skip to main content


Title: Cues conditioned to withdrawal and negative reinforcement: Neglected but key motivational elements driving opioid addiction
Opioid use disorder (OUD) is a debilitating disorder that affects millions of people. Neutral cues can acquire motivational properties when paired with the positive emotional effects of drug intoxication to stimulate relapse. However, much less research has been devoted to cues that become conditioned to the aversive effects of opioid withdrawal. We argue that environmental stimuli promote motivation for opioids when cues are paired with withdrawal (conditioned withdrawal) and generate opioid consumption to terminate conditioned withdrawal (conditioned negative reinforcement). We review evidence that cues associated with pain drive opioid consumption, as patients with chronic pain may misuse opioids to escape physical and emotional pain. We highlight sex differences in withdrawal-induced stress reactivity and withdrawal cue processing and discuss neurocircuitry that may underlie withdrawal cue processing in dependent individuals. These studies highlight the importance of studying cues associated with withdrawal in dependent individuals and point to areas for exploration in OUD research.  more » « less
Award ID(s):
1922598
NSF-PAR ID:
10293696
Author(s) / Creator(s):
; ; ; ; ;
Date Published:
Journal Name:
Science Advances
Volume:
7
Issue:
15
ISSN:
2375-2548
Page Range / eLocation ID:
eabf0364
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Abstract Objective

    To determine whether the introduction of prescription drug coverage under Medicare Part D increased opioid prescriptions, patient care‐seeking for pain, and pain diagnoses among elderly Medicare‐eligible adults.

    Study Setting

    Office visits by adults aged 18 years or older from the 2000‐2016 National Ambulatory Medical Care Survey (12 375 207 253 office visits), and respondents from the 2000‐2017 Medical Expenditure Panel Survey (4 023 418 681 individuals).

    Study Design

    We compared care‐seeking for pain, provider‐assigned pain diagnoses, and opioid prescriptions before and after the Medicare eligibility age of 65, and before and after Part D's implementation using a regression discontinuity, difference‐in‐differences design. Analyses were adjusted for age, sex, race, and year.

    Principal Findings

    Patient care‐seeking for pain increased by 11.4 office visits per 100 people (95% confidence interval 2.0‐20.8), or 29%, in response to the implementation of Part D. Opioid prescriptions and diagnoses of pain‐related conditions did not change significantly, but the financing of opioid prescriptions shifted from private to public payers at age 65.

    Conclusions

    The introduction of Medicare Part D was not associated with increased opioid use among older adults. Rather, opioid use among the elderly has been driven by high levels of opioid use among commercially insured adults who subsequently age into Medicare. Our findings raise the question of whether more judicious prescribing to younger adults coupled with concerted efforts to deprescribe opioids when appropriate may prevent problematic opioid use among the elderly.

     
    more » « less
  2. The survival of an organism is dependent on its ability to respond to cues in the environment. Such cues can attain control over behavior as a function of the value ascribed to them. Some individuals have an inherent tendency to attribute reward-paired cues with incentive motivational value, or incentive salience. For these individuals, termed sign-trackers, a discrete cue that precedes reward delivery becomes attractive and desirable in its own right. Prior work suggests that the behavior of sign-trackers is dopamine-dependent, and cue-elicited dopamine in the NAc is believed to encode the incentive value of reward cues. Here we exploited the temporal resolution of optogenetics to determine whether selective inhibition of ventral tegmental area (VTA) dopamine neurons during cue presentation attenuates the propensity to sign-track. Using male tyrosine hydroxylase(TH)-CreLong Evans rats, it was found that, under baseline conditions, ∼84% ofTH-Crerats tend to sign-track. Laser-induced inhibition of VTA dopamine neurons during cue presentation prevented the development of sign-tracking behavior, without affecting goal-tracking behavior. When laser inhibition was terminated, these same rats developed a sign-tracking response. Video analysis using DeepLabCutTMrevealed that, relative to rats that received laser inhibition, rats in the control group spent more time near the location of the reward cue even when it was not present and were more likely to orient toward and approach the cue during its presentation. These findings demonstrate that cue-elicited dopamine release is critical for the attribution of incentive salience to reward cues.

