original buprenorphine/naloxone combination preparation was designed to prevent intravenous use of the crushed buprenorphine tablets.  Since then, there has been some evidence that the naloxone component also reduces the euphorigenic component from buprenorphine and makes increased self administration less likely (1).  Patients maintained on low dose buprenorphine alone report positive subjective ratings with both additional intravenous and intranasal buprenorphine indicating potential abuse liability (2).  The combination buprenorphine/naloxone occurred after a number of overdoses in Europe and it confers decreased intravenous abuse liability, but it does not eliminate it (3).  In an earlier high dose study of intravenous and sublingual buprenorphine doses up to 16 mg in experienced opioid users produced consistently positive but variable mood effects.   In morphine maintained heroin users intravenous buprenorphine was the only opioid not administered at levels greater than placebo compared with intravenous fentanyl, oxycodone, or heroin (4).  That is an expected effect due to the partial antagonist effect of buprenorphine.  The authors comment that in research setting buprenorphine inconsistently precipitates withdrawal in opioid dependent subject in research settings.  For example moderate to severe withdrawal occurs in subjects taking 60 mg/day of methadone but no to mild withdrawal (from 2 and 8 mg buprenorphine doses) in subjects taking 25-30 mg/day of methadone.  Other studies  looking at rapid dose induction in heroin dependent men resulted positive ratings and experiencing the buprenorphine as an opioid agonist rather than an antagonist.  This same variability is noted clinical, largely by patient history and there seem to be a small number of patients who can escalate the dose beyond the theoretical ceiling due to opioid antagonism.  There is limited information on escalating the oral dose of buprenorphine or buprenorphine/naloxone.  In one study (5), 19 subject were maintained on 4 mg/day of buprenorphine alone and then were given 2 mg increments at 2 hour intervals for a total of three doses of buprenorphine alone.  In this study the authors thought that abuse liability based on subjective ratings was low.   All of this variability can be observed at the clinical level and it is very important that the prescribing clinicians know the individual and their response patterns very well.  

4. The existential condition of 20 year olds:    

One of the unique aspects of the current opioid epidemic is the number of young people that it affects.  Unused medicine cabinet opioids have been identified by the CDC as an important gateway drug to heroin use.  Using prescription opioids increased the likelihood of heroin use 55 times.  This same cohort is caught in a culture that is swinging toward increased permissiveness of substance use with broadened legalization of cannabis and excessive stimulant prescriptions for attention deficit~hyperactivity disorder and a subculture of performance enhancement in colleges and universities.  One of the logical extensions of these cultural currents is to see drugs as a solution to a problem and opioids are viewed as being no different.  A unique aspect of alcohol and drug taking in American culture has been that the early twenties is a time to do it and get it out of your system.  A large number of young opioid addicts who continue to use and routinely go off and on buprenorphine maintenance will say that they felt like they were too young to stop using.  They wanted to keep on going for a while before they stopped.  Most 20 year olds have a sense of invulnerability and that also plays a role in the use of dangerous drugs and alcohol.              

5.  Inadequate dosing

One of the main lessons that an addiction psychiatrist learns early on is that opioid use and withdrawal is a great mimic of psychiatric conditions specifically insomnia, anxiety and depression.  Practically everyone in withdrawal experiences these syndromes at one point or another.  There is a natural tendency during a psychiatric interview to describe practically all of the recent history as being dominated by the withdrawal symptoms.  Conversely, when the correct dose of buprenorphine is prescribed all of the insomnia, depression, and anxiety clears and it clears completely.  There are no associated psychiatric problems and the patients does not need any additional pharmacological therapies.  This cannot be emphasized enough because opioid users will naturally end up on benzodiazepines and z-drugs for sleep and anxiety and both are contraindicated with opioids.  Even antidepressants are a potential problem due to case reports of buprenorphine based products and antidepressants causing serotonin syndrome.  That is an admittedly rare syndrome, but potentially very serious if it occurs.        

