Maria Foy PharmD BCPS CPE Pharmacy Care CoordinatorPalliative Care Abington Hospital Jefferson Health Tanya J Uritsky PharmD BCPS CPE Clinical Pharmacy Specialist Pain Management and Palliative Care ID: 908530
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Slide1
Quieting Down Opioid Prescribing
Maria Foy, PharmD, BCPS, CPEPharmacy Care Coordinator/Palliative CareAbington Hospital Jefferson Health
Tanya J. Uritsky,
PharmD
,
BCPS, CPE
Clinical Pharmacy Specialist, Pain Management and Palliative Care
Hospital of the University of
Pennsylvania
Slide2Disclosures
Tanya Uritsky has nothing to discloseMaria Foy is on the speaker’s bureau for Astra Zeneca
Slide3Goals and Objectives
At the completion of this activity, the participant should be able to:Recommend
an opioid de-escalation protocol based on current opioid dosage and length of therapyProvide dosing for inpatient ketamine during the de-escalation processUtilize co-analgesics for the treatment of chronic pain
Slide4Question
Symptoms of central sensitization may include (select all that apply):AllodyniaHyperalgesia
SwellingBradycardia
Slide5Pain System Changes and Opioids
Tanya J. Uritsky, PharmD, BCPS, CPE
Slide6The Pain Pathway
Bingham B, et al. , Nature Clinical Practice, 2009; 5(1):1-37. Accessed at: www.nature.com/clinicalpractice/rheum
Slide7“Inflammatory Soup”
Lower threshold for activation
Increased rate of firingPlays a role in allodynia, hyperalgesia and in central sensitizationPeripheral Sensitization
Slide8Central Sensitization
Amplification of neural signaling that elicits pain hypersensitivityAn uncoupling of the clear stimulus-response relationship that defines nociceptive pain
Manifests as:Hyperalgesia/secondary hyperalgesiaAllodyniaProlonged pain after transient stimulusCan persist long after healing of the injuryWoolf CJ. Pain, 2011;152(3 Suppl):S2-S15.
Slide9Taking A Closer Look
Pain afferents - Glutamate, Substance P, Calcium
Central -NMDA activation, reduced endogenous opioid, reduced serotonin/5HT2A up-regulation, norepinephrine changes, dopamine changes Microglial Cells/Astrocytes -glutamate, cytokines, K/Ca channel dysregulationRaouf, et al. 2010
Slide10Glial Cell Activation
Adapted from: https://
www.practicalpainmanagement.com/pain/other/glial-cell-activation-neuroinflammation-how-they-cause-centralized-pain, online May 2015; accessed September 21, 2017NeuroinflammationChronic FatigueDepressionCentralized PainInsomniaOverstimulation of sympathetic nervous systemIntellectual Decline
Pituitary Over-Stimulation
Activated Glial Cells
Slide11Pain Memory
Adapted from: https://www.practicalpainmanagement.com/pain/other/glial-cell-activation-neuroinflammation-how-they-cause-centralized-pain, online May 2015; accessed September 21, 2017
Slide12What You See
Major SymptomsConstant painInsomnia, depression, fatigueSecondary SymptomsAnxiety, anorexia, hopelessness, allodynia
BehaviorReclusiveness, immobilityBecoming house/bed boundSympathetic Nervous System ExcitationHypertension, tachycardia, hyperthermia, hyperhidrosis, mydriasis, etc.https://www.practicalpainmanagement.com/pain/other/glial-cell-activation-neuroinflammation-how-they-cause-centralized-pain, online May 2015; accessed September 21, 2017
Slide13But Why?
