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The -Pain Nexus: Safe Opioid Prescribing at this Cultural Moment October 4, 2019

Daniel L. Millspaugh, MD Nothing to Disclose Director, Opioid Stewardship Program Director, Comprehensive Pain Management US Opioid Prescribing ~30% of World’s , ~5% World’s Population

FDA and IQVIA 2018 ✓ Poor Illicit Quality Control  Prescriptions ✓ Also  Cocaine & Meth in 2010 ✓ Polypharmacy ✓  Life Expectancy (3 yrs.) Polypharmacy Alcohol in 7-22% also

Warner et al. National Vitals Statistics Report 2016; 65:10 Regional Variation in Overdose Deaths 2014-2016 c/w 2002-2004

Economic Distress + Opioid OD Deaths Monnat 6/20/19. Institute for New Economic Thinking Motivation & Reward Mesocorticolimbic Circuitry (ACC)

PRIORITIZING

• Natural Rewards • • Mood • Chronic Pain • Sleep

Hedonic Valuation Hedonostat Opioids LIKING

Dopamine WANTING (drive) Hyman et al. 2006, modified ANRV278-N E29-20 ARI 9 M ay 2006 14:29 Neurocircuitry of Addiction

Nicotine, + alcohol Opiates Opioid Glutamate inputs – (e.g. from cortex)

Alcohol VTA Opiates GABA interneuron ? – PCP – Alcohol ? Stimulants NMDAR + DA D1R + CREB Nicotine NAChR DA or ΔFosB

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. Figure 4

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n Actions of opiates, nicotine, alcohol, and phencycline (PCP) in reward circuits. Ventral tegmental area

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o (VTA) dopamine ( ) project to the nucleus accumbens (N Ac) ( ). Different

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a interneurons, schematically diagrammed above, interact with VTA neurons and N Ac neurons. T he

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2 rewarding properties of opiatesare mediated by µ opiate receptors found in two locations in brain reward

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8 circuits. VTA dopamine neuronsare tonically inhibited by GABAergic interneurons that expressµ opiate

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d receptors. Opiates acutely inhibit these interneurons thusdisinhibiting the dopamine projection neurons,

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D and produce reward in a dopamine-independent manner. N icotine, acting on nicotinic acetylcholine

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5 receptor channel and cannabinoids acting via CB1 cannabinoid receptors in the VTA (not shown), also

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information about rewards to motivate goal- there is strong evidence (e.g., in intact non-

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v directed behaviors(Robinson et al. 2005); i.e., human primates) to suggest that, under nor-

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y they cannot act on their preferences. Overall, mal circumstances (e.g., in the absence of

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n however, theconclusionstobedrawn from le- lesions), dopamine plays a central role in A sionsor from dopamine-deficient TH knock- reward-related learning (Schultz et al. 1997, out mice are not entirely clear. T he knockout Schultz 2006). Finally, dopamine appears to mice, for example, likely have developmental be required for motivated behaviors aimed compensations to the lack of dopamine, re- at obtaining rewards. Based on such consid- quire intermittent l -dopa (which transiently erations, Berridge & Robinson (1998) have restores dopamine) in order to survive, and proposed that dopamine transmission in the require behavioral activation by caffeine to N Ac mediates the assignment of “incentive exhibit learning. It appears dopamine is not salience” to rewards and reward-related cues, needed for hedonic responses. T helesion and such that these cues can subsequently trig- knockout mice suggest that, under certain ger a state of “wanting” for the goal object circumstances, dopamine is not required for as distinct from “liking.” An animal can still reward-related learning. At the same time, like something in the absence of dopamine

www.annualreviews.org • Neural Mechanismsof Addiction 573 Substance Use Disorder Risks Exposure, Gateway, Common Liability Models of Susceptibility