The second issue is dose adequacy in terms of cravings about opioids.  By definition cravings are an intense urge to use opioids.  At the height of opioid withdrawal they occur with the withdrawal symptoms.  As buprenorphine maintenance is established they may occur at times during the day when there are breakthrough withdrawal symptoms.  Eventually even when the acute withdrawal symptoms are treated cravings can persist.  The ideal response is that cravings to use are eliminated as well as any thoughts about using or acquiring opioids.  This is possible during treatment but results vary from person to person especially as the physician attempts to establish the proper maintenance dose of buprenorphine.  In my experience cravings and intense thoughts about using are poor prognostic factors due to heightened relapse potential.    

The subpopulation of people addicted to opioids from chronic pain treatment can generally benefit from seeing physicians with expertise in pain management with buprenorphine preparations.  It may require split dosing and other adjustments.

6.  The lack of appropriate prescribing 

This can occur in several ways.  There can be a lack of physicians who are licensed to prescribe buprenorphine.  There can also be physicians available to prescribe it who are not able to maintain patients on the drug.  Finally there are physicians who are overcharging for the services they provide and that leads to patient dissatisfaction and discontinuing the buprenorphine strictly on that basis.

All of these problems can be addressed.  They can be addressed by providing good medical care.  They can also be addressed by addressing the 30 year old problem of rationing services for addiction and mental health services.  Any person going in to be seen by a physician for opioid use problems needs to feel like they are understood.  They have to be able to communicate with that physician about their addiction.  They have to know that their physician understands addiction and is not just there to provide prescriptions.

Treating opioid addiction is more than prescribing a medication.  It requires a relationship  with a competent physician.  That competent physician needs to be technically competent to prescribe the drug and discuss all of the above issues with every patient with an opioid addiction and every one of those patients who will take buprenorphine.

That is the same as the general plan for just about any complex medical problem.      

George Dawson, MD, DFAPA

References:

1: Jones JD, Sullivan MA, Vosburg SK, Manubay JM, Mogali S, Metz V, Comer SD. Abuse potential of intranasal buprenorphine versus buprenorphine/naloxone in buprenorphine-maintained heroin users. Addict Biol. 2015 Jul;20(4):784-98. doi: 10.1111/adb.12163. PubMed PMID: 25060839.

2:  Jones JD, Madera G, Comer SD. The reinforcing and subjective effects ofintravenous and intranasal buprenorphine in heroin users. Pharmacol Biochem Behav. 2014 Jul;122:299-306. doi: 10.1016/j.pbb.2014.04.012. PubMed PMID: 24793093; PubMed Central PMCID: PMC4094364.

3: Comer SD, Sullivan MA, Vosburg SK, Manubay J, Amass L, Cooper ZD, Saccone P,Kleber HD. Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusers. Addiction. 2010 Apr;105(4):709-18. doi: 10.1111/j.1360-0443.2009.02843.x. Erratum in: Addiction. 2010 Jul;105(7):1332. PubMed PMID: 20403021.

4: Comer SD, Sullivan MA, Whittington RA, Vosburg SK, Kowalczyk WJ. Abuse liability of prescription opioids compared to heroin in morphine-maintained heroin abusers. Neuropsychopharmacology. 2008 Apr;33(5):1179-91. PubMed PMID: 17581533.

5: Singhal A, Tripathi BM, Pal HR, Jena R, Jain R. Subjective effects ofadditional doses of buprenorphine in patients on buprenorphine maintenance. Addict Behav. 2007 Feb;32(2):320-31. PubMed PMID: 16814937.

6: Umbricht A, Huestis MA, Cone EJ, Preston KL. Effects of high-dose intravenous buprenorphine in experienced opioid abusers. J Clin Psychopharmacol. 2004 Oct;24(5):479-87. PubMed PMID: 15349002.

The Reality Of Burprenorphine Therapy

It is increasingly popular for politicians and healthcare businesses to discuss their ideas about how to end the opioid epidemic that they started.  One of the common themes is widespread availability of both buprenorphine maintenance therapy and naloxone opioid antagonist therapy for acute overdoses.  I am certainly not opposed to either and in fact work in an addiction treatment environment where these are two of several medication assisted therapies used to treat addictive disorders.  I am skeptical of the idea that broad prescribing of these therapies in either primary care clinics or some treatment settings will ever occur.  Naloxone will be more readily available because there is a movement to create easy access without a prescription.  That will never happen with buprenorphine.  Last week - an article in JAMA backs up my skepticism (1).

