Delta Opioid Receptor Agonist Potential Use in Mitigating Opioid Withdrawal Symptoms

Abstract

The opioid epidemic continues to pose one of the most urgent public health crises worldwide, with relapse frequently fueled by affective symptoms of withdrawal, anxiety, and depression. Current treatments such as methadone and buprenorphine, target mu- opioid receptors (MORs), address cravings and somatic symptoms but provide limited relief for affective symptoms. Delta-opioid receptors (DORs), may offer therapeutic advantages, showing anxiolytic and antidepressant-like effects in preclinical models without the abuse liability of MOR agonists or the dysphoria linked to kappa-opioid receptor (KOR) agonists. This meta-analysis synthesized evidence from 42 controlled preclinical comparisons. Random-effects models indicated that DOR agonists produced large reductions in anxiety-like behaviors (Hedges’ g= 1.40, 95% CI [0.98, 1.82]) and depression-like behaviors (g= 1.72, 95% CI [0.85, 2.59]). In withdrawal models, DOR agonists significantly reduced withdrawal-induced anxiety (g= 1.85, 95% CI [1.08, 2.61]) and moderately improved withdrawal-induced depression (g= 0.76, 95% CI [0.14, 1.37]). Comparative analyses indicated that DOR agonists have substantial advantages over MOR agonists (g = 2.68, 95% CI [1.45, 3.90]) and exhibit favorable profiles relative to KOR agonists, particularly in terms of analgesia and adverse effect outcomes. These findings highlight DOR agonists as promising candidates for addressing both the emotional and physiological dimensions of opioid withdrawal. Although heterogeneity and limited chronic models remain challenges, this analysis establishes a strong foundation for translational research into DOR-targeted therapies for opioid use disorder.