Estimates suggest as many as one in every 10 people with BPD dies by suicide.

Individuals with OUD are 14 times more likely to die by suicide relative to the general population, and opioids are found in 20% people who dies by suicide in the US. Alarmingly, risk is even higher when people with BPD use opioids. BPD is associated with a greater quantity and frequency of opioid use, increased risk for analgesic misuse, and markedly elevated rates of comorbid OUD. Moreover, a comorbid BPD diagnosis (observed in 19-44% of individuals with OUD) is associated with more severe and persistent symptom presentation in both disorders, and a significantly higher likelihood of adverse consequences (including death by overdose and suicide).

Despite the complexity and seriousness of these highly comorbid disorders, available agents largely fall short of affecting overall symptom severity BPD-OUD; and no available treatments reliably reduce suicide risk in this population.

Therefore, understanding the pathophysiology of BPD-OUD is crucial to the development of potentially life-saving interventions tailored to this high-risk population.

Recent evidence supports a role for the kappa opioid system (KOR) in the pathophysiology and maintenance of BPD, OUD, and their comorbid presentation. The opioid system is instrumental in the regulation of core features of BPD-OUD, including impulsivity, social functioning, and the experience of pain. Evidence from both human and preclinical studies suggests KOR signaling mediates the effect of stress on the development of psychiatric symptoms including addiction. Elevated dynorphin (a KOR-associated opioid peptide), which can result from chronic stress, and agonism of KOR are both associated with symptoms of BPD-OUD (e.g., dissociation or cognitive dysfunction). Similarly, preclinical studies show KOR involvement in impulsive behavior and social dysfunction. Further, postmortem work has linked KOR expression including lower KOR availability in the amygdala and anterior cingulate (ACC) specifically to suicide mortality.

Clinical trials of KOR antagonists are underway in BPD and ongoing in OUD; unfortunately, those with BPD-OUD remain understudied and are frequently excluded from clinical trials due to risk and clinical complexity.

Thus, there is strong support for KOR as a potential target in BPD-OUD. However, the role and clinical relevance of KOR in BPD-OUD is not yet well understood.