Buprenorphine Training

1. Buprenorphine Training Sidarth Wakhlu, M.D. Distinguished Teaching Professor Associate Director Addiction Division Addiction Psychiatry Fellowship Director Associate Professor of Psychiatry UT Southwestern

3. Outline • History of heroin, opioid maintenance and buprenorphine • Drug Abuse Treatment Act (DATA) 2000 • Current state of heroin addiction • Current state of prescription opioid addiction (POA) • Opioid Addiction and Women (Heroin and POA) • Buprenorphine Pharmacology and comparison with Methadone • Opioid Withdrawal Management • Goals of Opioid Maintenance Treatment • Buprenorphine Induction Protocols

4. Historical aspects

5. Diacetylmorphine In 1874, English chemist C.R. Alder Wright ventured out into making a non-addictive form of morphine. In doing so he combined anhydrous morphine alkaloid and acetic anhydride . This produced what is known as diacetylmorphine (heroin) Acetylation

6. “Heroic” In 1898, Heinrich Dreser of Germany saw the commercial value in Wright’s invention and began testing on rabbits, himself and fellow co-workers at the drug company he worked at in Germany, Bayer. Dreser later then termed Wright’s invention as “Heroin.” This was due to the results from testing his co-workers who said they had a “heroic” like feeling while using the drug

8. HEROIN “It’s not hypnotic and their is no danger in acquiring a habit!” – Boston Medical and Surgical Journal 1900

9. 1st opioid epidemic after introduction of heroin as a cough suppressant • Between 1912-1923 about 40 Morphine Clinics were established • These clinics dispensed morphine to patients with a history of an Opioid Use Disorder (OUD) • 2nd opioid epidemic took place post WW II • In 1964 first methadone study conducted by Nyswander/Dole at the Rockefeller Institute • In 1972 during the Nixon administration, first methadone clinic established in New York City • The Narcotic Addict Treatment Act (NATA) 1974 allowed Schedule II, III, IV and V medications to be dispensed not prescribed for detoxification and maintenance of OUD

10. Buprenorphine discovered in 1966 at Reckitt & Coleman (now Reckitt & Benckiser, Indivior) • In 1978, Jasinski et al. noted the possible clinical utility of buprenorphine as a treatment for opioid detoxification and maintenance • In 1985 received FDA approval as Buprenex, parenteral buprenorphine for pain treatment (0.3mg IV/IM every 6 hours) , placed in schedule V • By the early 1990s, studies by Johnson et al. and Ling et al., made it clear that buprenorphine could be used effectively for the treatment of heroin addiction • Drug Abuse Treatment Act (DATA) 2000 passed by Congress • Buprenorphine received FDA approval on October 8, 2002 • Just prior to FDA approval of buprenorphine for OUD, DEA moved it to schedule III

11. Drug Abuse Treatment Act (DATA) of 2000 • Allowed “Qualified” physicians to treat opioid use disorder (OUD) outside methadone facilities with Schedule III, IV and V medications FDA approved for OUD • Addiction certification from approved organization, or • Physician in clinical trial of qualifying medication, or • Complete 8-hour course from approved organization • DEA issues (free) to qualifying physicians a new DEA number to use medication for opioid dependence • As of today, only one medication formulation is approved for this use • Rare example of a bipartisan effort (Senators Orrin Hatch, Joe Biden and Carl Levin)

12. Epidemiology of heroin and POA

13. Scope of Heroin Use in the US (National Survey of Drug Use and Health, NSDUH) • NSDUH: Past year heroin use • 2016: 948,000 • 2014: 914,000 • 2012: 669,000 • 2007: 373,000 • NSDUH: Past month heroin use • 2016: 474,000 • 2015: 591,000 • 2014: 435,000 • 2012: 335,000 • 2007: 161,000

14. This increase has been seen in…. • Men • Non-Hispanic whites • Ages 18-25 years • Living in the North East • Suburban and rural communities • Household income less than $20,000 per annum • People addicted to prescription opioid drugs/cocaine/alcohol/marijuana • People without insurance

18. 11.5 million people misused prescription opioid medication (2016)

19. 1.8 million people with Prescription opioid addiction (2016)

22. Fentanyl encounters • The number of fentanyl encounters more than doubled in the US from 5,343 in 2014 to 13,882 in 2015 • Extremely high rates were found in Ohio, Massachusetts and New Hampshire • The steady increase in fentanyl encounters from 2013 to 2015 indicates that the supply of illicitly made fentanyl continues to increase primarily east of the Mississippi river with small increases west of the Mississippi • Research chemical U-47700 (unscheduled synthetic opioid) found in counterfeit oxycodone pills • Other synthetic opioids in the market: acetylfentanyl,carfentanil, butyrfentanyl (alveolar hemorrhages),W-18, MT-45 (ototoxic) and AH-7921

