Daniel L. Millspaugh, MDNothing to Disclose
Director, Opioid Stewardship Program
Director, Comprehensive Pain Management
The Opioid-Pain Nexus: Safe Opioid Prescribing at this Cultural Moment
October 4, 2019
US Opioid Prescribing~30% of World’s Opioids, ~5% World’s Population
FDA and IQVIA 2018
✓ Poor Illicit Quality Control
✓ Also Cocaine & Meth
✓ Polypharmacy
✓ Life Expectancy (3 yrs.)
Prescriptions
in 2010
PolypharmacyAlcohol in 7-22% also
Warner et al. National Vitals Statistics
Report 2016; 65:10
Regional Variation in Overdose Deaths2014-2016 c/w 2002-2004
Monnat 6/20/19. Institute for New Economic Thinking
Economic Distress
+
Opioid OD Deaths
Motivation & RewardMesocorticolimbic Circuitry
Hyman et al. 2006, modified
PRIORITIZING
Dopamine
WANTING (drive)
Opioids
LIKING
Hedonic Valuation
Hedonostat
• Natural Rewards
• Addiction
• Mood
• Chronic Pain
• Sleep
(ACC)
AN RV278-N E29-20 ARI 9 May 2006 14:29
VTA NAc
Nicotine,
alcohol
Nicotine NAChR
NMDAR
D1Ror
D2R
Alcohol
Alcohol
PCP
–
–
–
+
+
+
+
?
?
–
Opioidpeptides
Opiates
Opiates
Stimulants
VTA
interneuron
Cannabinoids
GABA
DA
Glutamate inputs
(e.g. from cor tex)
Glutamate
inputs
(e.g. from
amygdala)
DA
Figure 4
Actions of opiates, nicotine, alcohol, and phencycline (PCP) in reward circuits. Ventral tegmental area
(VTA) dopamine neurons (bottom left) project to the nucleus accumbens (N Ac) (bottom right). Different
interneurons, schematically diagrammed above, interact with VTA neurons and N Ac neurons. T he
rewarding propertiesof opiatesare mediated by µ opiate receptors found in two locations in brain reward
circuits. VTA dopamine neuronsare tonically inhibited by GABAergic interneurons that expressµ opiate
receptors. Opiatesacutely inhibit these interneurons thusdisinhibiting the dopamine projection neurons,
which then release dopamine in the N Ac and other terminal fields. In addition, there areµ opiate
receptors expressed by N Ac and dorsal striatal neurons. Opiates can stimulate these receptors directly
and produce reward in a dopamine-independent manner. N icotine, acting on nicotinic acetylcholine
receptors (N AChRs) in the VTA, cause dopamine release. Ethyl alcohol, acting on GABAA receptors in
the VTA, can also cause dopamine release. Phencyclidine (PCP), which blocks the N MDA glutamate
receptor channel and cannabinoids acting via CB1 cannabinoid receptors in the VTA (not shown), also
produce dopamine release. Cannabinoids, alcohol, and PCP can also act directly on the N Ac. PCP,
phencyclidine (“angel dust” ).
information about rewards to motivate goal-
directed behaviors(Robinson et al. 2005); i.e.,
they cannot act on their preferences. Overall,
however, theconclusionsto bedrawn from le-
sionsor from dopamine-deficient T H knock-
out mice are not entirely clear. T he knockout
mice, for example, likely have developmental
compensations to the lack of dopamine, re-
quire intermittent l -dopa (which transiently
restores dopamine) in order to survive, and
require behavioral activation by caffeine to
exhibit learning. It appears dopamine is not
needed for hedonic responses. T helesion and
knockout mice suggest that, under certain
circumstances, dopamine is not required for
reward-related learning. At the same time,
there is strong evidence (e.g., in intact non-
human primates) to suggest that, under nor-
mal circumstances (e.g., in the absence of
lesions), dopamine plays a central role in
reward-related learning (Schultz et al. 1997,
Schultz 2006). Finally, dopamine appears to
be required for motivated behaviors aimed
at obtaining rewards. Based on such consid-
erations, Berridge & Robinson (1998) have
proposed that dopamine transmission in the
N Ac mediates the assignment of “ incentive
