Buprenorphine

Daryl Shorter, M.D.

Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine

© Alcohol Medical Scholars Program

I.     Introduction

        A.  Opioid (e.g., heroin) use is epidemic (Slide 2)

                1.  2.23 million persons with Opioid Use Disorder (OUD) (defined below) [[1]]

                2.  426,000 OUD with heroin

                3.  1.8 million OUD from Rx pain relievers

        B.  For those with OUD, stopping opioid use is challenging

        C.  Treatment substituting long acting opioids for drug of abuse started in 1963

        D.  Classic Rx for opioids = methadone (Dolophine)

        E.  Methadone substitution (i.e., maintenance) has both +’s and –‘s

        F.  Buprenorphine maintenance developed in response to problems with methadone

        G.  This lecture will review (Slide 3)

                1.  Definitions and descriptions of key problems

                2.  Course of Opioid Use Disorder

                3.  Treatment of Opioid Use Disorder

                4.  Role of buprenorphine in OUD long-term Rx

II.  Definitions and descriptions of key opioid problems

        A.  Brain effects for all opioids (Slide 4)

                1.  Decrease pain via action at μ-opioid receptor in brain

                2.  Suppress cough

                3.  Increase constipation

                4.  Cause euphoria (μ-opioid receptor)

        B.  Opioids include (Slide 5)

                1.  Heroin – no medical use

                2.  Morphine – Rx for pain

                3.  All prescription pain meds (unless anti-inflammatory)

                        a.  Oxycodone (Oxycontin)

                        b.  Hydrocodone (Vicodin, Lorcet, Lortab)

                        c.  Methadone (Dolophine)

                        d.  Buprenorphine (Subutex)

                        e.  Tramadol (Ultram)

        C.  Persistent opioid problems (Opioid Use Disorder)

                1.  DSM-5 (5th edition of diagnostic manual of American Psychiatric Assn) definition (Slide 6)

                2.  Characterized by 2+ of 11 symptoms (in same 12 months)

                        a.  Taken in larger amounts of over longer period

                        b.  Unsuccessful efforts to cut down or control use

                        c.  Much time spent obtaining, using, or recovering

                        d. Craving or strong desire/urge to use

e.  Failure to fulfill major role obligations

f.  Continued use despite negative social consequences

g.  Important activities are reduced or given up

h.  Use in physically hazardous situations

i.  Use despite knowledge of physical/psychological problem

j.  Tolerance (defined by either)

        .  amounts needed to achieve same effect

        .  effect with continued use of same amount

k.  Withdrawal (defined later) manifested by either

        .  Withdrawal syndrome (dysphoria/nausea/vomiting/etc)

        .  Opioids taken to relieve/avoid withdrawal

        D.  Opioid Withdrawal (Slide 7)

                1.  Syndrome for all chronically used opioids

                2.  Symptoms: opposite of acute effects (from DSM-5, 3+ needed)

                        a.  Dysphoric (sad) mood

                        b.  Nausea/vomiting

                        c.  Muscle aches

                        d.  Lacrimation (tearing) or rhinorrhea (runny nose)

                        e.  Pupillary dilation, piloerection (goose flesh), or sweating

                        f.  Diarrhea

                        g.  Yawning

                        h.  Fever

                        i.  Insomnia

        E.  Overdose

                1.  Fatal overdose (Slide 8)

                        a.  Overdose deaths

                                .  Second only to auto accidents as causes of accidental death [[2]]

                                .  17,000 opioid overdose deaths in US, 2010 [[3]]

                        b.  Death primarily from respiratory depression [[4]]

2.  Nonfatal overdose (NFO)

        a'.  Rates also a concern

.  ~7 NFOs for every fatal overdose [[5]]

.  From 1999-2006, methadone-related hospitalizations 400% [[6]]

                                        b'.  Clinical diagnosis of overdose (Slide 9)

                                                .  Altered level of consciousness

                                                .  Respiratory depression (respiratory rate < 12/min)

                                                .  Miotic (pinpoint) pupils

                                                .  Circumstantial evidence of opioid use (i.e., needle track marks)

                                        c'.  Management of overdose

                                                .  Reverse overdose with opioid antagonist, naloxone (Evzio)