Lowers pain threshold Stress
Poor sleepOperant learningIndividual beliefs and expectations Predictors of chronic painAnxiety disorderPhysical, psychological, emotional trauma or abuseDepression
Slide14The Common Denominator
Central Sensitization
PTSDFibromyalgiaChronic Fatigue SyndromeMigrainesTension HeadacheFunctional GI disorders
Multiple Chemical Sensitivities
Restless Legs Syndrome
Myofascial Pain Syndromes
Temporomandibular Disorders
Interstitial Cystitis
Primary Dysmenorrhea
Slide15Treatments of Central Sensitization
KetamineGabapentinPregabalinDuloxetine, milnacipran
, lamotrigineCox-2 inhibitorsCognitive Behavioral TherapyAerobic exercise/physical therapyChronic pain rehabilitationMassage therapyRelaxationAcupuncture
Slide16Question
Common attributes of both central sensitization and addiction are:A. ConfusionB. Allodynia
C. HyperalgesiaD. Environmental Factors
Slide17When should opioid
tapering be considered?Lack of functional improvementPain not effectively treated
Intolerable side effectsPatient preferenceUnacceptable risk Nonadherence with treatment planConcern for OUD or SUDAberrant behaviors Concomitant medicationsHigh-dose opioid therapyPsychologic comorbiditiesMayo Clin Proc. 2015;90(6):828-842; VA/DoD 2017
Risks
Benefits
Slide18General Principles
Recommendations vary in guidelines and primary literatureLimited evidence exists comparing tapering strategiesMust be patient-centered – no single strategy will apply to all patients
Mayo Clin Proc. 2015;90(6):828-842; VA/DoD 2017
Slide19Opioid De-escalation
Should only be attempted after a discussion with patient and shared decision-making regarding a treatment plan:
Consider non-opioid and non-pharmacologic therapeutic options for pain controlDiscuss options for treatment for concomitant substance use disorder, as necessaryRecommend options for mental and behavioral health treatment, as appropriate Mayo Clin Proc. 2015;90(6):828-842; VA/DoD 2017; Ment Health Clin. 2015;5(3):102-108; VA PBM Academic Detailing Service 2016
Slide20Opioid De-escalation
Initial rate of reduction can be variable and is related to risk stratificationPatient risk (OUD, mental health conditions, other comorbidities, illicit behaviors)
Duration of opioid therapy Opioid formulationReduction of 5-20% every 4 weeks is commonOften first reduce the dose of the medication to the smallest commonly available unit dosage and then increase the amount of time between doses PRN use of short-acting therapy generally does not need to be tapered
Slide21Factors Determining Taper Duration
Faster taper recommendedSlower taper required
Lower risk patientLonger opioid treatment durationLong-acting opioid therapyConsider 10-25% reduction every 4 weeksMayo Clin Proc. 2015;90(6):828-842; VA/DoD 2017; Ment Health Clin. 2015;5(3):102-108; VA PBM Academic Detailing Service 2016 Higher risk patientShorter opioid treatment durationShort-acting opioid therapyConsider > 25% initial dose reduction
Slide22Taper Examples
Slowest taper
Slow taperFast TaperRapid TaperDurationYearsMonths to yearsWeeksDaysMethodReduce by 2-10% every 1-2 monthsReduce by 5-20% every 4 weeks
Reduce by 10-20% every week
Reduce by 20-50% of first dose if needed, then reduce by 10-20% daily
Adapted
from: VA PBM
Academic
Detailing
Service 2016
Patient Case
RA is a 59 yo WM with a history of chronic lumbar pain from a MVA, for which he has been prescribed opioid therapy for the last nine years. Pain is thought to be primarily neuropathic in origin. Patient and provider are concerned about worsened pain and function, despite recent opioid
dose increases. Patient’s provider would like to taper RA’s opioid therapy in favor of alternatives for pain and requests your assistance.
