1. Buprenorphine : A New Approach for Opioid Treatment Thomas E. Freese, Ph.D. Pacific Southwest Addiction Technology Transfer Center UCLA Integrated Substance Abuse Programs National Conference on Problem Gambling Kansas City, MO June 8, 2007

2. My Opinions Concerning Medication Management There are many strongly felt emotions held by addiction and other helping professionals towards medication management and the use of pharmacotherapies to treat substance dependence… …What are yours?

3. A Brief History of Opioid Treatment

5. 1964: Methadone is approved. 1974: Narcotic Treatment Act limits methadone treatment to specifically licensed Opioid Treatment Programs (OTPs). 1984: Naltrexone is approved, but has continued to be rarely used (approved in 1994 for alcohol addiction). 1993: LAAM is approved (for non-pregnant patients only), but is underutilized.

6. A Brief History of Opioid Treatment, Continued 2000: Drug Addiction Treatment Act of 2000 (DATA 2000) expands the clinical context of medication-assisted opioid treatment. 2002: Tablet formulations of buprenorphine (Subutex ® ) and buprenorphine/naloxone (Suboxone ® ) were approved by the Food and Drug Administration (FDA). 2004: Sale and distribution of ORLAAM ® is discontinued.

7. Understanding DATA 2000

8. Drug Addiction Treatment Act of 2000 (DATA 2000) Expands treatment options to include both the general health care system and opioid treatment programs. Expands number of available treatment slots Allows opioid treatment in office settings Sets physician qualifications for prescribing the medication

9. DATA 2000: Physician Qualifications Physicians must: Be licensed to practice by his/her state Have the capacity to refer patients for psychosocial treatment Limit their practice to 30 patients receiving buprenorphine at any given time Be qualified to provide buprenorphine and receive a license waiver 100 patients

10. A physician must meet one or more of the following qualifications: Board certified in Addiction Psychiatry Certified in Addiction Medicine by ASAM or AOA Served as Investigator in buprenorphine clinical trials Completed 8 hours of training by ASAM, AAAP, AMA, AOA, APA (or other organizations that may be designated by Health and Human Services) Training or experience as determined by state medical licensing board Other criteria established through regulation by Health and Human Services DATA 2000: Physician Qualifications

11. Development of Subutex®/Suboxone® U.S. FDA approved Subutex ® and Suboxone ® sublingual tablets for opioid addiction treatment on October 8, 2002. Product launched in U.S. in March 2003 Interim rule changes to federal regulation (42 CFR Part 8) on May 22, 2003 enabled Opioid Treatment Programs (specialist clinics) to offer buprenorphine.

12. Treatment Admissions for Opioid Addiction

13. Who Enters Treatment for Heroin Abuse? 90% of opioid admissions in 2000 were for heroin 67% male 47% White; 25% Hispanic; 24% African American 65% injected; 30% inhaled 81% used heroin daily SOURCE: SAMHSA, Treatment Episode Data Set, 1992-2000.

14. Who Enters Treatment for Heroin Abuse? 78% had at least one prior treatment episode; 25% had 5+ prior episodes 40% had a treatment plan that included methadone 23% reported secondary alcohol use; 22% reported secondary powder cocaine use SOURCE: SAMHSA, Treatment Episode Data Set, 1992-2000.

15. Who Enters Treatment for Other Opiate Abuse? 51% male 86% White 76% administered opiates orally 28% used opiates other than heroin after age 30 19% had a treatment plan that included methadone 44% reported no secondary substance use; 24% reported secondary alcohol use SOURCE: SAMHSA, Treatment Episode Data Set, 1992-2000. (Non-prescription use of methadone, codeine, morphine, oxycodone, hydromorphone, opium, etc.)

16. Primary Heroin Treatment Admissions vs. Primary Other Opiate Treatment Admissions: A Side-by-Side Comparison SOURCE: SAMHSA, Treatment Episode Data Set, 1992-2000.