salience” to rewardsand reward-related cues,
such that these cues can subsequently trig-
ger a state of “wanting” for the goal object
as distinct from “ liking.” An animal can still
like something in the absence of dopamine
www.annualreviews.org • Neural Mechanismsof Addiction 573
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Neurocircuitry of Addiction
Hyman et al. 2006
CREB
ΔFosB
Substance Use Disorder RisksExposure, Gateway, Common Liability Models of Susceptibility
▪ Exposure (% SUD in NMU)
o EtOH 9%, MJ 11%, Heroin 67%
o Rx Opioid Abusers ➔ OUD 16%
▪ Genetics 40-70%
▪ Epigenetics – ACEs & stress
▪ Adolescence – impulsivity, PFC fxn
▪ SUD & Mental Health Conditions
o >40% with SUD had MHC
o Multiple SUDs common
Facing Addiction in America, HHS, 2016
▪ Context – McCabe et al. Pain 2016
o Medical use only in HS seniors NOT
associated w/ SUD at 35
o NMUPO + Medical AOR 1.49,
NMUPO only 2.61 for SUD Sx
o SUD most commonly AUD
▪ 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 -opioids affect both
▪ Cochrane Review, Noble et al. 2010: weak evidence of significant pain relief, inconclusive fxn & QOL
▪ Annals of IM, Chou et al. 2015: Nolong-term opioid studies (similar to other analgesics); unable to evaluate pain, fxn, QOL outcomes
▪ Neuropathic pain – improved efficacy with longer duration Txo Lancet Neurology, Finnerup et al. 2015 –
tramadol 2nd & strong opioids 3rd line
o Pain Physician, Howard 2012 – methadone (NMDA), buprenorphine, Nav blockers
▪ Inflammatory Pain – later stages may be opioid responsive
▪ German Guideline: contraindicated for primary HA and Functional PS (e.g., FM, IBS)
CDC Opioid Guidelinefor Adults with Chronic Pain – 2016
Cornerstone for
regulations and statutes,
e.g., new TJC standards
Increasing pushback occurring
3 days, 7 days
50 MME/day, 90 MME/day
Pain Management Best PracticesHHS Inter-Agency Task Force Report – May 2019
www.hhs.gov/sites/default/files/pmtf-final-report-2019-05-23.pdf
Medications Section
www.hhs.gov/sites/default/files/pmtf-final-report-2019-05-23.pdf
Deprioritized,
not eliminated
Opium & Opiates
▪Opium is dried latex from seed
pod of opium poppy (Papaver
somniferum)
▪Phenanthrene alkaloidsoMorphine (12%)
oCodeine
oThebaine (semi-synthetics)
Exogenous OpioidsOpium-Derived Phenathrenes (opiates) Fully Synthetic
Morphine Thebaine CodeinePhenyl-
piperidines
Diphenyl-
heptanes
Synthetic
Phenathrenes
Morphine§
Heroin
Hydrocodone
Oxycodone
Hydromorphone
Oxymorphone
Buprenorphine
Naloxone
Nalbuphine
Naltrexone
Codeine§* Meperidine
Fentanyl
Sufentanil
Alfentanil
Remifentanil
Carfentanil
Methadone
Propoxyphene (Darvon)
Levorphanol
Butorphanol
Benzomorphans Other
Diphenoxylate (Lomotil)
Loperamide (Imodium)
Tramadol*
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
Pro-
opiomelanocortinβ-endorphin(also ACTH, MSH)
μ/MOR
κ/KOR
δ/DOR
HPA+, analgesia, acupuncture,
massage, placebo, stress opponent
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 ActionG-Protein Coupled Receptors
Al-Hasani et al. 2011
desensitization
Ca2+ influx
K+ efflux
cAMP
Inhibition
Transcriptome Δ
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
Methadone ++ + + + + - YesCYP3A4, CYP2B6, CYP2C8,
CYP2C19, CYP2D6, CYP2C9
Levorphanol +++ ++ ++ + + -- UGT2B7*
Tramadol + + + ? CYP2D6*, CYP3A4
Tapentadol + +UGT1A9, UGT2B7, CYP2C9/19
(no active metabolites)
DependenceAbstinence Syndrome
▪ Onset: 8-12 hrs (IR drugs)
▪ Peak: 2-4 days
▪ Duration: 7-10 days (IR)
▪ Anxiety/Agitation
▪ Muscle effectso Tension
o Cramps
o Aching
▪ Bone Aching
▪ Sleep Disturbance
▪ Sweating
▪ Hot & Cold Flushes
▪ Piloerection
▪ Lacrimation
▪ Rhinorrhea/Sneezing
▪ Abdominal Cramps
▪ Nausea
▪ Vomiting
▪ Diarrhea
▪ Palpitations
▪ HTN
▪ Tachycardia
▪ Mydriasis
▪ Yawning!