Slide24Patient Case
Active problemsChronic low back painDepressionHypertensionHyperlipidemia
Pertinent labs are WNLUDS, PDMP, refill history have been appropriateCurrent medications:Morphine SR 30mg TIDSertraline 50mg daily Lisinopril 10mg dailyAtorvastatin 40mg dailyAspirin 81mg daily
Slide25Patient Case
How quickly should RA’s therapy be tapered?Rapidly over the next two weeks, due to his high riskQuickly over the next month, due to his concern for adverse effects
Slowly over the next several months, due to his duration of therapyVery slowly over the next year, due to his high opioid dose
Slide26Patient Case
How quickly should RA’s therapy be tapered?Rapidly over the next two weeks, due to his high riskQuickly over the next month, due to his concern for adverse effects
Slowly over the next several months, due to his duration of therapyVery slowly over the next year, due to his high opioid dose
Slide27Possible Taper Schedule
Current regimen: morphine SA 30mg TIDMonth 1: 30mg QAM, 15mg at noon, 30mg QPMMonth 2: 30mg QAM, 15mg at noon, 15mg QPMMonth 3: 15mg TIDMonth 4: 15mg Q12HMonth 5: 15mg once daily, then stop
Mayo Clin Proc. 2015;90(6):828-842; VA/DoD 2017; Ment Health Clin. 2015;5(3):102-108; VA PBM Academic Detailing Service 2016
Slide28How might this tapering plan differ if a fast taper were required due to patient risk?
Slide29What additional pharmacotherapy could you recommend for RA?
Slide30Withdrawal Symptom Management
Withdrawal symptoms are not life-threatening, but may occur even with a gradual taperShort-term medications may be considered to limit withdrawal symptomsDo NOT use benzodiazepines or opioids to manage withdrawal symptoms
Slide31Withdrawal Symptom Management
Symptom
Possible Treatment Aches, pains, myalgias NSAIDS, acetaminophenDiarrhealoperamideConstipationlaxative - reduce and stop with time
Nausea,
vomiting
Prochlorperazine
, haloperidol, ondansetron
Anxiety, irritability, lacrimation, cramps, rhinorrhea, diaphoresis, insomnia
Hydroxyzine, quetiapine
Insomnia
trazodone
Autonomic symptoms (hypertension, nausea, cramps, diaphoresis, tachycardia)
clonidine;
r
eassess in 3 to 7 days
- t
aper upon symptom resolution
Adapted
with
permission
from:
Ment
Health
Clin
. 2015;5(3):102-108.
Slide32Co-analgesic Therapy
Maria Foy, PharmD, BCPS, CPE
Slide33Patient-Centered Non-Opioid Therapies
Based on focused history, diagnoses, pain assessment, pain type Nociceptive (arthritis, joint/muscle pain)
acetaminophen, NSAIDsNeuropathic (diabetic neuropathy, PHN) anticonvulsants, antidepressantsPatient-specific risk for adverse eventsHistory of GI bleed, renal or hepatic dysfunction, age, uncontrolled hypertensionPatient-specific indications for dual benefit of a particular medicationInsomnia, obesity, depression, anxietyStart one new agent at a timeMay trial multiple agents in a therapeutic category
Slide34Options for Alternative Therapy
N-methyl-D-aspartate (NMDA) antagonistsAcetaminophenNon-steroidal anti-inflammatory agents (NSAIDs)Tricyclic antidepressants (TCAs)Serotonin-norepinephrine reuptake inhibitors (SNRIs)
AnticonvulsantsTopicals
Slide35NMDA Antagonists
Activation of N-methyl-D-aspartate (NMDA) receptors associated with hyperalgesia, neuropathic pain, and reduced functionality of opioid
receptorsAntagonists may play a role in improvement Limiting factors for useSide effects (CNS effects, cardiovascular, GI)Provider expertise and training Ketamine and methadone most commonly usedUS Pharm. 2011;36(5):HS4-HS8; Comprehensive Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches 2013
Slide36Ketamine for Chronic Pain
FDA approved indicationsAnesthetic agent for diagnostic and surgical procedures not requiring muscle relaxation
Induction of anesthesiaA supplement to low potency anestheticsNitrous oxide Off Label UsesPrevention/reversal of central sensitizationTreatment of pain not responding to opioidsTreatment for neuropathic painTreatment for acute pain in opioid tolerant patients