17. Opioids and the Brain: Pharmacology and Half-Life

18. What Happens When You Use Opioids? Acute Effects: Results of Chronic Use: Withdrawal Symptoms: Let’s talk about each of these.

19. Possible Acute Effects of Opioid Use Surge of pleasurable sensation = “rush” Warm flushing of skin Dry mouth Heavy feeling in extremities Drowsiness Clouding of mental function Slowing of heart rate and breathing Nausea, vomiting, and severe itching

20. Consequences of Opioid Use Addiction Overdose Death Use related (e.g., HIV infection, malnutrition) Negative consequences from injection: Infectious diseases (e.g., HIV/AIDS, Hepatitis B and C) Collapsed veins Bacterial infections Abscesses Infection of heart lining and valves Arthritis and other rheumatologic problems

21. Opioid Withdrawal Syndrome Intensity varies with level & chronicity of use Cessation of opioids causes a rebound in function altered by chronic use First signs occur shortly before next scheduled dose Duration of withdrawal is dependent upon the half-life of the drug used: Peak of withdrawal occurs 36 to 72 hours after last dose Acute symptoms subside over 3 to 7 days Protracted symptoms may linger for weeks or months

22. Opioid Withdrawal Syndrome Acute Symptoms Pupillary dilation Lacrimation (watery eyes) Rhinorrhea (runny nose) Muscle spasms (“kicking”) Yawning, sweating, chills, gooseflesh Stomach cramps, diarrhea, vomiting Restlessness, anxiety, irritability

23. Opioid Withdrawal Syndrome Protracted Symptoms Deep muscle aches and pains Insomnia, disturbed sleep Poor appetite Reduced libido, impotence, anorgasmia Depressed mood, anhedonia Drug craving and obsession

24. An Overview of Buprenorphine

25. Development of Tablet Formulations of Buprnorphine Buprenorphine is marketed for opioid treatment under the trade names of Subutex® (buprenorphine) and Suboxone® (buprenorphine/naloxone) Over 25 years of research Over 5,000 patients exposed during clinical trials Proven safe and effective for the treatment of opioid addiction

26. Buprenorphine: A Science-Based Treatment Clinical trials have established the effectiveness of buprenorphine for the treatment of heroin addiction. Effectiveness of buprenorphine has been compared to: Placebo (Johnson et al. 1995; Ling et al. 1998; Kakko et al. 2003) Methadone (Johnson et al. 1992; Strain et al. 1994a, 1994b; Ling et al. 1996; Schottenfield et al. 1997; Fischer et al. 1999) Methadone and LAAM (Johnson et al. 2000)

27. Buprenorphine as a Treatment for Opioid Addiction A synthetic opioid Described as a mixed opioid agonist- antagonist (or partial agonist) Available for use by certified physicians outside traditionally licensed opioid treatment programs

28. The Role of Buprenorphine in Opioid Treatment Partial Opioid Agonist Produces a ceiling effect at higher doses Has effects of typical opioid agonists—these effects are dose dependent up to a limit Binds strongly to opiate receptor and is long- acting Safe and effective therapy for opioid maintenance and detoxification

29. Partial vs. Full Opioid Agonist Dose of Opiate Opiate Effect death Full Agonist (e.g., methadone) (e.g. Naloxone) Antagonist Partial Agonist (e.g. buprenorphine)

30. 1. Patient can participate fully in treatment activities and other activities of daily living easing their transition into the treatment environment 2. Limited potential for overdose 3. Minimal subjective effects (e.g., sedation) following a dose 4. Available for use in an office setting 5. Lower level of physical dependence Advantages of Buprenorphine in the Treatment of Opioid Addiction

31. Combination tablet is being marketed for U.S. use 6. Discourages IV use 7. Diminishes diversion 8. Allows for take-home dosing Advantages of Buprenorphine/Naloxone in the Treatment of Opioid Addiction

32. Disadvantages of Buprenorphine in the Treatment of Opioid Addiction 1. Greater medication cost 2. Lower level of physical dependence (i.e., patients can discontinue treatment) 3. Not detectable in most urine toxicology screenings

33. Why was Buprenorphine/Naloxone Combination Developed? Developed in response to increased reports of buprenorphine abuse outside of the U.S. The combination tablet is specifically designed to decrease buprenorphine abuse by injection, especially by out of treatment opioid users.