    SIGNIFICANCE STATEMENTActivity of dopamine neurons in the ventral tegmental area (VTA) during cue presentation is necessary for the development of a sign-tracking, but not a goal-tracking, conditioned response in a Pavlovian task. We capitalized on the temporal precision of optogenetics to pair cue presentation with inhibition of VTA dopamine neurons. A detailed behavioral analysis with DeepLabCutTMrevealed that cue-directed behaviors do not emerge without dopamine neuron activity in the VTA. Importantly, however, when optogenetic inhibition is lifted, cue-directed behaviors increase, and a sign-tracking response develops. These findings confirm the necessity of dopamine neuron activity in the VTA during cue presentation to encode the incentive value of reward cues.

     
    more » « less
  3. This paper examines network prominence in a co-prescription network as an indicator of opioid doctor shopping (i.e., fraudulent solicitation of opioids from multiple prescribers). Using longitudinal data from a large commercially insured population, we construct a network where a tie between patients is weighted by the number of shared opioid prescribers. Given prior research suggesting that doctor shopping may be a social process, we hypothesize that active doctor shoppers will occupy central structural positions in this network. We show that network prominence, operationalized using PageRank, is associated with more opioid prescriptions, higher predicted risk for dangerous morphine dosage, opioid overdose, and opioid use disorder, controlling for number of prescribers and other variables. Moreover, as a patient’s prominence increases over time, so does their risk for these outcomes, compared to their own average level of risk. Results highlight the importance of co-prescription networks in characterizing high-risk social dynamics. 
    more » « less
  4. West, Brooke (Ed.)
    Objectives An Opioid Treatment Desert is an area with limited accessibility to medication-assisted treatment and recovery facilities for Opioid Use Disorder. We explored the concept of Opioid Treatment Deserts including racial differences in potential spatial accessibility and applied it to one Midwestern urban county using high resolution spatiotemporal data. Methods We obtained individual-level data from one Emergency Medical Services (EMS) agency (Columbus Fire Department) in Franklin County, Ohio. Opioid overdose events were based on EMS runs where naloxone was administered from 1/1/2013 to 12/31/2017. Potential spatial accessibility was measured as the time (in minutes) it would take an individual, who may decide to seek treatment after an opioid overdose, to travel from where they had the overdose event, which was a proxy measure of their residential location, to the nearest opioid use disorder (OUD) treatment provider that provided medically-assisted treatment (MAT). We estimated accessibility measures overall, by race and by four types of treatment providers (any type of MAT for OUD, Buprenorphine, Methadone, or Naltrexone). Areas were classified as an Opioid Treatment Desert if the estimate travel time to treatment provider (any type of MAT for OUD) was greater than a given threshold. We performed sensitivity analysis using a range of threshold values based on multiple modes of transportation (car and public transit) and using only EMS runs to home/residential location types. Results A total of 6,929 geocoded opioid overdose events based on data from EMS agencies were used in the final analysis. Most events occurred among 26–35 years old (34%), identified as White adults (56%) and male (62%). Median travel times and interquartile range (IQR) to closest treatment provider by car and public transit was 2 minutes (IQR: 3 minutes) and 17 minutes (IQR: 17 minutes), respectively. Several neighborhoods in the study area had limited accessibility to OUD treatment facilities and were classified as Opioid Treatment Deserts. Travel time by public transit for most treatment provider types and by car for Methadone-based treatment was significantly different between individuals who were identified as Black adults and White adults based on their race. Conclusions Disparities in access to opioid treatment exist at the sub-county level in specific neighborhoods and across racial groups in Columbus, Ohio and can be quantified and visualized using local public safety data (e.g., EMS runs). Identification of Opioid Treatment Deserts can aid multiple stakeholders better plan and allocate resources for more equitable access to MAT for OUD and, therefore, reduce the burden of the opioid epidemic while making better use of real-time public safety data to address a public health epidemic that has turned into a public safety crisis. 
    more » « less
  5. Opioid addiction is a chronic, relapsing disorder associated with persistent changes in brain plasticity. Reconfiguration of neuronal connectivity may explain heightened abuse liability in individuals with a history of chronic drug exposure. To characterize network-level changes in neuronal activity induced by chronic opiate exposure, we compared FOS expression in mice that are morphine-naïve, morphine-dependent, or have undergone 4 wk of withdrawal from chronic morphine exposure, relative to saline-exposed controls. Pairwise interregional correlations in FOS expression data were used to construct network models that reveal a persistent reduction in connectivity strength following opiate dependence. Further, we demonstrate that basal gene expression patterns are predictive of changes in FOS correlation networks in the morphine-dependent state. Finally, we determine that regions of the hippocampus, striatum, and midbrain are most influential in driving transitions between opiate-naïve and opiate-dependent brain states using a control theoretic approach. This study provides a framework for predicting the influence of specific therapeutic interventions on the state of the opiate-dependent brain. 
    more » « less