Tolerance & OIHHighly Plastic, Allostatic Load ➔Overload
▪ Fentanyl > Morphine > Methadone
> Endomorphin
▪ Euphoria > Analgesia > RD/OIVI >
Constipation
▪Goldilocks Phenomena
o Ultra-low Naloxone: Tolerance (filamin
A); Suboxone relevance
o Low & high Morphine pro-nociceptive
▪OIH MOA (like nociplastic pain)
o Glutamate activity (NMDA,
KOR, AMPA Δs, Uptake) - LTP
o Spinal Dynorphin
o Descending facilitation
oMOR & G-protein coupling Δs
o Nociceptin activity Δs
o Neuro-inflammation (microglia, BDNF,
Cl- current Δs)
Velayudhan et al. 2013
Endogenous Opioids “Purposes”
▪Pain/Nociception Regulation
▪Salience Network –
Motivational Valence
▪Stress Management
oOpponent to stress
oActivity of LC (BP/HR)
▪Brain Opioid Theory of Social
Attachment (BOTSA)
oBeyond oxytocin/vasopressin
oSocial grooming – trust
oLaughing, music, dramas
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
o Medical Staff involved
o Risk Assessment (OUD, OIVI)
o Broaden Toolbox
o PDMP facilitation
▪SUPPORT Act (federal)
o CHIP Prevention/Tx (MH/SUD parity)
o Buprenorphine NP waivers permanent
o Research $
o E-prescribing of CS by 2021
o MAT/OAT must be offered
o PDMP must me checked for Medicaid
▪ FDA
oCommissioned 2017 Report –
like OSP
oAcute Pain Guidelines
(SUPPORT Act)
oNew Opioid REMS (IR & LA)
opioidanalgesicrems.com
knowledgeplus.nejm.org
Up to 10 hrs CME
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 toolboxoNon-opioids: APAP, NSAIDs, AEDs, antidepressants, topical…
oBehavioral: CBT, ACT, mindfulness mediation, MBSR, biofeedback
oRehabilitative: PT, exercise, biobehavioral (e.g., yoga)
o Interventional: injections/blocks, nerve stimulators, pumps, TENS
oComplementary: 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
Chen et al. Cell Report 2/27/2018
Gabapentinoids NMDA MOA
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 AssessmentThe 5 A’s, Patient Assessment & Documentation Tool
▪ Analgesia
▪ Activity (ADLs+)o Physical, vocational, social, sleep
▪ Affect
▪ Adverse Eventso N/V, constipation, pruritus, sweating,
sedation, cognitive Δ, overdose
▪ Aberrant Behaviors
o Purposeful sedation
o Request early refill
o Reports lost/stolen
Rx/pills
o Rx from other(s)
o Requests Drug by
Name
o Increased dose w/o
authorization
o Changes Route
o Uses for stress
o Hoarding medications
o Arrest/victimization
o Alcohol or Illicit Abuse
o Appears unkempt,
intoxicated or impaired
*PEG = Pain, Enjoyment, General Activity (30 scale)
PE
G*
Measure & Inform
▪Prescribing patterns
oBy Service, Provider & Indication
oEvidence-based guidelines
▪Naloxone for OIVI use statistics
▪Serious adverse events/outcomes
▪Remainder and disposal rates
Children’s Mercy ED/UCMichelle DePhillips et al., PEC 2017 & Personal Communication
• Younger
• Non-injury Dx
• Resident
• Urgent Care
Excess
Doses
Workflow (EMR) Integration
Kansas & Missouri▪ Kansas and KS Medicaid (PA)
o K-TRACS: kansas.pmpaware.net
o Dx: CA, SCD, Palliative (12 mo)
o Post-op/Trauma: ≤ 90 MME/day, ≤ 21 days
o CNCP: ≤ 90 MME/d, 14/60 d, PA criteria o/w
o Methadone: terminal CA
o Fentanyl patch: CA & Palliative
▪ MO State Level
o ≤ 7-day acute limit: documented o/w
o Prior Authorization prohibited for MAT
o STLC PDMP: missouri.pmpaware.net
▪ MO HealthNeto Opioid Resources – dss.mo.gov/mhd/opioid.htm
o Opioid Policy Advisory Council (OPAC)
o Dx: CA, SCD, CNCP (6 mo), Palliative (1 yr)
o Initial: ≤ 50 MME/d., ≤ 7 d. (sentences)
o Subsequent: ≤ 90 MME/day
o “Accumulation”: ≤ 200 MME/day
o Pharmacy: 30 day “emergency” fill – stable 6 mo
o (800) 392-8030, opt. 3, or CyberAccess
o Opioid Prior Authorization (on OSP)
o Opioid Attestation form (have to ask)
o Complimentary (>21): PT & Acup, CBT, Chirop
o OxyContin not on Preferred Drug List (bankruptcy)
