SUBOXONE for Opioid Addiction Medication Assisted Therapy. Dr. Jennifer Melamed MBChB, ABAM, CISAM, CCSAM

Transcription

1 N SUBOXONE for Opioid Addiction Medication Assisted Therapy Dr. Jennifer Melamed MBChB, ABAM, CISAM, CCSAM

2 CONTENTS Part 1 Introduction to N SUBOXONE Part 2 Pharmacology of N SUBOXONE Part 3 Pharmacokinetics of N SUBOXONE Part 4 Minimizing Risk with N SUBOXONE Part 5 Managing Patients on N SUBOXONE Part 6 Pain and Opioid Dependence Part 7 Treatment of Pain in Patients Maintained on N SUBOXONE

3 Part 1 Introduction to N SUBOXONE

4 INDICATIONS For medication assisted treatment of opioid drug dependence Within a framework of medical, social, and psychological treatment For people age 18+ who have agreed to be treated for opioid dependence In order to prescribe Suboxone in BC: Valid Methadone exemption Online course Not approved in Canada in pain control

5 Collaborative Prescribing Agreement (CPA) Criteria Treatment of opioid dependence where Methadone is contraindicated (e.g. for patients at high risk of, or with, QTc prolongation or those with a hypersensitivity to Methadone) OR where there is an inadequate response or intolerance to Methadone. CPA signed = Automatic coverage In order for patients to pay privately for N SUBOXONE, the following needs to be written on duplicate prescription SUBMIT AT ZERO COST TO PHARMACARE CONFUSION ++

6 Why the Benefit of Another Option: About 25% of Canada s estimated 80,000 illegal opioid users on methadone in Popova S, Rehm J and Fischer B. Public Health 2006;120: About 33% of opioid dependent persons have no desire to be in a methadone program. Fischer B et al. Substance use and misuse 2002;37(4): Over 50% wished some other ideal treatment was available. Fischer B et. al. Journal of Urban Health 2005;82(2): Methadone difficult to access in non-urban areas McCarty et al. Journal Subt Abuse Treat 2004;26:

7 IDENTIFICATION & INGREDIENTS Sublingual tablet Contains a fixed combination of buprenorphine and naloxone in a 4:1 ratio in 1 tablet 2 strengths: Buprenorphine 2 mg/naloxone 0.5 mg Buprenorphine 8 mg/naloxone 2 mg Efficacy and safety equivalent to buprenorphine with lower potential for misuse

8 N SUBOXONE vs. N SUBUTEX Rationale Developed to deliver the same efficacy as Buprenorphine while reducing potential for misuse Naloxone, an opioid antagonist, added to deter misuse Parenteral version of antagonist naltrexone; used to reverse overdose Naloxone undergoes extensive first-pass metabolism and is not absorbed into the systemic circulation when taken orally or sublingually However, injection allows naloxone to enter systemic circulation and compete with buprenorphine for receptor occupancy which results in symptoms of opiate withdrawal Narcan 0.4mg needed to reverse full agonists in overdose Narcan 10-15mg needed for Buprenorphine overdose

9 Relative contraindication CONTRAINDICATIONS to N SUBOXONE Pregnant women (Naloxone) Breastfeeding women Uncontrolled alcoholism Allergy to any of the components of N SUBOXONE Acute severe respiratory illness Paralytic ileus Severe liver dysfunction? Increased transaminases > 3-5x upper limit normal

10 Part 2 Pharmacology of N SUBOXONE

11 BUPRENORPHINE: A PARTIAL MU OPIOID RECEPTOR AGONIST Semi-synthetic highly lipophilic Opioid Primary activity in man: Partial mu opioid agonist Kappa receptor antagonist (Inhibits dysphoria) High affinity (moderate efficacy) for mu receptor Will displace other high efficacy opiates, if present, and induce withdrawal symptoms Dissociates slowly from the receptors Ceiling on agonist effects Narcan 0.4mg needed to reverse full agonists in overdose Narcan 10-15mg needed for Buprenorphine overdose Johnson RE, et al. Drug Alcohol Depend; 2003.