26. Opioid OD deaths • Opioids were involved in 42,249 deaths in 2016 (Total drug ODs 64,000) • Heroin was involved in 15,446 deaths in 2016 • Opioid overdose deaths were five times higher in 2016 than 1999 • In 2016, states with the highest rates of death due to drug overdose • West Virginia (52.0 per 100,000) • Ohio (39.1 per 100,000) • New Hampshire (39.0 per 100,000) • Pennsylvania (37.9 per 100,000) • Kentucky (33.5 per 100,000)

27. Drug overdose death rates for adolescents aged 15–19, by sex: United States, 1999–2015 Source: NCHS, National Vital Statistics System, Mortality

28. Percent distribution of drug overdose deaths for adolescents aged 15–19, by intent and sex: United States, 2015 Source: NCHS, National Vital Statistics System, Mortality

29. Women and opioid addiction

30. Women and Heroin Use • Compared to men, women who use heroin are • Younger • Likely to use smaller amounts and for a shorter time • Less likely to inject • More influenced by drug using sexual partners • Female heroin overdose deaths have tripled in the last few years, between 2010-13, increase in overdose deaths from 0.4 to 1.2/100,000 population

31. POA in women • Between 1999-2010 • 400% increase in overdose deaths in women as compared to 265% in men • 18 women die of overdose daily • For every woman that dies of an overdose, 30 report to emergency rooms with opioid misuse or abuse • Women ages 45-54 & Non-Hispanic White and Native American/Native Alaskan women have the highest risk of overdose • Prescription opioid analgesics are involved in 1 in 10 suicides • Between 2004-2013 NICU admissions for Neonatal Abstinence Syndrome (NAS) has increased from 7/1000 births to 27/1000 births with LOS increase from 13 to 19 days

32. POA in Women • Compared to men, women are • More likely to have chronic pain • More likely to be prescribed opioids • More likely to receive higher doses and for a longer duration • More likely to engage in doctor shopping • More likely to receive a concurrent prescription for a sedative-hypnotic • More likely to hoard POA and sedative-hypnotics • Less likely to crush and snort or inject • Become addicted more quickly (Telescoping)

33. POA in Women • Use prescription opioids to deal with negative affective states & stress while men use them for pleasurable effects & euphoria • Use them first thing in the morning to get through the day and men tend to use prescription opioids primarily in the evening • Telescoping • Accelerated progression from initiation of substance abuse to onset of addiction and first admission to treatment • Women present with a more severe clinical profile i.e. more medical, behavioral, psychological and social problems than men despite having used less of the substance and for a shorter period

35. Buprenorphine

36. Buprenorphine: Pharmacology • 25-100 times more potent than morphine • Partial agonist at the mu opioid receptor (MOR) • Potent kappa receptor antagonist (depression) • Agonist at the nociception or OR-like 1 (ORL1) receptor (analgesia) • High affinity but moderate intrinsic activity • Displaces full mu agonists from the MOR • Lipophilic molecule • High volume of distribution and distributes well in tissues including brain • 96% protein bound

37. Buprenorphine: Pharmacology • Metabolized in the liver through CYP3A4 to norbuprenorphine (active metabolite) • Buprenorphine and norbuprenorphine under glucuronidation to buprenorphine-3-glucuronide (analgesic) and norbuprephine-3-glucuronide (no analgesic activity) • Buprenorphine and norbuprenorphine do not inhibit CYP450 and have few drug interactions • Long half life 20-73 hours (Sublingual/Transdermal preparations) • Onset 30-60 minutes and peak effects are between 1-4 hours • Bioavailability 29% (Sublingual formulation) • Suboxone has a 4:1 ratio of Buprenorphine/Naloxone, naloxone is in the combination as an abuse deterrent • Only indication for Subutex (Buprenorphine monoproduct) is pregnant OUD patients

38. Methadone Buprenorphine Partial mu agonist Kappa antagonist S/L bioavailability 29% T1/2 37hrs,metabolized by CYP450 3A4 Induction requires patients to be in withdrawal Tablets/Film/Buccal film approved for opioid addiction Transdermal patch approved for pain (Butrans) • Full mu agonist • NMDA antagonist and is an SNRI • Oral bioavailability 80% • T1/2 24 hrs,metabolized by CYP450 3A4, also 1A2 & 2D6 • Biphasic elimination alpha 8-12 hours and beta elimination 30-60 hours • Induction does not require patient to be in withdrawal • Approved for opioid addiction (liquid/wafer) and analgesia (tablets)

