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Psychopharmacology (Berl). 2014 August ; 231(16): 3229–3238. doi:10.1007/s00213-014-3504-7.

Effects of Mindfulness-Oriented Recovery Enhancement on

Reward Responsiveness and Opioid Cue-Reactivity
Eric L. Garland, PhD,
Huntsman Cancer Institute

Brett Froeliger, PhD, and

Medical University of South Carolina

Matthew O. Howard, PhD

University of North Carolina at Chapel Hill

Abstract
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Rationale—Dysregulated reward processing is a hallmark feature of drug addiction; however

scant research has evaluated restructuring reward processing in the context of addiction treatment.

Objectives—We examined effects of Mindfulness-Oriented Recovery Enhancement (MORE) on

reward responsiveness (RR) and opioid cue-reactivity in a sample of chronic pain patients with
opioid use problems. We previously reported that MORE decreased pain, opioid misuse and
craving relative to a social support control group (SG). Here we examined whether these outcomes
were linked to changes in RR in a subset of participants.

Methods—Participants were chronic pain patients (71% women, age = 46.6±13.9) who received
MORE (n=20) or SG (n=29). RR was measured before and after 8 weeks of treatment via heart
rate (HR) and heart rate variability (HRV) responses during a dot-probe task that included opioid-,
pain-related and natural reward stimuli, as well as craving ratings.

Results—The MORE group, who reported decreased opioid misuse and opioid craving during
treatment, evidenced less subjective opioid cue-reactivity, greater HR decelerations, and greater
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increases in HRV to all cues after treatment compared to the SG; HR and HRV effects were most
pronounced for natural reward cues. Within the MORE group, HR deceleration to natural reward
cues was correlated with increased subjective arousal to the cues, whereas HR deceleration to
opioid cues was correlated with decreased subjective arousal. Effects of MORE on craving were
mediated by enhanced RR.

Conclusions—Results suggest that during treatment with MORE, cardiac-autonomic

responsiveness to non-drug reward increases, while reactivity to opioid reward decreases. Studies
are needed to discern whether changes in RR were a result or a determinant of reductions in opioid
misuse and craving. RR may play a role in addiction treatment.

Corresponding author: Eric L. Garland, 395 South, 1500 East, University of Utah, Salt Lake City, UT 84112, [email protected].
Conflict of Interest: None
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Keywords
mindfulness; chronic pain; opioid misuse; addiction; reward; heart rate variability; attentional bias;
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positive affect; allostasis; cue-reactivity

Introduction
Reward responsiveness to salutary objects and events is fundamental for flexible adaptation
to changing environmental contexts. The perceived reward value of such stimuli, encoded in
dopaminergic activations of mesocorticolimbic brain circuits, motivates approach behaviors
which preserve the physical and psychological well-being of the individual. However, the
processing of natural rewards may be usurped by psychoactive drugs which capitalize on the
mesocorticolimbic dopamine system to drive addictive behavior (Volkow et al. 2004).
Theory suggests that addiction occurs when motivation to obtain natural rewards is re-
organized around seeking drug-induced reward and the desire to alleviate dysphoria induced
by withdrawal and aversive experiences (e.g., stress and pain) (Alcaro and Panksepp 2011).
Due to dysregulation of neural circuitry subserving stress and reward, individuals with
substance use disorders may become insensitive to natural reward from healthful and
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socially affiliative stimuli, while becoming dependent on drugs to preserve a sense of well-
being (Koob and Le Moal 2008). Thus, the neurobiological effects of chronic drug use may
foster impulsive selection of immediate, drug-induced reward over both delayed and
immediate non-drug rewards (de Wit 2009).

