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.