Substance Abuse Medications.docx

February 16, 2023 Jillian McLlarky, PharmD [email protected] Lecture Outline/Disclosures Review pharmacotherapeutic options for treatment of  Alcohol Use Disorder (AUD)  Opioid Use Disorder (OUD) Apply new knowledge to a patient scenario I have no financial interests or other conflicts of int...

February 16, 2023 Jillian McLlarky, PharmD [email protected] Lecture Outline/Disclosures Review pharmacotherapeutic options for treatment of  Alcohol Use Disorder (AUD)  Opioid Use Disorder (OUD) Apply new knowledge to a patient scenario I have no financial interests or other conflicts of interest to disclose Patient Case CC: 50 year old male who presented to TMH with inability to care for himself and difficulty ambulating at home PMH: AUD (w/hx of DTs), pancreatitis (hospitalized ~ 2-3 wks ago), OUD on methadone, hepatitis C SH: reports drinking 3 pints vodka/day; past IVDU; lives alone, works construction PE: T 98.5, 131/96, HR 78, RR 16, SpO2 93% RA, 6’2” 86.2 kg Neuro: AAO x 3, slurred speech Patient case (continued) Notable Labs: Cr 0.44 mg/dL, Glu 106, Hgb 15.2 g/dL, Plt 196 x109/L, Tbili 0.4, AST 49, ALT 239, Alk Phos 230, Prothrombin time 11.4, INR 1.1, ETOH 319, breathalyzer 0.27, Utox not done (+ for cannabinoids, methadone ~ 3 wks prior) Allergies: NKDA Home meds: folic acid 1mg daily, methadone 130 mg daily, thiamine 100 mg daily Neurobiology of addiction Reward pathway (limbic system) Key neurotransmitters in development of addiction:  Dopamine, Glutamate, GABA, Serotonin Alcohol Withdrawal (GABA/Gluatmate) 6 Alcohol Withdrawal Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar)  Validated scale for rating symptom severity (maximum score is 67)  < 10: very mild withdrawal  10-15: mild withdrawal  16-20: moderate withdrawal  > 20: severe withdrawal Benzodiazepines for Acute Alcohol Withdrawal MOA: binds to the benzodiazepine receptors on the postsynaptic GABA nuron, enhancing the inhibitory effect of GABA on neuronal excitability Side Effects: CNS depression (especially in combination the opioids), hypotension, abuse and dependence Dosing: symptom triggered using the CIWA-AR protocol, objective data (vitals) or a scheduled taper Generic (Trade) name Dosage forms Peak effect (oral) Half-life (parent) Active Metabolites? CYP drug interactions Chlordiazepoxide (Librium) Oral 0.5 – 4 hrs 5 – 30 hrs Yes Yes Diazepam (Valium) Oral Injectable 0.5 – 1 hr 20 – 50 hrs Yes Yes Lorazepam (Ativan) Oral Injectable 2 – 4 hrs 10 – 20 hrs No No Patient case (continued) 50 yo ♂ in acute alcohol withdrawal PMH: AUD (w/hx of DTs), OUD, hepatitis C SH: former smoker, past IVDU, reports drinking 3 pints vodka/day Allergies: NKDA What would be an appropriate regimen to initiate for this patient? Why? If you decide that a patient needs a benzodiazepine taper, what benzodiazepine would you use? Why? Alcohol Withdrawal / Refractory DTs Patient may be refractory to benzodiazepines if he/she  In first hour requires > 50 mg diazepam, or > 10 mg lorazepam  In first 3-4 hours requires > 200 mg diazepam, or > 40 mg lorazepam If refractory DTs develop, consider:  phenobarbital  propofol  dexmedetomidine For alcohol withdrawal, the following are contraindicated or have questionable efficacy  antipsychotics  anticonvulsants  beta-blockers  baclofen Other Agents for Treatment of Acute Alcohol Withdrawal Generic Name Mechanism of Action Side Effects Clinical Considerations Phenobarbital Barbiturate that enhances the inhibitory effect of GABA while reducing overstimulation of glutamate Hypotension and bradycardia Drowsiness, ataxia, vertigo Respiratory depression Stevens-Johnson syndrome/ toxic epidermal necrolysis (SJS/ TEN) and drug reaction with eosinophilia and systemic symptoms Metabolism: hepatic and should be avoided in patients with fulminant liver failure Half-life: 79 hours (53-118) Beneficial for patients who have refractory DTs or if there is a concern for benzo seeking LOTS of drug interactions Propofol Sedative hypnotic with agonism of GABAA receptor and reduces glutamatergic activity through NMDA receptor blockade Hypotension Cardiac conduction disturbances (PRIS) Hypertriglyceridemia (baseline triglycerides and then every 3-7 days after) CNS depression Metabolism: hepatic Patients must be intubated if giving large