Clinical Pathways To Recovery II: Pharmacology
In 1966 Rockefeller University researcher Mary Jane Creek and colleagues published a paper introducing methadone as a treatment for heroin addiction (“Fifty years after landmark methadone discovery, stigmas and misunderstandings persist”, Rockefeller University News and Highlights, 2016). When a subsequent study established that methadone could be administered once daily “methadone maintenance” became a standard “treatment” (more on the quotation marks in a bit) for heroin addiction. The U.S. Food and Drug Administration approved methadone as a component of treatment for heroin and other opioid addiction in 1973 and by 2016 1.3 million people worldwide were on methadone maintenance. This is the beginning of pharmacologic approaches to treatment for substance use disorder.
Previously, Danish researchers studying compounds to treat parasitic stomach infections self-administered (before modern clinical trials this was not uncommon) a small dose of disulfiram to check its side effects. Later they became ill after an alcoholic drink. They concluded that an interaction of disulfiram and alcohol was responsible and thus was born the drug Antabuse. Antabuse causes severe, unpleasant outcomes when combined with alcohol in the system and is used as part of aversion therapy. It was administered to patients with extreme resistance to treatment which at that time was, mostly, abstinence through Alcoholics Anonymous. In the 1950s the FDA approved Antabuse for treatment but after several severe, negative outcomes including deaths Antabuse was scaled back as treatment and then administered only in much lower doses.
These early experiences with pharmacologics dampened the enthusiasm for this kind of treatment, and twelve step abstinence was ascendant at that time and in most respects that remains the case. However, for many in this field the laboratory science about addiction is welcomed. Nonetheless, the introduction of these treatments has progressed slowly. Notable events include the approval of Narcan (naloxone) by the FDA to treat opioid overdose, and approval for buprenorphine to treat a variety of substances of addiction in 2002. (“Timeline: History of Addiction Treatment”, Anjali Talchekar, edited by Kindra Sclar, reviewed by Scot Thomas, updated December 2024, American Addictions Centers).
There are two, general categories of pharmacologic treatment – agonists and antagonists. Agonists activate neurotransmitter receptors in the brain mimicking the effect of a specific drug and are often used to ease withdrawal. Agonists typically only produce mild neurological stimulatory effects and are therefore much less habit-forming than drugs of misuse.
Antagonists block neurotransmitter receptors in the brain, and like agonists are designed to target receptors activated by particular drugs. Antagonists intend to reduce the likelihood of use of a targeted drug by limiting the “high” and reducing the reward from use. They are also deployed to prevent overdose by reducing the effects of the illegal drug after use. Antagonists also intend to reduce use because they do not produce drug-like effects.
There are mixed use pharmaceuticals. Mixed agonist–antagonists both stimulate neurotransmitter receptors in the brain, and at the same time they block the neurotransmitter receptors from being activated by a specific drug class. The drug actions of both stimulating and blocking are non-permanent as they are active only when present in the body.
Naltrexone is an antagonist approved for use in treating alcohol abuse disorder and opioid use disorder. Sold as Revia and Vivitrol, naltrexone can be administered orally or via monthly injection. Naltrexone requires a period of abstinence before first administration. Naltrexone is most often used to ease withdrawal symptoms and help the newly recovering individual through withdrawal from alcohol or opioids. There are methods using naltrexone to allow continued alcohol use, contrary to wide acceptance of abstinence as primary treatment. The Sinclair Method is the most well-known among these approaches. We discussed this approach and its limitations in previous articles. Antabuse is still in use though less favored due to more severe side effects.
Methadone is an agonist that mimics the effect of opioids. Methadone is normally administered orally and often in controlled environments that avoid overuse and resale. Like naltrexone, methadone can be used as a short term aid to provide help from withdrawal in early stages toward abstinence. As discussed earlier, methadone maintenance was and is still prescribed for a longer term.
Buprenorphine is a mixed agonist and antagonist and can be taken orally or transdermal via a patch. Buprenorphine is most often used to treat opioid use disorder working to ease cravings by mimicking the high and to block effects.
These drugs all come with unpleasant side effects that are tolerated to varying degrees by patients. Headaches, body aches, nausea, unpleasant tastes and smells are the most often reported. These adverse effects are common among all pharmaceuticals not just addiction treatment.
There are anticonvulsants not FDA approved for treatment of alcohol use disorder but are occasionally deployed. Gabapentin and Toplomorate are included in this category.
The Recovery Resaearch Institute (https://www.recoveryanswers.org/) lists five, primary goals of pharmacology for use in substance use disorder:
· Improve rates of patient survival
· Increase retention in treatment programs
· Decrease illicit opiate use and substance-related criminal involvement
· Increase patients’ ability to gain and maintain employment
· Improve outcomes in pregnancies affected by substance use
Most often and optimally these pharmaceuticals are not used alone but in concert with psychotherapy and/or twelve step approaches.
