Neurocircuitry basis of the opioid use disorder–post-traumatic stress disorder comorbid state: conceptual analyses using a dimensional framework

Summary

Understanding the interface between opioid use disorder (OUD) and post-traumatic stress disorder (PTSD) is challenging. By use of a dimensional framework, such as research domain criteria, convergent and targetable neurobiological processes in OUD–PTSD comorbidity can be identified. We hypothesise that, in OUD–PTSD, circuitry that is implicated in two research domain criteria systems (ie, negative valence and cognitive control) underpins dysregulation of incentive salience, negative emotionality, and executive function. We also propose that the OUD–PTSD state might be systematically investigated with approaches outlined within a neuroclinical assessment framework for addictions and PTSD. Our dimensional analysis of the OUD–PTSD state shows how first-line therapeutic approaches (ie, partial μ-type opioid receptor [MOR1] agonism) modulate overlapping neurobiological and clinical features and also provides mechanistic rationale for evaluating polytherapeutic strategies (ie, partial MOR1 agonism, κ-type opioid receptor [KOR1] antagonism, and α-2A adrenergic receptor [ADRA2A] agonism). A combination of these therapeutic mechanisms is projected to facilitate recovery in patients with OUD–PTSD by mitigating negative valence states and enhancing executive control.

Introduction

Individuals with opioid use disorder (OUD) often present with post-traumatic stress disorder (PTSD), with a prevalence of OUD–PTSD comorbidity ranging between 20% and 50%.1, 2, 3 The underlying cause for the frequent co-occurrence is likely to be multifactorial in nature. For instance, a previous history of physical or emotional trauma can predispose an individual to develop OUD. Notably, some prescription opioids used for pain or OUD treatment might not only have an analgesic effect but also alleviate other debilitating symptoms (eg, depressed mood and suicidal ideation).4, 5, 6, 7, 8, 9 See later for discussion on buprenorphine. Following relief from these symptoms, and on sustained opioid consumption, OUD can develop. Effectively mitigating OUD and PTSD is especially important, given that opioid misuse or behaviours that are associated with seeking opioids can put a patient in danger of future trauma and worsen their symptom severity in a cyclical manner, which is in line with previous observations of patients with OUD–PTSD having an increased risk of severe OUD.¹⁰

Patients diagnosed with OUD, PTSD, or both disorders are generally sensitive to various endogenous or exogenous triggers, stressors, or aversive stimuli. Patients with OUD, even in a so-called recovered state, can have heightened psychological stress or perceive environmental cues that trigger opioid withdrawal, opioid cravings, and in many cases, eventual illicit use of opioids. The result of an inability to escape occurrences of emotional or physical trauma, on either conscious or subconscious (eg, during nightmares) levels, can create learned threat behaviours, and hyper-reactivity towards those threats, real or imagined, and various environmental stimuli is often a parallel outcome.

OUD has been conceptualised as a three-stage cycle—ie, binge or intoxication, withdrawal or negative affect, and preoccupation or anticipation—that represents three functional psychobiological constructs: incentive salience or pathological habits, reward deficit or stress surfeit, and executive dysfunction.11, 12 We hypothesise that this psychobiological framework and such allostatic processes (eg, hyperkatifeia¹³) are of special relevance for the OUD–PTSD comorbid condition (figure 1). Hyperkatifeia is defined as the increased intensity of the constellation of negative emotional or motivational symptoms and signs that are observed during withdrawal from drugs. Its occurrence is conceptually paralleled by hyperalgesia (ie, hypersensitivity to physical pain). Moreover, hyperkatifeia encompasses feelings of dysphoria or enhanced irritability, as well as increased anxiety, stress, anhedonia, and to a lesser extent emotional numbing. In animal (eg, rodent and non-human primate) addiction models, hyperkatifeia is reflected by the elevation of reward thresholds, altered pain thresholds, anxiety-like behaviour, and dysphoric-like responses. Whether and how hyperkatifeia is expressed not only in patients with OUD but also in patients with PTSD or OUD–PTSD warrants exploration. We hypothesise that this negative emotional state, which drives negative reinforcement, is derived from dysregulation of neurochemical circuits that are initially involved in drug reward and incentive salience (ie, μ-type opioid receptor [MOR1] and dopamine systems), and in parallel, from activation of brain stress systems (ie, through the effect of dynorphins on κ-type opioid receptors [KOR1s]).11, 13, 14, 15, 16