▪ Exposure (% SUD in NMU) ▪ Context – McCabe et al. Pain 2016 o EtOH 9%, MJ 11%, 67% o Medical use only in HS seniors NOT o Rx Opioid Abusers ➔ OUD 16% associated w/ SUD at 35 ▪ Genetics 40-70% o NMUPO + Medical AOR 1.49, ▪ Epigenetics – ACEs & stress NMUPO only 2.61 for SUD Sx o SUD most commonly AUD ▪ Adolescence – impulsivity, PFC fxn ▪ SUD & Mental Health Conditions o >40% with SUD had MHC o Multiple SUDs common Facing Addiction in America, HHS, 2016 ▪ 2011 IOM: Relieving Pain in America o Major public health problem o 100 million adults o $635 billion/year o $19.5 billion/year for children ▪ 2016 National Pain Strategy New IASP Pain Definition

An aversive sensory and emotional experience typically caused by, or resembling that caused by, actual or potential tissue injury

Notes: 1. Always subjective and biopsychosocial 2. Pain and Nociception are different phenomena 3. Learn concept of pain and its applications through experiences Pain Processes & Pathways ▪ Learning ▪ Action ▪ Interpretation ▪ Perception ▪ Modulation ▪ Transmission ▪ Transduction Opioids for CNCP?

▪ Nociception & Pain Perception - ▪ Neuropathic pain – improved efficacy opioids affect both with longer duration Tx o Lancet Neurology, Finnerup et al. 2015 – ▪ Cochrane Review, Noble et al. 2nd & strong opioids 3rd line 2010: weak evidence of significant o Pain Physician, Howard 2012 – pain relief, inconclusive fxn & QOL (NMDA), , Nav blockers ▪ Annals of IM, Chou et al. 2015: No ▪ Inflammatory Pain – later stages may long-term opioid studies (similar to be opioid responsive other ); unable to ▪ German Guideline: contraindicated for evaluate pain, fxn, QOL outcomes primary HA and Functional PS (e.g., FM, IBS) CDC Opioid Guideline for Adults with Chronic Pain – 2016

Cornerstone for regulations and statutes, e.g., new TJC standards

50 MME/day, 90 MME/day Increasing pushback occurring

3 days, 7 days Pain Management Best Practices HHS Inter-Agency Task Force Report – May 2019

www.hhs.gov/sites/default/files/pmtf-final-report-2019-05-23.pdf Medications Section

Deprioritized, not eliminated

www.hhs.gov/sites/default/files/pmtf-final-report-2019-05-23.pdf & Opiates

▪ Opium is dried latex from seed pod of opium poppy () ▪ Phenanthrene alkaloids o (12%) o o (semi-synthetics) Exogenous Opioids

Opium-Derived Phenathrenes (opiates) Fully Synthetic Phenyl- Diphenyl- Synthetic Morphine Thebaine Codeine piperidines heptanes Phenathrenes Morphine§ Codeine§* Meperidine Methadone Heroin Propoxyphene (Darvon) Buprenorphine Benzomorphans Other (Lomotil) Tramadol* (Imodium)

§ Naturally-derived; other opium-derived are semi-synthetic * Prodrugs, CYP2D6 metabolism – new FDA contraindication/warning (<12,T&A, OSA) Endogenous Opioid System

Precursors Ligands Receptors Notes μ/MOR Pro- β-endorphin HPA+, analgesia, acupuncture, κ/KOR opiomelanocortin (also ACTH, MSH) massage, placebo, stress opponent δ/DOR

Pro- Enkaphalins δ (also μ) GI motility, less respiratory depression

Pro- κ Dysphoria, μ opponent, mood Pro- Nociceptin NOR Pain threshold modulation ? Endomorphins μ Analgesia selective, fewer SEs

