BPD and Opioid Use Disorder (OUD)

Estimates suggest as many as one in every 10 people with BPD dies by suicide (Temes et al., 2019; Girardi et al., 2022).

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 (Arregui et al., 1992; Temes et al., 2019). BPD is associated with a greater quantity and frequency of opioid use, increased risk for analgesic misuse, and markedly elevated rates of comorbid OUD (Tragesser et al., 2010). Moreover, a comorbid BPD diagnosis (observed in 19-44% of individuals with OUD) (Trull et al., 2010; Darke et al., 2004; Darke et al., 2005; Darke et al., 2007; Trull et al., 2007) is associated with more severe and persistent symptom presentation in both disorders, and a significantly higher likelihood of adverse consequences (Hasin et al., 2011; Campbell et al., 2015) (including death by overdose and suicide) (Maloney et al., 2009).

Despite the complexity and seriousness of these highly comorbid disorders, available agents largely fall short of affecting overall symptom severity BPD-OUD (Ripoll, 2013, Lieb et al., 2010, & Hancock-Johnson et al., 2017) 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 (New et al., 2010), social functioning (Kennedy et al., 2006), and the experience of pain (Agren et al., 1991). Evidence from both human (Pietrzak et al., 2014) and preclinical (Knoll et al., 2010, Chartoff et al., 2012, Peters et al., 2011) studies suggests KOR signaling mediates the effect of stress on the development of psychiatric symptoms (Knoll et al., 2010; Anderson et al., 2019) including addiction (Metcalf & Coop, 2008). Elevated dynorphin (a KOR-associated opioid peptide), which can result from chronic stress (Esterlis et al., 2017), and agonism of KOR are both associated with symptoms of BPD-OUD (e.g., dissociation (Walsh et al., 2001) or cognitive dysfunction (Bruchas et al., 2010)). Similarly, preclinical studies show KOR involvement in impulsive behavior and social dysfunction (Knoll et al., 2010 & Bruchas et al., 2011). Further, postmortem work has linked KOR expression (Hurd et al., 1997 & Lutz et al., 2018) including lower KOR availability in the amygdala (Hurd, 2002) and anterior cingulate (ACC) (Lutz et al., 2018) 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.

Our goals for this study include:

  • Determining whether comorbid presentation of BPD-OUD is associated with lower KOR availability.

  • Determining whether history of suicide behavior is associated with lower KOR availability in BPD-OUD.

  • Examining the association between KOR availability and other endophenotypic correlates of suicide risk in BPD-OUD: impulsivity, and pain sensitivity.

Citations

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This study is possible thanks to support from the Yale Biomedical Imaging Institute.