A review of the barriers to deployment of pharmacologics published in 2015 is still current in many ways (“Barriers to Use of Pharmacotherapy for Addiction Disorders and How to Overcome Them”, Elizabeth M Oliva, Natalya C Maisel, Adam J Gordon, Alex H S Harris, Current Psychiatry Reports, April 2015).
Concerning system level barriers they note, “Several interrelated system-level barriers have impeded utilization of pharmacotherapy for alcohol and opioid dependence, including government and insurance policies, program characteristics (e.g., treatment philosophy), lack of pharmaceutical industry support, and logistical issues (e.g., lack of access to prescribing physicians). Pharmacotherapy for opioid dependence has been especially affected by additional federal requirements and regulations involved in provision of care.”
The authors also point to provider barriers including, “These studies tend to describe barriers that fall broadly into two categories: informational barriers (e.g., lack of knowledge) and provider perceptions and concerns (e.g., pharmacotherapy is ineffective, low self-efficacy to prescribe properly).” The latter is a continuation of the ascendency of twelve step approaches since 1950 with their focus on abstinence from any illicit drug and often from legal, FDA approved pharmaceuticals. The study also noted that patients too lack information about these pharmaceutical treatments.
There are two common criticisms of pharmacologic treatment for substance use disorder. The most common among the general public has to do with abuse by providers, pharmacists and patients. In a very recent incident the U.S. Department of Justice agreed with a major, pharmacy provider on penalties and remediation for illegally supplying opioids (“Pharmacy Agrees to Pay Up to $350M for Illegally Filling Unlawful Opioid Prescriptions and for Submitting False Claims to the Federal Government”, U.S. Department of Justice Press Relesase, April 21, 2025). The pharmacy chain was identified in the press release but it is not necessary here.
From that press release, “The government’s complaint alleges that from approximately August 2012 through March 1, 2023, one of the nation’s largest pharmacy chains, knowingly filled millions of unlawful controlled substance prescriptions. These unlawful prescriptions included prescriptions for excessive quantities of opioids, opioid prescriptions filled significantly early, and prescriptions for the especially dangerous and abused combination of three drugs known as a “trinity.” There are two, unstated, ancillary issues here. One is that people with access to these prescriptions, presumably with a substance abuse diagnosis, are aware of and participating with this illegal use. Commonly they are using these prescriptions themselves but also it is likely that there is a secondary market. The second issue is that licensed providers are irresponsibly or maliciously providing these prescriptions. There are numerous examples especially in Florida that was known for many years as the locus of excessive and illegal opioid prescriptions.
The second criticism, more commonly noted by treatment providers, is that too often these drugs are used as the primary “treatment” (coming back to that term as promised). The Recovery Research Institute site discussing these drugs specifically notes they are most often used in concert with psychotherapy and/or twelve step programs. Certainly, there is provider bias here since twelve step therapies have been the prevalent basis for treatment for decades. At the same time it is also fair to note that many providers and many patients tend to think of these drugs as maintenance instead of transitional.
However, and as we have pointed out in the case of relapse, this is not true solely for the disease of substance use disorder but also for many chronic diseases such as heart disease, diabetes and recently obesity. There are effective drugs for cardiac arrhythmias, but most cardiologists will recommend diet and exercise. There have been effective drugs to treat adult onsite diabetes for decades, but physicians will almost always talk about diet and weight as well as exercise. The increasing prevalence of obesity has led to the discovery of effective drug treatments that are tolerated by many, but responsible physicians will also recommend diet changes. In each instance there are also side effects certainly including wear and tear on the liver.
We live in a society where we hope and even expect that biomedical science will provide an answer to our issues that will not involve sacrifice or change on our part. Our research labs, often in universities, have accommodated us. Most recently the development of semiglutide medications such as Wegovy have led to miraculous results for diabetes, weight loss and heart disease. Yet, these drugs do not work for all, they have often difficult side effects, and they allow us to continue habits that are not good for us in so many other ways. Perhaps the development of these pharmaceuticals will one day mimic the effects like Wegovy and treatment centers will go the way of Weight Watchers that recently filed for Chapter 11.
We are not opposed to these advances in biomedical sciences. Given enough time and money it is quite possible that solutions will evolve. Perhaps it will be in the form of a pharmaceutical. Perhaps it will be in the form of gene therapy even in utero. Neither is the case yet.
While experiments to use naltrexone to allow alcoholics to continue to drink continue, it is still the case that abstinence is the goal. That occurs best in psychotherapy and/or twelve step approaches as of today. If these pharmacologics can aid in increasing success, then let us deploy them. Further, and as we have discussed elsewhere, we have allowed abstinence to be viewed at best as abnormal and at worst a penance for immoral behavior. In America today 30% of adults do not use alcohol, 84% do not use marijuana recreationally, 93% do not use other Schedule I narcotics. Abstinence is the norm, not the exception. Yes, let us support biomedical advances. Let us deploy pharmaceuticals responsibly and when we do so always with psychosocial treatments.
Gene Gilchrist
May 2025
Louisville, Kentucky