Research with animals and humans links drug addiction-related changes in dopamine
transmission to altered reward function across multiple drugs of abuse including cocaine,
methamphetamine, nicotine, alcohol, and opioids (Heinz et al. 2004; Kalivas and Volkow
2005; Lee et al. 2009; Lintas et al. 2012; Gipson et al. 2013). Further, compared to healthy
controls, drug-dependent individuals exhibit significantly less reward responsiveness and
attenuated brain response to natural rewards (Volkow et al. 2010; Augustus Diggs et al.
2013). Decreased responsiveness to images depicting immediate natural rewards as
indicated by cue-elicited event-related brain potentials has been observed among opiate
dependent individuals and is robustly predictive of future opiate consumption (Lubman et al.
2007, 2008, 2009).
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Dyregulated reward responsiveness may link chronic pain with the development of opioid
misuse and addiction (Garland et al. 2013a). Chronic pain coupled with opioid dose
escalation results in neuroadaptations to limbic-striatal circuits in the brain, resulting in
increased sensitivity to pain and decreased reward derived from healthful objects and events.
The motivation to allay the resultant dysphoria manifests as craving, an attentional bias
(AB) towards opioid-related cues (Garland et al. 2012b), and ultimately, compulsive opioid
use. This conceptual model yields the following prediction: if dysregulated reward
processing links chronic pain to opioid misuse, then restructuring reward responsiveness
may be a means of ameliorating this pathogenic process. Thus, treatments that target reward
processing are needed. Cognitive training regimens centered on restoring sensitivity to

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naturally rewarding stimuli may increase reward responsiveness and counter processes at the
heart of addictive behavior.
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We recently conducted an early-stage randomized controlled trial (RCT) of Mindfulness-

Oriented Recovery Enhancement (MORE) (Garland et al., 2010; 2014), a new multimodal
intervention designed to address chronic pain, craving, and opioid misuse behaviors, which
integrates training in savoring natural rewards with training in mindfulness (Kabat-Zinn
1982) and cognitive reappraisal (Kober et al. 2011) techniques. In this RCT, MORE
significantly decreased pain severity and functional impairment, as well as opioid craving
and opioid misuse (Garland et al. 2014). While the mindfulness and cognitive reappraisal
components of this intervention may be useful for reducing chronic pain and negative affect
(Rosenzweig et al. 2010; Ochsner & Gross, 2005), training in savoring, i.e., intentionally
focusing attention on pleasant events, may help to increase responsiveness to non-drug
rewards (Garland et al. 2010; Geschwind et al. 2011), thus reducing appetitive drive for
opioids.

The primary aim of the current study was to examine psychophysiological data to explore
the effects of MORE on reward responsiveness and opioid cue-reactivity in a sample of
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opioid (mis)using chronic pain patients. We examined whether the observed decreases in
opioid craving and misuse following MORE were linked with changes in responsiveness to
cues representing opioids and non-drug rewards. We used a biological marker, heart rate
(HR), to index reward responsiveness. While overall HR reflects summation of
parasympathetic and sympathetic influences, heart rate variability (HRV) in the high
frequency range reflects parasympathetic control of the heart (Berntson et al. 1997) and is
thought to index integrative activity in a network of central (e.g., prefrontal and cingulate
cortices) and autonomic nervous system structures (e.g., vagus nerve) involved in cognitive
control over attention, emotion, and reward responses (Thayer et al. 2009; Garland et al.
2012a). Thus, to probe whether cue-elicited cardiac responses were driven by
parasympathetic modulation of the central-autonomic network during reward processing, in
the present study we examined high frequency HRV in addition to HR.

Because parasympathetic influences on the myocardium tend to decrease HR, we

hypothesized that (a) compared to participation in a support group (SG), participation in
MORE would be associated with enhanced reward responsiveness as indicated by greater
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decreases in HR and increases in HRV during emotional attention to cues representing

natural rewards. We also hypothesized that (b) such reward responsiveness would be
associated with opioid craving. Lastly, we hypothesized that (c) enhanced responsiveness to
natural rewards would statistically mediate the effects of MORE on opioid craving.

Materials and Methods

Participants and Procedure
The current study examined data from a subset of individuals (14 men and 35 women, mean
age = 46.6, SD = 13.9) from a previously published study of MORE vs a SG for chronic
pain and prescription opioid misuse (Garland et al. 2014). Individuals who had complete HR
data (MORE n = 20; SG n = 29) from a psychophysiological assessment conducted one

