1. Clinical Use of Buprenorphine Finding The Right Dose Paul P. Casadonte MD California Society of Addiction Medicine 2002

2. Clinical Case Presentation Janet T is a 37 year old single white female, head of an Internet design corporation, seeking treatment for $ 100/day IV heroin use. She is determined to stop, as she is to be featured on the cover of a Women’s magazine in several months. She met criteria for treatment, had no evidence of medical disorder. Her screening udst was positive for opiates and benzodiazepines prescribed for “panic disorder.” She was advised to abstain from opiates for at least 6 hours prior to the appointment.

3. Clinical Case She returned for induction, appeared in withdrawal and was given a dose of 4 mg buprenorphine. 30 minutes later she reported chills, anxiety, and was given another 4 mg. 10 later minutes she was retching and screaming. An additional 8 mg was given, for a total of 16 mg in 40 minutes. The retching and panic continued for 30 minutes, as which point she became comfortable.She left the Clinic after an hour of observation was given a prescription for 16 mg a day for 3 days, and asked to return for continued treatment.

4. Clinical Case She was stabilized on 16 mg a day, discontinued use, udst negative for opiates,. She came for weekly visits and medication for 6 weeks. She did not come at week 7, and when contacted reported that she had resumed use at 3 bags/day. She had learned to stop buprenorphine 8 hours before heroin use, and to resume buprenorphine 6 hours after heroin. She continued reduced intermittent weekend heroin use for several weeks, and insisted this was what kept her functional.

5. Buprenorphine presents a low risk of clinically significant problems No reports of respiratory depression in clinical trials of buprenorphine Overdose of buprenorphine combined with other drugs may cause problems. Use special caution in patients using benzodiazepines While buprenorphine has lower level of physical dependence, it may be possible to precipitate withdrawal with opioid antagonist in buprenorphine-maintained patients Introduction

6. Pre- Induction: Some thoughts Patient selection: who is a candidate? Office procedures: what changes do I make? Resources necessary: what do I need to do this task? Remember: You have 30 slots!! Keep in mind: The Law runs for 3 years-do not mess up!!

7. Pre-Induction: Assessment Telephone screen Clinical Interview Physical Examination ECG > 40 Laboratory evaluations Urine Drug Screens

8. Assessment Recommended Inclusion Criteria For Private Off ice Treatment Physically healthy History of responsible behaviors No pending legal charges Lower level of Psychiatric disorders Able to store medication Limited Criminal history

9. Assessment Possible Exclusion Factors Dependent on Alcohol Dependent on Benzodiazepines Stimulant abusers Circle of addict-only friends Ambivalent about treatment

10. Pre-Induction Tasks Complete medical and laboratory assessment Have patient sign a consent for treatment and contract Arrange an appointment for induction Advise not to drive alone to appointment Emphasize the need to abstain from opiates for 8-12 hours. Attempt to obtain the truth about amount of use

11. Pre-Induction Determine how and where you will start medication Be prepared for vomiting, pain, etc if you do not have a patient in withdrawal at time of induction. Determine how comfortable you are with a sick patient. Try to avoid having other patients waiting while inducting.

12. Dependence on Heroin/pain medications You will have instructed patient to abstain from any opioid use for 8-12 hours (so they are in mild withdrawal at time of first buprenorphine dose) If patient is not in opioid withdrawal at time of arrival in office, then assess time of last use and consider either having him/her return another day or wait in the office. Use standard withdrawal evaluations to assess. Buprenorphine Induction-Day 1

13. Advise on possible effects of buprenorphine First dose: 2-4 mg sublingual buprenorphine Advise on how the medication must be taken. Monitor in office for 1-2 hours after first dose. Re-dose if needed: if opioid withdrawal subsides then reappears- however the withdrawal may be due to excess buprenorphine. Recommended maximum first day dose of 8-12 mg. May give a prescription for 2-3 days or have return the next day Buprenorphine Induction

14. Patient dependent on short-acting opioids? Withdrawal symptoms present 12-24 hrs after last use of opioids? Give buprenorphine 2-4 mg, observe 1+ hrs Withdrawal symptoms continue or return? Repeat dose up to maximum 8 mg for first day Withdrawal symptoms relieved? Manage withdrawal symptomatically Yes No Stop; not dependent on short-acting opioids No Yes Figure 1 Induction for Patient Physically Dependent On Short-acting Opioids, Day 1 Withdrawal symptoms return? Daily dose established. GO TO SWITCH DIAGRAM (Fig.4 ) No Daily dose established. GO TO SWITCH DIAGRAM (Fig 4.) No Return next day for continued induction. GO TO INDUCTION DAY 2 DIAGRAM (Fig3.) Yes

15. May begin with buprenorphine monotherapy tablets (i.e., without naloxone) for first 2-3 days, then switch to buprenorphine/naloxone combination tablets. When switching to combination tablets, do direct switch to same dose of buprenorphine (i.e., from 8 mg daily go to 8/2 mg daily) Buprenorphine Induction

16. If starting with combination tablets directly, you may use same amount as mono buprenorphine. It is safe and easy to begin on combo tablets. The combo tablets will not produce withdrawal in 99% of patients. Buprenorphine Induction

17. Patients dependent on long-acting opioids: Methadone LAAM Buprenorphine Induction

18. Buprenorphine Induction Long Acting Opioids Patients may be buying street methadone Amount of use is often not accurate Unlikely to be buying street LAAM If on a methadone program, advise need to discuss with staff. If stable on methadone and wants simply to switch to buprenorphine, assess benefits and risks.