                                                .  Supportive breathing, blood pressure, etc as needed

III.  Course of Opioid Use Disorder (Slide 10)

        A.  Age of onset       

                1.  Nonmedical use of prescription medications (NUPM) (Slide 11)

                        a.  perception in risk of NUPM among adolescents

                        b.  availability of Rx pain killers

                        c.  adolescents reporting NUPM: 48% college students [[7]]

                        d.  Mean age of first use = 22 years

                2.  Heroin use

                        a.  9% of adolescents say is “fairly easy” to obtain [1]

                        b.  Mean age of first use = 25 years

        B.  Progression from NUPM to heroin use

                1.  40% heroin users had NUPM before heroin [[8],[9]]

                2.  Predictors of progression [[10]]

                        a.  Prescription opioid dependence

                        b.  Early age prescription opioid use for high

                        c.  Using prescription opioids for euphoria

                        d.  Use of prescription opioids through non-oral route (e.g., IV)

        C.  Health implications of chronic opioid misuse [[11]] (Slide 12)

                1.  Accidental injury associated with opioids

                        a.  1.5-5x risk of falls & fractures [[12],[13],[14]]

                        b.  ~3x risk of mortality from motor vehicle accidents [[15],[16]]

                2.  Early death from medical illness

                        a.  OUD 4x risk of overall mortality [[17]]

                        b.  Cardiovascular disease (CVD)

                                .  Rx opioid use associated with CVD mortality [[18]]

                                .  Female Rx opioid users at risk of coronary heart disease

                                .  ~1.3-2x risk of myocardial infarction (MI) [[19]]

                3.  Consequences of intravenous drug use

                        a.  risk of HIV  (~7% of IV heroin users found to be HIV+) [[20]]

                        b.  rates of Hep C transmission in line with treatment admissions for IV opioid use [[21]]

        D.  Social implications (Slide 13)

                1.  Criminal behavior

                        a.  ~45-85% report criminal involvement at time of entering treatment [[22],[23]]

                        b.  ~$50,000/yr law enforcement and victimization costs for untreated OUD [[24]]

                2.  Education/employment

                        a.  Opioid use ΰ lower GPAs, 3x more likely to skip school [[25]]

                        b.  3-7.5x more likely to be suspended or expelled from school

                        c.  ~65-85% of persons with OUD unemployed when entering treatment [[26]]

                3.  Violence

        E.  Rates of relapse are quite high (Slide 14)

                1.  6 months after completing treatment: ~50% abstinent [[27]]

                2.  10 years after treatment: ~25% abstinent [[28]]

IV.  Treatment of Opioid Use Disorder (Slide 15)

        A.  Goals (Slide 16)

                1.  Reduce symptoms of withdrawal

                2.  Reduce craving

                3.  Prevent relapse 

                4.  Re-establish physiologic balance and improve daily functioning

        B.  Case Presentation – Jimmy (slide 17)

                1.  32-year old male who presents to the emergency department

                2.  Reports 12-year history of opioid misuse (incl. hydrocodone, oxycodone, and heroin)

                3.  Last use of heroin was approximately 12 hours prior

                4.  Numerous symptoms of opioid withdrawal at the time of presentation

                        a.  Anxiety

                        b.  Sweating

                        c.  Nausea (reported)

                        d.  Pupillary dilation

        B.  Rx administered according to phase

                1.  Phase 1: Opioid withdrawal

                        a.  Acute management

                                .  Consider using Clinical Opioid Withdrawal Scale (COWS) (Slide 18)

                                        a’.  11-item assessment of opioid withdrawal symptoms

                                        b’.  Includes pulse, sweating, pupil size, yawning, and anxiety

                                        c’.  Scores characterize withdrawal:

                                                1’’.  5-12 = mild

                                                2’’.  13-24 = moderate

                                                3’’.  25-36 = moderately severe

                                                4’’. ≥36 = severe

                                .  One approach: symptom management using clonidine (Catapres) (Slide 18)

                                        a’.  Clonidine

                                                1’’.  Alpha-2-adrenergic agonist to adrenalin

                                                2’’.  Treats hypertension

                                                3’’.  withdrawal

                                        b’.  Rx other symptoms as needed (examples)

                                                1’’.  Loperamide (Imodium) for diarrhea

                                                2’’.  Ibuprofen (Advil) for bone/muscle pain

                                                3’’.  Medications for insomnia

                                        c’.  Symptom-triggered clonidine (Slide 20)