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week before, and one week after, the 8-week treatments were selected for the present study.
Participants were recruited from primary care, pain, and neurology clinics, and met study
inclusion criteria if they reported recurrent pain on more days than not stemming from
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chronic non-cancer-related pain conditions and had taken opioids analgesics daily or nearly
every day for at least the past 90 days (Chou et al. 2009). At each assessment point,
participants completed self-report measures of generalized opioid craving, opioid misuse,
and opioid-related pain relief, and then participated in a lab protocol which involved
measurement of HR during completion of a dot probe task. The protocol was approved by
the Florida State University IRB, and all procedures complied with the standards set forth in
the Helsinki Declaration of 1975. Participants were assessed for comorbid psychiatric
disorders with the Mini-International Neuropsychiatric Interview 6.0 (MINI) (Sheehan et al.
1998) and excluded if they were suicidal or psychotic. There were no significant between-
groups differences in clinical characteristics (see Table 1). Although all participants reported
symptoms of physiological dependence (i.e., tolerance and withdrawal) on the MINI
resulting from regular and prolonged use of opioids, a smaller percentage (28.6%) met
opioid use disorder criteria. However, most (87.5%) participants reported opioid analgesic
misuse as defined by a validated cut-point on the Current Opioid Misuse Measure (COMM;
Butler et al. 2007). Participants were paid $200 for the study.
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Self-Report Measures
A single item “How much do you want your opioids right now?” anchored on a 10-point
scale (1 = not at all, 10 = extremely) assessed current generalized opioid craving once during
the assessment session in the week prior to intervention and once during the assessment
session in the week following intervention. Participants were asked to rate their pain “right
now” from 0 to 10 scale and their degree of opioid-induced pain relief on a 0 – 100% scale
with two question items drawn from the Brief Pain Inventory (BPI; Cleeland 1994) once at
the beginning of each pre- and post-treatment laboratory assessment session.

Dot Probe Task

HRV was measured during a dot probe task (E-Prime: PST Inc., Pittsburgh, PA). Each trial
began with a fixation cross (i.e., crosshair) presented for 500 ms. Next, two images matched
for visual complexity, composition, and figure-ground relationships appeared side by side on
the computer screen for either 200 or 2000ms. Pairs of photos containing one emotionally-
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salient image and one neutral image were presented. Three blocks of cues (opioid-related,
pain-related, and pleasure-related) were presented in randomized, counterbalanced order
across participants. A set of 12 photographs representing each type of cue were selected
from the International Affective Picture System (IAPS) (Lang et al. 1997a) and media
libraries on the Internet. For instance, opioid-related cues included images of pills and pill
bottles. Pain-related cues included images of severe injuries, painful medical procedures,
and human faces grimacing in pain. Pleasure-related cues included images of babies,
beautiful landscapes, and romantic couples. A set of 36 neutral images were selected from
the IAPS and each was paired with an emotionally-salient image that matched the photos for
visual features such as color, figure-ground relationships, and presence of human faces.
Presentation duration and left/right position of the images was randomized and
counterbalanced within each block of 64 trials. Both pictures disappeared, and a target probe

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replaced one of the images after a 50 ms inter-stimulus interval. Probes appeared for 100 ms,
and probe location was counterbalanced. Participants indicated the location of the target by
responding with a button press, and the reaction time was recorded (presented here as
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Supplementary Material). Subjective opioid cue-reactivity relative to pre-stimulus baseline

was assessed immediately after the opioid cue block on the dot probe task with a single
question “How much do you want your opioids right now?” anchored on a 10-point scale (1
= not at all, 10 = extremely). Participants rated the arousal elicited by the opioid-, pain-, and
pleasure-related images on a 10-point scale (Lang et al. 1997) .