Slide37Ketamine Dosing
Indication
Initial DoseMax DoseRouteCommentsRefractory pain0.1 mg/kg/hr0.5 mg/kg/hrIV/SCContinuous infusionPost-op pain < 50 kg0.1-0.2 mg/kg/hr0.2 mg/kg/hrIV
Continuous infusion
Post-op
pain
> 50 kg
4 mg/
hr
10 mg/
hr
IV
Continuous infusion
Complex Regional Pain Syndrome
10 mg/
hr
30 mg/
hr
IV
Initial:
continuous infusion
Maintenance: intermittent infusions
Slide38Ketamine Adverse Effects
Hypotension , hypertension, tachycardiaPsychomimetic effects (hallucinations, dreamlike state)Increased intracranial pressureExcessive sedationExcessive salivationNausea, vomiting
Tonic clonic movement, tremors, diploplia
Slide39Ketamine Clinical Pearls
Ketamine produces opioid sparing effectsConsider decreasing opioid dosing by 25-50% at initiation of ketamine therapy, followed by 25% every 12-24 hours as toleratedSigns of withdrawal
indicate too rapid of a opioid dose reduction. Treat with a slower taper or bolus dose of ketamineCo-administration of a benzodiazepine or haloperidol is recommended to prevent or minimize psychomimetic effects Consider lorazepam 0.5-1 mg IV/po q6-8h Give dose prior to initiation of infusionIf significant adverse reactions occur, stop the infusion. Side effects should subside in 15-30 minutes
Slide40Methadone
3 mechanisms of analgesia Mu receptor agonist, NMDA receptor antagonist, norepinephrine reuptake inhibitorVariable half life Average of 24 hours, range of 8-56 hoursMultiple cytochrome P450 drug-drug interactions
Can prolong the QTC intervalHigher dosingCongenital predisposition to pro-longed QTCDose increases should not occur before a minimum of 5-7 daysPain control at day 3 can identify risk of overdose at day 5
Slide41Acetaminophen
Dose: 650-1000mg Q4-6 hoursRecommend scheduled use, not PRNLimit to 3-4g/day in healthy patients, 2g/day in hepatic impairmentBe aware of duplication of therapy
No antiplatelet effect (< 2g/day)
Slide42Acetaminophen Toxicity
Acute hepatotoxicity Seen with ingestion of 7.5-15 gramsFatal at 20-25 g
Heavy alcohol consumption, fasting, or malnutrition may increase metabolism to toxic metaboliteChronic toxicity Ingestion of >4 g/day chronicallyArguments to lower maximum dose ongoingConsuming >2 alcoholic drinks/day with doses greater than 2 g/dayAlcoholic liver disease
Slide43NSAIDs
Naproxen, ibuprofen, meloxicam, diclofenac, sulindac, etodolac, indomethacin Caution in renal disease, cardiovascular disease, heart failure, history of GI bleed
Consider celecoxib in patients with history of GI intolerance
Slide44NSAID Adverse Effects
NSAID therapy adverse effects (AE) associated with various body systemsGastrointestinal, CardiovascularHepatic, Renal,Central Nervous, RespiratorySpecial considerations for children and pregnant or lactating women
Chronic therapy and higher doses associated with increased AE risk
Slide45Tricyclic Antidepressants
Tertiary amines Amitriptyline, imipramine Slightly more efficacious for pain, but less well toleratedSecondary amines
Nortriptyline, desipramineMore well toleratedDose at bedtime, due to likelihood of sedation (antihistaminergic properties)Consider in:Younger patients for neuropathic painPatients with concomitant insomnia or depressionCaution in:Elderly because of anticholinergic effectsCardiovascular disease
Slide46TCA Adverse Effects
SedationDry mouth,
Blurred visionConfusion, deliriumConstipationOrthostatic hypotensionWeight gainCardiovascular effectsConduction blocksTachycardiaVentricular arrhythmias
Slide47Selective Norepinephrine Reuptake
InhibitorsDuloxetine, venlafaxine, desvenlafaxine, milnacipran
, levomilnacipranConsider for neuropathic pain in patients with concomitant depression/anxietyMay increase blood pressureNausea and vomiting common DuloxetineAlso indicated for musculoskeletal pain and fibromyalgiaAvoid in hepatic insufficiency, CrCl <30 mL/minVenlafaxine IR product dosed BID or TIDAdjust dose based on renal functionAbrupt withdrawal associated with serious abstinence syndrome
