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.

A Letter From The Surgeon General

Like most physicians in the United States, I got a letter from US Surgeon General Vivek H. Murthy, MD last week.  The focus of the letter was recruiting the assistance of physicians in solving what he describes as "an urgent health care crisis facing America: the opioid epidemic."  As an addiction psychiatrist about one out of every three new patients that I see is addicted to opioids.  I have been lecturing on this topic for 6 years now, so I have more than a passing interest in what the SG has to say.  I have to say that Dr. Murthy wrote an excellent letter.  I was particularly impressed with his second paragraph describing how the was a combination of good intentions to treat pain and aggressive marketing by pharmaceutical companies and the single most important sentence in the letter:

"Many of us were taught-incorrectly-that opioids are not addictive when prescribed for legitimate pain."

Since I was already out practicing for about a decade at the time, I was spared that initiative.  I never assumed that opioids were not addictive, only that some people were more predisposed to addiction than others and that some had such strong adverse effects that they were very unlikely to become addicted.  But in routine psychiatric practice, even before the epidemic it was common to see patients who demanded increasing amounts of addictive drugs or who were hospitalized for adverse effects.  I had treated numerous people who appeared to have dementia, but were longstanding users of opioids, benzodiazepines, and even older sedative hypnotics.

Dr. Murthy goes on to detail the costs in terms of 2 million people with prescription opioid disorder, increasing heroin use, and increasing numbers of cases of HIV and hepatitis C.  He acknowledges that treating pain with opioids and finding the correct balance between analgesia and addiction will not be easy.  He encourages physicians to take the pledge to turn the tide on the opioid epidemic at www.TurnTheTideRx.org and reading the enclosed pocket card to the CDC Opioid Prescribing Guideline.  He also encourages physicians to approach addiction as a chronic illness rather than a moral failing.  That will probably result in some blowback from the addiction is not a disease crowd.  I hope that it is clear from my previous postings that in popular surveys, most people consider addiction to be a disease.  At the scientific level, I think it makes the most sense.  A lot of the confusion in this area comes from a lack of appreciation about how substance use disorders are stratified.  Volkow came up with a good definition in a New England Journal of Medicine paper earlier this year (1) - separating substance use disorders in general from addiction and defining addiction as severe DSM-5 substance use disorders. (the DSM-5 refrains from using the term addiction).

The enclosed card entitled "Prescribing Opioids For Chronic Pain" touches on a few of the high points.  My section by section critique follows (the entire card is below in the supplementary section for review).  Section 1 focuses on pain ratings using the old 0  to 10 scale where 10 is the "worst pain you can imagine".  The unstated problem with that approach is that it is not quantitative and cannot be taken in isolation.  There are people for example where this rating is completely unreliable.  Section 2 is a consideration of non-opioid therapies.  It lists the usual medication prescribed for chronic pain.  The problem here is that acute pain is often an entry point for addiction.  There are many people getting opioids like oxycodone and hydrocodone for what used to be considered trivial injuries, like an uncomplicated ankle sprain.  The  other acute pain entry point for addiction is post operative pain.  There have been studies that show a significant number of patients are still taking opioids a year after their surgical procedure.  It is common for me to interview very young patients who were given opioids for trivial injuries or surgery who became addicted to these drugs.  Physicians need to be very clear on appropriate pain treatments and not offer choices.  For example,  I was told by a friend that he was in a situation where patients were offered acetaminophen, ibuprofen, oxycodone, or oxymorphone.  This is exactly the wrong way to approach the treatment of pain.  In a culture where many people consider themselves to be drug savvy - the overwhelming choice will always be the most euphoria producing opioid.

 Section 3 is a discussion of the treatment plan.  Treatment contracts can be useful here, because most patients need more than a discussion.  They need a document that they can refer to.  It also gives the physician clear anchor points that can be used when discussing a taper or need to discontinue the medication.  Section 4 involves the complicated assessment of harm and misuse.  For most physicians this means the capability to expand their diagnostic capacity from the primary condition and the associated pain disorder to being able to make the diagnosis of addiction.  In some cases there are clear markers (toxicology screens), but in many cases, the patient has developed an addiction as a direct result of the physician's prescription and the line between therapeutic use and addiction is less clear.

The card also provides clear examples of milligram morphine equivalents (MMEs).  This is a term used frequently in the research literature.  When comparing patients on different opioids it is useful to convert whatever opioid they are taking to MMEs.  Mortality and morbidity with opioid prescriptions are generally associated with daily doses greater than 90-100 MME range.  The card points out that this is about 90 mg of hydrocodone or 18 tablets of hydrocodone/acetaminophen 5/300 or 60 mg of oxycodone or 4 tablets of oxycodone sustained release 15 mg.  In patients with addictions it is common to see chronic use of 120-240 mg oxycodone per day.