HRV Measurement
Disposable Ag-AgCl electrodes were attached to participants' right and left pectoral
muscles. Electrocardiogram (ECG) data were sampled at 1000 Hz and recorded
continuously throughout the protocol on a Biopac MP150 (Biopac Systems, Goleta, CA).
Next, participants were instructed to remain motionless and silent for a 5-minute baseline,
after which they participated in the dot probe task. R-R intervals were detected in the ECG
using automated routines in Acqknowledge 4.1 (BIOPAC, Inc.) and then visually inspected
to correct artifacts.
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Study interventions
The manualized MORE intervention (Garland 2013) involved group training in mindfulness,
cognitive reappraisal, and savoring skills integrated into a manualized 8-session group
intervention designed to address pathogenic factors involved in chronic pain and
prescription opioid misuse. Sessions were 2 hours in length, and administered by a Masters-
level social worker who had practiced mindfulness for over a decade and had clinical
experience delivering mindfulness training to persons with psychiatric disorders. This
clinician was supervised by the developer of MORE (an experienced, licensed
psychotherapist). The first author reviewed video/audio-recordings of the sessions to
monitor therapist adherence to the MORE treatment manual. MORE participants were asked
to engage in daily 15 minute mindfulness practice sessions at home guided by a CD.
Germane to the present study, participants were taught a savoring practice, which involved
using mindfulness to intentionally orient and sustain attention on the sensory features
(visual, auditory, olfactory, kinesthetic, proprioceptive) of a pleasant experience or object
(e.g., a beautiful nature scene like a sunset) while attending to and appreciating any positive
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emotions arising in response to the pleasant event. For example, in a 20-minute long
meditation session, participants were instructed to mindfully attend to the colors, textures,
and scents of a bouquet of fresh flowers, and to absorb and appreciate the emotions of
contentment and joy arising from this savoring practice. Similar savoring techniques using
different sensory targets were discussed across multiple treatment sessions and given as
homework practice. The active control condition in this study consisted of 8 weekly, 2-hour
support group sessions, in which a Master's-level clinical social worker (different from the
MORE facilitator) facilitated discussion and disclosure of emotions on topics pertinent to
chronic pain and long-term opioid use. This support group format was based on the
evidence-based Matrix Model intensive outpatient treatment manual (Rawson and McCann
2006). The first author reviewed video/audio-recordings of the sessions to monitor therapist

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adherence to the support group treatment manual. Support group participants were asked to
engage in 15 minutes of journaling a day on chronic pain-related themes at home.
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Statistical Analysis
With regard to the analysis of HR, Kubios 2.0 (Biosignal Analysis and Medical Imaging
Group, University of Finland) was used to calculate beats-per-minute (BPM) and for
spectral analysis of HR, applying a fast Fourier transform to extract normalized high
frequency HRV from a de-trended, end-tapered interbeat interval time series. HRV in the
respiratory frequency band (0.15 – 0.40 Hz) was selected as our estimate of vagally-
mediated HRV. HR and HRV indices were averaged across the 5-minute baseline and each
of the dot probe cue conditions. HRV data were skewed and log-transformed for subsequent
analyses.

For hypothesis testing, we used the following multistage analytic approach. First, we
conducted repeated-measures ANOVA (RM-ANOVA) to test whether MORE led to greater
reductions in subjective opioid cue-reactivity than the SG. Second, we conducted a RM-
ANOVA to examine whether participants in MORE and SG significantly differed on pre-
and post-treatment HR values at rest and during each of the dot probe cue conditions. We
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were particularly interested in HR cue responsiveness; that is, the planned contrast between
cue-elicited levels of HR and resting state HR. Third, we computed Pearson correlations to
examine associations between: HR responses to opioid, pain, and pleasure cues; stimulus
arousal ratings; current pain; and opioid craving. Fourth, we conducted a series of path
analyses to examine natural reward responsiveness (as indexed by HR responsiveness to
pleasure cues) as a potential mediator of the effects of MORE on reductions in opioid
craving, while simultaneously testing for alternative mediational pathways. Changes in HR
responsiveness to opioid cues and changes in opioid-induced pain relief might also mediate
the effects of MORE on opioid craving. To simultaneously test these alternative hypotheses,
all three potential mediators were included in a multivariate path model predicting change in
generalized opioid craving and controlling for confounding by baseline opioid use disorder
status. We conducted a sensitivity analysis on an additional path model that controlled for
changes in opioid misuse as measured by the COMM and changes in current pain levels on
the BPI. The Sobel test assessed the significance of indirect effects (Baron and Kenny
1986). Adequacy of model fit was determined via fit indices (Kline 1998), including a χ2/df
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ratio of between 1 and 3 (Carmines and McIver 1981), comparative fit index (CFI) > .90 and
the root-mean square error of approximation (RMSEA) ≤ 0.08 (Browne and Cudeck 1993).
Fifth, we conducted a path analysis with the same mediators listed above to examine effects
of reward responsiveness on subjective opioid cue-reactivity. Finally, to determine the
autonomic source of the observed cue-elicited changes in HR, we conducted a RM-
ANCOVA to examine whether MORE and SG participants differed on post-treatment HRV
cue responses from resting state levels of HRV, controlling for pre-treatment resting HRV.

