Reward Deficiency and Anti-Reward in Pain Chronification

Neuroscience and Biobehavioral Reviews 68 (2016) 282–297

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Review article

Reward deﬁciency and anti-reward in pain chroniﬁcation

a,b,c,f,∗ a,b,f a,b,d,f e,f a,b,c,f

D. Borsook , C. Linnman , V. Faria , A.M. Strassman , L. Becerra , g

I. Elman

Center for Pain and the Brain, Boston Children’s Hospital and Massachusetts General Hospitals, USA

Department of Anesthesia, Critical Care and Pain Medicine, Boston Children’s Hospital, USA

Department of Psychiatry, Mclean and Massachusetts General Hospital, USA

Department of Psychology, Uppsala University, Uppsala, Sweden

Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Hospital, USA

Harvard Medical School, Boston MA, USA

Department of Psychiatry, Boonshoft School of Medicine, Wright State University and Dayton VA Medical Center, Dayton, OH, USA

a r t i c l e i n f o a b s t r a c t

Article history: Converging lines of evidence suggest that the pathophysiology of pain is mediated to a substantial degree

Received 18 November 2015

via allostatic neuroadaptations in reward- and stress-related brain circuits. Thus, reward deﬁciency (RD)

Received in revised form 26 May 2016

represents a within-system neuroadaptation to pain-induced protracted activation of the reward circuits

Accepted 27 May 2016

that leads to depletion-like hypodopaminergia, clinically manifested anhedonia, and diminished motiva-

Available online 28 May 2016

tion for natural reinforcers. Anti-reward (AR) conversely pertains to a between-systems neuroadaptation

involving over-recruitment of key limbic structures (e.g., the central and basolateral amygdala nuclei, the

Keywords:

bed nucleus of the stria terminalis, the lateral tegmental noradrenergic nuclei of the brain stem, the hip-

Reward

Motivation pocampus and the habenula) responsible for massive outpouring of stressogenic neurochemicals (e.g.,

Aversion norepinephrine, corticotropin releasing factor, vasopressin, hypocretin, and substance P) giving rise to

Analgesia such negative affective states as anxiety, fear and depression. We propose here the Combined Reward

Amygdala deﬁciency and Anti-reward Model (CReAM), in which biopsychosocial variables modulating brain reward,

Habenula motivation and stress functions can interact in a ‘downward spiral’ fashion to exacerbate the intensity,

Nucleus accumbens

chronicity and comorbidities of chronic pain syndromes (i.e., pain chroniﬁcation).

Dopamine

license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Stress Pain

Contents

1. Introduction ...... 283

2. Pain and reward neurobiology ...... 283

2.1. The reward-aversion continuum ...... 284

2.2. Brain circuitry of reward, aversion, and the RD-AR state in addiction ...... 287

2.3. Reward circuitry and the RD state ...... 287

2.4. Aversion/stress circuitry and the AR state...... 287

3. The RD-AR state in chronic pain...... 288

3.1. Chronic pain and RD/hypodopaminergia ...... 288

3.2. Chronic pain and AR/stress ...... 288

3.3. Reward/aversion circuitry of NAc and Hb: role in chronic pain...... 288

4. General model of RD-AR in pain centralization/chroniﬁcation ...... 289

4.1. Pain and addiction ...... 289

∗

Corresponding author at: Center for Pain and the Brain, Boston Children’s Hos-

pital, Boston, MA, USA.

E-mail address: [email protected] (D. Borsook).

http://dx.doi.org/10.1016/j.neubiorev.2016.05.033

D. Borsook et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 282–297 283

4.2. Pain and depression...... 291

4.3. Pain catastrophizing ...... 291

5. Treatment opportunities in CReAM ...... 292

5.1. Opioid ineffectiveness/resistance...... 292

5.2. Pharmacotherapies for CReAM ...... 293

5.3. Brain modulation therapies for CReAM ...... 293

6. Conclusions ...... 293

Acknowledgements ...... 294

References ...... 294

1. Introduction lel may be drawn to drug dependence, where patients over time

lose the initial “high” of a stimulant, and eventually “need drugs

Critical for the survival of organisms, pain is also a reason why just to be normal”, but such ‘normality’ may become hard to bear

lives of so many people become plainly unbearable. In addition to due to increased stress (Volkow et al., 2016). Similarly, in persis-

tremendous personal suffering, pain exerts an enormous economic tent pain, the rewarding properties of pain relief may diminish

toll on patients, their families and society as a whole. It is reported over time and the averseness of uncontrolled pain and nega-

to afﬂict over 100 million Americans, costing an estimated $600 tive events becomes more and more overwhelming (Elman and

billion annually (Gaskin and Richard, 2012) due to the loss of pro- Borsook, 2016; Elman et al., 2011). These processes interact with

ductivity, medical expenses, and long-term disability (Institute of and are affected by functions in so called ‘classic pain circuitry’

Medicine (IOM), 2011 http://iom.nationalacademies.org/reports/ in the central nervous system; regions involved in pain process-

2011/relieving-pain-in-america-a-blueprint-for-transforming- ing include somatosensory (e.g., thalamus, primary somatosensory

prevention-care-education-research.aspx). Over 25 million Amer- cortex, posterior insula cortex), emotional (e.g., cingulate, basal

icans experience daily pain (Nahin, 2015). The fact that these ganglia, amygdala, hippocampus) and descending modulatory con-

numbers are steadily rising (Freburger et al., 2009), in spite of the trol (e.g., periaqueductal gray) systems.

overall improving standards of health care, emphasizes the urgent Chronic pain might be operationalized in distinct ways; how-

need for novel insights informing better diagnosis, prevention, and ever, the present approach offers several advantages. First, it has

treatment of pain patients. deﬁned neuroanatomical and neurofunctional components (Blum

Documented attempts to understand pain and to counteract its et al., 2012b; Elman et al., 2013). Second, it rests on ﬁrm clinical

deleterious effects date back to the earliest accounts of written research grounds i.e., RD and AR are involved in the centraliza-

human history. Yet, the relative inefﬁcacy of the currently avail- tion of pain (See Box 1 for deﬁnition) which is theorized to play a

able pharmacological agents (Backonja et al., 1998; McNicol et al., key role and contribute to comorbid aberrant emotional and cog-

2013; Skljarevski et al., 2009), even when administered in combi- nitive processing (Borsook et al., 2012; Bushnell et al., 2013; Elman

nation (Gilron et al., 2005), renders pain one of the most challenging et al., 2013). Third, it attempts to model the unremitting course

problems faced by modern medicine. The International Association of chronic pain that renders the innate homeostatic and pharma-

for the Study of Pain (IASP) deﬁnes pain as an “emotional experi- cological analgesic processes ineffective, leading to impairments

ence associated with actual or potential tissue damage,” thus pointing in normative compensatory mechanisms and shifting the set point

to affective neuroscience as promising direction for tackling this for the hedonic and sensory homeostasis towards the development

conundrum. However, while the involvement of the central ner- of refractory pain conditions accompanied by persistently negative

vous system in pain is well recognized, there is still a gap between affective states (Elman et al., 2013).

remarkable basic discoveries and their translation into understand- The following text is divided into four sections containing:

ing of clinical symptomatology, and into mechanistically informed (1) a brief summary of Pain and Reward Neurobiology; (2) Neu-

therapeutic interventions for chronic pain syndromes (deﬁned as roanatomical and clinical manifestations of Reward Deﬁciency (RD)

longer than 12 weeks duration; National Institutes of Health, 2011). and Anti-reward (AR) States in Chronic Pain along with the role of

In addition to various genetic, epigenetic (Crow et al., 2013), (3) General Model of RD-AR in Pain Centralization/Chroniﬁcation

and environmental factors (Shutty et al., 1992), interpersonal vari- (see Fig. 1) and in its comorbidities; we have termed this model

ability in the engagement of emotional corticolimbic circuitry by Combined Reward Deﬁciency Antireward Model (CReAM) for

pain may explain why some patients develop chronic pain condi- chronic pain; and ﬁnally (4) Treatment Opportunities in CReAM,

tions and others do not. This is supported by consistent ﬁndings where the focus rests on the pharmacological, brain modulation

of chronic painful symptoms in stress-related mood and anxiety and psychological therapies informed by CReAM.