12 ACTIVITY OF BUPRENORPHINE MU RECEPTOR: Partial Agonist In absence of full agonist (heroin), buprenorphine binds to receptors and causes reinforcing effect Feeling normal If full agonist (heroin) is present, buprenorphine displaces agonist and causes withdrawal symptoms Center for Substance Abuse Treatment; DHHS; 2004.

13 BUPRENORPHINE: A SAFE CEILING Unlike full agonists, agonist effects of buprenorphine reach a ceiling Less likely to cause respiratory depression in overdose Ceiling can be compromised by concomitant alcohol or other central nervous system depressants, (BENZODIAZEPINES) or when buprenorphine is misused 1 Johnson RE, et al. Drug Alcohol Depend; N SUBOXONE Product Monograph.

14 Pharmacology & Pharmacokinetics Main effect NSUBOXONE (Semi-Synthetic) Methadone (Synthetic) Mu partial agonist Kappa agonist Mu full agonist NMDA antagonist Peak plasma levels 1-3 hours 2-4 hours Bio-availability 50% SL 70%-80% Oral Half-life 37 hours 28 hours Elimination Renal, fecal Renal, fecal Clinically apparent drug interactions Selected ARVs (minimal effect) Active metabolites Norbuprenorphine None Optimal dose 8-16mg (16mg = 92% receptors bound) Rifampin, phenytoin, several ARVs mg (?target dose) Adapted from: Gavin Bart MD, FACP, FASAM (2012): Maintenance Medication for Opiate Addiction: The Foundation of Recovery, Journal of Addictive Diseases, 31:3,

15 Regulation of Stress Response Short acting opiates result in: Suppression of ACTH, cortisol Blunted diurnal variation of ACTH, cortisol Increased ACTH, cortisol in withdrawal Result: Dysregulated pain perception + hyperalgesia Kindling effect: Worsening withdrawal symptoms, increased cravings and risk of relapse These stress response markers normalized in Suboxone-maintained patients Failure to normalize correlates with craving and relapse

16 Regulation of Stress Response Thus: MAT IS NOT SIMPLY REPLACEMENT OF ILLICITLY USED OPIATE FOR A MEDICALLY SUPERVISED OPIATE MAT corrects many of the micro-biological processes contributing to relapse

17 Regulation of Stress Response Source: Gavin Bart MD, FACP, FASAM (2012): Maintenance Medication for Opiate Addiction: The Foundation of Recovery, Journal of Addictive Diseases, 31:3,

18 Part 3 Pharmacokinetics of N SUBOXONE

19 BUPRENORPHINE ABSORPTION Plasma levels increase proportionally with sublingual N SUBOXONE dose Peak plasma levels in 90 minutes Plasma distribution t½ ~2 to 5 hours, but note long duration of action due to slow dissociation from receptors ( 24 hours) Addition of naloxone does not alter pharmacokinetic properties of buprenorphine

20 METABOLISM & ELIMINATION Metabolism Mediated by liver cytochrome P-450 3A4 isoenzyme Severe hepatic impairment may warrant dose adjustment Elimination Buprenorphine: feces (70%), urine (30%) Naloxone: primarily in urine Buprenorphine: Mean plasma elimination t½ 32 hours Naloxone 1.2 hours

21 Part 4 Minimising Risk with N SUBOXONE

22 USE OF N SUBOXONE WITH ALCOHOL AND OTHER CNS DEPRESSANTS Misuse of N SUBOXONE in combination with excessive use of alcohol or other CNS depressants CAN BE FATAL sedative effect of buprenorphine Dizziness, drowsiness, impaired thinking Can respiratory depression Limit use with benzodiazepines Death due to respiratory depression of central origin Tightly regulate benzodiazepine doses, especially where misuse is suspected

23 OBSERVATIONS INTERACTION OF BUPRENORPHINE & BENZODIAZEPINES Clinical data from France deaths: Buprenorphine present Benzodiazepines and/or other CNS depressants present in 99.3% (136/137 cases) BENZODIAZEPINES ATTENUATE THE CEILING EFFECT OF BUPRENORPHINE In presence of Benzodiazepines, N SUBOXONE can no longer be assumed to be partial agonist resembles full agonist with associated risks

