Naltrexone Overview. Todd Korthuis, MD, MPH ECHO-MAT Conference February 14, 2017

Transcription

1 Naltrexone Overview Todd Korthuis, MD, MPH ECHO-MAT Conference February 14, 2017

2 Pharmacotherapy for Opioid Use Disorder % Mu Receptor Intrinsic Activity Full Agonist: Methadone ( How High ) Partial Agonist: Buprenorphine 10 0 no drug low dose Drug Dose Antagonist : Naltrexone high dose ( How Much )

3 Naltrexone for Opioid Use Opioid antagonist Blocks opioid μ, κ, and δ receptors Requires patient fully detoxified Oral formulation 50mg once daily Effective for treatment retention & opioid abstinence 1 Few drug-drug interactions 2 No CYP 450 metabolism Disorder Poor adherence limits effectiveness 1 Minozzi Cochrane McCance-Katz 2001

4 XR-Naltrexone for Opioid Dependence Intramuscular injection lasts 28d Efficacious compared to placebo: Comer: 60 U.S. heroin users at 8 weeks 1 Krupitsky: 250 Russian heroin users at 24 wks 2 Also effective for treatment of alcohol dependence 3 Improves retention in treatment 1 Comer Arch Gen Psych Krupitsky Lancet Garbutt JAMA 2005

5 Naltrexone Safety Minor side effects in treatment of alcohol and opioid dependence 1 Long-term mortality comparable to BUP/NX, Methadone in Australian cohort studies 2 Limited hepatotoxicity VA Data No increased hepatotoxicity 3 Russian RCT (42% HIV+, 88% HCV+) No difference in SAE or liver enzyme elevation by HIV or HCV status 4, 5 1 Lobmaier Reece Tetrault Krupitsky Mitchell McCance-Katz 2001

6 After 6 months Relapse: 43% Naltrexone 64% Usual Treatment Overdoses: 0 Naltrexone 7 Usual Treatment Lee NEJM

7 CTN-0055 Main Results XR-NTX acceptable to patients and providers Among AUD: Treatment Initiation by 4 weeks 92% XR-NTX vs. 93% TAU Treatment Retention at 16 weeks 83% XR-NTX vs. 50% TAU Among OUD: Treatment Initiation by 4 weeks 42% XR-NTX vs. 100% TAU Treatment Retention at 16 weeks 100% XR-NTX vs. 50% TAU

8 XR-NTX Induction General Principles Induction procedures will vary based on: Individual patient s medical needs Clinician s comfort level All patients should be advised regarding potential for precipitated withdrawal if they have recently taken opioids 8

9 Goal of XR-NTX Induction To safely initiate XR-NTX Avoid precipitated withdrawal Avoid opioid relapse prior to XR-NTX dosing 9

10 Recommended Clinical Detoxification and Naltrexone Induction Procedures Sigmon, Nunes, Woody et. al. Opioid Detoxification and Naltrexone Induction Strategies: Recommendations for Clinical Practice. Am J Drug Alc Abuse, 2012; 38(3):

11 Tailoring XR-NTX Induction to Patient 1. Alcohol use disorder and no recent opioid use 2. Opioid use disorder and no recent opioid use 3. Opioid and/or alcohol use disorder with recent opioid use 11

12 XR-NTX Induction Alcohol use disorder and no recent opioid use Proceed directly to XR-NTX, if: Negative self-report of opioid use, and UDS negative for opioids If in doubt, perform naloxone challenge 12

13 XR-NTX Induction Opioid use disorder and no recent opioid use Proceed to XR-NTX when: Negative self-report of opioid use UDS negative for opioids Negative naloxone challenge Preferred, but may be omitted per clinician discretion (e.g. patient enrolling on release from jail) 13

14 14 XR-NTX Induction Opioid and/or alcohol use disorder with recent opioid use: Always requires naloxone challenge Tailor to level of anticipated opioid withdrawal Mild Non-opioid medications for symptom management Moderate-Severe Non-opioid medications for symptom management Opioid-Assisted Detox Buprenorphine May consider outpatient home detox Methadone

15 Streamlined Naltrexone Induction Procedures 5-Day Columbia Induction Protocol* Bup/nx Oral Naltrexone XR- Naltrexone Withdrawal Prophylaxis Monday 2mg-8mg - - Supportive Meds Tuesday - - Supportive Meds Wednesday - 1-3mg - Supportive Meds Thursday mg - Supportive Meds Friday - 25mg 380mg im Supportive Meds *Sullivan, Bisaga, & Nunes, AJP 2017

16 Extended-Release Naltrexone Directions for Use

17 The XR-NTX Kit 17 One vial of XR-NTX microspheres One vial of diluent One 5-mL syringe One 1-inch 20-gauge preparation needle Two 1.5-inch 20-gauge administration needles with aqua needle protection device Two 2-inch 20-gauge administration needles with orange needle protection device

18 XR-NTX Storage XR-NTX is shipped in temperaturecontrolled conditions XR-NTX should always be kept refrigerated at temperatures 2 8 C, F, not frozen Unrefrigerated XR-NTX microspheres can be stored at temperatures not exceeding 25 C or 77 F for no more than 7 cumulative days prior to administration

