Dr. Mark Gold's Research You Can Use
Opioid addiction has become America’s leading public health crisis of epidemic proportions. Stanford University’s recent analysis of the present treatment, prevention, and public health viewpoint suggested that almost 510,000 deaths resulting from prescription opioids and street heroin are to be expected from 2016 to 2025 in the US if no changes are made.
Amid all the proposals, analyses and potential solutions suggested, most focus has been laid upon the expansion of access to and the circulation of naloxone and medication-assisted treatment (MAT) drugs such as methadone, buprenorphine, and naltrexone. Additionally, it is just as important to continue investing in research to develop new treatments supported by neuroscience evidence.
What is naltrexone?
Naltrexone is the long-acting version of naloxone, a novel medication and the linchpin of research regarding the pharmacology of the opioid system. Naloxone successfully opposes opioids from binding to the “Mu” opioid receptor on neurons, completely blocking the opioid’s ensuing euphoric and sedative effects. Acting as an antagonist, it reverses the possibly deadly consequences of an opioid overdose.
Food and Drug Administration (FDA) first approved intravenous naloxone for an opioid overdose reversal in 1971 and was soon endorsed as a standard emergency treatment at several academic medical centers. In 2014, the FDA approved an intramuscular autoinjector form that was easily administrable by any individual. In 2017, the nasal spray form, NARCAN, was approved.
Conceptually identical to CPR or the Epi-Pen, naloxone reverses critical and fatal consequences of an illness, instead of curing the disease itself. The priority easily remains the rescue, resuscitation, and revival of the patient, in order to give them another chance at recovery. None of the present treatments and policy proposals exert any substantial influence on the reduction of opioid-induced deaths in the long-term. Yet, naloxone is considered the most impactful amongst other current interventions.
First synthesized in 1963, the drug remained mostly dormant for several years until it garnered interest in 1972 when Congress passed the Drug Abuse Office and Treatment Act to facilitate the development of non-addictive treatments for heroin addiction. This development came at a time when methadone (an agonist) was the only available medication for opioid addiction. Naltrexone generated broad appeal as an alternative without the sedating, euphoric, potentially addictive and even fatal side effects of methadone.
The evolution of naltrexone
Despite being a wonder drug and tremendously promising, early naltrexone trials in 1974 were often compounded by the participants’ non-compliance to consume oral naltrexone instead of heroin on a daily basis.
Many sporadically stopped taking it and used heroin instead. As a result, relapse was inevitable and continued to be a significant factor limiting the efficacy of daily oral naltrexone.
To counter the issue of non-compliance, an extended-release form was introduced, administered through monthly injections, namely Vivitrol. This modification was noticed to bring a considerable improvement in compliance as compared to the oral formulation.
The manufacturers of Vivitrol, Alkermes, received FDA approval in 2006 for alcohol-use disorder and in 2010 for opioid-use disorder. An even longer-acting implantable form of naltrexone has been developed since, although it is still in testing and remains to be clinically approved.
The mid-1970s saw significant progress made at Yale on unraveling the neurobiology of opioid withdrawal and how noradrenergic discharge makes withdrawal symptoms intolerable. It was initially discovered that excessive discharge of norepinephrine from the locus coeruleus, a nucleus in the pons of the brainstem involved in physiological responses to stress and panic, regulated the symptoms of opioid withdrawal. Afterward, it was demonstrated how clonidine was directly able to restrict this discharge, subduing withdrawal symptoms.
Patients safely detoxed, followed by Alcoholics Anonymous or a residential treatment center, or oral form of naltrexone. Naltrexone was inexpensive, long-acting, safe and effective. No major central nervous system side effects were reported, and the drug completely blocked the effects of heroin. Patients on naltrexone attempted to overcome this blockage by consuming large amounts of heroin but complained of not being able to get high and wasting their money instead.
The challenge presented, however, was accurately predicting which patient would respond to naloxone, given the small to moderate effects yielded by the naltrexone therapy. The genetic and imaging results regarding patient response to naltrexone from various studies over the years remained inconsistent.
Bridging the gap
The opioid crisis has been nothing less than an evasive target: it began with the overprescribing and misuse of prescription opioids in the 1990s and facilitated the increase in heroin use and an influx of more recent and stronger synthetic opioids such as fentanyl.