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Results
Effects of MORE on Subjective Opioid Cue-Reactivity
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MORE led to significantly greater pre-post intervention reductions in subjective opioid cue-
reactivity on the dot probe task (M = -.68, SE = .45) than the SG (M = .84, SE = .48),
F(1,43) = 4.98, p = .03, η2partial = .11.

Effects of MORE on HR Responses During Attention to Emotional Information

RM-ANOVA was conducted on mean HR values (see Table 2) with treatment group,
condition (rest, opioid, pain, and pleasure cue), and time (pre- and post-treatment) as factors.
While neither the main effect of time nor condition were significant, there was a significant
group X time effect, F(1,46) = 4.47, p = .04, η2partial = .09, indicating that, on average, the
MORE group experienced significantly greater reductions in HR from pre-post treatment
(see Figure 1). There was a significant group X time X condition effect, F(1,46) = 5.20, p = .
005, η2partial = .10. Planned comparisons revealed that relative to participants in the SG,
participants in the MORE intervention exhibited significantly greater pre-post changes in
HR response (i.e., deceleration) during attention to pleasure, F(1,46) = 9.80, p = .003,
η2partial = .18, opioid , F(1,46) = 9.25, p = .004, η2partial = .17, and pain cues, F(1,46) = 6.42,
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p = .02, η2partial = .12. Importantly, there was no significant change in resting state HR,
indicating that the effects of MORE on HR were specific to attention to emotional
information and not due to a generalized relaxation response.

Zero-order correlations
Within the MORE group, HR decelerations to pleasure cues were significantly correlated
with increased arousal ratings for such cues, r = -.51, p = .04. In contrast, within the MORE
group, HR decelerations to opioid and pain cues were significantly correlated with decreased
arousal ratings for such cues, r = .52, p = .038, and r = .50, p < .05, respectively. Stimulus
arousal and HR responses were uncorrelated in the SG. Across both groups at pre- and post-
treatment, current pain levels were not significantly correlated with resting HR, nor were
they significantly correlated with cue-elicited HR. In contrast, across both treatment groups,
individuals who exhibited larger decreases in HR to pleasure cues experienced greater
reductions in opioid craving over the course of treatment, r = -.34, p = .02.
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Test of Enhanced Reward Responsiveness as a Mediator

To test our third hypothesis: that the effects of MORE on opioid craving would be
statistically mediated by enhanced natural reward processing, formal mediation analyses
were appropriate. Our multivariate path model predicting change in generalized opioid
craving (see Figure 2) exhibited excellent fit, χ 2/df = .92; CFI = 1.00; RMSEA = .00 (.00, .
13), R2 = .26. According to the Sobel test, the indirect effect of MORE on reducing opioid
craving by enhancing physiological (HR) responsiveness to pleasure cues was statistically
significant, z = 2.43, p = .015. Thus, we found that increased reward responsiveness as
indicated by HR significantly mediated the effect of MORE on opioid craving. In contrast,
neither HR responses to opioid cues nor changes in pain relief over the course of treatment
were significant mediators of the craving-reducing effects of MORE. In alternate path

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models, including indirect paths to HR responses to pain cues, change in current pain levels,
and change in self-reported opioid misuse on the COMM did not change the valence or
significance of the direct and indirect effects above, but did significantly worsen model fit,
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so these variables were omitted in the final models. The supplementary multivariate path
model predicting change in subjective opioid cue-reactivity also exhibited good fit, χ2/df = .
90; CFI = 1.00; RMSEA = .00 (.00, .11), R2 = .81; however, the indirect effect of MORE on
subjective opioid cue-reactivity by enhancing physiological (HR) responsiveness to pleasure
cues was not statistically significant.

Between-Groups Differences in HRV During Attention to Emotional Information

To determine the source of the HR decelerations observed at post-treatment, RM-ANCOVA
was conducted on post-treatment HRV values with treatment group and condition as factors,
and pre-treatment resting state HRV as a covariate. The group X condition interaction was
significant, F(1,49) = 4.31, p = .04, η2partial = .09; planned Helmert contrasts indicated that
across all cue conditions, participants in MORE experienced significantly greater increases
in HRV from rest than the SG participants. Post-hoc tests revealed that this effect was
largely driven by natural reward responsiveness; participants in MORE exhibited
significantly greater increases in HRV from rest during emotional attention to pleasure cues,
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F(1,49) = 5.28, p = .026, η2partial = .10, but did not differ significantly with regard to HRV
response to opioid or pain cues.