The JAMA article looks at 3234 buprenorphine prescribers in the 7 states with the most buprenorphine prescribers.  In their introduction the authors talk about the policy initiatives to increase the maximum patients per prescriber from 30 to 100 patients after a year.  The average monthly patient census per month varied from 7 - 22 patients and a median monthly patient census of 13 patients.  The duration of treatment episode was 53 days.  This illustrates that the monthly census was well below the allowed limits and the duration of treatment was well below the recommended maintenance guideline of 12 months.  They cite evidence that novice prescribers wanted more access to substance use counselors or other prescribers with more experience as potential limiting factors.

The authors of this article do not offer other explanations for the low rate of buprenorphine prescribing.  I have a few.  I really do not like stigma arguments.  To me stigma seems like an excuse for not being able to overcome societal biases toward a particular problem.  I don't see how you can train to be a physician and not have most of these biases wrung out of you.  With addictions and mental illnesses there may be a stronger bias based on personal experience.  Some physicians may have come from a family where the the father was an alcoholic or a heroin addict living homeless on the street and everybody was used to that idea.  Some physicians may have come from families where the father was still drinking and dying of cirrhosis and the familiy opinion was that he "has a right to drink himself to death" rather than get treatment that he did not want in order to stop drinking.  Other physicians may have come from families where father and his father both had severe alcoholism.  Grandfather drank himself to death by the time he was 50.  Father got treatment for his alcohol problem and was in stable recovery for years.  All of these personal experiences and the reactions to them will affect how a physician approaches alcoholism and addiction.

Those biases are all part the the inevitable decision-making process that leads physicians down specific career paths.  I have lost count of the number of times that another specialist told me that they really liked psychiatry and were considering the residency except for certain features of the field.  A couple of examples include needing to try to predict suicide and aggression and live with the consequences or dealing with a certain diagnostic group like patients with severe personality disorders.  People are less specific about addictions, probably because as medical students and interns we all see the severe effects.  Most of the acute care hospitals where physicians train have 30-50% of their admissions based on the acute effects of alcohol or drug use.  That includes many admissions for acute hepatitis, hepatic encephalopathy from cirrhosis, acute alcohol poisoning, acute overdoses on addictive drugs, and various psychiatric morbidities like delirium and psychosis from the acute effects of addictive drugs.  It is less obvious but addictive drugs and alcohol are also overrepresented as reasons for admission to surgical trauma units and burn units.  Most interns and residents see these effects first hand and develop both short term and long term perspectives on these problems.

This seems like another case of managers and politicians not appreciating the intense interpersonal aspects of medicine.  Physicians are all not foot soldiers just waiting for the next assignment from a policy maker.  Physicians have probably carefully selected the type of practice they want to be in and there are more than the technical aspects of the speciality that were considered.  It takes a unique skill set to treat people with addictions.  Treating and maintaining an opioid addict in treatment long enough with buprenorphine maintenance for them to realize any benefit is a very unique skill.  Being affiliated with other buprenorphine prescribers is also a necessity to provide cross coverage for patients.  Speciality care centers for addiction seem like an idea to me that does not get a lot of consideration.  Trying to run a buprenorphine maintenance program in a practice environment that is rationed to the degree it currently is does not seem feasible to me.  Adding buprenorphine maintenance as just another task for a busy primary care physician practicing primary care medicine is not likely to work.  It should be obvious that these physicians have  more than enough to do right now.

There is a lot more to it than increasing the maximum numbers of opioid addicted patients on buprenorphine maintenance and trying to treat as many people as possible.  The data from this paper illustrates that.  There is also the issue of the preventing the pool of opioid users from increasing while trying to treat those who are currently dependent on these drugs.  That seems like the best long term option to me.

Addressing this complicated problem takes more than a licensed buprenorphine prescribing physician sitting behind a desk who is willing to prescribe it.  It takes better infrastructure including managers who are enlightened enough to get that physician the kind of resources they need to do the work.  I never hear politicians or policymakers talking about that.


George Dawson, MD, DFAPA


Reference:

1: Stein BD, Sorbero M, Dick AW, Pacula RL, Burns RM, Gordon AJ. Physician Capacity to Treat Opioid Use Disorder With Buprenorphine-Assisted Treatment. JAMA. 2016 Sep 20;316(11):1211-1212. doi: 10.1001/jama.2016.10542. PubMed PMID: 27654608.