doses or a continuous infusion Can be considered in treatment resistant alcohol withdrawal Dexmedetomidine Selective alpha2- adrenergic agonist that has anesthetic and sedative properties Hypotension Bradycardia Agitation Drowsiness Never monotherapy for alcohol withdrawal Typically used as a benzodiazepine sparing agent in patients in treatment resistant withdrawal Pharmacological Treatment for Alcohol Use Disorder Drug Proposed MOA APA evidence rating Dosing Notes Naltrexone (ReVia, Vivitrol) blocks Mµ-opioid receptor 1 B 50-100 mg PO daily, or 380 mg IM (gluteal) q 4 weeks can be started while patient is still actively drinking cannot be given to patient taking opioids (prescription or other sources) C/I: acute hepatitis, liver failure also used for OUD Acamprosate (Campral) re-balance of GABA/glutamate neurotransmission 1 B 666 mg PO TID (decrease if ↓ Clcr, or low body weight) initiate after abstinence is achieved may have greater impact on maintaining abstinence (vs reduction of heavy drinking) Disulfuram (Antabuse) inhibits alcohol dehydrogenase 2 C 500 mg PO daily x 1-2 wks, then 125-500 mg PO daily C/I: severe cardiac disease, psychosis, severe liver disease consider “hidden” ethanol (mouthwash, cough syrups) Topiramate (Topamax) promotes GABA, opposes glutamate 2 C 200-300 mg/day can initiate in patient who is still actively drinking increase dose slowly to minimize cognitive impairment may take 4+ weeks to see therapeutic effect Gabapentin (Neurontin) structurally similar to GABA 2 C 900-1800 mg/day sedating abuse potential Patient case (continued) 50 yo ♂ in acute alcohol withdrawal PMH: AUD (w/hx of DTs), OUD, hepatitis C SH: former smoker, past IVDU, reports drinking 3 pints vodka/day Allergies: NKDA Labs upon discharge: BMP and CBC wnl; AST 49, ALT 239, Alk Phos 230, Tbili/Dbili wnl, INR 1.2 Meds upon discharge: folic acid 1mg daily, methadone 130 mg daily, thiamine 100 mg daily If this patient is open to trying medication for AUD, which would you recommend, and why? Naltrexone Acamprosate Disulfuram Topiramate Gabapentin Opioid Withdrawal Acute (short-term)  symptoms: GI (abdominal pain, cramps, nausea/vomiting/diarrhea) pain (bone, muscle) psych (anxiety, insomnia)  signs: tachycardia, HTN, fever, sweating, piloerection, mydriasis, tearing, yawning, rhinorrhea, myoclonus, hyperreflexia Protracted  anxiety, depression, sleep disturbances, fatigue, irritability, dysphoria Clinical Opiate Withdrawal Score (COWS) Medication Assisted Treatment/Recovery (MAT/MAR)  NOT detox  NOT addiction Physical dependence *Opioid withdrawal management alone without ongoing treatment is not recommended    blunts euphoria, reduces cravings Patients are at increased risk for OD when methadone MAT is started  long half-life (8-59 hrs)  additive effect with other opioids and CNS depressants US Regulations  available only through Supervised Opioid Treatment Programs (OTP) exceptions allowed for hospitalized patients and patients in acute withdrawal who are awaiting placement into an OTP prevent diversion and reduce risk of overdose Adverse effects  constipation, mild drowsiness, excess sweating, peripheral edema  reduced libido, erectile dysfunction Drug interactions  substrate for CYP 3A4, 2B6, 2C19, 2D6, 2C9 QTc prolongation - may be dose related  Assess for underlying cardiac risk factors and interacting medications Euphoria felt to a lower extent than traditional opioids Effects reach a ceiling at a much lower dose Combat withdrawal symptoms associated with long term opiate use NEW US Regulation in 2023  Any physicians, PAs and NPs that can prescribe schedule III drugs can now prescribe buprenorphine Buprenorphine formulations: sublingual tablets, monthly extended-release injections (weekly or monthly), subq implant Initial dosing: 2-4 mg of short acting films or tablets  can precipitate withdrawal- do not initiate until patients have objective symptoms of withdrawal Drug interactions  CYP 3A4 inhibitors (eg, azole antifungals, macrolide antibiotics, protease inhibitors)  CYP 3A4 inducers (eg, carbamazepine, phenytoin, efavirenz)  sedating medications (eg, benzodiazepines, alcohol) avoid combination, warn patients Still carries a risk for diversion Buprenorphine/Naloxone Partial agonist/antagonist (4:1 ratio)  Buprenorphine: partial opiate