Mary Jeanne Kreek, MDAlmost exactly a half-year ago we highlighted an excellent review article on opioid use disorder (OUD) by Drs. Carlos Blanco and Nora Volkow of the National Institute on Drug Abuse (NIDA) (https://atforum.com/?s=blanco+and+volkow+review). Now we’re featuring another review article from another legend in the field: Mary Jeanne Kreek, MD, who heads the Laboratory of the Biology of Addictive Diseases at Rockefeller University. Dr. Kreek is renowned for her pioneering work as a member of the 1960s team that developed methadone maintenance treatment. Some 382,000 people in the U.S. receive methadone—more than three times the number of patients being treated with buprenorphine, and more than 16 times the number taking extended-release naltrexone.
The review by Dr. Kreek and colleagues, “Current status of opioid addiction treatment and related preclinical research,” appeared in the October 2 issue of Science Advances.
| Current State of OUD Treatment Two good treatments are available—methadone and buprenorphine—but neither is used as widely as needed. This is “due largely to stigma, insufficient medical education or training, inadequate resources, and inadequate access to treatment.” |
The authors lead off with a brief introduction to the history of addiction, then touch on opioid synthesis, the extraction of morphine from opium, and the development of heroin and its derivatives.
Excessive Availability of Prescription Opioids
A discussion of the overabundance and increased usage of prescription opioids covers several factors that contribute to the change in prescribing habits. These factors result in a large excess of prescription opioids available for misuse, “which can then progress to OUDs and use of illicit drugs such as heroin.”
Epidemiology and Current Treatment
The authors present some interesting facts that may not be widely known:
- More than 16 million people in the U.S. have an addictive disease
- Objects of addiction, the most common first, are alcohol, cannabis, opioids, cocaine
- At least 1 million to 2 million people in the U.S. are addicted to heroin and other short-acting opioids
- Fewer than 10% of people with opioid addiction can achieve long-term abstinence without treatment with methadone or buprenorphine
- “No behavioral or cognitive treatments alone have been shown to be effective for patients with opioid addiction (or severe OUD)”
Genetics and Addictive Diseases
By interest and training, Dr. Kreek has long been involved in the molecular, neurobiological, and genetic basis of addictive diseases. The depth of her knowledge is especially apparent in several sections of the article, where readers will find discussions of topics such as the role of μ-opioid receptor systems (one of the mechanisms through which opioids exert their actions) in physical dependence and withdrawal; RNA-sequencing studies; and human molecular genetics, in terms of opioid use disorders.
Some Quick Points
We’ve pulled a few key points from the article.
Compliance
The major factor determining compliance in medication-assisted treatment: taking the medication daily. Not a problem with methadone maintenance treatment, the authors point out, because of federally mandated daily trips—although federal requirements limit the number of clinics.
Vulnerability
Factors that can affect vulnerability to OUDs include genetic background, environment, stress, and prolonged exposure to μ-opioid agonists given for analgesia. With Dr. Kreek’s interest and expertise in genetics, she sees as a future area of development “personalized approaches leveraging genetic factors for prediction of OUD vulnerability and prognosis, or for targeted pharmacotherapy.”
Diagnostic Criteria
The authors believe that the etiology of OUD is multifactorial, and that a variety of factors contribute to the vulnerability of people who develop the disorder. They cite DSM-5 as a source for defining OUD (Compton et al.).
Current Treatment of OUD
(Consult the full article for details on dosing and other information about usage.)
Methadone
- Compliance is the major factor in effectiveness; 60% to 80% of patients in good-quality methadone programs respond well and stay for more than a year
- Retention is greater in methadone maintenance programs than in buprenorphine programs
- Moderate to high methadone doses are necessary (starting: 30 to 40 mg/day, increased to 80 mg/day to 150 mg/day); much lower doses are used to treat chronic pain
Buprenorphine
- For maintenance in OUD, oral buprenorphine must be given sublingually (there are injections as well)
- Recently developed sustained-release buprenorphine implants are effective for as long as 30 days
Opioid Antagonist Medications
Naltrexone
- Opioid use must be discontinued for several days before naltrexone treatment begins; otherwise naltrexone will cause withdrawal
- Depot injections provide sustained release for about one month
Naloxone
- The most commonly used opioid antagonist against overdose, naloxone, has saved thousands of lives in overdose situations
A section on human molecular genetics zeroes in on variants of genes; then two brief sections wrap this review article.
The Future
Research Areas With High Potential
- Promising areas of research: agents with less potential for abuse, or less risk of overdose or toxicity
- Under development: agents likely to have a better profile (they are less likely to cause side effects)
- Another approach: agents to dual-target receptors; a recent example provides better analgesia, with less respiratory depression and less potential for abuse
Knowledge Gaps and Key Research Directions
The team notes that research is ongoing for agents that will be more effective than those currently available for chronic pain—eg, neuropathic and inflammatory pain—with less risk of overdose and abuse potential.
Goals include an agent that, if possible, can be used orally or sublingually; one that will reverse drug craving; return brain function and any other functions damaged by drug use; an agent that is sharply targeted to site of action, or to an area typically damaged by the drug of abuse—not just directed at symptoms.
Another current goal: ”finding ways to prevent OUDs from developing after relatively brief exposure to opioid analgesics, with the aim of preventing the development of severe OUDs.”
References
Kreek MJ, Reed B, Butelman ER. Diseases and Disorders: Current status of opioid addiction treatment and related preclinical research. 2019; Sci Adv. Oct 2;5(10):eaax9140. eCollection 2019 Oct. doi:10.1126/sciadv.aax9140
Compton WM, Dawson DA, Goldstein RB, Grant BF. Crosswalk between DSM-IV dependence and DSM-5 substance use disorders for opioids, cannabis, cocaine and alcohol [Epub ahead of print May 1 2013]. Drug Alcohol Depend. 2013;132(1-2):387-390. doi: 10.1016/j.drugalcdep.2013.02.036CC
Saha TD, Kerridge BT, Goldstein RB, et al. Nonmedical prescription opioid use and DSM-5 nonmedical prescription opioid use disorder in the United States. J Clin Psychiatry. 2016; 77(6):772-780. doi:10.4088/JCP.15m10386