19. If using street methadone, advise he will be ill unless on 30 mg or less of methadone. Begin induction 24 hours after last dose of methadone, 48 hours after last dose of LAAM Assess for withdrawal before dosing. Give no further methadone or LAAM once buprenorphine induction is started Induction for patients using long-acting opioids

20. First day dose of 8-12 mg sublingual buprenorphine It may be difficult to determine if the withdrawal is due to methadone or LAAM withdrawal or buprenorphine precipitated withdrawal. Need for active patient support Need for nerves of steel! Buprenorphine Induction

21. Patient dependent on long-acting opioids? 24 hrs after last dose, give buprenorphine 2 mg 48 hrs after last dose, give buprenorphine 2 mg Withdrawal symptoms present? Give buprenorphine 2 mg Repeat dose up to maximum 8 mg/24 hrs Withdrawal symptoms relieved? Manage withdrawal symptomatically No Yes Figure 2: Induction for Patient Physically Dependent On Long-acting Opioids, Day 1 If LAAM, taper to ≤ 40 mg for Monday/Wednesday dose If methadone, taper to ≤ 30 mg per day Yes Daily dose established Daily dose established No GO TO INDUCTION FOR PATIENT PHYSICALLY DEPENDENT DAY 2 DIAGRAM (Fig3.) Withdrawal symptoms continue? Yes No

22. On second thru fourth day, have patient return to the office for assessment, dosing, prescription Adjust dose accordingly based on patient’s experiences on first day (i.e., higher dose if there were withdrawal symptoms after leaving your office; lower dose if patient was over-medicated at end of first day) Buprenorphine Induction

23. Continue adjusting dose by 2-4 mg increments until an initial target dose of 12-16 mg is achieved for the second day. If continued dose increases are indicated after the second day, have the patient return for further dose induction (with a maximum daily dose of 32 mg) This may not be possible, so use the telephone well Buprenorphine Induction

24. Patient returns to office on 8 mg Withdrawal symptoms present since last dose? Give buprenorphine 10-12 mg Withdrawal symptoms continue? Administer 2-4 mg doses up to maximum 16 mg (total) for second day Withdrawal symptoms relieved? Manage withdrawal symptomatically Yes No Maintain patient on 8 mg per day. GO TO SWITCH DIAGRAM (Fig 4). No Figure 3: Induction for Patient Physically Dependent On Short- or Long-acting Opioids, Days 2+ Withdrawal symptoms return? Daily dose established. GO TO SWITCH DIAGRAM (Fig. 4) Yes No Yes No Return next day for continued induction; start with day 2 total dose and increase by 2-4 mg increments. Maximum daily dose: 32 mg Daily dose established. GO TO SWITCH DIAGRAM (Fig. 4)

25. Conversion to buprenorphine/naloxone If indicated, switch patient to buprenorphine/naloxone combination tablets after 2-3 days of buprenorphine monotherapy dosing. Use mono product for pregnant women. Buprenorphine Induction

26. Figure 4: Switch from Buprenorphine to Buprenorphine/naloxone Patient on buprenorphine monotherapy (up to 32 mg/day) Patient pregnant? Yes No Continue buprenorphine monotherapy Other compelling reason to continue buprenorphine monotherapy? Transfer to buprenorphine/ naloxone therapy

27. Induction The First Days Be prepared for continuous contact in early days Anxiety, fear, opiate use are common. Strongly discourage opiate use, it complicates all Advise that too much medication may cause withdrawal Give medication for several days. Advise not to increase without consultation. May use ancillary medications to cover withdrawal

28. Increase dose to point of comfort May take up to one week Expect average daily dose will be somewhere between 8/2 and 32/8 mg of buprenorphine/naloxone Higher daily doses more tolerable if taken sequentially rather than all at once-use bid or t.i.d doses Multiple doses are more reassuring early in treatment Buprenorphine Induction and Stabilization

29. Figure 5: Induction/Stabilization Continued illicit opioid use? Withdrawal symptoms present? Yes No Induction phase completed? Yes Compulsion to use, cravings present? No Daily dose established Continue adjusting dose up to 32/8 mg per day No Continue illicit opioid use despite maximum dose? Yes No Daily dose established Yes Maintain on buprenorphine/naloxone dose, increase intensity of non-pharmacological treatments

30. The patient should receive a daily dose until comfortable. See as frequently as necessary. Use additional medications for sleep or initiate antidepressants Once stabilized, the patient can shift to alternate day dosing –but no rush! Buprenorphine Induction/Stabilization

31. Stabilization/Maintenance

32. Buprenorphine/Naloxone Taper for Maintained Patients Comprehensive treatment plan, patient desire and acceptance. Ideally issues related to opiate use resolved. Taper can be over a period of days, weeks, months. Ancillary medications, psychological support, referral. Advise re-induction if relapse is an issue-but remember 30 patient limit.

33. Heroin Detoxification Assess the motivation and the reality of detoxification. Determine the length of time patient desires Work out a written schedule and agreement. Induct and Stabilize ( 3-7 days) Taper when use is discontinued No ideal taper schedule, many variables intrude Aftercare, ancillary medications, re-induction if relapse

34. Clinical Case Outcome Janet continued intermittent opiate use, alternating buprenorphine with heroin for a period of 3 weeks with medication she had saved. At one point she experienced significant withdrawal and friends took her to an emergency room. The doctor saw her as an addict and she was given 10 mg IM methadone, which made her very sick. She was discharged from the protocol. She is obtaining buprenorophine from France at this time.

35. Summary Carefully screen patients prior to induction. Be prepared for patient and doctor anxiety. Closely monitor patient during induction. Best to keep patient at office for an hour on first day. Give sufficient medication to allow dose changes by phone. Buprenorphine works wonders and is effective and safe. HAVE FUN!!!