24 USE OF N SUBOXONE WITH ANTIRETROVIRAL DRUGS N SUBOXONE can be administered with non nucleoside reverse transcriptase inhibitors (NNRTIs) without dose adjustment N SUBOXONE can be administered with protease inhibitors (PIs) without dose adjustment Only Ritonavir had significant effect on buprenorphine pharmacokinetics

25 Part 5 Managing Patients on N SUBOXONE

26 PHARMACOTHERAPY PHASES IN N SUBOXONE TREATMENT Therapy divided into 4 phases Induction Stabilization Maintenance Medically supervised withdrawal

27 PHASE 1 INDUCTION First appointment: Assessment - Determine patient is a suitable candidate for N SUBOXONE Treatment contract to be signed Urine to screen for opiates, Benzodiazepines, Stimulants Remember Oxycontin, Hydromorphone need to be requested

28 PHASE 1 INDUCTION Second appointment - Induction Patient needs to be in mild to moderate withdrawal prior to initiation of N SUBOXONE Time from last drug use Depends on half-life of opiate used Immediate release opioids - First dose min 6-8 hrs after last use Delayed release opioids - First dose min 12-24hrs after last use Methadone First dose 36 hrs or longer after last use Precipitate withdrawal can occur if N SUBOXONE therapy is started too soon after last opioid dose DO NOT GUESS USE CLINICAL OPIATE WITHDRAWAL SCALE (COWS)

29 Assessing Signs and Symptoms of Withdrawal Ways to assess withdrawal Written scales (eg, COWS) Clinical experience Signs and symptoms The National Alliance of Advocates for Buprenorphine treatment. f

30 INDUCTION DAY 1 INITIAL DOSING Goal: Safely suppress opioid withdrawal as rapidly as possible with adequate doses of N SUBOXONE Initial dose: 2-4 mg of N SUBOXONE Assess patient after 1 hour to ensure no precipitate withdrawal Monitor 1-2 hrs further. May require 2-4mg further if still in withdrawal Additional 2-4mg may be sent home with patient for use in first 24hrs Maximum 8-12mg buprenorphine on Day 1 (16mg?) Contact to be maintained with patient in first 24hrs

31 INDUCTION DAY 2 FOLLOW UP DOSING Patient to be seen in office If no signs of withdrawal = continue dose used in last 24 hrs If withdrawal = add 2-4mg Suboxone to a maximum of 16mg over 24 hrs PATIENT MAY NEED TO BE SEEN ON DAY 3 IF DOSE MANIPULATION WAS REQUIRED ON DAY 2 Induce rapidly! Rapid induction is key to early treatment retention 1 Titrate doses rapidly according to clinical response Review frequently 1 Doran C, et al. Heroin Add & Rel Clin Probl; 2005.

32 INDUCTION DAY.Methadone Decrease methadone to 30 mg/day before starting N SUBOXONE 1 Patients can be transferred from higher doses of methadone to N SUBOXONE 2 Seek consultation Treat any withdrawal symptoms with non-opioid medications Clonidine, loperamide, sleep aids, NSAIDs, etc. 1N SUBOXONE Product Monograph 2 DiPetta G et al. Heroin Add & Rel Clin Probl; 2005.

33 DOSING TO CLINICAL EFFECT Past a certain point, higher doses do not decrease receptor availability Receptor availability: 16mg: 92% reduction 32mg: 98% reduction NOT statistically significant 16mg & 32mg: Similar blockade of 24mg IM Hydromorphone 3mg SL N SUBOXONE = 1mg N SUBOXONE = 30-50mg Parenteral Morphine Greenwald M.K. et al Journal of Neuropsychopharmacology 2003; 28 (11):

34 PHASE 2 & 3 STABILIZATION & MAINTENANCE: FINE-TUNING THE DOSE Goal: Find the dosage necessary to keep patient comfortable and adherent Goals: Prevent opioid withdrawal symptoms Suppress opioid cravings Prevent use of self-administered opioids Address goals of rehabilitation with each patient Duration: Months to years, up to a lifetime Dispensing: N SUBOXONE is taken on a daily basis Daily witness for 2 months. Recommended by Health Canada unless stability is achieved sooner (CAMH states there is no evidence identified supporting this for buprenorphine/naloxone) Any deviation to be documented in chart

35 PHASE 4 MEDICALLY SUPERVISED WITHDRAWAL No scientific evidence that medical withdrawal is effective treatment Patients are at high risk for relapse during withdrawal 1,2 If the patient and physician decide to take this approach: Titrate downward using N SUBOXONE 2 mg and 8 mg doses Ensure that the patient has immediate access to maintenance treatment at all times Monitor patients on an ongoing basis for relapse Mild withdrawal can occur 1 Kakko J, et al. Lancet; Center for Substance Abuse; DHHS, 2004.