Spinal Cord: μ 70%, δ 20%, κ 10% Opioid Mechanism of Action G-Protein Coupled Receptors

desensitization

Ca2+ influx K+ efflux Inhibition cAMP

Transcriptome Δ Al-Hasani et al. 2011 Receptor/Channel Affinity

Drug MOR KOR DOR NOP NE 5HT NMDA QT Metabolism Morphine +++ + + UGT2B7 [➔M6G, M3G] Hydromorphone ++ + UGT2B7 Oxycodone ++ + + CYP3A4, CYP2D6 Hydrocodone + + + CYP2D6, CYP3A4 Fentanyl +++ CYP3A4 CYP3A4, CYP2B6, CYP2C8, Methadone ++ + + + + - Yes CYP2C19, CYP2D6, CYP2C9 Levorphanol +++ ++ ++ + + -- UGT2B7* Tramadol + + + ? CYP2D6*, CYP3A4 UGT1A9, UGT2B7, CYP2C9/19 Tapentadol + + (no active metabolites) Dependence Abstinence Syndrome ▪ Onset: 8-12 hrs (IR ▪ Bone Aching ▪ Vomiting drugs) ▪ Sleep Disturbance ▪ Diarrhea ▪ Peak: 2-4 days ▪ Sweating ▪ Palpitations ▪ Duration: 7-10 days ▪ Hot & Cold Flushes ▪ HTN (IR) ▪ Piloerection ▪ Tachycardia ▪ Anxiety/Agitation ▪ Lacrimation ▪ Mydriasis ▪ Muscle effects o Tension ▪ Rhinorrhea/Sneezing ▪ Yawning! o Cramps ▪ Abdominal Cramps o Aching ▪ Nausea Tolerance & OIH Highly Plastic, Allostatic Load ➔Overload

▪ Fentanyl > Morphine > Methadone ▪ OIH MOA (like nociplastic pain) > Endomorphin o  Glutamate activity (NMDA, KOR, AMPA Δs, Uptake) - LTP ▪ Euphoria > Analgesia > RD/OIVI > o  Spinal Dynorphin Constipation o  Descending facilitation ▪ Goldilocks Phenomena o MOR & G-protein coupling Δs o Ultra-low Naloxone:  Tolerance (filamin o Nociceptin activity Δs A); Suboxone relevance o Neuro-inflammation (microglia, BDNF, o Low & high Morphine pro-nociceptive Cl- current Δs)

Velayudhan et al. 2013 Endogenous Opioids “Purposes”

▪ Pain/Nociception Regulation ▪ Brain Opioid Theory of Social ▪ Salience Network – Attachment (BOTSA) Motivational Valence oBeyond / ▪ Stress Management oSocial grooming –  trust oOpponent to stress oLaughing, music, dramas oActivity of LC (BP/HR) oDysregulated in antisocial PD oInsecure relationships style “…give patients all the opioids they need, but none that they don’t.” - Barry Meisenberg (Anne Arundel MC)

ANTI-Opioid PRO-Opioid

PRO-Patient Regulations, Statutes, Guidelines… ▪ New TJC Standards ▪ FDA o Medical Staff involved o Commissioned 2017 Report – o Risk Assessment (OUD, OIVI) like OSP o Broaden Toolbox o Acute Pain Guidelines o PDMP facilitation (SUPPORT Act) ▪ SUPPORT Act (federal) o New Opioid REMS (IR & LA) o CHIP Prevention/Tx (MH/SUD parity) opioidanalgesicrems.com o Buprenorphine NP waivers permanent o Research $ knowledgeplus.nejm.org o E-prescribing of CS by 2021 o MAT/OAT must be offered Up to 10 hrs CME o PDMP must me checked for Medicaid Opioid Stewardship Program

▪ Supply (wise prescribing, disposal) ▪ Demand (big toolbox, expectation shaping) ▪ Mitigate risk (assessment, contracts, UDS, PDMP,

naloxone, ETCO2) ▪ Measure & inform (EBP, data analytics) ▪ Integrate in workflow (links bar, point of prescribing) Reduce Supply