Discussion
Study findings indicate that MORE reduces opioid cue-reactivity and enhances natural
reward processing. These results provide preliminary support for the hypothesis that
therapeutic enhancement of reward responsiveness is linked with reduced opioid craving in
a drug-dependent sample, though causal directionality of this relation cannot be conclusively
established with the present data. The current study has implications for understanding of
the role of allostatic dysregulation of natural reward in addiction treatment (Koob and
LeMoal 2001).

The allostatic model posits that prolonged exposure to drugs and stressful experiences
results in an upward shift in basal reward threshold, leading to a reward deficit and
dysphoric mood which encourages increased consumption of drugs as a means of achieving
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an overall positive affective balance. Ironically, this attempt to reach a positive affective
state comes with a cost: the continued use of drugs further increases brain reward thresholds,
making the individual increasingly insensitive to naturally-rewarding experiences while
becoming increasingly sensitive to stress and pain (Koob and Le Moal 2001). Thus,
addiction results in progressive deviation of brain reward systems from their normal
homeostatic operating level that fuels increasing dependence on drugs as a means of
maintaining dwindling positive affect (Koob and LeMoal 2008). In the case of chronic pain
patients who are dependent on prescription opioid analgesics, recurrent episodes of pain may
result in stress and negative affect, which when prolonged, dysregulates mesocorticolimbic-
striatal reward circuitry and promotes addictive behaviors (Garland et al. 2013a). While

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evidence exists to support this theory, there is a dearth of data regarding whether this
allostatic process can be reversed by restoring reward processing.
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In the present study, we observed a significant association between mindfulness-based

enhancement of natural reward processing and reduction in opioid craving; formal mediation
analysis indicated that the effects of MORE on opioid craving were statistically mediated by
increased reward responsiveness. One interpretation of these findings suggests that allostatic
processes in addiction may be countered by a behavioral intervention designed to enhance
savoring of natural rewards. Alternatively, changes in opioid misuse as a result of behavioral
treatment may result in reduced opioid craving and increased responsiveness to natural
reward. Due to the fact that HR data was only collected pre- and post-treatment in the
present study, there is no way to conclusively determine whether changes in reward
responsiveness led to decreased opioid misuse and craving or whether changes in opioid use
and craving caused changes in reward responsiveness. Indeed, if chronic exposure to opioids
blunts responsiveness to non-drug rewards via opioidergic-dopaminergic interactions, then
reduction in opioid dose as a result of treatment may have led to the restoration of reward
responsiveness observed in the present sample. Although path analysis indicated the
presence of a statistically significant indirect effect of MORE on opioid craving through
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enhanced responsiveness to natural reward, due to study design limitations, the causal order
of these effects cannot be disentangled.

In contrast to the observed mediational relationship between reward responsiveness and

generalized opioid craving, changes in HR response to pleasure cues did not mediate the
effect of MORE on subjective opioid cue-reactivity. This incongruity accords with the
observation that cue-reactivity elicited in a laboratory environment, i.e., phasic cue-specific
craving, is a distinct construct from generalized craving in everyday life, i.e., tonic craving
(Sayette and Tiffany 2012; Tiffany and Wray 2013). Further, our findings accord with a
meta-analysis of cue-reactivity in addiction research conducted by Carter and Tiffany (1999)
which showed that physiological and subjective cue responses were largely uncorrelated.
Our results suggest that although MORE reduces both general opioid craving and subjective
opioid cue-reactivity, these treatment-related reductions are mediated by different processes,
and enhanced reward responsiveness seems to be most closely linked with decreases in tonic
appetitive drive towards opioids.
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As evidence of our hypothesis that MORE enhances reward responsiveness, following

treatment we observed robust HR decelerations from resting, baseline levels during
exposure to natural reward cues. Attention to emotional cues has been shown to consistently
result in significantly greater decreases from resting, baseline HR than attention to neutral
cues (Kreibig 2011). Thus, HR decelerations indicate a robust response to emotional stimuli,
rather than a lack of response. In support of this notion, prior research indicates that highly
arousing, pleasant visual cues elicit greater HR decelerations than less arousing cues
(Bradley et al. 2001). Such decreases in HR may be coordinated by activation of the central-
autonomic network in response to emotional stimuli (Lane et al. 2009). Analyses indicated
that the HR decelerations observed in this study resulted from enhanced parasympathetic
activation (high frequency HRV). Preclinical models of appetitive conditioning indicate that
increases in HRV elicited by conditioned stimuli are associated with a reward expecting