disorders. For instance, the vast majority (up to 80%) of patients

with Major Depressive Disorder (MDD) reports comorbid pain

2. Pain and reward neurobiology

conditions (Leuchter et al., 2010). Additionally, pre-surgical pain

catastrophizing scores have been shown to predict the severity

Any attempt to enhance our understanding regarding the brain

of chronic post-surgical pain (Havakeshian and Mannion, 2013)

mechanisms underlying the transformation from health to chronic

whilst the evolution of chronic pain depends, in part, on the

pain faces a major challenge: how to operationalize such a com-

propensity toward repeated engagement of corticolimbic stress

monplace condition that has been given as many explanations as

and reward circuits (Apkarian et al., 2013; Baliki et al., 2012).

there are treatises that have dealt with it. The concept of a pain

Here we discuss the role of neuropathological entities known

connectome has recently emerged to encompass the multitude of

as ‘reward deﬁciency’ (RD) and “anti-reward” (AR), clinically evi-

brain connections that constitute an altered state in chronic pain

dent in respectively decreased sensitivity to natural reinforcers

(Kucyi and Davis, 2015). However, constraining such a connec-

and in stress-like negative affective states as valid components

tome to some core networks has proven difﬁcult, as the human

of chronic pain. Chronic pain appears to impact both hedonic and

experience of pain can engage and modulate everything from

aversion related behaviors so that rewarding stimuli become less

basic sensory perceptions to manifestations of culture (Elman and

rewarding, and aversive stimuli become more aversive. A paral-

Borsook, 2016). In a clinical context, some examples include the role

284 D. Borsook et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 282–297

Box 1: Deﬁnition of terms.

Allostasis: attaining temporal stability in response to challenge via supraphysiological changes in systems that normally promote

homeostasis (McEwen and Stellar, 1993).

Allostatic load: the burden on the system with the consequent ‘wear and tear’ as a result of repeated and/or dysregulated allostatic

changes that acutely support an attempt for stabilization of regular function (McEwen and Stellar, 1993).

Anti-reward: a condition wherein interference with homeostatic functioning of the reward and reinforcement circuitry due to recurrent

stimulation by drugs and/or by pain triggers between-system adaptation, recruiting central and basolateral amygdala nuclei, the bed

nucleus of the stria terminalis, the lateral tegmental noradrenergic nuclei of the brain stem, the hippocampus and the Hb that in concert

contribute to massive outpouring of stressogenic corticotropin-releasing factor, norepinephrine and dynorphin. This is manifested in

negative affective states, anhedonia and motivational states that are rigidly and exclusively focused on seeking drugs or on the relief

of pain.

Centralization of pain: the process by which the initial pain (e.g., injury) transforms to chronic pain with complex comorbid changes

including altered psychological status (anxiety, depression), addiction, altered reward and antireward function (see Borsook et al.,

2013c).

Central sensitization of pain: as a result of a nociceptive barrage, changes in sensitivity of the central pain/nociceptive pathways may

result in a prolonged and usually reversible increased in excitability to stimuli resulting in clinical manifestations of hypersensitivity

(viz., dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, after-sensations, and enhanced temporal summation)

(Woolf, 2011).

Cross sensitization: a state when prior exposure to one stimulus (i.e., pain) increases subsequent response to a different stimulus

(e.g., stress, drugs, allergies or smell) and in the reversed order, e.g., enhancement of pain following prior stress exposure.

Denervation hypersensitivity: this is the state of supersensitive/enhanced response to a signal/neurotransmitter as a result of an

interrupted synaptic (input/receptor) activation or function.

Feed-forward interaction: contrary to the negative feedback concept, positive feedback is an autonomous, self-sustaining feed-forward

loop wherein whereby a stimulus mounts escalating responses that are amplifying the original stimulus.

Habituation: the term is used to denote a decrease in a behavioral or physiological response to a repeated stimulus (e.g., drug,

painful).

Hedonic tone: the amount of pleasurable or positive feelings a person experiences at a given time point.

Homeostasis: in the context used here, it is the maintenance of a physiological equilibrium of the internal environment or function

in the face of external changes (e.g., stress, drugs etc).

Intervening variable: a subjective state that connects physiological necessities with motivations and ensuing behaviors.

Motivational/incentive salience: a “wanting” process by which an organism determines the motivational value of a particular object

beyond the emotional experience it evokes i.e., “liking.”

Opponent-proponent systems: a situation when a stimulus or an affective (i.e., proponent) process evokes an affective (opponent)

process of the reversed valence. The latter may be particularly apparent with the cessation of the former (e.g., a sense of euphoria

ensuing with termination of pain).

Pain: an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of

such damage (IASP; http://www.iasp-pain.org). Pain is considered to be a chronic condition when it lasts longer than 3 months.

Pain chroniﬁcation: the process of maintenance of ongoing pain that may increase in severity over time. The process may include

increased levels of depression or anxiety that contribute to maintenance or severity of pain.

Phasic and tonic dopamine release: tonic dopaminergic neurotransmission refers to the sustained release of dopamine due to

ongoing, background of neuronal activity whereas phasic dopaminergic transmission refers to the sudden release of dopamine due to

transient, spontaneous bursts of neuronal ﬁring, usually in response to a stimulus or an event (Grace, 1991, 1995; Jarcho et al., 2012).

Tonic ﬁring refers to spontaneously occurring baseline spike activity. Phasic activation of the DA system involves a burst-spike ﬁring

pattern and is dependent on glutamatergic excitatory synaptic drive onto DA neurons. Burst spike ﬁring triggers a high amplitude,

transient, phasic DA release intrasynaptically within the targeted areas (Floresco et al., 2003; Grace, 1995).

Primary and secondary hypodopaminergia: decreased dopamine levels due to an innate biological process/disease (primary) or as

a result of exogenous factors (secondary).

Pseudo-addiction: the term describes drug-seeking behavior that occurs in a pain dependent manner (i.e., patients may have inade-

quate pain treatment).

Reward-aversion continuum: the ongoing subjective evaluation of pleasurable/rewarding and aversive processes; in the context of

pain it refers to pain relief (rewarding) vs. pain onset/presence/persistence (i.e., pain vs. analgesia).

Reinforcement: an increase in a likelihood of repeated action. In a biological context, rewards are associated with survival of individual

and species (e.g., obtaining food, water and sex).

Reward: any stimulus that is perceived as positive or pleasurable (Hyman and Malenka, 2001).

Reward-deﬁciency: diminution in the capacity to experience joy and pleasure along with paucity of drive and motivation arising in

the context of hypofunctionality of the brain circuits mediating reward, reinforcement and motivation (Comings and Blum, 2000; Elman

et al., 2009). The reward deﬁciency state may have a genetic antecedent expressed in the dopamine D2 receptor polymorphisms (Blum

et al., 2013) rendering susceptible individuals to baseline or easily acquired reward deﬁciency. Chronic pain may result in alterations

in the reward cascade with subsequent increase in discomfort and inability to garner good feelings from normally rewarding stimuli.

The hallmarks of such maladaptations include anhedonia, numbing, apathy and decreased motivation for natural reinforcers.

Reward and reinforcement circuitry: comprised of an ‘in-series’ pathway linking the ventral tegmental area, NAc and ventral pallidum

via the medial forebrain bundle (Gardner, 2011).

Sensitization: pain-induced changes in the mesolimbic dopaminergic circuitry including dopamine terminal ﬁelds (e.g., striatum,

amygdala, and mPFC) underlying normal opponent and proponent processes that transform these processes into heightened incentive

salience assigned to pain, analgesia and to related cues.

of expectations and physician-patient interaction in placebo and rewarding properties of pain relief (Becerra et al., 2001; Navratilova

nocebo responses (Carlino and Benedetti, 2016), or the intrinsically et al., 2015).

D. Borsook et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 282–297 285

Fig. 1. Combined Reward Deﬁciency-Antireward Model (CReAM) of Chronic Pain.

