BUPRENORPHINE UPDATE Christian J. Teter, Pharm.D., BCPP Associate Professor, Psychopharmacology College Of Pharmacy, University Of New England Portland, ME E-Mail: cteter@une.edu Image Source: pubchem.ncbi.nlm.nih.gov Disclosure Statement This speaker has no conflict of interest to disclose. There will be no off label drug use discussed in this presentation. Learning Objectives 1. Differentiate between signs and symptoms of opioid intoxication as compared to opioid withdrawal. 2. List the potential advantages of buprenorphine treatment as compared to methadone treatment. 3. Recommend the appropriate therapeutic monitoring required upon the initiation of buprenorphine treatment. 4. Identify medications that should be avoided or used with caution when taken concomitantly with buprenorphine. Christian J. Teter, PharmD, BCPP 1
Abbreviations 4 ADME = absorption, distribution, metabolism, elimination OUD = opioid use disorder PD = pharmacodynamics PK = pharmacokinetics SAMHSA = Substance Abuse and Mental Health Association SUD = substance use disorder Buprenorphine: A Guide for Nurses 5 SAMHSA (key resource) Public domain; FREE; PDF available for download Introduction Drug Addiction Treatment Act of 2000 (DATA 2000) Office-based treatment for OUDs Schedule III-V FDA-approved medications Expanded access to OUD treatment Focus of this lecture is on the clinical use of buprenorphine medications Clinicians must always refer to state and federal laws in regards to appropriate buprenorphine use Christian J. Teter, PharmD, BCPP 2
Opioid Pharmacology Primer Opioid receptor types Mu opioid receptor (MOR) Kappa opioid receptor (KOR) Delta opioid receptor (DOR) Opioid receptor activity Agonists Antagonists Partial agonists Basic opioid pharmacology Affinity Intrinsic activity Dissociation Buprenorphine possesses slow dissociation rate Long duration of action Unpredictable reversal with opioid antagonists Comparatively less physical dependence Full Opioid Agonists Bind to and activate receptor site As dose is increased, effect is increased until maximum response is attained Examples: Heroin Oxycodone Methadone Opioid Antagonists Bind to the receptor without causing activity An antagonist can block the receptor from being activated by partial or full agonist Examples: Naloxone Naltrexone Christian J. Teter, PharmD, BCPP 3
Partial Opioid Agonists Bind to and activate the receptor Activity reaches plateau at which an increase in dose does not result in increased activity Examples: Buprenorphine Pentazocine Buprenorphine Pharmacology High-affinity partial mu opioid agonist Competes with other opioids Slow dissociation Long duration of action Unpredictable reversal Ceiling effect May lower abuse liability Safer in overdose Limit efficacy (?) ceiling effect Buprenorphine Pharmacokinetics (PK) 12 Absorption Distribution Metabolism Elimination Route of administration impacts ADME Christian J. Teter, PharmD, BCPP 4
Buprenorphine PK Pharmaceutical delivery system Sublingual buprenorphine = good bioavailability Sublingual naloxone = low bioavailability Oral buprenorphine and naloxone = poor (gastro-intestinal) bioavailability Injection Naloxone precipitates opioid withdrawal Deter abuse via this route of administration APPROPRIATE USE Growing Number and Variety of Buprenorphine/naloxone Formulations Sublingual Tablets Various strengths Sublingual Film Various strengths Buccal Film Various strengths Image source: Suboxone Sublingual Film NOTE: patient education very important! Buprenorphine PK Absorption Oral (poor); sublingual (fair) C max and AUC linear (4 to 16 mg) **Formulation-specific administration instructions must be closely followed for adequate absorption** Distribution Highly protein bound ( 96%) Alpha and beta globulin Christian J. Teter, PharmD, BCPP 5
Metabolism Buprenorphine PK N-dealkylation to norbuprenorphine (active metabolite) via cytochrome P450 3A4 Glucuronidation Elimination Buprenorphine and norbuprenorphine found in urine (30%) and feces (69%) Elimination half-life from plasma = 32-37 hours* Longer due to slow dissociation rate Buprenorphine Drug-drug Interactions Cytochrome P450 3A4 Inhibitors (examples): Azole antifungals Macrolide antibiotics HIV protease inhibitors Grapefruit juice Inducers (limited data) CNS depressants Reports of death when combined with benzodiazepines Opioids May precipitate withdrawal Full opioid agonist Depends upon baseline opioid status Drug-drug Interactions (examples) 18 Buprenorphine Atazanavir Combination of buprenorphine + atazanavir (without ritonavir) results in both lower atazanavir levels and greater buprenorphine exposure; AVOID this bidirectional-interacting drug combination Conivaptan Conivaptan is a potent inhibitor of CYP3A4; manufacturer recommends its use be avoided with medications metabolized by CYP3A4 CYP3A4 inhibitors (in addition to specific medications listed) May raise buprenorphine levels; monitor for greater than expected buprenorphine effects Christian J. Teter, PharmD, BCPP 6