39. Methadone Buprenorphine Schedule III Prescribed to treat opioid addiction Studied in pregnancy (MOTHER STUDY) No cardiotoxicity Has increased access to care Less Stigma associated • Schedule II • Dispensed for addiction treatment, prescribed for pain • Approved in pregnancy • May prolong QTc • Limited to people in large metropolitan areas • Highly stigmatized treatment

40. 100 90 80 70 60 50 40 30 20 10 0 Full Agonist (Heroin, methadone) % Efficacy Partial Agonist (Buprenorphine) Antagonist (Naloxone) -10 -9 -8 -7 -6 -5 -4 Log Dose of Opioid

41. Opioid withdrawal

42. Opioid withdrawal treatment Efficacy • Extremely high relapse rates > 90% • High risk for HIV, OD upon relapse • Abstinence based approach is not the best treatment for opioid addiction • Treatment outcomes for behavioral interventions alone for opioid use disorders are dismal • Outcomes for better for medication without behavioral interventions, but best for both combined

43. Opioid withdrawal treatment: Methadone • Prior to starting withdrawal treatment • Psychiatric Assessment including a detailed Addiction History including ROS • Clinical Opiate Withdrawal Scale (COWS) • Review Vital Signs and Urine Drug Testing • CBC & Comprehensive metabolic profile • EKG • Day 1-2: 20mg BID • Day 3-4: 15mg BID • Day 5-6: 10mg BID • Day 7-8: 5mg BID • Day 9: 2.5mg BID • Plus hypnotic agent

44. Opioid withdrawal treatment: Buprenorphine • Prior to starting withdrawal treatment • Psychiatric Assessment including a detailed Addiction History including ROS • Clinical Opiate Withdrawal Scale (COWS) • Review Vital Signs and Urine Drug Testing • CBC & Comprehensive metabolic profile • Patient has to be in (at least) mild opioid withdrawal • Day 1: 4mg when they get home and 4mg 4 hours later • Day 2-6: Continue 8mg daily • Day 7: Re-assess , may increase dose to 10-12mg daily • Taper dose by 2mg every 1-2 weeks as tolerated • Plus add hypnotic agent

45. Opioid maintenance treatment

46. Goals of OMT: Eliminate or reduce illicit opioid use Eliminate drug cravings and withdrawal symptoms Decrease HIV/Hepatitis seroconversion Decrease in criminal behavior Improve social and occupational functioning & normalize brain functioning

47. FDA approved Rxs for Opioid Use Disorder (OUD) Methadone Buprenorphine/Naloxone (Suboxone tablet & film, Zubsolv,Bunavail buccal film) Buprenorphine (Subutex) L-Alpha Acetyl Methadol (LAAM) Naltrexone

48. Methadone Induction Protocol • Prior to induction • Psychiatric Assessment including a detailed Addiction History including ROS • Clinical Opiate Withdrawal Scale (COWS) • Review Vital Signs and Urine Drug Testing • CBC & Comprehensive metabolic profile • EKG • Day 1: 30mg daily (patients don’t have to be in WD to be induced) • Day 2-5: 40mg daily • Day 6 onwards: 50mg daily • Re-assess in 2 weeks and consider dose increase • Dose range 60-120mg • Need to add hypnotic agent

49. Buprenorphine Induction Protocol (Heroin/Short Acting Opioids) • Prior to induction • Psychiatric Assessment including a detailed Addiction History including ROS • Clinical Opiate Withdrawal Scale (COWS) • Review Vital Signs and Urine Drug Testing • CBC & Comprehensive metabolic profile • When patient in mild opioid WD, start with Buprenorphine 4/1mg now, repeat another 4/1mg 4 hours later • Day 2-6: 8/1mg daily • Day 7: See them back in clinic and consider increase to 10-12mg daily • Dose range 8-16mg • Need to add hypnotic agent

50. Buprenorphine Induction Protocol (Methadone/Long acting opioids) • This can be a challenge • Taper patient down to 30mg or less of methadone • Wash out period for 48-72 hours • During this time manage symptomatically with Gabapentin 300-600mg TID + Clonidine 0.1-0.2mg TID (outpatient) or Lorazepam 2mg TID + Clonidine 0.1-0.2mg TID (inpatient) plus a hypnotic agent • Induce with Buprenorphine/Naloxone 2/0.5mg, if patient tolerates it well then administer Buprenorphine/Naloxone 6/1.5mg 30-40 minutes after the initial dose • Day 2-6: 8/1mg daily • Day 7: Consider increase to 10-12mg daily • Dose range 8-16mg • Need to add hypnotic agent