The ﬁgure is a schematic overview of the chronic pain’s self-sustaining and progressively worsening nature. Acute pain activates dopamine transmission in the brain’s reward

and motivational centers, whereas prolonged periods of pain produce the opposite effect (within system adaptation) clinically manifested by anhedonia and diminished

motivational/incentive salience of natural reinforcers, that is to say the Reward Deﬁciency State (RD). Allostatic adjustment (processes that attempt to normalize the stress

on the system) to excessive dopaminergic trafﬁcking in response to recurrent pain leads to a between system adaption involving the central and basolateral amygdala nuclei,

the bed nucleus of the stria terminalis, the lateral tegmental noradrenergic nuclei of the brain stem, the hippocampus and the Hb that in concert contribute to massive surges

of CRF, norepinephrine, glutamate and dynorphin leading to the Anti-Reward State (AR) (see text). Thus, recurrent pain or ongoing pain may contribute surges of these

stress-related chemicals. While stressogenic CRF and norepinephrine inﬂux contribute to the subjective sense of stress and similar negative affective states and dynorphin

further worsens the anhedonia associated with the RD, glutamatergic sensitization promotes overlearning of the motivational salience of pain, analgesia and cues that predict

the onset or severity of pain so that pain is constantly perceived to be worse than expected (viz., catastrophizing). These effects result in an unstable positive feedback loop

wherein the combined reward RD and AR model (CReAM) drives further enhancement of pain and thus contributes to progressive worsening of the clinical condition and

the buildup of the allostatic load that is unchecked by physiological negative feedback mechanisms leading to a diseased condition of the brain to the point of end-stage

outcomes of chronic pain (i.e., intractability). (+) Signs represent stimulation.

2.1. The reward-aversion continuum Pain and reward are opponent processes (Becker et al., 2012),

but the latter is usually eclipsed by the former, so that the sense of

Dopaminergic neurons in the ventral tegmental area (VTA) euphoria only becomes noticeable with the cessation of a painful

and their projections into the Nucleus Accumbens (NAc) com- condition. The inter-subject variability regarding the proponent-

prise a putative ‘homeostat’ (Goldstein and McEwen, 2002) that opponent processes interactions may be quite substantial, and a

compares hedonic information with a pre-set point. Speciﬁcally, reverse situation is also possible. For example, in the extreme case

reward signals in the brain motivate actions that increase the prob- of algophilia, pain can be experienced as pleasant. Masochistic

ability that the behavior will be repeated in the future, whereas and/or sadomasochistic behaviors occur with some frequency in

aversive signals inhibit actions that are likely to result in fruit- the population and are associated with generally adaptable psy-

less pursuits or in painful consequences (Wickens, 2008). The chosocial functioning. Conversely, self-mutilating acts in patients

opponent-process theory (OPT) of emotion postulates that hedonic with borderline personality disorder, trichotillomania and excori-

tone is derived from valuationally opposite reward and aversion ation disorder (American Psychiatric Association, 2013) highlight

processes (Solomon and Corbit, 1973, 1974) mediating hedonic the fact that pain and pleasure are not only opposites on a contin-

homeostasis viz., equilibrium of emotional and motivational states. uum, but may also be properties of a hedonic pain control system

For example, evocation of fear may in turn contribute to posi- with negative feedback processes.

tive emotions as is the case for roller coasters, automobile racing, A key feature of the OPT is that repeated activation of one process

skydiving and horror movies or ‘traumatic bonding’ developed results in a progressive weakening of that process and strength-

by victims toward their tormentors i.e., “Stockholm syndrome.” ening of the opponent process. Based on this concept, Koob and

(Cantor and Price, 2007). colleagues advanced a model of the neurobiological basis of addic-

tion that emphasizes the close interface between the reward and

286 D. Borsook et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 282–297

Fig. 2. Top: interface of Reward and Anti-Reward Circuitry. Reward and anti-reward neurobiological systems are formed from hierarchically organized corticolimbic regions

along with the clusters of hypothalamic and brainstem nuclei. The central nodes in the respective systems, namely the nucleus accumbens (NAc) and the Hb also constitute

their major interface. The meso-accumbens dopamine pathway, extending from the ventral tegmentum (VT) of the midbrain to the forebrain regions such as the NAc,

amygdala and medial prefrontal cortex (mPFC), is the crucial component of the brain reward and reinforcement system that purportedly mediates in the maintenance of

hedonic homeostasis. The habenula, an epithalamic nucleus with projections from the spinothalamic tract and to the periaqueductal gray matter (PAG), is a brain region

with integrated sensory, emotional and motivational functions that modulates pain intensity, aversion and motor responses. Increased dopamine neurotransmission from

the ventral tegmentum to the NAc is associated with euphorogenic responses to both natural rewards and to drugs of abuse. The habenula, on the other hand, opposes

this action by providing inhibitory tone to dopamine neurons (with the input from other areas of the corticolimbic limbic system and basal ganglia) via interpeduncular

and rostromedial tegmental nuclei projections, resulting in decreased dopamine transmission in the NAc and in the medial prefrontal cortex (mPFC), clinically visible as

decreased motivation and anhedonia. The functional reciprocity between NAc and Hb is also evident in the increase of the latter’s ﬁring to absence of an expected reward

or to predictors of no-reward and the decrease of their ﬁring when an expected reward occurs. Recurrent dopaminergic trafﬁcking consequent to pain eventually results in

hypodopaminergic reward deﬁciency state in the NAc and in the mPFC and eventually gives rise to the between-system anti-reward adaptation, recruiting the Hb along with

the central and basolateral amygdala nuclei, the bed nucleus of the stria terminalis, the lateral tegmental noradrenergic nuclei of the brainstem, the hypothalamic supraoptic

nucleus and the hippocampus that in concert contribute to massive outpouring of stressogenic corticotropin releasing factor (CRF), norepinephrine and dynorphin manifested

in negative affective states, anhedonia and enhanced motivational salience attributed to pain and to relevant cues. Other major neurotransmitter systems contributing to

aversive anti-reward states including serotonin and acetylcholine are regulated by the Hb via respective raphe nuclei, locus coeruleus and nucleus of Meynert. Thus, the NAc

and Hb are involved in reinforcement and are interconnected with the major brain regions involved in the modulation of pain, stress and emotions. As such, down regulation

of reward circuitry in conjunction with sensitization of anti-reward structures contributes to the transition from the controlled pain situation to intractable and escalating

painful states accompanied by emotional anguish.

Bottom: connectivity Maps for the Accumbens and for the Habenula. Reward and anti-reward circuitry has been examined recently through human neuroimaging experiments.

As this literature grows, it has become increasingly possible to use “big data” methods such as text-mining, meta-analysis and machine-learning techniques to aggregate and

synthesize neuroimaging ﬁndings (Yarkoni et al., 2011). These methods provide a convenient way to illustrate and decode brain states as shown for the two model structures

below.

Nucleus accumbens: automated Neurosynth meta-analysis of 329 studies of the feature “reward”. Lexigraphical features for NAc (MNI ± 10, 8, −10) include reward, rewards,

money, incentive, and addiction. The meta-analysis was performed by automatically identifying all studies in the Neurosynth database that loaded highly on the feature

“reward”, and then performing meta-analyses to identify brain regions that were consistently or preferentially reported in the tables of those studies (see http://neurosynth.

org/) (Yarkoni et al., 2011).

Habenula: functional co-activation map of 140 studies, and top lexigraphical features for Hb (MNI ± 4, −24, 2): monitoring, incentive, sadness, anticipation, disgust, and

no-go. Note, not enough studies have investigated anti-reward to produce an automated meta-analysis. Instead, we investigated what regions co-activate with the Hb, and

what features are commonly associated with activation of the Hb region (Yarkoni et al., 2011).

