A µ-opioid receptor superagonist analgesic with minimal adverse effects

Nature

This study identifies a novel µ-opioid receptor (MOR) agonist with supramaximal intrinsic efficacy and a unique pharmacological profile that produced effective analgesia in rodents with minimal adverse effects. N-desethyl-fluornitrazene (DFNZ) was derived from a class of synthetic benzimidazole opioids called nitazenes. DFNZ has impaired brain penetrance, a unique spatiotemporal MOR cellular signaling profile, and diminished efficacy at the MOR–galanin 1 receptor (GAL1) heteromer. DFNZ does not induce respiratory depression, tolerance, or MOR downregulation after repeated exposure. Compared with other MOR agonists, DFNZ has limited effects on dopamine neurotransmission in the nucleus accumbens and weaker reinforcing effects in the drug self-administration procedure. These results provide novel insights about MOR and nitazene pharmacology, have important implications for pain and addiction treatment, and challenge the prevailing dogma that high-efficacy MOR agonists cannot constitute safe and effective therapeutic agents.

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Methadone Dose and Patient-Directed Discharge in Hospitalized Patients with Opioid Use Disorder

JAMA Network

This retrospective observational cohort study of 554 individuals examined rates of patient-directed discharge (PDD) among hospitalized patients with opioid use disorder who received methadone during the first 72 hours of hospitalization from July 2019 to June 2022. Higher doses of methadone were associated with a decreased rate of PDD. For each additional 10 mg of methadone received in the first 24 hours, there was a decrease in odds of PDD at 48 hours (adjusted OR 0.71). This study highlights the importance of adequate treatment of opioid withdrawal to reduce the risk of PDD.

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Do US Adults View Drug and Alcohol Addiction as a Health Condition?

Journal of Addiction Medicine 

Participants (n=5250), part of Gallup’s random sample of US households, completed a web-based survey that explored their beliefs about addiction.  Asked if addiction is a health condition 77% of US adults agree, 16% disagree, and 6% don’t know. Men are more likely to disagree (20%) than women (15%). Those who have struggled with addiction but not in recovery were more likely to disagree (22%) than those in recovery (13%) or with no personal addiction experience (16%). Those with less education and income were more likely to disagree. Those who disagree that addiction is a health condition are less likely to believe it is treatable by doctors (OR=0.3), believe that medications are effective treatments (OR=0.4), or help friends or family with addiction (OR=0.5). 

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Cannabis cessation and neurocognitive recovery: Patterns, predictors, and clinical implications—a systematic review

The American Journal on Addictions 

Researchers conducted a literature review of the neurocognitive effects of cannabis use and recovery from those effects. They found a range of neurocognitive effects including neuroreceptor adaptation, decrease in memory, processing speeds, and attention. Deficits increased with higher frequency and amount of use, but recovery can occur.  Receptor normalization can occur within weeks of abstinence while cognitive recovery can take months and years. Adolescent-onset users have more severe and persistent deficits, suggesting effects to neurodevelopment beyond reversible neuroadaptation. The authors suggest treatment for cannabis use disorder should focus on both the disorder and its neurocognitive effects. 

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Cost-effectiveness of contingency management for methamphetamine use disorder: A model-based analysis

Addiction

This study used a microsimulation model of methamphetamine use behavior among individuals with methamphetamine use disorder (MethUD) to assess the cost-effectiveness of contingency management (CM) for MethUD. Both 12-week and 24-week CM programs were modeled, using a maximum incentive of $750/patient, per SAMHSA guidelines. The model simulation was run for a cohort of 10,000 individuals with MethUD and looked at lifetime cost. Compared to no treatment, the model predicted an estimated net gain of 0.70 QALYs per person at a cost of $6850/QALY for a 12-week program, with an incremental cost-effectiveness ratio (ICER) of $9830/QALY. For a 24-week program, the benefit was 0.81 QALYs at a cost of $10,000, yielding an ICER of $12,312/QALY. This suggests that both durations of CM for MethUD are highly cost-effective, even at the maximum level of incentives.

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Glucagon-like peptide-1 receptor agonists and risk of substance use disorders among US veterans with type 2 diabetes: cohort study

The BMJ

This study investigated whether initiation of glucagon-like peptide-1 (GLP-1) receptor agonists is associated with both reduced risks of incident alcohol, cannabis, cocaine, nicotine, opioid, and other substance use disorders (SUDs) in people with no history of SUDs (protocol 1) and with reduced risk of SUD-related adverse clinical outcomes among people with a pre-existing SUDs (protocol 2).  Researchers found that use of GLP-1 receptor agonists was consistently associated with reduced risks of developing various incident SUDs, suggesting a broad preventive effect across multiple substance types. Use was also associated with reduced risks of adverse clinical outcomes in people with pre-existing SUDs. These observational data suggest a potential role for GLP-1 receptor agonists in both the prevention and treatment of various SUDs, warranting further evaluation.

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Does the total consumption model apply to cannabis use?

Addiction

This repeated cross-sectional study based on annual surveys tested whether the total consumption model and its extension, the theory of collectivity, apply to adolescent cannabis use in Sweden. Frequency of cannabis use was measured by a question on how many occasions the respondent has used hashish or marijuana. The seven response alternatives ranged from 0 to 50 times or more. Increases in mean frequency use were associated with a higher prevalence of high-frequency users.  Adolescent cannabis use in Sweden appears to conform to key predictions of the total consumption model and its extension, the theory of collectivity.

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Spirituality and Harmful or Hazardous Alcohol and Other Drug Use 

JAMA Psychiatry

This meta-analysis of 55 rigorous studies on spirituality and harmful or hazardous drug use (alcohol, tobacco, marijuana, or illicit drugs) examined the association between spiritual exposures and related drug use outcomes.  It documented a significant protective association of 13% related to both prevention and recovery. The risk reduction, which extended across all 4 drug categories, reached 18% for individuals with greater than weekly religious service attendance.  These results have implications for clinicians and communities regarding future strategies to address harmful or hazardous alcohol or other drug use.

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Emergency Department–Initiated Buprenorphine for Opioid Use Disorder

JAMA Network

This multicenter randomized study examined if 7-day extended-release injectable buprenorphine compared with sublingual buprenorphine to improve treatment engagement at 7 days.  It included 1,994 adult patients presenting to the emergency department with untreated opioid use disorder and a Clinical Opiate Withdrawal Scale (COWS) score of 4 or higher.  In treatment at 7 days, 40.5% were in the extended-release group and 38.5% were in the sublingual buprenorphine group, demonstrating no significant difference between groups. The study concluded that a 7-day extended-release injectable preparation of buprenorphine does not improve treatment engagement.

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Use of gabapentin with or without a prescription in substance use treatment settings: A national analysis of urine drug testing data, 2016–2023 

Drug and Alcohol Dependence

Gabapentin prescriptions have increased due to off-label use, including managing withdrawal/comorbidities in substance use disorder (SUD) treatment, despite gaps in evidence bases and corresponding increases in nonmedical use. This retrospective, serial cross-sectional study sought to identify trends in gabapentin use with and without a prescription in SUD treatment settings.  Researchers found that gabapentin prescribing significantly increased in SUD treatment settings despite a lack of strong evidence bases for its utility. While rates of gabapentin use outside a prescription were nearly double that for prescribed use, this appears to be decreasing over time. Polysubstance use and potential gaps in multimorbidity care may contribute to the use of gabapentin without a prescription.

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