The card provides advice on starting low and going slow with the dose escalation as well as a suggested taper of 10% per week.  It suggests limited supplies, much more limited for acute pain.  It cautions against prescribing opioids and benzodiazepines concurrently - a practice that remains all too common.  A sentence about how that happens might be useful.  Chronic pain is typically associated with anxiety, depression, and insomnia.  Patients typically are focused on symptomatic relief in all three areas.  That can result not only in benzodiazepine prescriptions but also the prescription of cross tolerant sleep medication like zolpidem or eszopiclone.  Another worse case scenario is the patient using extra opioids for treating these associated symptoms and that is very problematic.  Educating patients about all of these contingencies easily exceeds the time that most primary care physicians have to spend with people.  That may be another reason to have ample documentation available to assist physicians.  There also needs to be a complete discussion of side effects and adverse effects from opioids.

The card transitions into treating an opioid use disorder with medication-assisted treatment like methadone, buprenorphine, or naltrexone.  At this point, I think that the expertise of most primary care physicians has been exceeded and they are looking for referrals to treat the addiction.  I think that the context of care needs to change.  It is very difficult to be in a primary care setting focused on pain as the disorder one week and then transition to addiction care the next.  Most patients will be unable to make that transition in the same clinic.  The idea of offering naloxone for those with high overdose potential on the same card is also confusing.  I could see how it might result in patients being treated for pain and getting prescribed opioids also getting naloxone.  I think that naloxone is more appropriately used with a defined addiction and plan to address the addiction.  The best approach to prevent oversedation and cognitive side effects is close monitoring and gradual dose increases.

All things considered this was a good first effort by the Surgeon General.  I would like to see him become active in changing the cultural attitudes in the US about opioids.  There is a myth that opioids are the magic bullet for pain relief and that is not true especially for chronic pain where the effects are modest and not typically better than non-opioids.  There is a large segment of the American culture that also values getting high and opioids are always discussed from that perspective.  Americans hoard opioid medications and give them away and trade them with other people for various reasons.  When a medication becomes an urban legend like opioids have - it is like the old travelling medicine shows.  Opioids are good for whatever ails you and they make you feel good as a useful side effect.

Countering all of those cultural biases about opioids is a big job - but I am reminded of Surgeon General Koop and his approach to altering American biases about tobacco smoke.                   




George Dawson, MD, DFAPA


References:  

1: Volkow ND, Koob GF, McLellan AT. Neurobiologic Advances from the Brain Disease Model of Addiction. N Engl J Med. 2016 Jan 28;374(4):363-71. doi: 10.1056/NEJMra1511480. Review. PubMed PMID: 26816013. (full text).


Supplementary:

TurnTheTideRx Pocket Card as graphics below.  You can also download the actual card as a pdf at this link:

NEJM and the Neurobiology of Addiction

[Original Graphic removed due to license expiration]


There are numerous articles in the popular press that attack the disease concept of addiction as well as many that attack the idea that addiction may be a biological based problem,  Volkow, Koob and McLellan have an interesting article in a recent edition of the New England Journal of Medicine that discusses both the neurobiology and some of the biases involved in stating that addiction is neither neurobiologically based or a neurobiologically based disease.  The article is relatively low in the details that reductionists like myself like to read but it is well referenced and a good overview of what is known about the neurobiology of addiction.  It is also a discussion of failed theories and what is currently known.  There is only one graphic and it is the basic one shown at the top of this post.  It shows a basic mapping of typical behaviors associated with addiction and is an elaboration of George Koob's previous all-encompassing one liner that sought to capture the behavioral pharmacology of addiction in one sentence:

"Addiction is a chronic relapsing syndrome that moves from an impulse control disorder involving positive reinforcement to a compulsive disorder involving negative reinforcement."

In this review the authors describe three stages of addiction; binge and intoxication, withdrawal and negative affect, and preoccupation and anticipation.  They are located in the table immediately below the brain graphic in the above infographic.  They break it down at a neurobiological level.  For the binge and intoxication stage increased dopamine release at the reward centers occurs.  With repeated stimulation the dopamine release is attenuated in response to the reward and shifts to anticipation of the reward.  Most authors discuss the initial phase of this process as occurring on the ventral striatum, in dopaminergic neurons from the ventral tegmental area innervating the nucleus accumbens.  I had some initial difficulty seeing the nucleus accumbens but it is there.  The larger message  is that plastic or experience dependent changes occur in not only the nucleus accumbens but also the dorsal striatum, hippocampus, amygdala, and prefrontal cortex.  I also liked the authors' inclusion of the word salience defined as a property of the prefrontal cortex in assigning relative value to a stimulus.  It is common to attend addiction conferences and hear the term being bantered about without any clear reference to the prefrontal cortex attributing salience to a particular stimulus.