                                                1’’.  For COWS score > 8, give 0.1-0.2mg Clonidine

                                                2’’.  On day 1, target dose of 0.3-0.6mg

                                                3’’.  May increase to 0.6-1.2mg/day, as necessary

                                                4’’.  Once stabilized, reduce daily dose by 50% each day

                                .  Alternate approach using opioid agonist (Slide 21)

                                        a’.  Methadone (Slide 22)

                                                1.’’  Rx up to 30mg day to symptoms

                                                2’’.  10-20% every 1-2 days over 2-3 weeks

                                                3.’’  Better than alpha-2-adrenergic agonist based

                                        b’.  Buprenorphine

                                                1.’’  Rx up to 8mg day to symptoms

                                                2’’.  by 2mg every 1-2 days over 7-10 day period

                                                3.’’  Better than alpha-2-adrenergic agonist based

                2.  Phase 2:  Long term Rx for Opioid Use Disorder (Slide 23)

                        a.  Opioid antagonist Rx (Slide 24)

                                .  Intramuscular naltrexone (Trexan)

                                        a’.  Administer every 30 days

                                        b’.  On naltrexone cannot get opioid high

                                        c’.  Low compliance: pts not like this Rx much

                                .  No other US FDA-approved antagonist Rx for chronic treatment

                        b.  Methadone maintenance treatment (MMT) (Slide 25)

                                .  Taken daily by mouth

                                .  Obtained through a federally-regulated Rx program

                                .  Optimal dose varies; target is 80mg/day

                                .  But MMT has drawbacks (Slide 26)

                                        a’’.  Overdose common in early Rx

                                        b’’.  Cannot be given from general practice office

                                        c’’.  Strict gov’t control and paperwork for those clinics

                                        d’’.  Stigma of daily clinic attendance                              

                        c.  Office-based buprenorphine Rx is next topic (Slides 27, 28)

                                .  Taken daily, sublingually

                                .  Obtained from waivered physicians

                                .  Individual dose may vary; target dose is 16-24mg/day

                                .  For stable patients, daily visits to provider no longer necessary

V.  Role of buprenorphine in maintenance Rx

        A.  Pharmacological properties (Slide 29)

                1.  Partial μ-opioid receptor agonist (binds to receptor and stimulates it)

                2.  Persists at receptor ΰ slow dissociation

                3.  = 24-36 hrs

                4.  Clinical impact of buprenorphine pharmacology (Slide 30)

                        a.  Less subjective euphoria than methadone

                        b.  Long-lasting clinical action and effectiveness at less-than-daily dosing

                        c.  Blocks intoxication effects from other opioids

                        d.  Reduced risk of overdose**

        B.  Pharmacokinetics

                1.  Is metabolized quickly if given orally

                2.  Well absorbed and slower metabolism if sublingual

        C.  Formulation (Slide 31)

                1.  Buprenorphine alone (Subutex – now only available in generic form in US)

                2.  Buprenorphine plus low-dose naloxone (Suboxone)

                        a’.  Naloxone is antagonist similar to naltrexone as discussed above

                                .  Short t½ of 30min to 1hr

                                .  Used to reverse opioid overdose; but causes withdrawal

                                3.  Best absorbed IV (not oral)

                        b’.  Goal: risk of diversion and IV misuse

                        c’.  Buprenorphine combined with naloxone in 4:1 ratio

                3.  Combo also available in sublingual liquid or buccal film

                        a’.  Dose is 4mg buprenorphine to 1mg naloxone

                        b’.  Buccal film might have misuse [[29]]

        D.  Side effects (Slide 32)

                1.  Neuro:  Sedation, dizziness, headache

                2.  GI:  Constipation, nausea/vomiting

                3.  Respiratory depression

        E.  Availability and Cost 

1.  Only Rx’d by MDs with special training

2.  Rx can be office-based

3.  Reimbursed by Medicaid and most health insurance

        F.  Risks and benefits of buprenorphine

                1.  Advantage:  less inadvertent OD vs methadone

                2.  Advantage:  convenience: not require special clinic

                3.  Problem:  cost more than methadone

                4.  Patients dropout ordirty urine in some studies

        G.  Buprenorphine Maintenance (Slide 33)

                1.  Rx initiation

                        a.  Goals: avoid precipitation of withdrawal and/or overdose

                        b.  Patient to discontinue opioid misuse for 12-36 hours prior

                        c.  Patient should demonstrate early withdrawal (e.g., COWS > 8)

