Opioids, pain, the brain, and hyperkatifeia: a framework for the rational use of opioids for pain

Abstract

Objective: Opioids have relieved more human suffering than any other medication, but their use is still fraught with significant concerns of misuse, abuse, and addiction. This theoretical article explores the hypothesis that opioid misuse in the context of pain management produces a hypersensitivity to emotional distress, termed hyperkatifeia.

Results: In the misuse of opioids, neural substrates that mediate positive emotional states (brain reward systems) are compromised, and substrates mediating negative emotional states (brain stress systems) are enhanced. A reflection and early marker of such a nonhomeostatic state may be the development of opioid-induced hyperkatifeia, defined as the increased intensity of the constellation of negative emotional/motivational symptoms and signs observed during withdrawal from drugs of abuse (derived from the Greek "katifeia" for dejection or negative emotional state) and is most likely to occur in subjects in whom the opioid produces a break with homeostasis and less likely to occur when the opioid is restoring homeostasis, such as in effective pain treatment. When the opioid appropriately relieves pain, opponent processes are not engaged. However, if the opioid is administered in excess of need because of overdose, pharmacokinetic variables, or treating an individual without pain, then the body will react to that perturbation by engaging opponent processes in the domains of both pain (hyperalgesia) and negative emotional states (hyperkatifeia).

Conclusions: Repeated engagement of opponent processes without time for the brain's emotional systems to reestablish homeostasis will further drive changes in emotional processes that may produce opioid abuse or addiction, particularly in individuals with genetic or environmental vulnerability.

Figure 1

Pathways for the supraspinal processing of pain superimposed on key elements of addiction circuitry implicated in negative emotional states. Blue structures are involved in the “fast” processing of pain via the spinothalamic tract and arrive indirectly at the amygdala. Pink structures are involved in the “fast” processing of pain via the spinal-parabrachial-amygdala pathway and arrive directly at the amygdala. Yellow structures are involved in the “slower” cognitive processing of pain. Addiction circuitry is composed of structures involved in the three stages of the addiction cycle: binge/intoxication (ventral striatum, dorsal striatum, thalamus), withdrawal/negative affect (ventral striatum, bed nucleus of the stria terminalis, central nucleus of the amygdala; red structures), preoccupation/anticipation (prefrontal cortex, orbitofrontal cortex, hippocampus). Notice significant overlap of the supraspinal processing of pain and addiction in the amygdala. Modified with permission from [25] and [26]. ACC = anterior cingulate cortex; AMG = amygdala; BNST = bed nucleus of the stria terminalis; DRG = dorsal root ganglion; DS = dorsal striatum; GP = globus pallidus; Hippo = hippocampus; Hyp = hypothalamus; Insula = insular cortex; OFC = orbitofrontal cortex; PAG = periaqueductal grey; PB = parabrachial nucleus; PFC = prefrontal cortex; PPC = posterior parietal cortex; S1, S2 = somatosensory cortex; SMA = supplementary motor area; Thal = thalamus; VS = ventral striatum.

Figure 2

Schematic diagram summarizing the hypothesized relationship between addiction and pain. Pathological emotional states are known to exacerbate pain. We hypothesize that, in parallel, the negative emotional state of drug withdrawal and protracted abstinence can also exacerbate pain; conversely, pain can exacerbate both pathological emotional states and addiction. Hyperalgesia, an increased sensitivity to pain, caused by opioid treatment could indicate the parallel development of hyperkatifeia, or increased sensitivity to negative emotions. Hypothetically, the converse could occur in addiction (hyperkatifeia reflecting underlying hyperalgesia). The conceptual framework for such changes involves a break from emotional homeostasis termed allostasis (stability through change) in neurobiological mechanisms in the extended amygdala.