        

POTUS Tweets Measures To Address Opioid Epidemic

In 2014, nearly 21,000 deaths in the U.S. involved prescription opioids. Here's what @POTUS is doing about it: https://t.co/M2HgnDDN6a

— The White House (@WhiteHouse) March 29, 2016

I happened to be on Twitter last night when I caught the above Tweet from POTUS.  Having a professional interest, I decided to follow the link at the White House blog to look at the proposed measures.  They were listed as:

1.  Increasing a key drug for medication assisted treatment.  That key drug is buprenorphine in a number of formulations for treating severe opioid dependence.

2.  Preventing opioid overdose deaths.  This appears to be $11 million in funding for various forms of treatment and increasing access to naloxone to reverse the effects of an acute overdose.

3.  Addressing substance use disorder parity with other medical and surgical conditions.

These are very modest and in some cases unrealistic proposals about about trying to stop a drug epidemic that is killing 20,000 people a year.  Let me tell you why:

1.  Increasing a key drug for medication assisted treatment.  That key drug is buprenorphine in a number of formulations for treating severe opioid dependence.

Buprenorphine as Suboxone and Subutex have been available for the treatment of opioid addiction in the US since 2002.  The current evidence suggests that buprenorphine has superior efficacy for abstinence from opioids and retention in treatment.  There is also evidence that patients on buprenorphine have fewer side effects and that they is a less severe neonatal abstinence syndrome in mothers maintained on buprenorphine versus methadone.   Buprenorphine is also used for acute detoxification and treatment of chronic pain.  One of the limitations of maintaining opioid addicts on buprenorphine is that a special license is required to prescribe it.  Physicians can obtain that license by by attending CME or online courses.  Even then, expansion to primary care physicians has been slow because they may have no colleagues in their practice with similar certification and that makes on call coverage problematic.  In addition, many clinics that are medically based are reluctant to provide this type of service to people who have opioid addictions.  Apart from the technical requirements of prescribing the various preparations of buprenorphine certain physician and patient characteristics may also be important.  Physicians have to be neutral and not overreact in situations where the patient exhibits expected addictive behaviors that may include relapse.  As an example, younger opioid users are frequently ambivalent about quitting and in some cases, use other opioids and reserve the buprenorphine for when their usual supply dries up.  They may sell their buprenorphine prescription and purchase opioids off the street.  It may not be obvious but physicians prescribing this drug need an interpersonal strategy on how they are going to approach these problems.    On the patient side,  there is the biology of how the opioids have affected the person.  Do they have severe withdrawal and ongoing cravings?  What is their attitude about taking a medication on an intermediate or long term basis in order to treat treat the opiate addiction?

In clinical trials, buprenorphine seems to be ideal medication for medication assisted treatment (MAT) of opioid dependence.  Like most medications, there are issues in clinical practice that are not answered and possibly may never be answered.  The issue of life-long maintenance is one.  Many people with addictions are concerned over this prospect.  Long term maintenance with buprenorphine has advantages over methadone in that it is easier to get a prescription rather than show up in a clinic every day to get a dose of methadone.  Most addicts are aware of the fact that withdrawal from both compounds can be long and painful.  This deters some people from trying it and relapse risk is high if a person attempts to taper off of it.  Despite the current consensus about use. there is still the problem of young addicts who feel that they are "not done using" and who go between using heroin and other opioids obtained from non-medical sources and buprenorphine.  

2.  Preventing opioid overdose deaths.  This appears to be $11 million in funding for various forms of treatment and increasing access to naloxone to reverse the effects of an acute overdose.

Naloxone kits that would allow for rapid reversal of opioid overdoses have been shown to be effective in partially decreasing the death rate.  At some treatment and correctional facilities opioid users are discharged with naloxone kits for administration in the event of an overdose.  Opioids are dangerous drugs in overdose because they suppress respiration and that can lead to a cardiac arrest.  There are several properties of opioids that heighten the overdose risk.  Tolerance phenomena means that the user eventually becomes tolerant to the euphorigenic and in some cases therapeutic effects of opioids and needs to take more drug.  If tolerance is lost when the user is not taking high doses for a while, using that same high dose can result in an overdose.  Taking poorly characterized powders and unlabelled pills acquired from non-medical sources compounds the problem.  The exact quantity of opioid being used is frequently unknown.  Adulterants like fentanyl - a much more potent opioid can also lead to overdoses when users do not expect a more potent drug.