34. What is the Ratio of Buprenorphine to Naloxone in the Combination Tablet? Each tablet contains buprenorphine and naloxone in a 4:1 ratio Each 8 mg tablet contains 2 mg of naloxone Each 2 mg tablet contains 0.5 mg of naloxone Ratio was deemed optimal in clinical studies Preserves buprenorphine’s therapeutic effects when taken as intended sublingually Sufficient dysphoric effects occur if injected by some physically dependent persons to discourage abuse.

35. Why Combining Buprenorphine and Naloxone Sublingually Works Buprenorphine and naloxone have different sublingual (SL) to injection potency profiles that are optimal for use in a combination product. SL Bioavailability Injection to Sublingual Potency Buprenorphine 40-60% Buprenorphine ≈ 2:1 Naloxone 10% or less Naloxone ≈ 15:1 SOURCE: Amass et al., 2004.

36. Buprenorphine/Naloxone: What You Need to know Basic pharmacology, pharmacokinetics, and efficacy is the same as buprenorphine alone. Partial opioid agonist; ceiling effect at higher doses Blocks effects of other agonists Binds strongly to opioid receptor, long acting

37. The Use of Buprenorphine in the Treatment of Opioid Addiction Induction Maintenance Tapering Off/Medically-Assisted Withdrawal

38. Induction

39. Induction Phase Working to establish the appropriate dose of medication for patient to discontinue use of opiates with minimal withdrawal symptoms, side- effects, and craving

40. Buprenorphine is administered sublingually.

41. What will the tablets look like? How will they taste? Light orange tablet Flavor = natural lemon & lime Sweetener = acesulfame potassium This is done to overcome the perceived bitterness of the naloxone hydrochloride in the Suboxone tablets. The orange color has been added to ensure clear differentiation between Subutex and Suboxone tablets.

42. Five Steps to Starting Bup/Nx 1. Have patient abstain or impose ~ 8 hr. interval between prior agonist use and buprenorphine administration 2. Mild withdrawal symptoms optimal 3. Verify that the urine sample is methadone- negative 4. Select appropriate substitution dose 5. Start with low dose and increase over several days

43. Direct Buprenorphine Induction from Long-Acting Opioids Controlled trials are needed to determine optimal procedures for inducting these patients. Data is also needed to determine whether the buprenorphine only or the buprenorphine/naloxone tablet is optimal when inducting these patients. SOURCE: Amass, et al., 2004; Johnson, et al. 2003.

44. Direct Buprenorphine Induction from Long-Acting Opioids Clinical experience has suggest that induction procedures with patients receiving long-acting opioids (e.g. methadone-maintenance patients) are basically the same as those used with patients taking short-acting opioids, except: The time interval between the last dose of medication and the first dose of buprenorphine must be increased. At least 24 hrs should elapse before starting buprenorphine and longer time periods may be needed (up to 48 hrs). Urine drug screening should indicate no other illicit opiate use at the time of induction.

45. Stabilization and Maintenance

46. Stabilization Phase Patient experiences no withdrawal symptoms, side-effects, or craving

47. Maintenance Phase Goals of Maintenance Phase: Help the person stop and stay away from illicit drug use and problematic use of alcohol 1. Continue to monitor cravings to prevent relapse 2. Address psychosocial and family issues

48. Maintenance Phase Psychosocial and family issues to be addressed: a) Psychiatric comorbidity b) Family and support issues c) Time management d) Employment/financial issues e) Pro-social activities f) Legal issues g) Secondary drug/alcohol use

49. Buprenorphine Maintenance: Summary Take-home dosing is safe and preferred by patients, but patient adherence will vary and this can impact treatment outcomes. 3x/week dosing with buprenorphine/naloxone is safe and effective as well (Amass, et al., 2001). Counseling needs to be integrated into any buprenorphine treatment plan.