We hypothesise that a common bond that engages and exaggerates OUD or PTSD involves executive dysfunction, producing loss of top-down control. This loss affects incentive salience and impulsivity throughout the addiction cycle and renders an individual unable to withstand urges in general. Similarly, circuits that are implicated within the negative valence and cognitive control systems also coincide with CNS regions underlying core PTSD symptoms.¹⁷ Considering elements of threat, fear, rumination, or a chronic negative outlook that are active in patients with OUD and patients with PTSD, negative valence systems are likely to work together with diminished cognitive control to sustain these disorders as standalone or comorbid conditions. Here, we applied a research domain criteria (RDoC) framework¹⁸ to define the underlying neurobiological mechanisms that facilitate the dysregulation of functional domains in individuals with OUD–PTSD, and we extend the proposed framework to mechanistically characterise current standard of care and provide a rationale for novel, combination treatment approaches for the individuals with OUD–PTSD (figure 1). RDoC is a dimensional framework for classifying mental disorders that uses measurable, biobehavioural dimensions that are linked to both neural circuits and psychopathology. Importantly, an RDoC-based analysis cuts across traditional diagnostic categories—an important aspect for comorbid psychiatric conditions, where traditional approaches and criteria are often inadequate.¹⁹ Hence, RDoC domains are not specific, as RDoC analysis defines so-called neurobiological biotypes where the individuals of each biotype are biologically more homogenous than are patients with a particular disorder diagnosed by DSM-5. Consequently, therapeutics that are targeted against a specific biotype—eg, anhedonia—are expected to be efficacious in a cohort of patients with anhedonia from different disorder (eg, depression, schizophrenia, and substance use disorders [SUDs]). In other words, RDoC-based therapeutics are predicted to be specific for a domain or biotype but not for a DSM-diagnosed disorder.

Implementation of the RDoC framework for individuals with OUD, PTSD, or OUD–PTSD, in conjunction with evidence of neuronal substrates that are involved in the facilitation of addiction or trauma but not yet included in RDoC (eg, interpeduncular nucleus), enabled the formulation of an OUD–PTSD network. We propose that such theoretical OUD–PTSD models can be systematically investigated with empirical approaches that are outlined within the addictions neuroclinical assessment (ANA) framework,²⁰ which we have expanded to encompass CNS mechanisms and symptomology that are related to PTSD (ie, PTSD neuroclinical assessment [PNA]). The proposed OUD–PTSD network was analysed from the perspectives of target expression (ie, opioid receptors and α-2A adrenergic receptors [ADRA2As]) and response to therapy. An understanding of receptor expression and pharmacodynamics of current treatments provided the necessary mechanistic and behavioural rationale for evaluating polytherapy approaches involving partial MOR1 agonism, ADRA2A agonism, and KOR1 antagonism. Furthermore, previous work has shown altered neuroimmune activity in individuals with OUD21, 22, 23 and individuals with PTSD.24, 25, 26 It is hypothesised that proinflammatory signatures might represent markers of OUD or PTSD susceptibility in conjunction with aberrant responses to opioids or trauma. Thus, on the basis of the proinflammatory profiles that can be separately observed in individuals with OUD and individuals with PTSD, we examined the rationale for targeting the neuroimmune system in the comorbid state. In summary, we aim to exemplify a systems-level neurobiological model of OUD–PTSD, which can be tested with empirical methods that we have defined and therapeutically modulated by a polytherapeutic approach.