Review
The downward spiral of chronic pain, prescription opioid misuse, and addiction: Cognitive, affective, and neuropsychopharmacologic pathways

https://doi.org/10.1016/j.neubiorev.2013.08.006Get rights and content

Highlights

  • Prescription opioid misuse among chronic pain patients is a public health threat.

  • Cognitive-affective factors interact with the neuropharmacology of opioid analgesia.

  • Opioid misuse may arise out of dysfunctional brain connectivity and allostasis.

  • We describe a conceptual model linking chronic pain and addictive opioid use.

  • Our model has implications for mindfulness-based treatment of these comorbidities.

Abstract

Prescription opioid misuse and addiction among chronic pain patients are emerging public health concerns of considerable significance. Estimates suggest that more than 10% of chronic pain patients misuse opioid analgesics, and the number of fatalities related to nonmedical or inappropriate use of prescription opioids is climbing. Because the prevalence and adverse consequences of this threat are increasing, there is a pressing need for research that identifies the biobehavioral risk chain linking chronic pain, opioid analgesia, and addictive behaviors. To that end, the current manuscript draws upon current neuropsychopharmacologic research to provide a conceptual framework of the downward spiral leading to prescription opioid misuse and addiction among chronic pain patients receiving opioid analgesic pharmacotherapy. Addictive use of opioids is described as the outcome of a cycle initiated by chronic pain and negative affect and reinforced by opioidergic-dopamingeric interactions, leading to attentional hypervigilance for pain and drug cues, dysfunctional connectivity between self-referential and cognitive control networks in the brain, and allostatic dysregulation of stress and reward circuitry. Implications for clinical practice are discussed; multimodal, mindfulness-oriented treatment is introduced as a potentially effective approach to disrupting the downward spiral and facilitating recovery from chronic pain and opioid addiction.

Introduction

Misuse of prescription opioid analgesics is an emerging public health concern that confers significant risks for overdose, unsafe drug interactions, and the full panoply of adverse social, legal, and adaptive consequences associated with dependence on any psychoactive drug. Though the prevalence of prescription opioid misuse across the general U.S. population has increased more than threefold over the past two decades (Hall et al., 2008), it is presently unclear to what extent this explosion in prevalence reflects an increase in opioid misuse by persons without a prescription for opioids versus an increase in nonmedical use of opioids by persons prescribed opioids for analgesia. This distinction notwithstanding, nationally representative surveys indicate that prescription opioid misuse is endemic among U.S. adolescents and adults; prescription opioids are now among the most commonly misused drugs in the U.S. (Wilson, 2007). For instance, results of the National Survey on Drug Use and Health (NSDUH) for 18–25 year-olds revealed that 23.8%, 11.1%, and 4.8% reported lifetime, past year, and past month misuse of prescription “pain killers” (Substance Abuse and Mental Health Services Administration, 2011). NSDUH findings further indicated that rates of initiation of nonmedical pain reliever use were second only to those of marijuana, with more than two million persons initiating nonmedical use of opioid analgesics annually. These findings underscore the pervasive availability and misuse of these agents in the U.S. The ready accessibility, prevalent misuse, and euphorigenic effects of prescription opioids would seem to create conditions for widespread dependence on these agents (Mendelson et al., 2008). Recent research does, in fact, suggest that rates of publically funded chemical dependency treatment and emergency department care for prescription opioid use have increased dramatically in recent years and it is estimated that well over a million Americans are currently dependent on prescription opioids (Manubay et al., 2011, Mendelson et al., 2008). As previously underscored, these statistics do not clearly differentiate opioid misusers with and without chronic pain; yet, this is a critically important distinction with serious clinical ramifications.