                2.  Induction phase (days 1-7) (Slide 34)

                        a.  Day 1

                                .  First dose = 4mg

                                .  Assess for adverse effects 30-60 min later

                                .  Repeat 4mg dose if withdrawal symptoms persist 2-4 hr after 1st dose

                                4.  Maximum dose day 1 = 8mg

                        b.  Days 2 – 7 (Slide 35)

                                .  dose until withdrawal symptoms are within 2 hrs of dose

                                .  Day 2 dose: often to 16mg

                                .  dose by Day 7 are employed (usual to 8 – 24mg/day)

                3.  Stabilization phase (Weeks 2 -8) (Slide 36)

                        a.  Dose adjustment may continue, with to 32mg/day as necessary

                        b.  In stabilization see:

                                .  opioid craving

                                .  No withdrawal symptoms

                                .  or absent opioid misuse

                                4.  No further dose adjustments needed

                4..  Maintenance phase (Months 3-12) (Slide 37)

                        a.  Optimal dose reached

                        b.  Work on relapse prevention to support abstinence

        H.  Evidence buprenorphine maintenance works (Slide 38)

                1.  Buprenorphine maintenance (at ≥16mg/day) better than placebo and naltrexone re:

                        a.  Treatment retention

                        b.  Opioid positive urines

                2.  Buprenorphine versus methadone (Slide 39)

                        a.  Both improve outcomes, but methadone with greater patient retention

                        b.  Buprenorphine carries benefit of office-based Rx and safer during induction

VII.  Conclusions (Slide 40)

        A.  Opioid Use Disorder (OUD) is common and dangerous.

        B.  Buprenorphine is a partial agonist at the μ-opioid receptor with a favorable safety profile.

        C.  Buprenorphine is an effective treatment for the office-based treatment of OUD.

        D.  Buprenorphine in combination with naloxone reduces misuse and diversion.

 

 

 

 

References:



[1]) Center for Behavioral Health Statistics and Quality. (2015).  Behavioral health trends in the United States: Results from the 2014 National Survey on Drug Use and Health (HHS Publication No. SMA 15-4927, NSDUH Series H-50. Retrieved from http://www.samhsa.gov/data/

[2]) Nosyk B, Anglin MD, Brecht ML, Lima VD, Hser YI. Characterizing durations of heroin abstinence in the California Civil Addict Program: results from a 33-year observational cohort study.  Am J Epidemiol 2013; 177: 675-82.

[3]) Jones CM, Mack KA, Paulozzi LJ.  Pharmaceutical overdose deaths, United States, 2010.  JAMA 2013; 309(7): 657-9.

[4]) White JM, Irvine RJ.  Mechanisms of fatal opioid overdose.  Addiction 1999; 94(7): 961-72.

[5]) Kuehn, BM.  Alarming nonfatal overdose rates found for opioids, sedatives ,and tranquilizers.  JAMA 2010; 303(20): 2020-21.

[6]) Coben JH, Davis SM, Furbee PM, Sikora RD, Tillotson RD, Bossarte RM.  Hospitalizations for poisoning by prescription opioids, sedatives, and tranquilizers.  Am J Prev Med 2010; 38(5): 517-524.

[7]) Brandt SA, Taverna EC, Hallock RM.  A survey of non-medical use of tranquilizers, stimulants, and pain relievers among college students: patterns of use among users and factors related to abstinence in non-users.  Drug Alcohol Depend 2014; 143: 272-6.

[8]) Pollini RA, Banta-Green CJ, Cuevas-Mota J, Metzner M, Teshale E, Garfein RS.  Problematic use of prescription-type opioids prior to heroin use among young heroin injectors.  Subst Abuse Rehabil 2011; 2(1): 173-80.

[9]) Peavy KM, Banta-Green CJ, Kingston S, Hanrahan M, Merrill JO, Coffin PO.  “Hooked on” prescription-type opiates prior to using heroin: results from a survey of syringe exchange clients.  J Psychoact Drugs 2012; 44(3): 259-65.

[10]) Carlson RG, Nahhas RW, Martins SS, Daniulaityte R.  Predictors of transition to heroin use among initially non-opioid dependent illicit pharmaceutical opioid users: A natural history study.  Drug Alcohol Depend 2016 (in press)

[11]) Degenhardt L, Hall W.  Extent of illicit drug use and dependence, and their contribution to the global burden of disease.  Lancet 2012; 379: 55-70.

