2.1.3 The role of opioids in modifying the experiencing of pain
Opioids have profound analgesic properties, reliably reducing both physical pain and psychological distress23. Molecularly, they bind to G-protein coupled opioid receptor subtypes(e.g., mu-μ, delta-δ, and kappa-κ) in multiple brain and spinal regions23. Each receptor type activates different cellular pathways, leading to varied physiological effects. The μ -opioid receptor is the primary target for most clinically used opioids and is chiefly responsible for their analgesic effects. The activation of the μ receptor generally leads to a decrease in the release of certain neurotransmitters including substance P, glutamate, and GABA23. In pain pathways, this results in the hyperpolarization of post-synaptic neurons, which thereby reduces synaptic activity and the inter-neuron communication of pain signals23. Secondary effects include reductions in blood pressure, heart rate, respiratory rate, as well as drowsiness24. Centrally, opioids agonists’ actions at the opioid receptor level have euphoria-inducing and anxiolytic properties limiting one’s awareness or appreciation of painful stimuli25.
Continued opioid use, whether motivated by pain or OUD, can lead to the neuroadaptive developments of tolerance and physical dependence, necessitating higher doses to achieve the same effects over time and resulting in withdrawal symptoms upon drug cessation. Chronic opioid exposure triggers modifications in the quantity and responsiveness of opioid receptors, a process known as receptor downregulation and desensitization26. As a consequence, receptors become internalized or less reactive, contributing to the phenomenon of tolerance26.
Human studies utilizing pain laboratory models have shown that individuals maintained on full-agonist opioids such as methadone for the treatment of OUD exhibit increased sensitivity and decreased tolerance to painful stimuli, as evidenced by studies conducted by the investigative teams of Clark, Compton, and Wachholtz27-29. Interestingly, Athanasos and colleagues found that despite inducing respiratory depression in some participants, high doses of morphine failed to enhance pain tolerance in methadone-maintained patients30. Additionally, Compton and colleagues reported that neither buprenorphine nor methadone treatments improved pain sensitivity for participants with OUD28. In a systematic review of 225 participants on opioid agonist therapy for OUD, De Aquino and colleagues found that the majority of participants do not experience analgesia despite receiving opioid doses up to 20 times greater than those used to treat acute pain in opioid-naïve participants31. Conversely, they remained vulnerable to respiratory depression despite receiving medications for OUD — suggesting tolerance to analgesic effects cannot be equated with tolerance to adverse effects from opioids. This intricate interplay of physiological changes underscores the complexities associated with opioid-induced neuroadaptations and pain management in individuals with OUD.
Psychological aspects of chronic pain in opioid use disorder
The presence of pain can significant worsen one’s quality of life. As a multifaceted phenomenon, it also brings wide-ranging consequences. For instance, mobility, sleep, concentration, mood, and overall physical functioning are negatively impacted by ongoing pain. Various psychological factors can worsen the pain experience, including negative expectancy (i.e., behaving in an avoidant manner as if expecting the pain to worse) or perceived controllability (i.e., sense of lack of control over their pain increases the perception of intensity). These factors bring additional repercussions, such as social isolation and avoiding physical activities or kinesiophobia (from the Greek terms “kinesis” [movement] and phobia [fear]). Collectively, these components of the pain experience can converge, and the individual may refrain from usual enjoyable activities and roles, contributing to depression, anxiety, and lower quality of life32, 33.
Physical pain and emotional pain intersect and can synergistically influence not only the overall experience of pain itself, but also influence co-occurring psychopathology (e.g., mood disorders and trauma-related disorders)34. For example, mood disorders predict both non-medical opioid use and the increased likelihood for developing chronic pain conditions35, 36. Persons with chronic pain are also more likely to be diagnosed with mood disorders and may be at higher risk of developing OUD37, 38; although there are conflicting data in the literature regarding the risk of progression to OUD39. However, despite the considerable overlap between these conditions, the influence of co-occurring psychopathology on the assessment of pain among people with OUD remains largely unaccounted for in most clinical settings.
Other important psychological factors that contribute to the pain experience in persons with chronic pain include pain catastrophizing and attentional bias40. Pain catastrophizing involves ruminative thoughts about pain, and a sense of hopelessness regarding pain improvement resulting in an amplification of pain41. Studied in both acute pain (e.g., whiplash injury after motor vehicle accidents) and chronic pain42-44 (e.g., fibromyalgia45, low back pain46, 47), pain catastrophizing is a risk factor for poorer pain treatment prognosis and outcomes in persons with OUD, as well as a predictor of pain chronicity48. Attentional bias refers to a cognitive fixation in which attention is automatically captured by pain- or opioid-related cues, serving as motivation for further medication use49, 50. In other words, as patients with chronic pain engage in re-occurring opioid use, pain (e.g., experiencing external or interoceptive painful stimuli) and opioid-related cues (e.g., pill bottles) can trigger craving and perceived worsening of pain. Clinically, it has been suggested that attentional bias may precede drug use in persons with OUD and be an early warning signal of return to non-medical opioid use51.
Research shows that persons with OUD tend to experience pervasive anhedonia and dysphoria with consequences such as increased sensitivity to social rejection, reward deficiency, and heightened pain experience52-54, contributing to opioid craving and further non-medical opioid use53, 55, 56. This dysphoria or hyperkatifeia (from the Greek term “katifeia” [dejection]) is referred to as encompassing negative emotional symptoms such as irritability, anxiety, and unease that derive from dysregulation of brain reward and stress systems, and has been demonstrated to worsen during protracted abstinence and seems to facilitate relapse57.
Further exemplifying the clinical relevance of these chronic pain-related psychological factors, emerging evidence demonstrates that interventions addressing both the physical consequences of pain and long-term opioid use, and the maladaptive psychological patterns, such as pain catastrophizing, produce superior clinical outcomes58. As an example from an adjacent long-term opioid use population, Martinson and colleagues studied 77 veterans with multiple chronic pain conditions in the primary care setting and offered six, 50-minute sessions of cognitive behavioral therapy for pain59. Approximately 52% of participants had long-term opioid use. They suggest that this psychological behavioral intervention significantly improves pain symptoms, physical function, family stability, sleep quality, satisfactions with outcomes of care, pain-related anxiety, generalized anxiety, pain catastrophizing, and depressed mood. As seen in most studies encompassing pain and long-term opioid use, a limitation of this study is that it does not formally assess for OUD, thus, we suggest careful extrapolation of these findings from long-term opioid use populations to those living with OUD.
In summary, the psychological consequences of both chronic pain and OUD, especially when compounded by negative coping strategies and thought patterns, can make pain feel overwhelming for persons with co-occurring OUD and chronic pain. The perception of pain in these patients is influenced by these significant psychological factors, which can be accurately assessed for and are amenable to effective interventions.
Social aspects influencing pain assessment in persons with OUD
As the fields of pain research and treatment have progressed towards an adoption of a biopsychosocial model as an alternative to a purely biomedical approach, social aspects in clinical evaluations and pain assessments have garnered growing interest60. This model argues that social factors (e.g., racial-ethnic disparities, social support networks, access to health care) are often as important as biological determinants in the origin, exacerbation, and maintenance of pain.