The issue of prescription opioid misuse is further complicated by the diversity of nosological categories used to classify opioid use patterns and their biopsychosocial consequences. As defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), prescription opioid abuse involves a maladaptive pattern of repeated opioid use that: results in failure to fulfill social, occupational, academic, or familial obligations; continues despite recurrent legal problems related to opioid use; persists in spite of interpersonal problems caused or exacerbated by opioids; and occurs in physically hazardous contexts. In contrast, DSM-IV defines prescription opioid dependence as involving physical symptoms of dependence, including tolerance and withdrawal, as well as behavioral symptoms including: taking higher doses than intended; an inability to reduce or stop taking opioids; spending substantial amounts of time using, obtaining, recovering, or thinking about opioids; and continued use in spite of adverse physical or psychological consequences (Zacny et al., 2003). However, some clinicians believe these behavioral criteria for abuse and dependence are inappropriate for opioid-using chronic pain patients, because patients who take opioids as prescribed may be unable to reduce their opioid use or may continue opioid use despite adverse health consequences due to the intractability of their chronic pain. Instead, many pain and addiction specialists use the American Pain Society (2002) criteria to identify prescription opioid addiction among chronic pain patients, including symptoms of impaired control over opioid use, compulsive opioid use, continued use despite harm, and craving for opioids (Sullivan et al., 2008, Wilson, 2007). Addictive tendencies among prescription opioid users may be presaged by the presence of opioid misuse behaviors such as selling medication or injecting oral formulas (Ives et al., 2006, Sullivan et al., 2008), although less serious forms of opioid misuse like unauthorized dose escalation are relatively common among undertreated chronic pain patients and may not indicate opioid addiction. The presence of more serious misuse behaviors may mark the transition from sanctioned use of opioids to development of opioid use disorders and addiction (Butler et al., 2007).

Parsing apart these conditions, structured psychiatric interviews conducted for the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) study of more than 43,000 U.S. adults identified 4.7% of respondents as lifetime prescription opioid misusers; whereas 1.4% of respondents met criteria for a DSM-IV prescription opioid use disorder (opioid abuse or dependence; Huang et al., 2006). Men, adults with Axis I and Axis II DSM-IV diagnoses, respondents residing in the West, and young or middle aged adults were at greatest risk for prescription drug misuse and a prescription opioid use disorder. Other studies have identified a history of alcohol or illicit drug misuse, anxiety, depression, and chronic pain as significant risk factors for prescription opioid misuse and dependence (Amari et al., 2011, Pohl and Smith, 2012, Turk et al., 2008). Individuals suffering from chronic pain disorders, who are at risk for becoming physically dependent on opioid analgesics when adhering to their prescribed medication regimen, may be particularly vulnerable to prescription opioid misuse (Butler et al., 2007, Ives et al., 2006, Sullivan et al., 2010).

Though the prevalence of prescription opioid misuse and addiction among chronic pain patients has yet to be firmly established by nationally representative, population-level surveys, chronic pain itself is highly prevalent in modern society; a meta-analysis of 13 studies reported a weighted mean prevalence of 35.5% for chronic pain of any kind and a weighted mean prevalence of 11% for severe chronic pain (Ospina and Harstall, 2002). Many patients with chronic pain have serious medical conditions that require long-term opioid pharmacotherapy, and a subset of these individuals are at significant risk for escalating from appropriate opioid use to misuse and finally to opioid addiction. The best available prevalence estimates for opioid misuse and addiction among chronic pain patients may be derived from research by Fishbain et al. (2007), who reviewed 67 methodologically rigorous studies including thousands of chronic pain patients and concluded that 3.3%, 11.5%, and 14.5% of these patients, in toto, became addicted to prescription opioids, engaged in opioid misuse behaviors such as unauthorized dose escalation or drug hoarding, and used illicit drugs, respectively. Thus, while prescription opioid addiction among chronic pain patients appears to be relatively rare, opioid misuse in this population is more common. Although relatively few studies have prospectively examined factors related to increased risk for prescription drug misuse among chronic pain patients receiving ongoing opioid pharmacotherapy, recent reports suggest that greater baseline pain intensity (Edwards et al., 2011, Jamison et al., 2009), psychological distress and behavioral problems (Jamison et al., 2010), and status as a cigarette smoker (Novy et al., 2012) predict greater risk for transitions to prescription opioid misuse, abuse and addiction. There is a pressing need for additional studies to better understand the risk factors for progression to opioid misuse and opioid use disorders among chronic pain patients receiving prescription opioid pharmacotherapy (Larance et al., 2011). Further, novel conceptual frameworks are needed to delineate the biobehavioral risk chain linking pain, opioid analgesia, opioid misuse, and addiction.