Their description of withdrawal and negative affect discusses how with repeated stimulation reward and motivational systems are focused on the more potent effects of addictive drugs rather than the usual correlates including food and fluids, social affiliation, sexual behavior, and even good decision making.  This used to be referred to as the Hijacked Brain Hypothesis which basically stated the same thing.  Any physician working in a large acute care hospital will see a significant number of patients admitted largely because they have been using intoxicants on a chronic basis and ignoring their basic need for food and fluids.  This behavior is consistent with a new set of priorities for the reward and motivational systems, that biases the system heavily in the direction of continued substance use.  The previous theory of increased sensitivity to dopamine and higher levels of dopamine in the dorsal and ventral striatum in persons with addiction was proven to be wrong.  In fact dopamine release is attenuated and the reward system becomes less sensitive to all activating stimuli.  This results in both the loss of drug-induced euphoria and the lack of reward effects for previous enjoyable and preferred activities.  Recovery of this effect takes a prolonged period of abstinence and a sustained effort to get back into previous activity patterns.  At the same time, the stress response mediated by corticotropin releasing factor and dynorphin are involved in further attenuation of reward system dopaminergic cells.  Combined with changes in the extended amygdala this results in a dysphoric state and decreased stress tolerance.  It is captured in the second part of Koob's sentence - addiction becomes "a compulsive disorder involving negative reinforcement."  At this point the person with an addiction is self administering a drug to "feel normal and function" rather than get high.

The preoccupation and  anticipation stage impaired dopaminergic and glutamatergic signalling in the prefrontal cortex inhibits more typical decision making and creates a bias in the direction of continued use.  Self monitoring processes that evaluate the decision, whether or not it was successful and whether or not it was adaptive are similarly affected by these systems.  The value of the reward is depicted in the graphic below from Fuster's text The Prefrontal Cortex:

           

 The authors clarify their use of the term addiction relative to the more commonly used DSM-5 terms. With the advent of DSM-5 the familiar definitions of use and abuse disappeared and there is a single use category.  Severe use disorder requires 6 or more of the 11 symptoms of the use disorder.  The authors equate severe use disorder with their use of the term addiction.  Thinking about the demographics of people with one or more severe use disorders fits their description of addiction.  It is also much more likely that this group of patients will have markers and behaviors that cannot be dismissed by those who criticize a neurobiological approach to addiction.

Apart from the neurobiology update, the other interesting aspect of this paper was the authors taking on critics of a neurobiological model of addiction.  They are generally the same crowd who is critical of the disease model of addiction.  This paper defines a more specific model of addiction and its features than the disease model, even though popular surveys illustrate that most people see addiction alcoholism, and severe psychiatric illnesses as diseases.  At some level the popular and medical definitions of disease encompass a diverse group of conditions and arbitrary definitions can be adopted to support and argument.  A favorite is always that there is no known observable lesion or pathology in conditions that are not diseases.  I have examined several of these arguments about addiction in a previous post.  The authors here include their examination of 7 arguments entitled:  Criticisms of the Brain Disease Model of Addiction and Counter‐ Arguments.  The only substantial way their differ from my examination of the criticisms of addiction being modulated by a distinct set of pathological neurobiological features is that they include two points about public policy specifically how research is funded and how patients have benefitted.  One of the most common misconceptions about psychiatric illness and addictions when they are approached from a neurobiological perspective is that critics seem to think that this is tantamount to the "medicalization" of a problem and that this means only a medical intervention or medication can be used to treat the disorder.  In the field of addiction, excellent work has been done showing a number of unique paths to recovery that may depend on speculative neurobiological mechanisms, but do not depend on the use of medications or contact with physicians.  Critics of neurobiology seem to see the brain as a turf war rather than a need for a deeper understanding of the most intricate organ in the body.

I encourage a careful reading of this paper, by anyone who wants a brief overview of how addiction may affect the brain.  This is not a comprehensive review by any means and at some point I will come back and point out some of the shortcomings.  If you are a psychiatrist or psychiatric resident - you need to know what is in this paper at the minimum.  That is true if you are involved in the diagnosis and treatment of addiction or not.  The systems discussed in this paper are involved in cognition and complex decision making.  Contrary to popular belief there are no decisions made that are devoid of an emotional component.  That fact does not come alive until you know the relationship between limbic structures and reward/motivational systems.  Thirty years ago, some of the free literature from pharmaceutical companies contained graphics highlighting some of these systems and how they may be affected in schizophrenia and psychosis.  In the intervening time period, the bulk of useful research in the area came from scientists and physicians doing research in addiction.

As the knowledge in this area increases, this neurobiology will have wider applicability across the entire spectrum of psychiatric disorders.  


George Dawson, MD, DLFAPA

References:

1: Volkow ND, Koob GF, McLellan AT. Neurobiologic Advances from the Brain DiseaseModel of Addiction. N Engl J Med. 2016 Jan 28;374(4):363-71. doi: 10.1056/NEJMra1511480. PubMed PMID: 26816013.

Attribution:

Graphic at the top is from reference 1, with permission from the Massachusetts Medical Society.  License date is Feb 1, 2016 - license number is 3801731329358 for 12 months from the date of the license.  According to the publisher I am classified as a free-lancer (not-for-profit publisher) and hence the change in my LinkedIn status to free-lance writer at Real Psychiatry.