Buprenorphine Clinical Overview Pharmacologic Tools for OUDs Opioid-specific (vs. adjunctive medications): Agonists Partial Agonists Antagonists Methadone Buprenorphine Naloxone Naltrexone Rationale for Opioid Agonist Treatment Prevents withdrawal Reduces craving Blocks or attenuates the high Decreases: Illicit opioid use Criminal activity Sexually transmitted diseases Christian J. Teter, PharmD, BCPP 7
Titrate to Stability Intoxication Withdrawal Withdrawal Intoxication Insufficient Opioid Excessive Opioid Withdrawal Intoxication Stabilization Signs of Opioid Intoxication and Overdose Opioid Intoxication Conscious Sedated, drowsy Slurred speech Nodding or intermittently dozing Memory impairment Mood normal to euphoric Pupillary constriction Opioid Overdose Unconscious Pinpoint pupils Slow, shallow respirations (e.g., below 10 breaths per minute) Pulse rate slow (e.g., below 40 beats per minute) Overdose triad: apnea, coma, pinpoint pupils (with terminal anoxia: fixed and dilated pupils) Opioid Withdrawal Symptoms Stage Grade Physical Signs/Symptoms Early Withdrawal (8 24 hours after last use) Fully Developed Withdrawal (1 3 days after last use) Grade 1 Grade 2 Grade 3 Grade 4 Lacrimation and/or rhinorrhea Diaphoresis Yawning, restlessness, insomnia Dilated pupils Piloerection Muscle twitching, myalgia and arthralgia Abdominal pain Tachycardia, tachypnea Hypertension Fever Anorexia or nausea Extreme restlessness Diarrhea and/or vomiting Dehydration Hyperglycemia Hypotension Curled-up (fetal) position Christian J. Teter, PharmD, BCPP 8
Buprenorphine Efficacy Multiple trials have confirmed the efficacy of buprenorphine for opioid agonist treatment Retention in treatment Thrice-weekly negative urines Please see Treatment Guidelines (next slide) Over a range of doses: Target dose 12 to 16 mg/day Little added benefit of buprenorphine doses > 32 mg (ceiling effect) Treatment Guidelines for Opioid Use Disorders 26 Level of American Psychiatric Association Intervention (APA) Treatment Guidelines (2006) First-line Opioid intoxication/overdose: naloxone British Association of Psychopharmacology (2012) Opioid intoxication/overdose: not included in review Second-line Opioid Withdrawal: buprenorphine or methadone Opioid Dependence: buprenorphine or methadone Opioid Withdrawal: clonidine Opioid Dependence: naltrexone Opioid Withdrawal: alpha-2-adrenergic agonists or buprenorphine or methadone (using tapered doses) Opioid Dependence: buprenorphine or methadone Opioid Withdrawal: slow release oral morphine (SROM) Opioid Dependence: naltrexone Source: Teter CJ. Substance Use Disorders. 2012-2013 Board Certified Psychiatric Pharmacist (BCPP) Examination Review and Recertification Course. College of Psychiatric & Neurologic Pharmacists: Lincoln (NE); 2012. Treatment Phases Induction Medically monitored Stabilization Dose adjustments Maintenance Indefinite Health care professionals in the community likely to become involved at this point in treatment. Christian J. Teter, PharmD, BCPP 9
Sample Regimen for Buprenorphine Induction Treatment of Opioid Withdrawal and Long-Term Relapse Prevention 28 Day Buprenorphine Sublingual/buccal Dosage 1 2 mg every 2 hours (maximum, 8 mg on first day) 2 Start with total dose of day 1 with additional 2 4 mg every 2 hours (maximum, 16 mg) 3+ Start with total dose of day 2, with additional 2 4 mg every 2 hours (maximum, 32 mg) 4 5 Maintain on dose required to alleviate withdrawal symptoms (a) (a) Patient will likely be transitioned to long-term maintenance dose indefinitely. Data from Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publication no. (SMA) 04 3939. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2004. Buprenorphine Side Effects Due to direct opioid effects or signs and symptoms of (potentially-induced) withdrawal: - Headache - Constipation - Pain (abdominal) - Nausea & vomiting - Insomnia - Anxiety - Diaphoresis - Depression Patient Education Example (essential!) KEY: formulationspecific administration must be followed; patient education! Image source: dailymed.nlm.nih.gov 30 Christian J. Teter, PharmD, BCPP 10