36 N SUBOXONE KEY TAKE Home POINTS: RISK MINIMIZATION Dose adequately Provide patients with counseling Monitor patients progress during therapy Use urine sampling if necessary Store supplies securely Keep out of the reach of children Use with care in patients with hepatic impairment Do not use in pregnant women or allow breastfeeding during use Educate patients to: Take as directed Avoid misuse with CNS depressants

37 Part 6 Pain and Opioid Dependence

38 N SUBOXONE Mechanism of Action Salient feature - extended duration of action Presumably related to slow dissociation from mu opioid receptors in the brain (HIGH AFFINITY) N SUBOXONE plasma concentrations are time dependent and correlate highly with mu opiate receptor availability (does not correlate with level of analgesia) Hydromorphone 24mg increased agonist symptoms only when 2/3 of receptors unoccupied (> 52 hrs) Time Post 16 mg Dose Receptor Availability 4 hours 30% 28 hours 54% 52 hours 67% 72 hours 82%

39 Optimal Full Agonist Pain Control Definitions Affinity Measure of the tightness that a drug binds to a receptor Intrinsic Activity (IA) Measure of the ability of a drug once bound to the receptor to generate an effect activating stimulus and produce a change in cellular activity. IA affects the MAGNITUDE of the response Drug Affinity Intrinsic Activity N SUBOXONE High Low Fentanyl Low Highest Hydromorphone Low High Fentanyl has been shown to have the best effect in pain control with patients on Suboxone

40 Pain Control Opioid addiction creates an opioid-induced hyperalgesia i.e. neuroplastic change in pain perception resulting in increased pain sensitivity to painful stimuli & decreased analgesic effect of opioids Patients traumatized by pain Treat aggressively in first hrs

41 Misconceptions Treatment of acute pain in patients on MAT 1. Maintenance dose provides analgesia 2. Use of opioids for analgesia may result in addiction relapse 3. Additive effect of analgesia and MAT may cause respiratory and CNS depression 4. Pain reporting is manipulation or drug seeking

42 Misconception 1 Maintenance Dose Provides Analgesia N SUBOXONE has a duration of action for analgesia of 4-8 hours Opioid withdrawal suppression lasts hours Analgesic tolerance develops due to neuroplastic changes (physical changes in the brain) that yield an increase in pain sensitivity

43 Misconception 2 Risk of Relapse No evidence that exposure to opioid analgesics in presence of acute pain increases rate of relapse in MAT maintained patient In fact, stress associated with unrelieved pain is more likely to be a trigger for relapse Acute pain decreases euphorogenic qualities of the opiate

44 Misconception 3 Respiratory & CNS Depression Tolerance develops rapidly to the respiratory and CNS depressive effects of opioids not to the constipating effect Beware polydrug dependance: Stimulant Crash

45 Misconception 4 Manipulation or Drug Seeking Physicians are fearful of providing opioids as they feel they are being manipulated Baseline dose of MAT typically blocks most euphoric effects of added opioids. Theoretical reduction of opioid analgesic abuse

46 Addiction vs Pseudo-Addiction Addiction diagnosed prospectively Aberrant behavior gets worse with rational treatment plan Pseudo-Addiction diagnosed retrospectively Aberrant behavior normalizes with rational plan

47 Part 7 Treatment of Pain in Patients Maintained on N SUBOXONE

48 Approach to Analgesia in OAT Similar in principle to non-mat patients Guidelines are an opinion based upon clinical experience from several acute pain services and literature recommendations Options employed should be chosen on the basis of the anticipated duration of pain, treatment setting and allowing for modification depending on response to chosen option

49 Questions?