[12]) Vestergaard P, Rejnmark L, Mosekilde L.  Fracture risk associated with the use of morphine and opiates.  J Intern Med 2006; 260(1): 76-87.

[13]) Portenoy RK, Farrar JT, Backonja MM, Cleeland CS, Yang K, Friedman M, Colucci SV, Richards P.  Long-term use of controlled-release oxycodone for non-cancer pain: results of a 3-year registry study.  Clin J Pain 2007; 23(4): 287-99.

[14]) Li L, Setoguchi S, Cabral H, Jick S.  Opioid use for noncancer pain and risk of fracture in adults: a nested case-control study using the general practice research database.  Am J Epidemiol 2013a; 178(4): 559-69.

[15]) Callaghan RC, Gatley JM, Veldhuizen S, Lev-Ran S, Mann R, Asbridge M.  Alcohol- or drug-use disorders and motor vehicle accident mortality: a retrospective cohort study.  Accid Anal Prev 2013; 53: 149-55.

[16]) Wilson FA, Stimpson JP, Pagan JA.  Fatal crashes from drivers testing positive for drugs in the U.S., 1993-2010.  Public Health Rep 2014; 129(4): 342-50.

[17]) Bogdanowicz KM, Stewart R, Broadbent M, Hatch SL, Hotopf M, Strang J, Hayes RD.  Double trouble: Psychiatric comorbidity and opioid addiction-all-cause and cause-specific mortality.  Drug Alcohol Depend 2015; 148: 85-92.

[18]) Khodneva Y, Muntner P, Kertesz S, Kissela B, Safford MM.  Prescription opioid use and risk of coronary heart disease, stroke, and cardiovascular death among adults from a prospective cohort (REGARDS Study).  Pain Med 2015.  Doi: 10.1111/pme.12916 [Epub ahead of print]

[19]) Li L, Setoguchi S, Cabral H, Jick S.  Opioid use for noncancer pain and risk of myocardial infarction amongst adults.  J Intern Med 2013b; 273: 511-26.

[20]) Wejnert C.  HIV infection and HIV-associated behaviors among injecting drug users – 20 cities, United States, 2009.  MMWR 2012; 61: 133-38.

[21]) Zibbell JE, Kashif I, Patel RC, Suryaprasad A, Sanders KJ, Moore-Moravian L, Serrecchia J, Blankenship S, Ward JW, Holtzman D.  Increases in Hepatitis C virus infection related to injection drug use among persons aged 30 years – Kentucky, Tennessee, Virginia, and West Virginia, 2006-2012.  MMWR 2015; 64: 453-8

[22]) Rosengren DB, Downey L, Donovan DM.  “I already stopped”: abstinence prior to treatment.  Addiction 2000; 95(1): 65-76.

[23]) Soyka M, Trader A, Klotsche J, Haberthur A, Buhringer G, Rehm J, Wittchen H.  Criminal behavior in opioid-dependent patients before and during maintenance therapy: 6-year follow-up of a nationally representative cohort sample.  J Forensic Sci 2012; 57(6): 1524-30.

[24]) Wall R, Rehm J, Fischer B, Brands B, Gliksman L, Stewart J, Medved W, Blake J.  Social costs of untreated opioid dependence.  J Urban Health 2000; 77(4): 688-72.

[25]) McCabe SE, Boyd CJ, Teter CJ.  Illicit use of opioid analgesics by high school seniors.  J Subst Ab Treat 2005; 28(3): 225-30.

[26]) Koo DJ, Chitwood DD, Sanchez J.  Factors for employment: a case-control study of fully employed and unemployed heroin users.  Subst Use Misuse 2007; 42: 1035-54.

[27]) Gossop M, Green L, Phillips G, Bradley B.  Lapse, relapse, and survival among opiate addicts after treatment: a prospective follow-up study.  Br J Psych 1989; 154: 348-53.

[28]) Hser YI, Anglin D, Powers K.  A 24-year follow-up of California narcotics addicts.  Arch Gen Psychiatry 1993; 50(7): 577-84.

[29]) Lavonas EJ, Severtson SG, Martinez EM, Bucher-Bartelson B, Le Lait, M, Green JL, Murrelle LE, Cicero TJ, Kurtz SP, Rosenblum A, Surratt HL, Dart RC.  Abuse and diversion of buprenorphine sublingual tablets and film.  J Subst Ab Treat 2014; 47: 27-34.