D. Borsook et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 282–297 287

stress systems (Koob et al., 2014; Koob and Le Moal, 2005). The neurological and psychiatric diseases (Borsook et al., 2013a; Klein

authors proposed that repeated drug-taking produces a decreased et al., 2013), including chronic pain (Baliki et al., 2010).

functioning of the reward systems, combined with a strengthening Neurons from the LHb send indirect negative feedback signals to

of the so-called “anti-reward” systems that subserve the opponent dopamine cells in midbrain regions including the VTA via the ros-

process of aversion. The former’s dysfunction is characterized by tromedial mesopontine tegmental nucleus also (Balcita-Pedicino

a diminished capacity to experience joy, pleasure and motivation et al., 2011). Thus, stimulation of the habenula leads to inhibition

(i.e., RD), whereas the latter manifests as the subjective experi- of dopamine release in neurons in the VTA (Omelchenko et al.,

ence of aversion and stress (i.e., AR). The focus of this article is to 2009) and substantia nigra (Christoph et al., 1986). Speciﬁcally, LHb

argue that the combined RD-AR state, initially proposed as a model neurons act on GABAergic neurons that inhibit dopamine release

of addiction, is also relevant for understanding chronic pain. This (Barrot et al., 2012) thus pointing to this structure’s important role

relevance is supported by the key role of these processes in the in adapting or responding to rewarding or stressful stimuli. There-

experience of emotional pain (Koob et al., 2014) and the current fore, a higher engagement of the Hb reduces the probability of

recognition that physical and emotional pain connote anatomi- phasic dopamine release in the reward system.

cally overlapping and functionally congruent entities (Eisenberger,

2012). 2.3. Reward circuitry and the RD state

2.2. Brain circuitry of reward, aversion, and the RD-AR state in A key brain mechanism of the rewarding effects of both natural

addiction reinforcers as well as drugs of abuse is the increase in NAc dopamine

levels (Carlezon and Thomas, 2009). The intervening variable (see

Knowledge of the human reward- and anti-reward circuitry Box 1 for deﬁnition) of subjective pleasure is sensed in the mPFC

comes in part from extensive investigations of rodent and primate (Berridge and Kringelbach, 2013; Goldstein and Volkow, 2002) that

models (Haber and Knutson, 2010; Hong et al., 2011; O’Doherty, exerts top down control of dopaminergic activity in the NAc via

2004; Thomas et al., 2001). While a major focus has been on the the cortico-striatal segment of the cortico-striato-thalamo-cortical

circuitry projecting from the VTA to the NAc (Russo and Nestler, circuit (Bimpisidis et al., 2013; Volkow et al., 2011). Increases or

2013), other brain regions e.g., amygdala and medial prefrontal decreases in the NAc’s dopamine concentrations prompt respective

cortex (mPFC) that are connected to these two structures are also habituation (Di Chiara et al., 2004) or sensitization (see deﬁni-

involved, (Oades and Halliday, 1987; Salgado and Kaplitt, 2015; van tion in Box 1) (Tremblay et al., 2002) in the key effector systems

Domburg and ten Donkelaar, 1991). Although the periaqueductal consisting of pre- and post-synaptic dopamine receptors. Presy-

gray (PAG) that is involved in a number of behaviors (Linnman et al., naptic dopamine transporters and enzymes involved in dopamine’s

2012) including pain modulation, is not classically part of reward synthesis and metabolism oppose and thereby balance abrupt

circuitry, it is connected to many regions of the brain involved in dopaminergic changes.

reward including the NAc (Ikemoto, 2010). A reduction in dopamine levels, or hypodopaminergia, within

The NAc and habenula (Hb) are two respective nodes with brain circuits mediating reward and motivation is the funda-

discrete functions related to reward and aversion. The habenula, mental neurobiological change that underlies the RD state. This

located above the posterior thalamus, is divided into medial (MHb) hypodopaminergia may be innate (primary) or acquired (sec-

and lateral (LHb) portions, and is primarily responsible for convey- ondary, e.g., drug-induced). As noted above, this state is clinically

ing information from the limbic forebrain to the limbic midbrain noticeable as a blunted capacity to enjoy or to experience pleasure

areas (Sutherland, 1982). The NAc, part of the ventral striatum, is along with decreased motivation for natural rewards (Comings and

a critical element of the mesocorticolimbic system, a brain circuit Blum, 2000; Volkow et al., 1997; Wise et al., 1978) including var-

implicated in reward, motivation, and salience attribution (Borsook ious activities that are driven by sociability, enthusiasm, esthetic

et al., 2013b). Recent optogenetic studies have shown that NAc awareness, altruism and self-fulﬁllment.

and LHb participate in distinct dopaminergic circuits for eliciting

reward and aversion, respectively: a reward circuit from the lat- 2.4. Aversion/stress circuitry and the AR state

erodorsal tegmentum to dopaminergic neurons in the VTA that

project to the NAc, and an aversion circuit in which the LHb inhibits Regions involved in aversion and stress responses include the

dopaminergic neurons in the VTA that project to the medial PFC central and basolateral amygdala nuclei, the bed nucleus of the stria

(Lammel et al., 2012). This provides a potential neuroanatomi- terminalis, the lateral tegmental noradrenergic nuclei of the brain-

cal model integrating reward (dopaminergic drive) and aversion stem, the hippocampus, and the Hb. The heightened sensitivity of

(dopaminergic inhibition). the aversion system that characterizes the AR state in addiction

A number of studies have suggested that the Hb conveys an aver- is generated via massive surges of corticotropin-releasing factor

sive or ‘anti-reward’ signal (Stopper and Floresco, 2014), is involved (CRF), norepinephrine, glutamate and dynorphin. The stressogenic

in negative prediction error processing (Salas et al., 2010), and in CRF and norepinephrine release contribute to the subjective sense

a number of aversive states (Hennigan et al., 2015; Meye et al., of stress and related negative affective states (e.g., fear, anxiety and

2015; Zuo et al., 2015). An inhibitory function may be related to depression) while dynorphin further worsens the anhedonia asso-

the integration of reward expectancy, reward, or punishment as ciated with the RD (Nestler and Carlezon, 2006). AR disrupts the

noted in a functional magnetic resonance imaging study (fMRI) normal function of brain areas involved in reward/motivation and

study of the human Hb (Ullsperger and von Cramon, 2003). Both stress processing, thereby reducing the impact of rewarding stim-

MHb and LHb neurons are excited by aversive stimuli or by the ulation and the ability to restrain stress responses. Although the AR

omission of an expected reward (Hikosaka, 2010). LHb inactiva- state may possess some heuristic value in dissuading an individual

tion abolishes choice biases, making rats indifferent when choosing from engagement in hazardous situations (Henchoz et al., 2013),

between rewards associated with different subjective costs and the generated allostatic load is clearly dysfunctional as it promotes

magnitudes, but not larger or smaller rewards of equal cost (Stopper isolation and social withdrawal, jeopardizing adequate coping and

and Floresco, 2014). NAc activity is related to reward prediction adjustment.

error, in that it encodes the discrepancy between expected and As part of AR processes, initial homeostatic adjustments to

actual reward outcome (Abler et al., 2006). Notably, altered neu- diminished tonic, resting state dopaminergic neurotransmission in

ral processing of prediction error is associated with a number of the NAc and prefrontal cortex produced by addictive drugs results

288 D. Borsook et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 282–297

in robust augmentations of phasic dopamine responses to stress supporting the idea that in chronic pain, hypodopaminergia tar-

and, via Pavlovian conditioning, to the relevant cues (Kalivas and gets changes in affective states contributing to centralization of

Volkow, 2011; Volkow et al., 2011) and/or to interoceptive bodily pain. Hence, whereas in healthy individuals low dopamine (primary

states (Verdejo-Garcia et al., 2012). Prefrontal activations caused by or secondary, see Box 1) is associated with enhanced pain sen-

these cues profoundly increase PFC glutamatergic output (Kalivas sitivity, chronic pain may further decrease dopaminergic activity

and Volkow, 2005) to an already hypofunctional NAc (Kalivas and through a feed-forward interaction (i.e., positive feedback; see Box

Volkow, 2005), thus further decreasing dopaminergic activity with 1) compromising both sensory and affective/cognitive processes

consequent worsening of the RD. (Jarcho et al., 2012). In addition, dopamine is involved in descending

The progressive RD-AR adaptation is metaphorically termed inhibitory modulation of pain transmission, which is an additional

the “dark side of addiction” (Koob and Le Moal, 2005) as it is link between hypodopaminergia and chronic pain (Potvin et al.,

unchecked by physiological negative feedback mechanisms, with 2009).

drugs (and/or natural rewards) providing only transient symp- Decreased levels of tonic dopamine result in increased sensi-

tomatic relief while worsening neuroadaptations. It may be quite tivity of remaining dopamine neurons (Grace, 1991; Pucak and

difﬁcult to stop and/or reverse the developed vicious cycle as opi- Grace, 1991) and heightened phasic dopamine release. The dimin-

oid analgesic drugs further worsen the RD and cause hyperalgesia ished dopaminergic tone contributes to the increased sensitivity of

to the point of systematic collapse (Apkarian et al., 2004; Goldstein pain patients to emotional stimuli, somewhat similar to the phe-

and Volkow, 2011) and subsequent end-stage outcomes such as nomenon of denervation hypersensitivity (see Box 1 for deﬁnition).

suicide (Fishbain, 1999; Gilbert et al., 2009).