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state (Inagaki et al. 2005). Concomitantly, cue-elicited increases in HRV are associated with
appetitive responses to food cues (Udo et al. 2013; Nederkoorn et al. 2000) and addictive
drugs such as nicotine and amphetamine (Culbertson et al. 2010; Erblich et al. 2011), and
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increases in alcohol cue-elicited HRV predicted the time-course of relapse up to six months
following alcohol treatment (Garland et al. 2012a). While increased autonomic
responsiveness to drug-related stimuli may signal heightened appetitive drive for the drug
and relapse vulnerability during a quit attempt, increased autonomic responsiveness to
healthful and socially-affiliative stimuli may buffer such risk and represent a reversal of the
usurpation of reward learning processes previously recruited by addictive drugs.

The primary limitation of this study was the lack of a quantitative measure of opioid dosing.
We were unable to obtain accurate opioid dosing data for the whole sample due to non-
responses and ambiguous responses (e.g., reporting the opioid dose without reporting
number of pills taken per day) on our self-report opioid dosing measure. Consequently, we
do not know whether enhancing reward responsiveness reduced opioid use, or whether
reduced opioid use led to the observed increases in reward responsiveness. Additional
research is needed to discern whether changes in reward responsiveness were a result or a
determinant of reductions in opioid misuse and craving. To that end, future studies should
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carefully track opioid dosing and other psychotropic medication usage via a multi-pronged
approach including self-report, prescription history, pill count, and urine and serum
toxicology screens. It should also be noted that the observed relations between stimulus
arousal and HR were inconsistent across cue types. Following treatment with MORE,
individuals who reported the greatest increases in arousal to pleasure cues experienced the
largest HR decelerations to those cues, whereas those who reported the greatest decreases in
arousal to opioid and pain cues experienced the largest HR decelerations to those cues. The
apparent paradox presented by the opposing directionality of the HR/arousal correlations for
different stimulus types may relate to the fact that parasympathetic nervous activity can be
elicited during appetitive responding (Inagaki et al. 2005), as well as during self-regulatory
effort – thereby increasing HRV and decreasing HR (Segestrom and Nes 2007). Thus, one
speculative interpretation of the discrepant findings in the current study is that MORE may
have up-regulated parasympathetic responsiveness to natural reward stimuli while enhancing
parasympathetic regulation of arousal elicited by opioid and pain cues. With regard to this
latter point, MORE significantly modulated opioid cue-reactivity, as evidenced by decreased
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HR responses to opioid cues and phasic cue-specific opioid craving. To further resolve this
discrepancy and elucidate the neural mechanisms underlying changes in reward
responsiveness, future studies should employ neuroimaging paradigms designed to probe
reward processing.

These limitations notwithstanding, this study provides support for a recently proposed
theoretical model of the neurocognitive mechanisms of mindfulness-based treatment of
addiction (Garland et al. 2013c), and may have important clinical implications. Because
addiction biases selection toward immediate drug-induced reward over non-drug reward,
enhancing responses to immediate non-drug rewards may be a therapeutically crucial step
towards restoring the valuation of delayed non-drug rewards so important to addiction
recovery, such as preservation of physical or social function. More research is needed to
determine whether learning to savor the immediate and momentary sensory pleasure

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inherent in healthful objects and experiences can provide the motivation necessary to sustain
addiction recovery (Davidson and White 2007).
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In sum, the current study suggests that MORE can reduce opioid cue-reactivity while
restructuring natural reward processing, and provides preliminary support for the hypothesis
that behavioral interventions may ameliorate craving by enhancing reward responsiveness. If
neural reward circuits provide a basic logic for goal selection (Shizgal and Hyman 2013),
training in selective attentive processing of natural rewards over drug rewards may provide
the learning signal necessary to undo addiction and switch reward processing back toward
its intrinsic valuation of adaptive and pro-regulatory objects and behaviors.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Acknowledgments
This work was supported by grant numbers DA032517 and DA037005 from the National Institutes of Health
awarded to E.L.G.; and a grant from the Fahs Beck Fund for Research and Experimentation, also awarded to E.L.G.
NIH-PA Author Manuscript

