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