Notwithstanding some negative affective states that may be 3.2. Chronic pain and AR/stress

jointly induced by RD and AR via hypodopaminergia and dynorphin,

there are important differences between these neuroadaptations, The recruitment of stress and emotional systems as a result of

including neuroanatomical, neurochemical and key clinical mani- excessive activation of the reward system in response to recur-

festations (see Table 1). For instance, RD and AR jointly contribute rent pain may lead not only to low detection capability for natural

to negative affective states through dynorphin which in turn mod- rewards within the dopaminergic system (i.e., RD) but also to a

ulates RD. On the other hand, other aspects of negative affective between-system adaption of heightened sensitivity to aversion and

states such as anxiety or stress are mostly contributed by stresso- stress, viz., the AR state. There are several lines of evidence that

genic hormones (CRF and norepinephrine). link chronic pain to AR. On the psychophysiological level, AR in

pain patients is evident via their hypersensitive responses to con-

ditioned stressful stimuli (Marcinkiewcz et al., 2009; Miguez et al.,

3. The RD-AR state in chronic pain 2014). Clinically, stress is an integral part of the chronic pain syn-

drome (McEwen and Kalia, 2010; Neeck and Crofford, 2000). Pain

3.1. Chronic pain and RD/hypodopaminergia patients exhibit heightened levels of stress and arousal (Thieme

et al., 2006) and stress also plays a key role in exacerbations of

Patients with chronic pain exhibit certain psychopathological pain symptomatology (Finan and Smith, 2013; Lauche et al., 2013).

and clinical features in common with addiction. Both pain (Wood, Furthermore, an exaggerated sympatho-adrenal tone as evidenced

2008; Wood et al., 2007) and opioids (Tanda et al., 1997) activate by increased heart rate (Chalaye et al., 2013), norepinephrine con-

dopamine transmission in the brain reward circuitry, including the centrations (Buscher et al., 2010) (Buvanendran et al., 2012), and

NAc, whereas prolonged periods of pain or opioid drug consump- skin conductance (Bonnet and Naveteur, 2004) are frequent clinical

tion produce the opposite effect (Wiech and Tracey, 2013) viz., RD ﬁndings in chronic pain patients (Currie and Wang, 2004). Also, the

(Assogna et al., 2011). Activation of mesolimbic reward circuitry, CRF receptor type 1 is implicated in visceral hyperalgesia (Larauche

including the NAc, occurs with both acute pain and pain relief et al., 2012), while heightened CRF cerebrospinal ﬂuid concentra-

(Becerra et al., 2013; Navratilova et al., 2012); the latter may reﬂect tions tend to parallel both sensory and affective pain components

the evocation of the opponent process. (McLean et al., 2006).

Evidence supporting a hypodopaminergic state in chronic pain

comes from both preclinical (Niikura et al., 2010) and clinical 3.3. Reward/aversion circuitry of NAc and Hb: role in chronic pain

(Hipolito et al., 2015; Kasahara et al., 2011; Loggia et al., 2014;

McDougle et al., 2015) data. Pain syndromes that have shown Stimulation of the Hb has been reported to produce analgesia in

altered dopaminergic processing include burning mouth syndrome a model of acute pain, the formalin test (Cohen and Melzack, 1986).

(Hagelberg et al., 2003), atypical facial pain (Hagelberg et al., 2003), However, we are unaware of similar studies in a chronic pain model,

and fibromyalgia (Wood et al., 2007). For example, in fibromyal- and a pain inhibitory effect would be difficult to interpret within the

gia patients vs. healthy pain-free controls a marked blunting context of a role in AR. Indeed, the literature is far from unambigu-

in striatal dopamine release was evident following induction of ous on this account and is still evolving. In fMRI studies, this brain

experimental pain (Wood et al., 2007 17610577). The high inci- region is activated by acute pain in healthy volunteers (Shelton

dence of central pain (including neuropathic pain) in Parkinson’s et al., 2012) and is tonically activated in patients with chronic pain

patients (Canavero, 2009; Defazio et al., 2008) suggests that pain (Erpelding et al., 2013). Importantly, pain-induced alterations in

is a common symptom in patients with hypofunctional nigrostri- functional connectivity of the Hb improve with analgesic therapy,

atal dopaminergic pathways (Coon and Laughlin, 2012), and that suggesting that resolution of chronic pain improves Hb’s communi-

low dopamine may contribute to increased pain (Wood, 2008). cation with the frontal and brainstem limbic regions (Shelton et al.,

Even among seemingly healthy individuals, low dopamine receptor 2012). Functional imaging in central pain thalamic stroke patients

availability is associated with enhanced pain responses (Pertovaara implicated Hb lesions in the onset and exacerbation of chronic pain

et al., 2004). Speciﬁc polymorphisms in the dopamine transporter (Sprenger et al., 2012). Both animal (Li et al., 1993; Xie et al., 1998)

gene (DAT-1) convey a high pain sensitivity stemming from a hypo- and human (Shelton et al., 2012) studies have shown connections

functional dopaminergic system (Treister et al., 2009). In healthy between the Hb and the PAG, a region involved in pain modulation

human volunteers, dopamine depletion (i.e., primary or secondary (Basbaum and Fields, 1979). Efferent projections from the LHb may

hypodopaminergia − see Box 1) inﬂuences pain affect and not involve a pathway to the dorsal reticular nuclei and activation of

sensory aspects of acute painful stimuli (Tiemann et al., 2014), this pathway may produce inhibition of avoidance or escape perfor-

D. Borsook et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 282–297 289

Table 1

Characteristics of reward deﬁciency and anti-reward processes.

Characteristic Reward deﬁciency Anti-reward

Type of neuroadaptation Within system Between systems

Neuroanatomy Mesolimbic dopaminergic circuitry, Extended amygdala (basolateral

including dopamine terminal ﬁelds amygdala, bed nucleus of the stria

(e.g., the striatum, amygdala, and terminalis & lateral tegmentum),

Prefrontal Cortex (PFC)) hippocampus & habenula

Neurochemistry ↓dopamine receptors, ↑dopamine ↑ in dynorphin, norepinephrine,

transporters & corticotropin-releasing factor &

↓ dopamine synthesis glutamate

↑ cAMP Response Element Binding

(CREB) protein,

↓ tonic dopamine & ↑ long-term

depression

Reciprocal interactions ↑ stress as it is not buffered by reward Dynorphin contributes to reward

deﬁciency

Clinical signiﬁcance ↓ in positive reinforcement of addictive Avoidance of potentially harmful

drugs situations (e.g., pain, fear & losses)

Clinical manifestation Anhedonia Hyperkatifeia, craving &

compulsivity

mance depending on the serotoninergic receptor subtype activated function of the structures involved in stress and reward, deﬁning

(Pobbe and Zangrossi, 2010). two interrelated patterns of brain alterations, namely RD and AR.

Activation of the NAc has been observed with both acute These changes may be complemented by genetic, epigenetic or dis-

(Becerra et al., 2001) and chronic (Baliki et al., 2013) pain. A signif- ease status, and contribute to the ‘failed state’ of brain function

icant role for the region in chronic pain has subsequently emerged in chronic pain, adding to the severity of comorbidities and pain

in human imaging studies (Baliki et al., 2010), including studies chroniﬁcation (see Box 1). We have previously termed such changes

suggesting a role in altered sensory processing (e.g., allodynia (Ren as the centralization of pain (Borsook et al., 2013c) (see below).

et al., 2016)) in chronic pain, and, more importantly, in predicting Here, we suggest that the combination of alterations in the normal

pain chroniﬁcation (Baliki et al., 2012). In an animal model of post- function of Reward and Anti-Reward brain systems provides the

surgical pain, pain relief seems to produce activation of dopamine basis for pain centralization (see Box 1). Below we integrate con-

neurons in the VTA and to increase dopamine release in the NAc cepts based on these systems, including interactions between RD

(Navratilova et al., 2012). In addition, activation of mesolimbic and AR function, and provide clinical examples of comorbid condi-

dopamine neurons in the VTA that project to the NAc, plays an tions (i.e., addiction, depression) or innate differences in hedonic

important role in mediating the suppression of tonic pain (Altier tone that may either be exacerbated by pain centralization, or that

and Stewart, 1999). LHb stimulation inhibits dopamine neurons (Ji may exacerbate pain centralization on the basis of CReAM (see

and Shepard, 2007). The interactions between the reward and anti- Fig. 4).

