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WHAT TO SAY WHEN PATIENTS ASK

Perpetual Hunger: The Neurobiological Consequences of Long-Term Opioid Use Jane Eisen, MD

INTRODUCTION/CLINICAL VIGNETTE (Group, 2-5 minutes)

Ms. Roman is a 26 yo single woman with long-standing chronic pain accompanied by long-standing opioid use. She has had many work-ups to identify the etiology of her diffuse pain symptoms without a clear cause identi- fied. Because of her pain, and concomitant prescribed opioid use, she has had poor functioning over the past 5 years. After a brief stint in LA when she took acting classes 3 years ago, she has largely been in her parents’ home, with minimal socializing and no work efforts. She reports difficulties with interpersonal relationships in addition to her chronic pain, feeling that she is frequently treated poorly or ignored by friends and acquaintances, so has increasingly isolated herself.

ROLE PLAY #1 (Pairs, 5 minutes)

One partner should play the role of patient and the other should play the role of clinician and attempt to answer the patient’s questions: 1) It seems that I am more sensitive to everything

compared to how I was before this huge pain prob- lem started, despite being on pain medication. Why is that?

2) All I can think about is my pain – everyone tells me to ignore it – I am on pain medication, I know. But I just can’t; it’s too intense.

3) Even if my pain weren’t limiting me so much, I’m always down because I keep getting hurt! I don’t think there’s any therapy that can fix my being mistreated by my supposed friends.

REVIEW NNCI RESOURCE (Individual, 10 minutes)

Perpetual Hunger: The Neurobiological Consequences of Long Term Opioid Use Biological Psychiatry Clinical Commentary by Tanner Bommersbach, David A. Ross, Joao P. De Aquino. ISSN: 0006-3223 Biological Psychiatry October 15, 2017; 82:e61–e63

DISCUSSION (Group, 15 minutes)

What were the key take-home points you learned from this clinical commentary?

ROLE PLAY #2 (Pairs, 5 minutes)

Role play a second time, again with one partner playing the role of patient and the other playing the role of clinician, and attempt to answer the patient’s questions, incorporating any additional information you learned from the reading: 1) It seems that I am more sensitive to everything

compared to how I was before this huge pain prob- lem started, despite being on pain medication. Why is that?

2) All I can think about is my pain – everyone tells me to ignore it – I am on pain medication, I know. But I just can’t; it’s too intense.

3) Even if my pain weren’t limiting me so much, I’m always down because I keep getting hurt! I don’t think there’s any therapy that can fix my being mistreated by my supposed friends.

WRAP UP (Individual, 2-5 minutes)

The keysheet includes key take-home points and example answers to our patient’s question(s) – of course, what’s written in the keysheet is only one possible explanation; your exact answers will vary, depending on your style and your individual patient. If time allows, take a few minutes now to read the keysheet and see how it matches up with the discussion and role play you’ve just had.

You might also use this time to consider what one thing you will do differently, in either your clinical or teaching encounters, as a result of this experience.

The keysheet also includes another section, "What Else To Say", which identifies additional learning opportunities that you may be interested in reviewing after this session.

*Note that time estimates listed are for a 45-minute session, but can be adjusted according to your session length.

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ANSWER SHEET

What were key take-home points you learned from this piece? We are beginning to understand neurobiological

mechanisms that lead to the well-described phe- nomenon of hyperalgesia. Chronic opioid exposure reduces the pain threshold by affecting both central and peripheral pain pathways:

• Chronic opioid use leads to inflammatory cytokine abnormalities ,which affects bottom-up nociceptive transmission.

• Chronic opioid use affects a number of changes to the mu, NDMA, and serotonin receptors centrally.

Additionally, based on neuroimaging studies, we can see that central processing of pain over time shifts from sensory to emotional and cognitive brain areas so that people with chronic pain overly focus on their experience of pain, leading to a sense of profound helplessness.

Another important change in chronic opioid use is the alteration of incentive salience whereby neuro- plastic changes in cognitive and reward circuits lead to sensitization to (or attentional bias towards) opioid and pain cues, at the expense of healthy interactions in the environment.

A third central change noted in those with chronic opioid use in the development of chronic emotional distress and dysregulation (hyperkatifeia), which further leads to opioid-seeking behaviors to alleviate negative affective states.

Individual variability regarding symptoms in one of 3 domains affected by chronic opioid use – pain sensitivity, incentive salience, and affective distress

– has been documented by neuroimaging, neuropsy- chological testing, and clinical studies.

Future directions for addiction medicine are to develop more personalized approaches, given this variability, to target treatments based on which specific domains are most affected.

Finally, given the long-standing brain changes with chronic opioid use, a chronic illness model, analo- gous to diabetes or hypertension, may have clinical utility, particularly in light of the potentially lethal consequences of relapse.

