Cues conditioned to withdrawal and negative reinforcement: Neglected but key motivational elements driving opioid addiction

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Science Advances  07 Apr 2021:
Vol. 7, no. 15, eabf0364
DOI: 10.1126/sciadv.abf0364


  • Fig. 1 Conditioned withdrawal cues reinstated heroin seeking after 2 weeks of abstinence and extinction.

    An odor cue that was previously paired with naloxone-precipitated heroin withdrawal reinstated lever-pressing following extinction. After 2 weeks of forced abstinence, lever-pressing was extinguished in a 1-day protocol. Rats with a history of short-access (ShA; 1 hour) and long-access (LgA; 12 hour) self-administration sessions increased their lever-pressing for the naloxone-paired (Nx) cue compared with the saline-paired (Sal) cue. The data are expressed as means ± SEM. *P < 0.05. Modified from (3), with permission.

  • Fig. 2 Greater pain sensitivity in individuals in withdrawal from heroin.

    Individuals during withdrawal from heroin exhibited a decrease in ischemic pain thresholds (withdrawal group; heightened sensitivity) in a submaximal effort tourniquet procedure compared with volunteers who were abstinent for 2.5 years (ex-users) and healthy volunteers (non-users). Participants reported when pain was first felt and when pain became intolerable, and the time (in seconds) was recorded. *P < 0.05. Modified (6), with permission.

  • Fig. 3 Women with OUD had greater opioid craving with higher stress severity.

    Ecological momentary assessment ratings of craving (1 = no craving) for opioids are shown across ratings of stress. Craving as a function of stress was greater in women than in men. P < 0.0001. Modified from (61), with permission.


  • Table 1 The presentation of cues that were conditioned to opioid withdrawal was sufficient to produce somatic and subjective signs of opioid withdrawal in men who were maintained on methadone for OUD

    UR, unconditioned response. Modified from (7), with permission.

    Skin temperatureDecreaseDecrease
    Heart rateIncreaseIncrease
    Motor responsesIncreaseIncrease
    Pupil diameterIncreaseChanges
    Subjective reactionSimulates opioid
    from UR at this dose
    (0.1 mg)
  • Table 2 Sex differences in opioid consumption and cue reactivity.

    ARSW, Adjective Rating Scale for Withdrawal; COWS, Clinical Opiate Withdrawal Scale; VAS, visual analog scale; M, male; F, female.

    SubjectsBehavioral measureSex differences
    HumanPrevalence of heroin or prescription opioid useM > F
    F > M increased rate of heroin use
    Rate of increased/decreased heroin or prescription
    opioid use across years (2007–2014)
    F < M decreased rate of prescription opioid
    use (12)
    Human; heroin-dependent, in-patient settingSelf-reported craving and physiological measures
    after viewing: heroin-related imagery
    F > M self-reported cravings and sadness, systolic
    blood pressure, heart rate
    Heroin paraphernaliaF > M diastolic blood pressure, self-reported
    decreased joy
    M > F self-reported anger (14)
    Human; opioid-dependent, buprenorphine
    tapering clinical trial
    Self- and clinician-reported withdrawal symptoms
    (ARSW, COWS) and craving (VAS)
    F > M withdrawal symptoms (ARSW, COWS) and
    subjective craving (VAS) (15)
    Human; healthy volunteersSelf-reported drug effects questionnaire after
    intramuscular morphine administration
    M > F self-reported positives effects and drug
    F > M self-reported negative subjective effects (72)
    Human; opioid-dependent, methadone- or
    Self-reported craving and mood using ecological
    momentary assessment
    F > M self-reported craving for opioids as a
    function of stress severity
    F > M self-reported craving for opioids in presence
    of stress and cues (73)
    Human; opioid-dependent, morphine-stabilized, in
    opioid tapering clinical trial
    COWS and self-reported withdrawal ratings after
    intramuscular naloxone injection
    More F in high withdrawal phenotype than low
    M = F in naloxone-precipitated withdrawal
    scores (78)
    Mouse; 1 or 6 hours for intravenous heroinSelf-administrationF > M self-administered heroin
    Somatic signs of withdrawalF = M somatic withdrawal signs (22)
    Mouse; 1 or 12 hours for fentanyl vaporFentanyl intake during transition from short
    (1 hour) to long (12 hours) access
    F > M intake in the first three sessions
    Escalation across 10 days of 12-hour accessM > F change in intake (escalation slope)
    across days
    Naloxone-precipitated withdrawalF > M somatic signs of withdrawal (23)
    Rat; 6-hour session for intravenous heroinDays to acquisition criteriaF > M rate of acquisition (faster to acquire)
    Infusions per sessionF = M total intake during acquisition (83)
    Rat; 4-hour sessions for intravenous heroinInfusions per sessionF > M infusions at 1.25 or 3.75 μg per infusion
    F = M infusions at 15–30 μg per infusion (84)
    Rat; 1-hour session for oral oxycodoneIntake across dosesF > M mg/kg intake at 1.0 mg/ml
    Naloxone-precipitated intakeF > M intake after naloxone injection
    Progressive ratioF = M breakpoint
    Stress-primed reinstatementF = M active lever presses (85)
    Rat; 2-hour session for intravenous fentanylIntake across dosesF > M infusions at 0.32–1 μg/kg dose
    Motivation (demand curve)F > M demand/essential value at 10 μg/kg per
    infusion (not 3.2 μg/kg per infusion)
    F = M baseline consumption (87)
    Rat; 6-hour session for intravenous oxycodoneBuprenorphine effect on reinstatementBuprenorphine reduced reinstatement in F but
    not in M
    Buprenorphine effect on reacquisition of
    Buprenorphine reduced reacquisition in F
    and M (89)
    Rat; 6-hour session for intravenous heroinIncubation of heroin craving after forced
    F and M incubated craving (increased responding)
    between abstinence days 1 and 21
    No incubation of craving between abstinence
    days 1 and 21 in F or M (88)
    Mouse; 3-hour session for oral oxycodoneIntake across dosesF > M mg/kg intake at the 0.30–1 mg/kg dose
    Cue-induced reinstatementF = M (86)

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