reward networks (central nodes in NAc and Hb, respectively) are

likely the reason why deep brain stimulation (DBS) in the treatment

4.1. Pain and addiction

of resistant depression appears to be effective both when electrodes

are placed in the NAc as well as when placed in the Hb (Schlaepfer

Cross sensitizing drugs (Cunningham and Kelley, 1992) may be

and Bewernick, 2013). Fig. 2 is a summary of interactions between

a mechanism involved in the complex interactions of chronic pain

the NAc and Hb and connections between these regions and others

and opioid-induced increases in pain i.e., opioid-induced hyper-

in the brain based on Functional Connectivity Mapping.

algesia (Angst and Clark, 2006) or the chroniﬁcation of pain with

The above two structures do not exist in isolation. They are

opioid use as exempliﬁed in migraine (Bigal and Lipton, 2009). The

rather embedded within a complex network of interrelated sys-

concept of cross-sensitization described in the addiction literature

tems, each of which exhibits a unique function within the context

typically refers to a situation where prior exposure to one stim-

of chronic pain. For instance, a decrease in dopamine activity

ulus (e.g., drug) increases subsequent response to itself (Angrist

(i.e., hypodopaminergia) underlying RD can promote an AR state

and Gershon, 1970; Post et al., 1982; Satel et al., 1991; Strakowski

via potentiation of glutamatergic neurotransmission (Kalivas and

et al., 1996), and to a different stimulus e.g., stress; (Goeders, 2003;

Volkow, 2005). In support of this notion, the administration of neu-

Southwick et al., 1999; Yehuda and Antelman, 1993). The reverse

roleptics can produce an aversive state in human patients (Bruun,

can also occur, that is the enhancement of drug (Antelman et al.,

1988; Naber, 1995). Furthermore, animal research indicates that

1980; Sorg and Kalivas, 1991) and stress effects (Goeders, 2003;

the inhibition of the dopamine system through pharmacological

Southwick et al., 1999; Yehuda and Antelman, 1993) following prior

or optogenetic means induces aversion and anxiety (Ilango et al.,

stress exposure. The sensitized stress responses in chronic pain may

2014; Liu et al., 2008; Sanberg, 1989). Electrophysiological studies

thus confer greater motivational salience to pain-related cues, i.e.,

report decrease in punishment during phasic suppression of ﬁring

cross-sensitization (Rome and Rome, 2000), and thus may increase

in dopamine neurons (Schultz et al., 1997). Thus, reduced dopamine

opioid analgesic drug consumption, which further increases stress

activity may produce both RD and AR states, which evoke additional

and consequently enhances cue responsivity and an ensuing tran-

interactions with other brain systems and/or with each other in a

sition from an excessive drug intake to a bona ﬁde addiction.

‘downward spiral’ manner to exacerbate chronic pain.

Although it is hypothesized that addiction develops via nega-

tive reinforcement mechanisms viz., the drug is used to ameliorate

4. General model of RD-AR in pain the averseness of pain and of accompanying negative emotional

centralization/chroniﬁcation states (Khantzian, 1997), we propose an adaptation of this idea

in the form of a positive reinforcement hypothesis i.e., reward

The general conceptual model is schematically outlined in Fig. 3 deﬁciency and anti-reward processes enhance drug use through

and summarized in Table 2. Chronic pain disrupts the normal ampliﬁcation of its rewarding and reinforcing properties (Elman

290 D. Borsook et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 282–297 ) 2 so al.,

than et

Fig. in

the pain

anxiety agents of

drugs’

(see

the pain

worse

Connor of ( signiﬁcance

be fear,

predict constantly

hyperalgesia with analgesic

opioid

i.e., is

CReAM severity to

amphetamines)

) that

pain depression

(e.g., Hypodopaminergia leads Dopaminergic properties possess 2000 cues

perceived Excessive Pain Pain-related that – motivational Overlearning synergism creation – of catastrophizing. onset expected and ) ) in

al., in

of et 2000 2014

states

and

symptoms form

implicated

symptoms

PTSD Dunlop

AR Hyman, elicits is (

the

affective buffers

and

Hasselmann, stress-related

Berke Reward 2012; pleasure stress-like, Dynorphin Anti-reward Glutamate Negative depression, other conditions anti-reward ( ) as

drug

1998 is

or leads

well

) of al.,

as and that

users et glutamate

enhance 2002

opioid of ampliﬁcation

properties reward-action effects abuse

pleasure

drug

to al.,

reward-like

of of

Manifestation Krystal rewards et

( (reward)

rewarding

through

processes

RD drugs its

Elman Hypodopaminergia AR produces association Antagonism of Clinical Reward ( reinforcing of analgesics Addiction “high” to sought Rewarding Memory effects Subjective natural use yet is

not pain

control; control;

its antagonists

expectation

pain pain

CRF interaction chronic

adrenergic,

utility

management tonic/phasic

and

salience,

pain

prediction

Potential Descending Descending kappa caused for Pain Altered dopamine/ glutamate approved pain analgesia & outcomes by

limbic

CRF,

al.,

Krebs ( other i.e.,

the et

interactions

in Stamatakis

(

decreases Mora ) ). of

secreting release ( Hb

enhancement

stress-like

2013 1994

) al., al.,

Up-regulation Reward hormones Mediation et Dynorphin inhibiting PFC–amygdala Anti-reward 2012 dopamine norepinephrine structures during responses et &

reward

activity

) responses neurons

salience facilitates

1995 error

inhibits

aspects VT

al.,

pain. to

pleasure)

mesolimbic

and

Tsai dopaminergic of reward-related dopaminergic ( activation (i.e., Role Reward Motivation, Input Habenula prediction and

anti-reward

serotonin

reward,

norepinephrine,

Opioids Hedonic

regions

␮ Neurochemicals Glutamate Dopamine dynorphin, CRF, acetylcholine & to

brain the PFC

& lateral

nuclei stria

raphe

nucleus,

central Elman nucleus tract,

( amygdala

the nucleus

bed ) the from

ventral &

& neurons nucleus

PFC including

between of

network:

& the locus

brainstem, 2013

amygdala VTA,

solitary regions

the Meynert al., 2 habenula,

NAc, supraoptic nucleus coeruleus nuclei, striatum of parabrachial of nuclei, et basolateral projecting hippocampus tegmental noradrenergic NAc, amygdala pallidum, terminalis, the Brain Mesolimbic Scattered The Striatum Table Interactions

D. Borsook et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 282–297 291

Fig. 3. Progression from homeostasis to allostatic load and the spiraling distress cycle.

Schematic diagram of potential mechanisms involved in the development of CReAM (RD + AR) in chronic pain patients. Pain disrupts the normal homeostatic function of the

structures involved in reward and aversion/stress processing thereby giving rise to potential competitive, independent (i.e., additive) or synergistic types of interactions. For

acute or mild pain competition may be the most notable one because opponent processes contribute to the self-limited nature by restoring the homeostatic equilibrium.

With ongoing pain, analgesics may be less effective and the counterbalance in the adaptive state is lost. In addition, because allostatic changes, reﬂected in the use of

analgesic agents, occur even when the treatment of pain is deemed adequate, the resultant allostatic load may be additive with that of the chronic pain (e.g., drive drug dose

escalations). Synergism may occur when the recursive partly shared positive feedback CReAM loops are produced by both chronic pain and potentially by the analgesics

themselves (Upadhyay et al., 2010) resulting in a “spiraling distress cycle” whereby there is an ampliﬁcation of the aversive physical and emotional aspects of pain. Such

processes may further contribute to treatment resistance (to current pharmacotherapies) in chronic pain.

et al., 2002). This results in an autonomous, self-sustaining feed- However, it should be pointed out that there is an opposing lit-

forward loop whereby trivial pain or stress can mount escalating erature noting that chronic pain patients are not more likely to

dopamine release in the striatum, priming catastrophizing and abuse opioids, particularly when preexisting psychological states

further escalating the “spiraling distress cycle” of chronic pain simi- (i.e., depression and anxiety) are controlled for (Edlund et al., 2007;

lar to addiction (Koob and Le Moal, 1997) This triggers the drive Elman et al., 2011; Fishbain et al., 1992). Pain is thus associated

to seek and consume drugs (i.e., craving), leading to secondary with respective deﬁcit and excess of reward, analgesia and stress.

drug-induced phasic dopaminergic bombardment (Grace, 2000) If deﬁcits (sensory and emotional) can be corrected then individu-

that eventually overpowers the homeostatic restraint (Koob and als may be protected from addiction (Elman et al., 2011). The same

Le Moal, 2001) and gives rise to the CReAM. is true with regard to stress.