Theoretical Advantages of Methadone vs. Buprenorphine Treatment Access Abuse Potential Adverse Events Medication Cost Drug Interactions Efficacy* Serious toxicity (e.g., respiratory depression) Methadone (full agonist) Advantage Advantage (severe dependence) Buprenorphine (partial agonist) Advantage Advantage Advantage Advantage Advantage *Methadone and Buprenorphine are both considered first-line, effective medications for the treatment of opioid use disorders. There may be an advantage for methadone among patients with severe opioid dependence given its full opioid agonist properties. Source: Teter CJ. Substance Use Disorders. 2012-2013 Board Certified Psychiatric Pharmacist (BCPP) Examination Review and Recertification Course. College of Psychiatric & Neurologic Pharmacists: Lincoln (NE); 2012. 31 Special Populations (pregnancy and lactation) Pregnancy Methadone remains the standard of care (e.g., long history of use in many patients) Opioid antagonists should be AVOIDED in pregnant women (risk of inducing withdrawal in mother and fetus) AVOID any combination [buprenorphine/naloxone] product Breast feeding Poor oral buprenorphine/naloxone absorption Baby should be exposed to low levels of medication Special Populations (age-related considerations) Children Clinician must be familiar with state-level laws in regards to parental consent for treatment Elderly Careful consideration of possible pharmacokinetic and pharmacodynamic changes must be taken into account Examples: Changes in body composition Changes in metabolic clearance Changes in renal clearance Other medications (i.e., interactions) Christian J. Teter, PharmD, BCPP 11
Special Populations (co-occurring conditions) Co-occurring Pain Higher doses of opioid agonists may be required to treat symptoms of pain Overcome buprenorphine partial agonist activity Careful assessment and monitoring required Dose adjustments as necessary Buprenorphine may not be optimal medication to treat an opioid use disorder in patients with co-occurring pain Full opioid agonist could be considered Careful assessment and monitoring required Special Populations (co-occurring conditions) Psychiatric Disorders Medications used to treat psychiatric disorders may interact with buprenorphine Example: Anxiety: benzodiazepines Likely AVOID buprenorphine in patients with acute psychiatric symptoms: Suicidality Acute psychosis Conclusions Christian J. Teter, PharmD, BCPP 12
Buprenorphine Advantages Efficacious (evidence that it works!) More severe patients may require a full opioid agonist Lower risk for abuse and diversion Not zero risk! Safer in overdose Ceiling effect Possibly less stigma than methadone Outpatient treatment Possibly greater access to opioid treatment Outpatient treatment Nurses/Pharmacist Roles Patient education on proper medication use **Key role for health care professionals, in regards to buprenorphine treatment** Various formulations and doses Unique administration instructions Medication adherence Historically poor among individuals with SUDs Side effects vs. withdrawal symptoms Drug interactions CYP3A4-based interactions Nurses/Pharmacist Roles Patient monitoring (key role for health care professionals) Substance use behaviors (broad scope) Includes: Treatment effectiveness Aberrant medication taking behaviors ( both discussed below) Medication-specific: Efficacy (e.g., no relapse; retention in treatment) Medication adherence Side effects (contrast with w/d symptoms) Drug interactions (particularly CYP3A4 mediated) Abuse, misuse, and/or diversion behaviors Laboratory monitoring Urine drug testing, liver function tests, renal function Christian J. Teter, PharmD, BCPP 13
Additional Information SAMHSA Resources (public domain) Primary website: http://www.buprenorphine.samhsa.gov/ Various website links for additional information PDFs available for download TAP 30 Center for Substance Abuse Treatment. Buprenorphine: A Guide for Nurses. 2009. DHHS Pub. No. (SMA) 09-4376. Rockville, MD: Substance Abuse and Mental Health Services Administration. TIP 40 Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publication No. (SMA) 04-3939. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004. Additional Information Teter CJ. Substance Use Disorders. 2012-2013 Board Certified Psychiatric Pharmacist (BCPP) Examination Review and Recertification Course. College of Psychiatric & Neurologic Pharmacists: Lincoln (NE); 2012. Teter CJ. Substance-Related Disorders. Pharmacotherapy Principles and Practice, 3rd Edition. Editors: Chisholm-Burns MA, Wells BG, Schwinghammer TL, Malone PM, Kolesar JM, and DiPiro JT. The McGraw-Hill Companies; 2013. Christian J. Teter, PharmD, BCPP 14