19 XR-NTX Preparation Must be prepared and administered by a healthcare professional Parenteral products should be visually inspected for particulate matter and discoloration prior to administration Do not substitute for the components in the carton Must be removed from refrigerator for at least 45 minutes prior to administration, and allowed to reach room temperature Use the preparation needle to add the diluent to the microspheres vial Mix powder and diluent by shaking vial vigorously for approximately 1 minute, ensuring the dose is thoroughly suspended

20 XR-NTX Preparation (Continued) Once suspension is reconstituted, administer immediately Withdraw suspension immediately into the syringe using same preparation needle Replace preparation needle with one of the administration needles provided (1.5 inches or 2 inches) Body habitus: assure that proper needle is selected and that the needle length is adequate for intramuscular administration Inadvertent subcutaneous injection of XR-NTX may increase likelihood of severe injection site reactions Prepare 4.2 ml of suspension to administer 4 ml immediately by deep intramuscular (IM) injection into the upper, outer quadrant of the gluteal muscle Dispose of used and unused items in proper waste containers

21 XR-NTX Administration XR-NTX given as an IM gluteal injection every 4 week Inject into the upper, outer quadrant of the buttock, deep into the muscle The buttock should be alternated per monthly injection XR-NTX must not be administered intravenously, subcutaneously, or in the adipose layer. Remember to aspirate for blood before injection. Should be administered with caution to patients with thrombocytopenia or any coagulation disorder

22 What Could Possibly Go Wrong? Precipitate Opioid Withdrawal Sudden onset of new diaphoresis, papillary dilatation, restlessness, rhinorrhea, arthralgias, vomiting, diarrhea, tremor, anxiety/irritability, or piloerection Needle clogging Firm pressure Switch needles is needed Can be avoiding by administering at room temp immediately Post-injection nausea Injection site reaction

23 Risk of Precipitated Withdrawal % Mu Receptor Intrinsic Activity Full Agonist (e.g. heroin) 70 ( How High ) Partial Agonist (e.g. buprenorphine) no drug low dose Antagonist (e.g naltrexone) high dose 23 Drug Dose ( How Much )

24 Management of Precipitated Withdrawal Prevention Goal: zero precipitated withdrawals Withdrawal symptoms typically mild for those with negative UDS Non-opioid medications for symptom management 24

25 Re-Induction onto XR-NTX Within 35 days of the previous dose Usually safe regardless of UDS or selfreported recent use since NTX blockade effective up to 35 days Beyond 35 days since previous dose Risk of re-developing physical dependence increased Negative opioid UDS required Naloxone challenge (if clinically indicated) 25

26 Thank You

27 Supplemental Slides

28 Naloxone Challenge why? A more comfortable XR-NTX induction Performed to confirm the absence of opioids The presence of opioids during naltrexone induction may precipitate uncomfortable withdrawal symptoms 28

29 Naloxone Challenge: Method Dose: min total 0.8 mg naloxone Preferred route: 1) IV, 2) SC, 3) IM, or 4) IN Observe for opioid withdrawal at least 10 minutes when IV 30 minutes when SC, IM, or IN Positive naloxone challenge: onset of new opioid withdrawal symptoms and/or signs of worsening symptoms COWS flow sheet 29

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31 Positive Naloxone Challenge Provide non-opioid medications to treat withdrawal symptoms. Encourage patient to continue to abstain from opioids. Have patient return daily for repeat UDS and naloxone challenge until both are negative. 31

32 Negative Naloxone Challenge If opioid withdrawal symptoms do not worsen or emerge following the naloxone challenge Proceed to XR-NTX administration 32

33 Provider Acceptance of XR-NTX Survey results from 107 providers in 12 HIV clinics 22% of providers said they currently intend to recommended XR-NTX Intent to Recommend XR-NTX Associated with: For Opioid Use Disorder aor (95% CI) For Alcohol Use Disorder aor (95% CI) High belief medication is effective 8.5 (1.6, 44.3) 9.2 (2.3, 36.5) Buprenorphine waiver 5.3 (1.3, 21.6) 1.06 (0.27, 4.08) High social norm 16.5 (3.9, 68.9) 5.3 (1.6, 17.2) Korthuis AMERSA abstract 2014

34 Patient Acceptability Survey of 657 community-based injection opioid users, Vancouver, BC 1 52% Willing to try XR-NTX for opioid use disorder Prescreening of 113 patients: 98% opioid users (n=60), 100% risky alcohol users (n= 82) were definitely or maybe willing to participate in a trial of XR-NTX. 1 Ahamad, Korthuis 2015 ASCP

35 Role of Buprenorphine for Naltrexone Induction (Moderate-Severe Withdrawal, Brief taper) Day 1 Day 2 Day 3 Buprenorphine Dose 4mg, repeat to total of 8-16mg Half of day 1 dose Half day 2 dose Wait 1-3 days for naloxone challenge Non-opioid meds for symptom relief 35

36 Role of Buprenorphine for Induction (Moderate-Severe Withdrawal, 7-day taper) Buprenorphine Dose Day 1 4mg, repeat to total of 12-16mg Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 12mg 10mg 8mg 4mg 2mg 2mg 36 Wait at least 3 days for naloxone challenge Non-opioid meds for symptom relief CTN 002

37 Role of Oral Naltrexone for Induction Opioid use disorder When unable to proceed to XR-NTX same day Give 25mg-50mg po and have patient return next day Alcohol use disorder As bridging measure until XR-NTX induction 12mg-50mg QD Waiting hrs after last dose of oral NTX to begin XR-NTX decreases nausea 37