50. Medically-Assisted Withdrawal (a.k.a. Dose Tapering)

51. Buprenorphine Withdrawal Working to provide a smooth transition from a physically-dependent to non-dependent state, with medical supervision Medically supervised withdrawal (detoxification) is accompanied with and followed by psychosocial treatment, and sometimes medication treatment (i.e., naltrexone) to minimize risk of relapse.

52. Medically-Assisted Withdrawal (Detoxification) Outpatient and inpatient withdrawal are both possible How is it done? Switch to longer-acting opioid (e.g., buprenorphine) Taper off over a period of time (a few days to weeks depending upon the program) Use other medications to treat withdrawal symptoms Use clonidine and other non-narcotic medications to manage symptoms during withdrawal

53. Transferring Patients Onto Buprenorphine: 3 Ways Significant Withdrawal Could Occur Insufficient agonist effects Dose too low?

54. If dose is too low, the patient will experience withdrawal -10-9-8-7-6-5-4 0 10 20 30 40 50 60 70 80 90 100 Intrinsic Activity Log Dose of Opioid Maintenance Level Dosage Level

55. Transferring Patients Onto Buprenorphine: 3 Ways Significant Withdrawal Could Occur Insufficient agonist effects Dose too low? May not fully substitute Not full agonist

56. If the patient needs a high level of medication to achieve maintenance, the ceiling effect of buprenorphine may result in withdrawal -10-9-8-7-6-5-4 0 10 20 30 40 50 60 70 80 90 100 Intrinsic Activity Log Dose of Opioid Maintenance level Bup’s effect

57. Transferring Patients Onto Buprenorphine: 3 Ways Significant Withdrawal Could Occur Insufficient agonist effects Dose too low? May not fully substitute Not full agonist Ceiling effect Precipitates Withdrawal

58. Buprenorphine will replace other opioids at the receptor site. The patient therefore experiences withdrawal -10-9-8-7-6-5-4 0 10 20 30 40 50 60 70 80 90 100 Intrinsic Activity Log Dose of Opioid Current intoxication level Bup’s effect

59. An Example of Detox Protocol: Results from 2 CTN Trials.

60. NIDA’s C linical T rials N etwork Established in 1999 NIDA’s largest initiative to blend research and clinical practice by bringing promising therapies to community treatment providers Network of 17 University-based Regional Research and Training Centers (RRTCs) involving 116 Community Treatment Programs (CTPs) in 24 states, Washington D.C., and Puerto Rico

61. CTN RRTC States with CTP CTN Nodes

62. Regional Research & Training Center Community Treatment Program Community Treatment Program Community Treatment Program Community Treatment Program Community Treatment Program CTN Node Community Treatment Program Community Treatment Program Community Treatment Program

63. The Research: CTN Protocols 0001 and 0002

64. The Two Buprenorphine- Naloxone Protocols NIDA-CTN 0001: Buprenorphine-Naloxone vs. Clonidine for Short-Term Inpatient Opiate Detoxification NIDA-CTN 0002: Buprenorphine-Naloxone vs. Clonidine for Short-Term Outpatient Opiate Detoxification Initiated in 8 Regional Nodes and 12 Community Treatment Programs

65. Pacific Betty Ford Center Great Lakes Shar House Ohio Valley Maryhaven Florida Operation PAR Center for DFL Long Island Phoenix House Site Participation: NIDA-CTN 0001

66. Pacific Aegis Ohio Valley Midtown New York ARTC Bellevue Delaware Valley Mercer Oregon Kaiser Permanente Site Participation: NIDA-CTN 0002

67. NIDA CTN 001/002 Buprenorphine- Naloxone Detoxification Protocols Two, open-label, randomized clinical trials Compared Buprenorphine-Naloxone (BUP/NX) and Clonidine for Short-Term (2 weeks) opioid Detoxification in Residential or Outpatient Settings