Government authorities and the medical community has grappled to manage this situation in various ways such as revising guidelines for the prescription of painkillers, limiting dosage and duration of opioid prescriptions, eradicating the production of synthetic opioids and expanding the availability of naloxone to police, first responders and opiate users themselves.
Addiction treatment is just as essential to curb deaths and infectious diseases, yet it remains to be mostly inaccessible, not covered by most insurances and prone to fluctuating quality.
Healthcare reforms have been aimed to encourage more evidence-based treatments and to integrate this treatment into the broader healthcare system. Medications are the gold standard of treatment for an opioid use disorder, and presently, three drugs have been approved by the FDA, all targeting the mu-opioid receptor.
Methadone and buprenorphine, both agonists, target cravings and withdrawals in the absence of euphoria and are utilized for long-term maintenance therapy. Contrastingly, naltrexone is an antagonist and blocks illicit opioids from having any effect.
In the U.S., medications are required to be imparted as part of a treatment program that includes counseling or behavioral therapy, namely MAT. Yet, there remains a considerable gap between patients who receive MAT and those who actually benefit from it.
This discrepancy is reflective of the shortcomings of treatment capacity and the associated stigma that medication to treat substance abuse disorder is merely substituting one addiction for another. Such a thought process only highlights the lack of understanding of the pharmacological and therapeutic effects of these drugs.
Treatment with methadone or buprenorphine allows a patient to combat withdrawal symptoms, improve mood and restore their physiological balance, as their brain gets a chance to heal as they work towards recovery.
Not all three medications are effective equally for all patients, and each has its own set of drawbacks. There still exists a dire need for researchers to establish appropriate treatment durations depending on the severity of opioid use disorder and to highlight the most effective strategies for the best combinations of medication and psychosocial interventions.
Continued research based on the genetic and clinical aspects that shape treatment response will ultimately present optimal personalized treatment selection.
Looking forward
Addiction is a complex, chronic disease that exerts long-lasting effects to the brain.
Due to a multitude of various neurotransmitter systems and circuits involved, improved neuroscience-informed diagnostic and prognostic markers are needed.
Other treatment approaches such as vigorous physical exercise and repetitive transcranial magnetic stimulation have shown to be promising post-addiction treatments. Neurosteroids are also backed by preclinical data pointing towards substantiated therapeutic effects for a range of illnesses, including addiction.
These new approaches and interventions toward addiction treatment need to be explored further in order to push for more sophisticated neuroscience-informed treatment, specifically in terms of effects on the brain circuit.
Conclusively, even though the efficacy of naltrexone cannot be denied as a wonder drug for opioid and alcohol use disorders, it is still premature to think of it as a treatment for addiction by itself. It is important to understand that it is limited by compliance. However, clearly, prevention of overdose, craving, and relapse is easier with a one-month form than daily naltrexone. It is ironic that an asset, not being physically dependent on the medication, is a liability as well.
The present state of mechanism-based treatments is still in its infancy, and greater resources need to be directed toward the development of biological markers using advanced neuroimaging techniques. Furthermore, addiction needs to be considered in the same category as other chronic illnesses that require long-term comprehensive care with a focus on prevention, mitigation, and long-standing results.
References:
- http://www.dana.org/Cerebrum/2018/Naltrexone_A_History_and_Future_Directions/
- https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32893-3/fulltext
- https://www.samhsa.gov/medication-assisted-treatment/treatment/naltrexone
About the Author:
Mark S. Gold, M.D. served as Professor, the Donald Dizney Eminent Scholar, Distinguished Professor and Chair of Psychiatry from 1990-2014. Dr. Gold was the first Faculty from the College of Medicine to be selected as a University-wide Distinguished Alumni Professor and served as the 17th University of Florida’s Distinguished Alumni Professor.
Learn more about Mark S. Gold, MD
About the Transcript Editor:
A journalist and social media savvy content writer with extensive research, print and on-air interview skills, Sana Ahmed has previously worked as staff writer for a renowned rehabilitation institute, a content writer for a marketing agency, an editor for a business magazine and been an on-air news broadcaster.
Sana graduated with a Bachelors in Economics and Management from London School of Economics and began a career of research and writing right after. Her recent work has largely been focused upon mental health and addiction recovery.
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Published on December 20, 2018
Reviewed by Jacquelyn Ekern, MS, LPC on May 30, 2019
Published on AddictionHope.com