This Week in the ASAM Weekly

Some weeks, there is a publication that when read first can influence how the others are appreciated. An article by Drs. Sullivan and Ballantyne explores the history and relationship between pain relief and the opioid epidemic through a philosophical view of pain, disease, and survival. Ultimately, the authors conclude that the depersonalization of pain coupled with a right to (painless) pain relief is rooted in the modern opioid epidemic (Mayo Clinic Proceedings). When the above publication is paired with a study demonstrating how isolating Esmethadone from racemic methadone has a rapid antidepressant effect without the expected downsides seen with methadone (respiratory depression or addiction liability) -- an appreciation for enantiomers emerges (Translational Psychiatry).

The coupling of physical and emotional suffering is a reality of the modern opioid-fentanyl crisis. A study of opioid agonist treatments and (globally) high overdose mortality rates in Scotland shows how essential, biological interventions alone will not be enough to reduce overdose deaths going forward, even in a country without a fentanyl crisis (The Lancet Public Health). Yet developing successful vaccine technologies for fentanyl not only has the potential to prevent suffering before it begins (NPJ Vaccines), but this is hopefully an indication that we are moving closer toward effective vaccines for addiction treatment.

Where the right to pain relief movement may have faulted in its framing of passive suffering and an obligation to excise it, Donovan X. Ramsey’s new book about the crack epidemic chronicles how society's response can be one of the most harmful parts of addiction -- especially for communities of color (NPR).

Please stay tuned for some great guest editorials in the coming weeks.

Thanks for reading,

Nicholas Athanasiou, MD, MBA, DFASAM
Editor in Chief

with Co-Editors: Brandon Aden, MD, MPH, FASAM, Debra R. Newman, PA-C, MSPAS, MPH, Jack Woodside, MD, John A. Fromson, MD

Lead

Questioning the Right to Pain Relief and Its Role in the Opioid Epidemic

Mayo Clinic Proceedings

The Harrison Act of 1914 helped establish opioids as specific painkillers that had a distinct capacity to induce addiction. This understanding of opioids as having distinct and separable analgesic and addictive potential was challenged by the 1970s discovery of an endogenous opioid system, which integrates pain and reward functions to support survival. Modern pain neurophysiology places the patient with pain in a passive position from which it makes sense to assert a right to pain relief. To prevent future opioid epidemics, the authors advocate for the abandonment of clinical outpatient use of pain intensity scores. They redefine the medical necessity of pain treatment as less about the reduction of pain intensity and more about the capacity to pursue personally valued activities.

Call for Applications: 4^th Edition Adolescent Writing Committees

ASAM is seeking experts in specific topic areas to serve on writing committees for the 4th Edition of The ASAM Criteria®, Adolescent Volume. These writing groups will be chaired by Lead Editors who report to the Editor in Chief. ASAM members and non-members are encouraged to apply, as are all members of the addiction medicine care team. Applications will be accepted through July 21, 2023.

Learn more here.

Research and Science

Association Between Stimulant Treatment and Substance Use Through Adolescence Into Early Adulthood

JAMA Psychiatry

A relationship has been debated about stimulant treatment of ADHD and subsequent substance use. In this cohort study, stimulant treatment for children 7-9 years of age with combined ADHD and the potential for substance use later in life was investigated. Using the Multimodal Treatment Study of ADHD, a randomized clinical trial of 14 months of treatment (medication and behavioral therapy) then segued to a longitudinal observational study. No evidence was found for increased alcohol, marijuana, cigarette smoking, or other substance use in those with prior stimulant treatment.

Trends in Cannabis-positive Urine Toxicology Test Results: US Veterans Health Administration Emergency Department Patients, 2008 to 2019

Journal of Addiction Medicine

This study investigated VA population trends in cannabis use among those who visited emergency departments over an 11-year period. The annual prevalence of cannabis-positive urine increased about 70% -- from 16.42% in 2008 to 27.77% in 2019. Of the close to 1,300,000 patients who visited an ED and received a urine drug screen (UDS), 21.62% tested positive for cannabis. Use was highest among those 18-34 years of age; by the end of the study period, this group had the highest increase in use at nearly 43%. Male patients had a higher prevalence of a positive UDS than female patients, but male and female patients exhibited similar increases in these findings over time.