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Fig.1.
Effects of Mindfulness-Oriented Recovery Enhancement (MORE) and Support Group (SG)
interventions on changes in heart rate (HR) from pre- to post-treatment during a 5-minute
resting baseline and during three blocks of cues on a dot probe task. The HR change score
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value on the Y-axis was calculated by subtracting pre-treatment HR during each of the four
conditions of the task (resting baseline, opioid cue, pain cue, and pleasure cue) from post-
treatment HR during each of the four conditions of the task, such that a negative value
indicates a decrease in HR at post-treatment from pre-treatment levels. Relative to the SG,
the MORE group evidenced significantly greater pre-post treatment decreases in HR to all
three cue types; however, there was no significant pre-post treatment change in HR during
the resting baseline. Group X time X condition effect, F(1,46) = 5.20, p = .005, η2partial = .
10. BPM = beats per minute.
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Fig. 2.
Multivariate path model (N = 49) depicting statistical mediation of the craving-reducing
effects of Mindfulness-Oriented Recovery Enhancement by heart rate responsiveness to
pleasure cues. This model controls for pre-randomization group differences in opioid use
disorder status (not depicted for visual parsimony). *p < 0.05
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Table 1

Baseline demographic and clinical characteristics of prescription opioid using chronic pain patients, by
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treatment group (N = 49).

Measure MORE (n = 20) Support Group (n = 49)

Female, N (%) 15 (75%) 20 (69%)
Age 46.0 ± 13.6 46.9 ± 14.4
Primary pain condition, N (%)
Low back pain 10 (50%) 18 (62%)
Fibromyalgia 5 (25%) 7 (24%)
Arthritis 0 (0%) 1 (3%)
Cervicalgia 1 (5%) 2 (7%)
Other 4 (20%) 1 (3%)
Opioid use disorder dx, N (%) 4 (20%) 10 (35%)
Opioid misuse (COMM), N (%) 18 (90%) 24 (83%)
Comorbid psychiatric dx, N (%)
Major depressive disorder 8 (40%) 18 (62%)
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Generalized anxiety disorder 5 (29%) 9 (38%)

Post-traumatic stress disorder 1 (5%) 3 (10%)
Substance use disorder (non-opioid) 4 (20%) 1 (3%)
Alcohol use disorder 4 (20%) 4 (14%)

Note. There were no significant between-groups differences on any of these variables on t-tests and chi-square tests. MORE = Mindfulness-
Oriented Recovery Enhancement; SG = Support Group. COMM = Current Opioid Misuse Measure (Butler et al., 2007)
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Table 2

HR and stimulus arousal responses during each of three cue conditions and at rest (baseline) on a dot probe task as evidenced by patients participating in
Mindfulness-Oriented Recovery Enhancement (MORE, n = 20) or a Support Group (SG, n = 29) treatment for chronic pain and opioid misuse.
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Pre-Treatment Post-Treatment

Baseline Opioid Cue Pain Cue Pleasure Cue Baseline Opioid Cue Pain Cue Pleasure Cue
Heart Rate
MORE 76.31 (18.48) 79.81 (19.81) 79.50 (19.63) 79.45 (18.87) 75.58 (10.58) 72.81 (12.61) 72.30 (13.69) 69.87 (18.64)
SG 79.00 (13.02) 77.64 (14.76) 77.20 (14.84) 77.85 (13.85) 81.74 (14.31) 82.30 (12.93) 81.07 (13.42) 82.58 (13.54)
Arousal
MORE --- 4.76 (1.59) 5.16 (1.53) 4.90 (1.38) --- 4.79 (1.13) 5.81 (1.34) 5.20 (0.79)
SG --- 4.34 (2.10) 5.21 (1.99) 4.33 (1.72) --- 4.37 (1.85) 5.52 (2.11) 4.22 (1.29)

Note: MORE = Mindfulness-Oriented Recovery Enhancement. SG = Support Group. HR = Heart Rate (in beats per minute). Stimulus arousal was rated on a 10-point Likert-type scale, with higher scores
indicating greater arousal. No resting state arousal ratings were obtained.

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