1) It seems that I am more sensitive to the slightest pain compared to how I was before this huge pain problem started, despite being on pain medication. Why is that?

Even though opioids are powerful at relieving pain at first, over time they change the “thermostats” for how the body regulates mood and sensitivity to painful stimuli so that most people with opioid dependence unfortunately develop exactly what you describe – hypersensitivity to pain. This is an effect of the opioids you are taking and it happens because of complex changes that take place in your brain in a number of neuroreceptors including the mu-opioid receptor.

It also happens because the pain signals from your body are amplified by chronic opioid use’s effects on the inflammatory system.

2) All I can think about is my pain – everyone tells me to ignore it – I am on pain medication, I know. But I just can’t; it’s too intense.

Several things happen to people in your situation with chronic opioid use and chronic pain. First, they develop actual increased pain sensitivity. Second, over time, the brain becomes overly-attuned to anything having to do with pain, snatching your attention and preventing you from focusing on anything else. Another factor here is that the focus on the sensations of pain shifts to the emotional and thinking centers of the brain so that your thoughts and feelings become overly focused on pain. All these brain changes help explain why it’s so hard for you to concentrate on anything other than your pain.

3) Even if my pain weren’t limiting me so much, I’m always down because I keep getting emotionally hurt! I don’t think there’s any therapy that can fix my being mistreated by my supposed friends.

We also now know that chronic opioid use leads to a dysregulation of moods so that negative states are intensified and positive states are minimized even long after people stop using opioids. No wonder you are sensitive to interactions with others! The slightest negative interaction is hugely amplified and any positive interactions are completely minimized. Psychotherapy can really help address the kind of interpersonal sensitivity you are describing.

WTS: WHAT TO SAY WHEN PATIENTS ASK

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WHAT ELSE TO KNOW

Below is a cartoon of the neural circuitry involved with the negative emotional state of withdrawal/negative affect stage including the reward circuitry (ventral teg- mental area and nucleus accumbens) and the extended amygdala with resulting changes in neurotransmitters.

From a clinical perspective, a focus on understanding

the reward deficit and/or stress surfeit component of the withdrawal/negative affect stage of opioid use disorder can also inform which behavioral treatments may be more effective in moderate to severe opioid use disorder. For example, versions of cognitive behavioral therapy that address coping mechanisms for stress and pain (physical and affective) may be more important than refinements in contingency management.*

Neural circuitry associated with the negative emo- tional state of the withdrawal/negative affect stage. (A) Extended amygdala and within-system neuroadap- tations. Note the loss of dopamine and opioid peptide function in ventral tegmental area–nucleus accumbens circuitry, with a hypothesized contribution of the habenula that suppresses neuron activity in the ventral tegmental area (inset panel). (B) Extended amygdala and between-system neuroadaptations.

Note the gain of stress neurotransmitter and neuro- modulator function and loss of antistress neurotrans- mitter and neuromodulator function throughout the neurocircuitry of the extended amygdala (inset panel). The extended amygdala is composed of several basal forebrain structures, including the bed nucleus of the stria terminalis, the central nucleus of the amygdala,

and possibly a transition area in the medial portion (shell) of the nucleus accumbens.

ACC, anterior cingulate cortex; BNST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; DA, dopamine; DS, dorsal striatum; dlPFC, dorsolat- eral prefrontal cortex; GABA, gamma-aminobutyric acid; GP, globus pallidus; HPC, hippocampus; LDT, laterodorsal tegmentum; NAC, nucleus accumbens; OFC, orbitofrontal cortex; PAG, periaqueductal gray; PPT, pedunculopontine tegmentum; Thal, thalamus; vlPFC, ventrolateral prefrontal cortex; vmPFC, ventromedial prefrontal cortex; VTA, ventral tegmental area. [Adapted from: 1) Koob GF (2008). A role for brain stress systems in addiction. Neuron 59:11–34. 2) George O, Koob GF (2013). Control of craving by the prefrontal cortex. Proc Natl Acad Sci U S A 110:4165–4166.]

WTS: WHAT TO SAY WHEN PATIENTS ASK

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* Review Neurobiology of Opioid Addiction: Opponent Process, Hyperkatifeia, and Negative Reinforcement George F. Koob https://doi.org/10.1016/j.biopsych.2019.05.023

AUTHOR CONTRIBUTIONS

Dr. Eisen is the Clinical Director of the McLean Hospital Depression and Anxiety Division. The National Neuroscience Curriculum Initiative is supported by the National Institutes of Health Grant Nos. R25 MH08646607S1 and R44 MH115546-01 ©National Neuroscience Curriculum Initiative.

WTS: WHAT TO SAY WHEN PATIENTS ASK