agonist  Naloxone: opioid antagonist Blocks effects of opioids Prevents patients from crushing the buprenorphine and injecting it so slightly lower risk of diversion Formulations: sublingual film, sublingual tablets Initial dosing: buprenorphine 2mg/ naloxone 0.5 mg  Prevent patients from getting effects from opioids by binding the mu receptor Formulations: oral, IM Treatment initiation should only occur when patients are medically supervised because administration can precipitate withdrawal May result in accidental overdose in patients with opioid dependence- risk is higher with naltrexone than other therapies Dosing: IM 380 mg every 4 weeks or oral 25 mg once daily Adverse effects: hepatoxicity, injection site reactions Pros and Cons Methadone Buprenorphine Naltrexone PROs Blunts cravings Can also be used to treat pain Blunts cravings Also treats pain All MDs, PAs and NPs can prescribe Non sedating All MDs, PAs and NPs can prescribe No physical dependence CONs Requires close monitoring Potential for overdose and/ or diversion Needs to be given in an OTP by specific providers May precipitate withdrawal Many different formulations including long acting injectables Potential for diversions May precipitate withdrawal Increase risk for opioid overdose No effect on cravings Patient case (continued) 50 yo ♂ in acute alcohol withdrawal who develops diffuse abdominal pain PMH: AUD (w/hx of DTs), OUD, hepatitis C SH: former smoker, past IVDU, reports drinking 3 pints vodka/day Allergies: NKDA Imaging: CT - acute pancreatitis; colitis; hepatic steatosis Home medications: folic acid 1mg daily, methadone 130 mg daily, thiamine 100 mg daily Initial inpatient medications: folic acid 1mg PO daily, omnipaque (for imaging), benzodiazepine per CIWA, multivitamin PO daily, pantoprazole 80mg IV x 1, Zosyn 3.375 g IV x 1, thiamine 100mg PO, 0.9% saline IV boluses (3L total) The patient is complaining of severe abdominal pain (6/10). Which of the following would you recommend? Ketorolac 60mg IV x 1 Morphine 4mg IV x 1 Methadone 130mg PO x 1 Percocet (oxycodone 5mg/acetaminophen 325mg) 2 tab PO x 1 Suboxone 4/1, 1 film SL TID Acute Pain in Patients with OUD Often require high opioid doses due to tolerance or hyperalgesia Acute pain is not the setting in which to attempt detoxification Difficult to assess baseline amount of opioid use, as patient may be using heroin (varying potencies/chemicals) or buying Rx opioids (fluctuating supplies)  outpatient use of opioids for acute pain may be risky; difficult to titrate General guidelines (consult pain/psychiatry/addiction services if available)  maximize non-opioid adjunctive medications  avoid partial agonists (nalbuphine, buprenorphine)  avoid fixed dose acetaminophen combinations (eg, Percocet, Vicodin)  prescribe in small quantities (1-2 weeks) with frequent follow-up Acute Pain in Methadone Maintained Patients Often require high opioid doses due to tolerance or hyperalgesia  methadone analgesia lasts 6-8 hrs (not effective as monotherapy) General guidelines (consult pain/psychiatry/addiction services if available)  confirm outpatient methadone dose continue as daily dose OR divide total daily dose into 3-4 doses/day if NPO, can give ½ usual daily dose IV (divide into 3-4 doses/day)  maximize non-opioid adjunctive medications  add short-acting opioid (eg, morphine) expect to use higher doses/more rapid titration than for opioid naïve patients  avoid partial agonists (nalbuphine, buprenorphine)  avoid fixed dose acetaminophen combinations (eg, Percocet, Vicodin) Acute Pain in Buprenorphine Maintained Patients Often require high opioid doses due to tolerance or hyperalgesia  buprenorphine can limit analgesic efficacy of other opioids General guidelines (consult pain/psychiatry/addiction services if available)  confirm outpatient buprenorphine dose, continue as daily dose add non-opioid adjunctive medications (eg, NSAIDs)  OR use buprenorphine alone (up to 32 mg/day, divided q 6-8 hrs)  OR replace buprenorphine with a short-acting agonist (eg, morphine) expect to use higher doses/more rapid titration than for opioid naïve patients prescribe on a scheduled basis, not as PRNs avoid fixed dose acetaminophen combinations (eg, Percocet, Vicodin) Restarting buprenorphine: patient must be opioid free for 12-24 hrs From: Patients Maintained on Buprenorphine for Opioid Use Disorder Should Continue Buprenorphine Through the Perioperative Period Pain Med. Published online February 14, 2018. doi:10.1093/pm/pny019 Pain Med | © 2018 American Academy of Pain Medicine.