68. Community Treatment Programs 2 Therapeutic Communities 1 Free-standing, Chemical Dependency Hospital 2 Detox Units with Integrated Addiction and Mental Health Services 1 Long Term Residential 4 Opioid Treatment Programs 1 HMO 1 Community Mental Health Center 6 Inpatient6 Outpatient Usual care approaches: 50% methadone, 50% clonidine Usual care approaches: methadone in OTPs and clonidine in HMO

69. Study Schema 1. Obtain Informed Consent 2. Perform Screening/Baseline Assessments Follow-up at 1 month Follow-up at 3 months Randomize (2:1) and Enroll N=240 Buprenorphine/Naloxone 13 days detoxification N=120 Clonidine 13 days detoxification Follow-up at 6 months

70. Primary Efficacy Endpoint It is hypothesized that BUP/NX detoxification, compared to clonidine, will be associated with a better treatment response. A treatment responder = anyone who completes the 13-day detoxification and whose last urine specimen is negative for opioids.

71. So, what did we find?

72. Bup/NxClonidineTotal Sex No. (%) Male Female 61 39 58 42 60 40 Race No. (%) White Black Hispanic Other 56 19 12 9 56 19 17 8 56 19 16 9 Age in Years: Mean (Range 21-61) 35.637.4- Employed (%) --66 Mean Education in Years (SD) --12.8 (1.7) Mean Years of Heroin Use (SD) --6.6 (8.1) Demographics 0001 (Inpatient)

73. Present and Opioid Negative 0001 (Inpatient) Present and opioid neg Bup/Nx (N) % Clonidine (N) % N7736 Day 3 or 45267.51644.4 Day 7 or 86381.81336.1 Day 10 or 115672.71027.8 Day 13 or 145976.6822.2

74. Present and Opioid Negative 0001 (Inpatient)

75. Bup/NxClonidineTotal Sex No. (%) Male Female 73 27 69 31 72 28 Race No. (%) White Black Hispanic Other 40 36 21 3 40 28 13 3 40 37 20 3 Age in Years: Mean (Range 21-61) 38.340.0- Employed (%) --56.8 Mean Education in Years (SD) --12.4 (2.1) Mean Years of Heroin Use (SD) --9.4 (9.6) Demographics 0002 (Outpatient)

76. Present and Opioid Negative 0002 (Outpatient) Present and opioid neg Bup/Nx (N) % Clonidine (N) % N15774 Day 3 or 43723.656.8 Day 7 or 85635.768.1 Day 10 or 115233.156.8 Day 13 or 144629.345.4

77. Present and Opioid Negative 0002 (Outpatient)

78. NNT: Number Needed to Treat NNT= Number of patients needed to treat to achieve 1 treatment success CTN 0001 (Inpatient) NNT for Bup/Nx 77/59 = 1.31 NNT for Clonidine 36/8 = 4.5 NNT Clonidine : BupNx = 3.44 CTN 0002 (Outpatient) NNT for Bup/Nx: 157/46 = 3.4 NNT for Clonidine: 74/4 = 18.5 NNT Clonidine : Bup/Nx = 5.44

79. Key Lessons Learned from the CTN Experience

80. Lessons Learned 1. Direct induction with BUP/NX is acceptable to a majority of opioid users. Ninety percent of patients completed induction, reaching a target dose of 16 mg within 3 days. 2. A substantial number of patients completed the short-term detox, regardless of setting or program philosophy. This program thus met a major goal of many programs to improve early treatment engagement. Short-term treatment can also help to establish an effective therapeutic alliance with local care providers.

81. 3. Ancillary medications were provided to a majority of patients taking BUP/NX but mostly for protracted withdrawal symptoms common among patients withdrawing from opioids. 4. BUP/NX is safe for use in a wide range of community treatment settings. There were few serious adverse events and most were not related to BUP/NX. Lessons Learned (continued)

82. 5. Patient interest in the BUP/NX detox was high and some programs developed wait lists, suggesting that the combination mixture will not deter patients from seeking buprenorphine treatment. 6. All sites expected patients to attend counseling regularly. Whether short-term BUP/NX detox would fare as well in primary care or office based settings where such services are not on site is not known.