In addition to the pharmacology of the drugs being used there is also a psychological aspect to overdoses.  Users often get to the point where they don't really care how much they are using in order to get high.  They will say that they are not intentionally trying to overdose, but if it happens they don't care.

The available literature on making naloxone available suggests that it is effective for reversing overdoses in a fraction of the at risk population that it is given to.  I would see at as the equivalent of an Epi-pen in that the majority of patients with anaphylactic reactions get these pens refilled from year to year but never use them.  When they are required they are life-saving.  The problem with a naloxone kit is that it assumes a user or bystander can recognize an overdose and administer naloxone fast enough to reverse the effects of opioids before the user experiences serious consequences.  Unfortunately addiction often leads to social isolation and not having a person available makes monitoring for overdoses much more problematic.  Naloxone kits should always be available opioid users, first responders, family members, and anyone involved in assisting addicts.  Detailed long term data on the outcomes over time is needed.  

3.  Addressing substance use disorder parity with other medical and surgical conditions.

The is the most critical aspect of the President's tweet.  One of the main reasons for this blog is to point out how people with addictions and severe mental illnesses have been disproportionately rationed since the very first days of managed care - now about 35 years ago.  Some of the first major changes involved moving medical detoxification out of hospitals.  So-called social detoxification was available with no medical supervision.  These non-medical detox facilities were very unevenly distributed with only a small fraction of the counties in any state running them.  Any admissions to hospitals were brief and "managed" by managed care companies.  In the case of addictions some of the management practices were absurd.  A standard practice was to determine how many days a person could be in residential treatment.  That often required a call to an insurance company nurse or doctor who had never seen the patient.  They could determine that the patient could be discharged at any time based on arbitrary criteria.  In some cases that involved just a few days and the patient was leaving with active cravings and in some cases an an active psychiatric disorder.  This practice continues today, despite party legislation that suggests that addictions and mental disorders should be treated like any other medical problem.

This is where the President's tweet is on very shaky ground.  His legislation  focuses on large systems of health care and yet these systems don't seem to be able to supply adequate treatment with either buprenorphine or naloxone kits.  The President is fully aware of the The Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008 (MHPAEA).  That act was supposed to provide equal treatment for mental illnesses and addictions that was on par with medical and surgical conditions.  I think it is no secret that special interests have shredded the intent of this bill to the point that it is useless.  Managed care systems still ration care for these disorders in their best financial interest.  The resources for treating these disorders are still not equal to the task. In the case of prescription painkillers the same system of care not providing adequate treatment for addiction is often where that addiction started.

All three of the President's points could be addressed by forcing health care companies to provide adequate care for addictions and mental illnesses instead of grants to provide services that they should be doing in the first place.  In an interesting recent twist the President (1) suggested that this discrimination was based on race.  He implied that as a result the police rather than doctors have been used to address the problem.

Let me be the first to say that President Obama is wrong.  There is no doubt that racial discrimination exists.  There is no doubt that it occurs in systems of health care (2,3).  There is also no doubt that all it takes is a diagnosis of addiction or mental illness to trigger highly discriminatory health care coverage - irrespective of a person's race.  It is all about how health care businesses make money in this country by rationing or denying treatment for these disorders.

To reverse that discrimination,  the government needs to take the MHPAEA seriously.  So far they have failed miserably and that is the problem on the treatment side in trying to address the opioid epidemic.  

George Dawson, MD, DLFAPA

References:

1:  Sarah Ferris.  Obama: 'We have to be honest' about race in drug addiction debate.  The Hill March 29, 2016.

2:   Eddie L. Greene, MD and Charles R. Thomas, Jr, MD.  Minority Health and Disparities-Related Issues: Part I.  Medical Clinics of North America July 2005; 89(4).

3:   Eddie L. Greene, MD and Charles R. Thomas, Jr, MD.  Minority Health and Disparities-Related Issues: Part II.  Medical Clinics of North America July 2005; 89(5).

  

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.