▪ Prescribe for need; Evidence-based Practice, Guidelines/CPG, Care Process Models (CPMs) etc. ▪ E-Prescribing for opioids – facilitates above ▪ Safe storage and proper disposal ▪ DEA: take-back events, collection sites (deadiversion.usdoj.gov) o FDA: coffee grounds, kitty litter, dish soap, disposal products o Notices when filling Rx and in Depart Reduce Demand

▪Education (R/B); expectation shaping ▪Bigger toolbox o Non-opioids: APAP, NSAIDs, AEDs, antidepressants, topical… o Behavioral: CBT, ACT, mindfulness mediation, MBSR, biofeedback o Rehabilitative: PT, exercise, biobehavioral (e.g., yoga) o Interventional: injections/blocks, nerve stimulators, pumps, TENS o Complementary: acupuncture, massage Multimodal Analgesia

▪More than one medication or intervention ▪Different mechanisms of action ▪Improve or maintain analgesia ▪Decrease side effects ▪Some from different classes have overlapping mechanisms or clinical effects Gabapentinoids NMDA MOA

Chen et al. Cell Report 2/27/2018 Risk Mitigation

▪ Initial risk assessment (CRAFFT, HEADS, ORT…) ▪ Ongoing assessments (5 A’s, PEG, UDS, PDMP) ▪ OUD treatment referral resources (MAT, OAT) ▪ Safe storage/disposal ( accidental & diversion) ▪ Harm Reduction: naloxone & injection sites ▪ OIVI risk stratification & response Ongoing Assessment The 5 A’s, Patient Assessment & Documentation Tool

▪ Analgesia ▪ Aberrant Behaviors o Changes Route o Uses for stress o Purposeful sedation ▪ Activity (ADLs+) o Hoarding medications o Request early refill PEG* o Physical, vocational, social, sleep o Arrest/victimization ▪ Affect o Reports lost/stolen o Alcohol or Illicit Abuse Rx/pills o Appears unkempt, ▪ Adverse Events o Rx from other(s) intoxicated or impaired o N/V, constipation, pruritus, sweating, o Requests Drug by sedation, cognitive Δ, overdose Name o Increased dose w/o *PEG = Pain, Enjoyment, General Activity (30 scale) authorization Measure & Inform

▪Prescribing patterns o By Service, Provider & Indication o Evidence-based guidelines ▪Naloxone for OIVI use statistics ▪Serious adverse events/outcomes ▪Remainder and disposal rates Children’s Mercy ED/UC Michelle DePhillips et al., PEC 2017 & Personal Communication

Excess • Younger Doses • Non-injury Dx • Resident • Urgent Care Workflow (EMR) Integration Kansas & Missouri ▪ Kansas and KS Medicaid (PA) ▪ MO HealthNet o Opioid Resources – dss.mo.gov/mhd/opioid.htm o K-TRACS: kansas.pmpaware.net o Opioid Policy Advisory Council (OPAC) o Dx: CA, SCD, Palliative (12 mo) o Dx: CA, SCD, CNCP (6 mo), Palliative (1 yr) o Post-op/Trauma: ≤ 90 MME/day, ≤ 21 days o Initial: ≤ 50 MME/d., ≤ 7 d. (sentences) o CNCP: ≤ 90 MME/d, 14/60 d, PA criteria o/w o Subsequent: ≤ 90 MME/day o Methadone: terminal CA o “Accumulation”: ≤ 200 MME/day o Fentanyl patch: CA & Palliative o Pharmacy: 30 day “emergency” fill – stable 6 mo o (800) 392-8030, opt. 3, or CyberAccess ▪ MO State Level o Opioid Prior Authorization (on OSP) o ≤ 7-day acute limit: documented o/w o Opioid Attestation form (have to ask) o Prior Authorization prohibited for MAT o Complimentary (>21): PT & Acup, CBT, Chirop o STLC PDMP: missouri.pmpaware.net o OxyContin not on Preferred Drug List (bankruptcy)