83. Who is Appropriate for Buprenorphine Treatment?

84. Patient Selection: Assessment Questions Is the patient addicted to opioids? Is the patient aware of other available treatment options? Does the patient understand the risks, benefits, and limitations of buprenorphine treatment? Is the patient expected to be reasonably compliant? Is the patient expected to follow safety procedures?

85. Patient Selection: Assessment Questions Is the patient psychiatrically stable? Is the patient taking other medications that may interact with buprenorphine? Are the psychosocial circumstances of the patient stable and supportive? Is the patient interested in office-based buprenorphine treatment? Are there resources available in the office to provide appropriate treatment?

86. Patient Selection: Issues Involving Consultation with the Physician Several factors may indicate a patient is less likely to be an appropriate candidate, including: Patients taking high doses of benzodiazepines, alcohol or other central nervous system depressants Significant psychiatric co-morbidity Multiple previous opioid addiction treatment episodes with frequent relapse during those episodes (may also indicate a perfect candidate) Nonresponse or poor response to buprenorphine treatment in the past

87. Several factors may indicate a patient is less likely to be an appropriate candidate, including: Active or chronic suicidal or homicidal ideation or attempts Patient needs that cannot be addressed with existing office-based resources or through appropriate referrals High risk for relapse to opioid use Poor social support system Patient Selection: Issues Involving Consultation with the Physician

88. Pregnancy Currently buprenorphine is a Category C medication. This means it is not approved for use during pregnancy. Studies conducted to date suggest that buprenorphine may be an excellent option for pregnant women. Randomized trials are underway to determine the safety and effectiveness of using buprenorphine during pregnancy. Patient Selection: Issues Involving Consultation with the Physician

89. Patients with these conditions must be evaluated by a physician for appropriateness prior to buprenorphine treatment: Seizures HIV and STDs Hepatitis and impaired hepatic function Use of alcohol, sedative-hypnotics, and stimulants Other drugs Patient Selection: Issues Involving Consultation with the Physician

90. Patient Selection: Additional Details Suitability determined by a physician What is the relevance to counselors? Patient’s appropriateness may change during treatment Potential patients or other providers may inquire about treatment More useful and informed communication with physician

91. Patient Selection Patients who do do not meet criteria for opioid addiction may still be appropriate for treatment with buprenorphine Patients who are risk of progression to addiction or who are injecting Patients who have had their medication discontinued and who are now at high risk for relapse

92. Use The SAMHSA Physician Locator Service To Find a Physician Authorized To Prescribe Buprenorphine in Your State www.buprenorphine.samhsa.gov.bwns_locator

93. Notice: The Drug Addiction Treatment Act of 2000 limits physicians or physician group practices to prescribing buprenorphine for opioid addiction to a maximum of 30 patients at one time. Because of this, some physicians listed on the Locator may not be accepting new patients at this time. If you are unable to find a physician within your area who is accepting new patients, please check our site later, as new physicians are being added weekly. To locate the physician(s) authorized to prescribe Buprenorphine nearest you, find your State on the map below and click on it.

94. Challenges for Addiction Treatment Professionals Not all physicians who are trained have consented to be listed on Physician locator. Community outreach is still critical. Linking patients to primary care who have not been within the medical mainstream Coordination with other professionals not accustomed to working with non-medical partners Covering the cost of medication

95. Attributes of Successful Care Coordination Understanding roles for each participant in the treatment team Ongoing communication across professions Personal contact between partners in the system

96. Barriers to Effective Care Coordination Misunderstanding respective roles Conflicting goals for treatment Confidentiality restrictions Control issues Misconception of other professional perspectives

97. Thomas E. Freese, Ph.D. tefreese@ix.netcom.com www.psattc.org www.uclaisap.org www.buprenorphine.samhsa.gov.bwns_locator