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non- commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re- use, please contact [email protected] Naloxone Co-Prescribing Required in Rhode Island, when prescribing an opioid, if any of the following is true:  When the opioid (alone or in combination with other opioids) is > to 50 oral morphine milligram equivalents (MME) per day  When a benzodiazepine has been prescribed in the past 30 days or will be prescribed at the current visit Must also document in medical record (medical necessity, why benefit > risk)  When patient has a prior history of OUD or overdose Must also document in medical record (medical necessity, why benefit > risk) If naloxone will not be co-prescribed must document in medical record In RI, anyone can get naloxone at any pharmacy without a prescription  All RI health insurers cover at least one type of generic naloxone; may involve a co-pay http://prescribetoprevent.org/wp2015/wp-content/uploads/Naloxone-product-chart.17_04_14.pdf 30 Naloxone Kits / Nasal Narcan® Naloxone kit typically contains prefilled syringe containing 2mg/2mL naloxone, and an atomizer (nasal adapter device) http://harmreduction.org/issues/overdose-prevention/overview/overdose-basics/responding-to-opioid-overdose/administer-naloxone Questions? "To him, all good things—trout as well as eternal salvation— come by grace and grace comes by art and art does not come easy." Norman Maclean (author, A River Runs Through It) AVAILABLE RESOURCES Not a comprehensive List © 2017 American Psychiatric Association. All rights reserved. Resources RI DOH – Safe Opioid Prescribing  http://health.ri.gov/healthcare/medicine/about/safeopioidprescribing/#pcp RI Dept of Behavioral Healthcare, Developmental Disabilities and Hospitals  http://www.bhddh.ri.gov/substance_use/index.php Surgeon General’s report “Facing Addiction in America”  https://addiction.surgeongeneral.gov Substance Abuse and Mental Health Services Administration (SAMHSA)  http://www.samhsa.gov (lots of free downloads, apps, etc) National Institute on Alcohol Abuse and Alcoholism (NIAAA)  https://www.niaaa.nih.gov (lots of publications, multimedia tools, etc) Prescribe to Prevent (prescribe naloxone, save a life)  http://prescribetoprevent.org/ Resources – continued Calculating total daily dosage for safer opioid prescribing  https://www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose-a.pdf PDMPs https://www.cdc.gov/drugoverdose/pdf/pdmp_factsheet-a.pdf Checklist for prescribing opioids for chronic pain  https://www.cdc.gov/drugoverdose/pdf/pdo_checklist-a.pdf Providers Clinical Support System (training resources for MAT) http://pcssmat.org Prevent Overdose RI  http://preventoverdoseri.org (resources for providers, RI overdose data)  http://health.ri.gov/publications/guidelines/provider/PositivePrescriptionMonitoringReport.pdf Resources – Project SHOUT Support for Hospital Opioid Use Treatment  CA statewide coalition, led by University of California, San Francisco (UCSF), supported by California Health Care Foundation (CHCF)  Guidelines  Webinars Methadone induction, acute pain management, pregnancy, discharge planning, etc  Toolkit P&T monographs, sample inpatient order sets, patient education https://www.projectshout.org/ Full guideline text available for free: https://psychiatryonline.org/doi/book/10.1176/appi.books.9781615371969 APA PRACTICE GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF PATIENTS WITH ALCOHOL USE DISORDER December 2017 © 2017 American Psychiatric Association. All rights reserved. Prescription Drug Monitoring Programs (PDMPs) To detect fraud and/or overprescribing of Rx controlled substances  Does not include methadone clinic doses Prescribers must review the PDMP every time an opioid prescription is written  many different types of providers can use PDMP in RI, including law enforcement and licensing boards Detailed reports for a specific patient, including prescriptions filled, who prescribed, and who dispensed  multiple prescribers or multiple pharmacies 38