The Opioid-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 Opioids, ~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 • Addiction • Mood • Chronic Pain • Sleep Hedonic Valuation Hedonostat Opioids LIKING Dopamine WANTING (drive) Hyman et al. 2006, modified AN RV278-N E29-20 ARI 9 M ay 2006 14:29 Neurocircuitry of Addiction Nicotine, + alcohol Opiates Opioid Glutamate inputs peptides – (e.g. from cortex) Alcohol VTA Opiates GABA interneuron ? – PCP – Alcohol ? Stimulants NMDAR + DA D1R + CREB Nicotine NAChR DA or ΔFosB D2R g r – o + Cannabinoids . s Glutamate y l w e n inputs i o v e (e.g. from e r s l VTA NAc u amygdala) a l u a n n n o a Hyman et al. 2006 s . Figure 4 r s l e a p n Actions of opiates, nicotine, alcohol, and phencycline (PCP) in reward circuits. Ventral tegmental area r r o u F bottom left bottom right o (VTA) dopamine neurons ( ) project to the nucleus accumbens (N Ac) ( ). Different j . r 8 a interneurons, schematically diagrammed above, interact with VTA neurons and N Ac neurons. T he 0 / m 2 rewarding properties of opiatesare mediated by µ opiate receptors found in two locations in brain reward o 2 r / f 8 circuits. VTA dopamine neuronsare tonically inhibited by GABAergic interneurons that expressµ opiate d 0 e n d receptors. Opiates acutely inhibit these interneurons thusdisinhibiting the dopamine projection neurons, o a o n l which then release dopamine in the N Ac and other terminal fields. In addition, there are µ opiate o n i t w receptors expressed by N Ac and dorsal striatal neurons. Opiates can stimulate these receptors directly a t o S D and produce reward in a dopamine-independent manner. N icotine, acting on nicotinic acetylcholine e . g 8 receptors (N AChRs) in the VTA, cause dopamine release. Ethyl alcohol, acting on GABA receptors in e A 9 l l 5 - o the VTA, can also cause dopamine release. Phencyclidine (PCP), which blocks the NMDA glutamate 5 C 6 - 5 receptor channel and cannabinoids acting via CB1 cannabinoid receptors in the VTA (not shown), also : y 9 t i produce dopamine release. Cannabinoids, alcohol, and PCP can also act directly on the N Ac. PCP, 2 . s r 6 e phencyclidine (“angel dust”). 0 v 0 i 2 n . i U c s M o r & u e A information about rewards to motivate goal- there is strong evidence (e.g., in intact non- s N a . x v directed behaviors(Robinson et al. 2005); i.e., human primates) to suggest that, under nor- e e T R . y they cannot act on their preferences. Overall, mal circumstances (e.g., in the absence of u b n 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%, Heroin 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. tramadol 2nd & strong opioids 3rd line 2010: weak evidence of significant o Pain Physician, Howard 2012 – methadone pain relief, inconclusive fxn & QOL (NMDA), buprenorphine, 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 analgesics); 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 Opium & Opiates ▪ Opium is dried latex from seed pod of opium poppy (Papaver somniferum) ▪ Phenanthrene alkaloids o Morphine (12%) o Codeine o Thebaine (semi-synthetics) Exogenous Opioids Opium-Derived Phenathrenes (opiates) Fully Synthetic Phenyl- Diphenyl- Synthetic Morphine Thebaine Codeine piperidines heptanes Phenathrenes Morphine§ Hydrocodone Codeine§* Meperidine Methadone Levorphanol Heroin Oxycodone Fentanyl Propoxyphene Butorphanol Hydromorphone Sufentanil (Darvon) Oxymorphone Alfentanil Buprenorphine Remifentanil Naloxone Carfentanil Nalbuphine Benzomorphans Other Naltrexone Diphenoxylate (Lomotil) Tramadol* Loperamide (Imodium) Tapentadol § 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-enkephalin Enkaphalins δ (also μ) GI motility, less respiratory depression Pro-dynorphin Dynorphins κ Dysphoria, μ opponent, mood Pro-nociceptin 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 oxytocin/vasopressin