It is also plausible that acute administration of opioid analgesic

drugs in chronic pain patients alleviates emotional numbing tem-

porarily by boosting the activity of the reward regions (Jakupcak

et al., 2010) while regular or habitual consumption leads to further

reward circuitry desensitization clinically manifested as emotional

4.2. Pain and depression

numbing (Volkow et al., 2007; Wang et al., 2012). Consequently,

chronic pain may become unbearable not only on a physical

Depressive symptoms are considered a key emotional compo-

level but also on a psychosocial level. Patients must cope with

nent of chronic pain (Fishbain et al., 1997) and it is commonly

debilitating pain and the associated stress it brings, to the point

hypothesized that such sequelae are mostly related to reduced

of developing pseudo-addiction i.e., compulsive seeking of opi-

motivation and anhedonia-like RD (Aguera-Ortiz et al., 2011;

oid drugs driven by the desire to try to ameliorate inadequately

Nestler and Carlezon, 2006). Consistent clinical ﬁndings of both

treated pain or to avoid a feared opioid withdrawal (see Box 1);

subjective (Blackburn-Munro and Blackburn-Munro, 2001) and

the term thus describes drug-seeking behavior that occurs in a

objective (Rouwette et al., 2012) stress markers in chronic pain

pain-dependent manner, as an active coping strategy to alleviate

patients call for the adaptation of this idea in the form of the CReAM,

undertreated pain, and is fully reversible. It is therefore distin-

in other words, a state of dynamic interactions between RD and AR

guishable from the construct of addiction, which by deﬁnition

causing spiraling deterioration of both pain and reward function.

is compulsory, maladaptive and hedonistic in nature (Weissman

Notably, patients with major depression, and no prior history of

and Haddox, 1989), and from and pseudo-opioid resistance (self-

pain, commonly present pain symptoms. This suggests endogenous

reported pain despite adequate analgesia owing to unwarranted

alterations in neural circuits resulting in the ‘add on’ phenotype (i.e.,

anxiety about a feared opioid dose reduction) (Elman et al., 2011). chronic pain).

292 D. Borsook et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 282–297

Fig. 4. Reward-antireward model (CReAM) in pain chroniﬁcation.

The ﬁgure shows the progressive changes that may occur in the evolution of chronic pain that include differences in process that involved in homeostatic, allostatic and

allostatic load. (1) Under normal homeostatic conditions, there is a balanced interaction between circuitry involved in reward and aversion i.e., normal ability to like and

dislike; (2) Under allostatic conditions (e.g., acute pain) there is a stressor that is mitigated by an opponent process (e.g., analgesics) that results in the normalization of the

−

process i.e., pain > pain relief; and (3) Under allostatic load, normative processes become disrupted such that antireward circuits dominate changes in brain processing in

chronic pain that contribute to the maladaptive state in chronic pain (i.e., altered sensory processing and comorbid changes that may include depression, anxiety). Note that

with the progression to chronic pain, there may be: (a) a diminished dopaminergic tone over time (i.e., hypodominergic condition) that contributes to a reward deﬁciency

syndrome; and (b) increasing levels of chronic stress based on ongoing aversive condition.

4.3. Pain catastrophizing (Volkow et al., 2010). In chronic pain states, pain relief is a highly

rewarding stimulus (Navratilova et al., 2015), such that the goal

Catastrophizing is an emotional state with a sense of impend- to avoid pain may supersede patients’ valued life goals. There may

ing doom or negative outcome that is predictive of pain intensity, thus be a dual impact: persistent pain and stress reduce dopamin-

disability and emotional distress (Edwards et al., 2006; Sullivan ergic transmission (making pleasant things less pleasant), and by

et al., 2001). Pain catastrophizing is deﬁned as a negative cognitive prioritizing pain avoidance over reward (for example not playing

and emotional response to pain involving elements of rumina- golf or not picking up a grandchild for fear of pain), patients may

tion, magniﬁcation and feelings of helplessness (Quartana et al., experience fewer rewarding situations altogether.

2009). A number of experiential pain induction paradigms have

found evoked responses and evoked connectivity that correlates

5. Treatment opportunities in CReAM

to the degree of pain catastrophizing. The ﬁrst study associat-

ing pain catastrophizing with brain functional responses (Gracely

Consideration of CReAM may give rise to novel therapeu-

et al., 2004) in ﬁbromyalgia patients has since been followed up by

tic strategies in chronic pain patients including pharmaco- and

several investigations in both healthy subjects (Henderson et al.,

psycho-therapies, brain-training or a combination of these. Impor-

2016; Seminowicz and Davis, 2006) and in clinical populations

tantly, the chosen strategies certainly need to be tailored the nature

(Blankstein et al., 2010; Hubbard et al., 2014), where the anterior

of the pain condition with its severity and evolution (i.e., chroni-

insula, anterior cingulate, and thalamus were consistently found

ﬁcation). Innate differences in hedonic tone and responsivity may

to correlate with pain catastrophizing. In women with chronic

alter the magnitude of RD (Blum et al., 2012a) and AR.

vulvar pain, catastrophizing correlated to parahippocampal and

substantia nigra alterations (Schweinhardt et al., 2008). Further,

5.1. Opioid ineffectiveness/resistance

catastrophizing is associated with heightened reports of craving

of opioid analgesics in patients with chronic pain (Martel et al.,

The use of chronic opioids in chronic pain is not effective in

2014). There are, however, no studies to date directly linking pain

all patients. In some conditions, including migraine, it may lead

catastrophizing and endogenous dopamine or opioid levels.

to disease chroniﬁcation (Bigal and Lipton, 2009), whereas in other

Avoidance behavior is a dynamic response that is not only inﬂu-

conditions it may result in pain sensitization and/or addiction. Even

enced by pain and associated responding but also by contextual

when effective in chronic pain, the efﬁcacy of analgesic drugs is

factors and competing goals such as obtaining a reward (Sheynin

rarely greater than 30% (Backonja et al., 1998). One underlying rea-

et al., 2015). Reward sensitivity is a trait that predisposes to a vari-

son may be the effects of chronic opioids on brain function and

ety of disinhibition disorders, including drug abuse and addiction

structure (Upadhyay et al., 2010). But it might also be related to

D. Borsook et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 282–297 293

their effects on dopamine, contributing to RD or AR. Thus, analgesic antagonists block norepinephrine/CRF anxiogenic responses and

therapy of the proponent pain stimuli could further deteriorate RD vice versa (Saigusa et al., 2012; Sommermeyer et al., 1995). Adverse

and AR and actually worsen rather than improve the pre-existing effects of typical anti-dopaminergic agents, which can be serious,

chronic pain condition. Changes in the mesolimbic dopaminergic may render them a less than optimal choice for the maintenance

circuitry induced by opioids, administered at doses exceeding the of patients with chronic pain. Nonetheless, the use of atypical anti-

homeostatic need for pain alleviation, may be responsible for the dopaminergics (acting on 5HT-2 and D2 receptors) may reverse the

ampliﬁcation of “hyperkatifeia” or negative affective states and of reward deﬁcit state (Green et al., 1999).

physical pain itself (Elman et al., 2011; Shurman et al., 2010). Hence, As noted above, part of AR relates to a hyper-noradrenergic pro-

the rationale for the use of cognitive and behavioral strategies (e.g., ﬁle. Noradrenaline increases pain facilitation (Martins et al., 2013)

cognitive restructuring, stress management and systemic desen- and drugs that inhibit noradrenaline may enhance anti-nociception

sitization) alongside non-addictive alternatives to opioids with (Burnham and Dickenson, 2013). Descending inhibitory processes

substantial analgesic properties. arise in multiple areas of the brain, including the anterior cingulate

cortex, and project to brainstem regions involved in the modulation

5.2. Pharmacotherapies for CReAM of pain (Jensen et al., 2009; Jensen et al., 2012; Mainero et al., 2011).

Thus, the rationale for the use of adrenergic antagonists relates

Behaviorally, RD is characterized by anhedonia, numbing, apa- to diminishing noradrenergic drive associated with AR that may

thy and decreased motivation for normally rewarding objects and produce, directly or indirectly, enhanced anti-nociception.