The purpose of this paper is to describe how the neuropharmacologic properties of prescription opioids interact with cognitive, affective, and physiological factors implicated in chronic pain and addictive behavior. We first review the neurobiology of opioid agents and pain processing in the human nervous system. Next, we present a conceptual model to describe how chronic pain, affective dysregulation, and opioid use interact to potentiate each other and foster opioid addiction. Lastly, we discuss clinical implications of the model for psychological treatment of chronic pain patients and for the prevention of opioid misuse in these populations.

Section snippets

Effects of opioids on neurotransmission

Opioidergic neurotransmission is necessary for the biologic integrity of the human nervous system. Both opioid medication and endogenous opioids (those naturally produced by the body such as beta-endorphin and enkephalins) interact with mu, kappa and delta opioid receptor-proteins on neuronal membranes widely distributed throughout the cerebral cortex, thalamus, hypothalamus, periaqueductal grey, interpeduncular median raphe nuclei, and spinal cord (Arvidsson et al., 1995, Lewis et al., 1983,

Neurophysiology of pain

Pain is a complex, biopsychosocial experience that arises from the interaction between sensory, cognitive, and affective factors. Acute pain is most often induced by noxious stimulation, tissue damage, and/or disease and is a beneficial process that helps to preserve the morphological integrity of the organism by motivating adaptive behavior. Acute pain is associated with activation in a widely distributed network of highly connected brain regions including primary and secondary somatosensory

The neurobiological progression from opioid use to dependence

Opioid therapy for chronic pain often provides effective analgesia but confers significant risk for the development of opioid use disorders in a subset of vulnerable individuals (Denisco et al., 2008, Passik, 2009), as described earlier in the introduction of this paper. Prolonged, medically appropriate opioid use produces physical dependence symptoms via neuroadaptations resulting in tolerance to opioids, withdrawal when opioids are discontinued, and, in some instances, opioid-induced

Emotional modulation of pain

The aversive nature of pain elicits a powerful emotional reaction that feeds back to modulate pain perception. Pain is often accompanied by feelings of anger, sadness and fear depending on how the pain is cognitively appraised. Persistent negative evaluations of noxious sensory events can lead to pain catastrophizing, where the individual interprets uncomfortable or even innocuous somatic sensations as indicating the presence of a serious or mortal threat and consequently underestimate their

Clinical implications

In light of the complex, insidious processes outlined in this paper, multimodal interventions are needed to target the manifold links in the risk chain between chronic pain and prescription opioid addiction. Novel therapies that can facilitate attentional regulation of opioid cue-reactivity and enhance positive emotion while ameliorating pain may be efficacious means of addressing this pernicious and prevalent social problem. In that regard, mindfulness-based therapies, which are held to

Conclusion

In summary, we theorize that the problem of co-occurring chronic pain and opioid addiction involves a cycle of behavioral escalation where nociception and stress trigger hypervigilance and catastrophizing, amplifying pain and provoking recurrent self-medication with opioids, which in turn biases attention towards opioid-related cues that come to elicit the habit of drug use despite ever diminishing analgesia. Uncontrolled use of opioids coupled with chronic pain dysregulates reward processing

Acknowledgements

This work was supported by grant DA032517, as well as a grant from the Fahs Beck Fund for Research and Experimentation, both awarded to E.L.G. The authors wish to acknowledge Dr. Norman Farb for providing the unlabeled shape used to generate the downward spiral model in Fig. 1.

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