The novel uncompetitive NMDA receptor antagonist esmethadone (REL-1017) has no meaningful abuse potential in recreational drug users 🔓

Translational Psychiatry

Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. Two studies were conducted to evaluate the abuse potential of esmethadone. Each study utilized a randomized, double-blind, active-, and placebo-controlled crossover design to assess esmethadone compared with oxycodone (Oxycodone Study) or ketamine (Ketamine Study) in healthy recreational drug users. In both studies, all doses of esmethadone were statistically equivalent to placebo on Drug Liking VAS Emax (p < 0.05). In the Ketamine Study, Drug Liking VAS Emax scores for esmethadone at all tested doses were significantly lower vs. dextromethorphan (p < 0.05) (exploratory endpoint). These studies indicate no meaningful abuse potential for esmethadone at all tested doses.

Mortality among individuals prescribed opioid-agonist therapy in Scotland, UK, 2011–20: a national retrospective cohort study

The Lancet Public Health

This study used information from Scotland’s national databases (National Health Service, prescription data and mortality data) from 2011 to 2020 to calculate drug-related death (DRD) rates for individuals with opioid use disorder. Individuals not prescribed opioid-agonist therapy (OAT) had DRD rates more than three times that of individuals on OAT (HR 3.37; 95% CI 1.7-6.5), while the overall DRD rates more than tripled over the study period, from 6.4 deaths/1000 person-years in 2011 to 21.5 in 2020. Similar increases in DRD rates were seen for those both on and off OAT which, as noted by the authors, indicates that OAT alone is not sufficient to combat DRD.

Learn More

A lipidated TLR7/8 adjuvant enhances the efficacy of a vaccine against fentanyl in mice 🔓

NPJ Vaccines

Novel therapies, specifically for fentanyl, are needed to prevent opioid use disorder (OUD) and overdose deaths. Vaccines have been tested previously for cocaine and nicotine, with variable success. In this study, the authors evaluate a vaccine against a fentanyl based hapten, F1, conjugated to diphtheria cross-reactive material (-1-CRM) in combination with pattern recognition receptor ligands (synthetic TLR7/8 agonist and TLR4 agonist) to assess if they may confer improved immunity over F1-CRM alone. F1-CRM in combination with TLR7/8 (INI-4001) did significantly increase F1-specific antibodies and reduced drug distribution of fentanyl in the brains of mice. Improved response was not seen in combination with TLR3 agonist (INI-2002). Additional studies are needed, but INI-4001 may serve as a novel therapy to reduce fentanyl overdose deaths.

Pharmacological GHSR (ghrelin receptor) blockade reduces alcohol binge-like drinking in male and female mice. 🔓

Neuropharmacology

Ghrelin has a known role in appetite, food consumption, and reward, and may also have a relationship with alcohol intake. In this study, the authors evaluate six ghrelin receptor (GHSR) antagonists and an anti-ghrelin vaccine in a mouse binge-drinking model. In the mouse model, five of the GHSR antagonists decreased alcohol-binge like drinking when given systemically. One of the antagonists did not decrease drinking when given systemically, but did decrease binge-like drinking when given centrally. No decrease in binge-like drinking was found with the anti-ghrelin vaccine. The authors note this study further supports the role of the ghrelin system in alcohol use and is a potential treatment target for alcohol use disorder.

Fentanyl-Associated Overdose Deaths Outside the Hospital 🔓

New England Journal of Medicine

This study used drug-overdose death data from the National Center for Health Statistics between 2016 and 2021 to compare the period before the COVID pandemic to the early years of the pandemic. Between 2016 and 2021, there was a 282% increase in drug-overdose deaths. This increase was primarily the result of fentanyl deaths that occurred out-of-hospital. No notable increases were seen for fentanyl deaths in-hospital, other opioid deaths (in or out-of-hospital), or nonopioid deaths (in or out-of-hospital). The percentage of deaths that were out-of-hospital was 83% for fentanyl, 76% for other opioids, and 68% for nonopioid deaths. The authors conclude that early in the pandemic “drug overdoses had increased in severity due to the increasing involvement of fentanyl.”

In The News

'When Crack Was King' follows four people who lived through the drug epidemic

NPR