Slide48Anticonvulsants
Gabapentin, pregabalin, topiramate, oxcarbazepine, carbamazepine, lamotrigine,
valproic acidGabapentin generally first line Renal dose adjustment requiredTitrate to a target dose of 1800 mg/day in divided dosesMax dose 3600 mg/dayPregabalin may be preferred over gabapentinImproved tolerability, faster onset, and ease of titrationRenal dose adjustment requiredMonitor for sedation, fluid retention
Slide49Anticonvulsants
Monitor for cognitive effects, especially with topiramateConsider
topiramate Obese patients due to appetite suppressionConcomitant substance use disorders (smoking cessation, alcohol use disorder, others)MigrainesCaution with carbamazepine due to drug-drug interactions
Slide50Topicals
Diclofenac gel or patch, menthol/methyl salicylate cream, trolamine salicylate cream, capsaicin cream or patch, lidocaine gel, cream, or patchGood options in patients at high risk for side effects from other agents
Diclofenac gel, capsaicin cream must be reapplied 3-4 times daily for optimal benefitDiclofenac gel ideal in patients who cannot take oral NSAIDs (minimal systemic absorption)Capsaicin cream onset of action: 2 – 4 weeksAvoid use with irritated or broken skin
Slide51Back to RA
Active problemsChronic low back painDepressionHypertensionHyperlipidemia
Pertinent labs are WNLUDS, PDMP, refill history have been appropriateCurrent medications:Morphine SR 30mg TID tapering plan in placeSertraline 50mg daily Lisinopril 10mg dailyAtorvastatin 40mg dailyAspirin 81mg daily
Slide52What additional pharmacotherapy could you recommend for RA?
Stop sertraline, start duloxetine 30mg daily x 1 week, then increase to 60mg dailyConsider cross taper of morphine to methadone, following baseline EKGStart meloxicam 30mg daily with food
Both A and B
Slide53What additional pharmacotherapy could you recommend for RA?
Stop sertraline, start duloxetine 30mg daily x 1 week, then increase to 60mg dailyConsider cross taper of morphine to methadone, following baseline EKGStart meloxicam 30mg daily with food
Both A and B
Slide54Self Assessment
Which of the following should be considered when determining the speed of an opioid taper?Patient genderDuration of opioid treatment
Opioid dose
Slide55Self Assessment
Which of the following should be considered when determining the speed of an opioid taper?Patient genderDuration of opioid treatment
Opioid dose
Slide56Key Takeaways
Opioid tapers must be individualized for patient needsRecommend slower tapers for those with a longer duration of opioid therapy and with lower risk of useConsider rapid tapers for higher risk patientsOptimization of non-opioid therapy can assist in tapering efforts
Ketamine use is becoming more common for treatment of refractory pain and for opioid sparing effects
Slide57References
Berna C, Kulich RJ, Rathmell JP. Tapering long-
term opioid therapy in chronic noncancer pain: evidence and recommendations for everyday practice. Mayo Clin Proc. 2015;90(6):828-842.Kral LA, Jackson K, Uritsky T. A practical guide to tapering opioids. Ment Health Clin. 2015;5(3):102-108.VA/DoD clinical practice guideline for management of opioid therapy for chronic pain. Washington, DC: Veterans Health Administration; 2017.Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain United States, 2016. MMWR Recomm Rep 2016; 65(1);1–49.
VA PBM Academic Detailing Service. Pain management opioid taper decision tool
–
A VA clinician’s guide. Washington, DC; Veterans Health Administration; 2016.
Vorobeychik
Y, Willoughby CD, Mao J. NMDA Receptor Antagonists in the Treatment of Pain. In: Deer T. et al. (
eds
) Comprehensive Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches. New York, NY. Springer. 2013.
Jamero D, Borghol A, Vo N, Hawawini F. The emerging role of NMDA antagonists in pain management. US Pharm. 2011;36(5):HS4-HS8.