goals. As such these processes are linked to diminished mesolim-

bic dopaminergic neurotransmission (Gardner, 2011; Solomon and

5.3. Brain modulation therapies for CReAM

Corbit, 1973), which may be targets for psychopharmacological

intervention (Gorelick et al., 2004; Schroeder et al., 2013). Cur-

Given that chronic pain may alter neural networks though

rently there are safe and non-addictive pharmaceutical agents that

CReAM-based changes, methods that counter these effects

may restore dopaminergic function to improve RD-related symp-

could contribute to symptomatic relief via adaptive plasticity

toms. Proprietal is one example – an investigational nutraceutical

(Karatsoreos and McEwen, 2011). Brain regions such as the NAc

that is composed of dopamine precursors with inhibitors of the

or Hb are promising targets due to their signiﬁcant interconnec-

dopamine-degrading enzyme catechol-O-methyl transferase. Such

tivity with primary pain and reward circuitry. A salient example

agents may provide therapeutic beneﬁts for patients with RD (Blum

of this can be gleaned from reports on deep brain stimulation of

et al., 2010; Blum et al., 1988; Miller et al., 2010; Trachtenberg and

the Hb in patients with apparently successful results in resistant

Blum, 1988).

depression (Schneider et al., 2013). Unlike in the acute state, such

Inasmuch as the within-system reward deﬁciency neuroad-

stimulation is clearly altering both afferent and efferent pathways

aptation mainly diminishes positive moods and motivations, the

in a brain hub that connects forebrain to hindbrain (brainstem)

between systems anti-reward neuroadaptation ampliﬁed this effect

structures (Hikosaka, 2010; Shelton et al., 2012), many of which

via dynorphin on top of increasing negative affective states through

are involved in pain processing. Newer transcranial magnetic stim-

the CRF and noradrenergic input (Koob and Le Moal, 1997, 2001,

ulation (TMS) techniques may offer the potential to carry out deep

2008). These perturbations could be ameliorated by the phar-

brain stimulation non-invasively (Spagnolo et al., 2013).

macological manipulation (not yet FDA approved) of kappa and

CRF systems. Kappa antagonists that reportedly diminish stress-

induced potentiation of drug reinforcement (McLaughlin et al., 6. Conclusions

2003), have anti-depressant activity (Mague et al., 2003) and

may inhibit the dynorphin-associated stress response (Land et al., Chronic pain is a major problem affecting millions of people

2008). It should be noted, however, that while kappa agonists, around the world at the time when its predisposing factors, pre-

have an antinociceptive effect, they also have negative side effects vention strategies, etiology, pathophysiology and treatment are far

including dysphoria (Chavkin, 2011). CRF receptor antagonists may from being fully elucidated. With this model considering the neu-

also prove to be promising by diminishing the stress response robiological overlap between pain processing and the reward and

(Bruijnzeel et al., 2010; Bruijnzeel et al., 2012; Carels and Shepherd, motivational circuitry, we considered the aspects of pain that are

1977), which may also stabilize aberrant learning mechanisms. Ele- pertinent to the CReAM.

vations in stress hormones and neurotransmitters (e.g., cortisol) Pain chroniﬁcation (see Box 1) certainly depends on the pre-

repeatedly paired with stressful situations can become conditioned morbid health of the relevant brain circuits (Baliki et al., 2012;

cues and elicit aberrant behaviors and emotions (Elman et al., 2003) Mansour et al., 2013) as well as maladaptive processing of RD and

(e.g., drug seeking and catastrophizing). Anti-glutamatergic agents AR states. The combination of preclinical and clinical ﬁndings sug-

may be effective analgesics (e.g., benzodiazepine), however, these gests that pain, by its chronic nature, leads to a hypodopaminergic

substances have a high potential for abuse. Indirect pharmacologi- condition in the reward circuitry, resulting in the diminution of

cal manipulations of glutamatergic activity for pain relief in humans the hedonic tone, viz., RD. At the same time, chronic pain patients

have been achieved with lamotrigine or topiramate (Wiffen et al., become sensitized to stressful stimuli in conjunction with the AR

2013), as well as newer agents including minocycline (Kapoor, markers of enhanced CRF, norepinephrine, dynorphin and glu-

2013). tamate (Elman et al., 2013). This contributes to the build-up of

Stress is a strong candidate for cross-reactivity with pain the allostatic load (Borsook et al., 2012; Von Korff et al., 2009)

(Gibson, 2012). The neuroanatomical substrate for such an and alters incentive salience of pain and analgesia, thus leading

effect may involve two closely linked and interacting networks to catastrophizing, pseudo-addiction, pseudo-opioid resistance in

(viz., dopaminergic reward pathways and the extrahypothala- conjunction with further worsening of anhedonia (Li et al., 2013),

mic norepinephrine/CRF system). As discussed above, alterations depressive symptoms (Danna et al., 2013) and similar negative

in the mesolimbic dopaminergic circuitry resulting from chronic affective states arising in the context of the RD status. In connec-

pain may transform regular motivational processes into height- tion with this, chronic pain may be conceptualized as a member

ened incentive salience (see Box 1) assigned to pain and of a potential group that may encompass other neuropsychiatric

analgesia. Mesolimbic dopaminergic and extrahypothalamic nore- syndromes deﬁned by the CReAM (e.g., addiction and major depres-

pinephrine/CRF systems are intimately linked; thus dopaminergic sion).

294 D. Borsook et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 282–297

Thus our insights could have important implications for the Bimpisidis, Z., De Luca, M.A., Pisanu, A., Di Chiara, G., 2013. Lesion of medial

prefrontal dopamine terminals abolishes habituation of accumbens shell

primary and secondary prevention of chroniﬁcation of pain. If

dopamine responsiveness to taste stimuli. Eur. J. Neurosci. 37, 613–622.

neurobiological vulnerability factors can be identiﬁed, they might

Blackburn-Munro, G., Blackburn-Munro, R.E., 2001. Chronic pain, chronic stress

be used to screen patients at risk for the development of such and depression: coincidence or consequence? J. Neuroendocrinol. 13,

1009–1023.

condition. Patients found to possess high vulnerability for the

Blankstein, U., Chen, J., Diamant, N.E., Davis, K.D., 2010. Altered brain structure in

development of chronic pain owing to preexisting diminution in

irritable bowel syndrome: potential contributions of pre-existing and

reward and/or enhanced stress function might be counseled to disease-driven factors. Gastroenterology 138, 1783–1789.

Blum, K., Trachtenberg, M.C., Ramsay, J.C., 1988. Improvement of inpatient

avoid excessive drug and stress exposure (primary prevention), or

treatment of the alcoholic as a function of neurotransmitter restoration: a pilot

targeted for early intervention even in the presence of mild pain

study. Int. J. Addict. 23, 991–998.

problems (secondary prevention). Blum, K., Chen, T.J., Morse, S., Giordano, J., Chen, A.L., Thompson, J., Allen, C.,

Smolen, A., Lubar, J., Stice, E., Downs, B.W., Waite, R.L., Madigan, M.A., Kerner,

Acknowledgements M., Fornari, F., Braverman, E.R., 2010. Overcoming qEEG abnormalities and

reward gene deﬁcits during protracted abstinence in male psychostimulant

and polydrug abusers utilizing putative dopamine D(2) agonist therapy: part 2.

The work was supported by grants from NINDS (NINDS K24 Postgrad. Med. 122, 214–226.

Blum, K., Gardner, E., Oscar-Berman, M., Gold, M., 2012a. Liking and wanting linked

NS064050) and The Mayday Fund/Louis Herlands Research Endow-

to reward deﬁciency syndrome (RDS): hypothesizing differential responsivity

ment (DB). The authors thank Catherine Hubbard for her comments

in brain reward circuitry. Curr. Pharm. Des. 18, 113–118.

on the earlier versions of the manuscript and Rosanna Veggeberg Blum, K., Oscar-Berman, M., Giordano, J., Downs, B., Simpatico, T., Han, D., Femino,

J., 2012b. Neurogenetic impairments of brain reward circuitry links to reward

for her help with the preparation of the manuscript for submission.

deﬁciency syndrome (RDS): potential nutrigenomic induced dopaminergic

activation. J. Genet. Syndr. Gene Ther. 3 (4).

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