Update on Buprenorphine: Induction and Ongoing Care

Transcription

1 Update on Buprenorphine: Induction and Ongoing Care Elizabeth F. Howell, M.D., DFAPA, FASAM Department of Psychiatry, University of Utah School of Medicine North Carolina Addiction Medicine Conference Asheville, NC April 13, 2013

2 Buprenorphine Semi-synthetic opioid derived from thebaine (naturally occurring alkaloid of opium poppy) times more potent than morphine Complicated and Unique Pharmacology: Mu opioid receptor partial agonist Non-selective Kappa opioid receptor antagonist or partial agonist Delta opioid receptor antagonist ORL-1 receptor partial agonist FDA Approved

3 Partial Agonist Activity Levels 100 % Mu Receptor Intrinsic Activity no drug low dose DRUG DOSE Full Agonist (e.g. heroin) At higher doses, even when partial agonist drug completely binds all mu receptors, maximum opioid agonist effect is never achieved Partial Agonist (e.g. buprenorphine) Like full agonists, partial agonist drugs produce increasing mu opioid receptor specific activity at lower doses high dose

4 Receptor Dissociation DISSOCIATION is the speed (slow or fast) of disengagement or uncoupling of a drug from the receptor - Buprenorphine s dissociation is slow - Therefore Buprenorphine stays on the receptor a long time and blocks heroin or methadone from binding Mu Receptor Bup dissociation is slow Therefore Full Agonists can t bind

5 Receptor Affinity AFFINITY is the strength with which a drug physically binds to a receptor Buprenorphine s affinity is very strong and it will displace full agonists like heroin and methadone Note receptor binding strength (strong or weak), is NOT the same as receptor activation (agonist or antagonist) Mu Receptor Bup affinity is higher Bound to Receptor Therefore Full Agonist is displaced

6 Repeated Administration and Withdrawal Two types of opioid withdrawal associated with mu opioid agonists: - Spontaneous withdrawal - Precipitated withdrawal

7 Repeated Administration and Withdrawal Spontaneous Withdrawal - Occurs when a person physically dependent on mu agonist opioids suddenly stops or markedly decreases the amount of use - For short-acting opioids (e.g., heroin, hydrocodone, oxycodone): usually begins 6-12 hours after last dose, peaks at hours, and lasts about 5 days (with possible protracted withdrawal?)

8 Repeated Administration and Withdrawal Spontaneous Withdrawal (continued) - For opioids with longer half-lives (e.g., methadone), there is a longer period before onset (methadone: hours), longer period before peak effects occur - Medications with longer half-lives generally have less severe spontaneous withdrawal syndrome

9 Repeated Administration and Withdrawal Precipitated Withdrawal - Occurs with administration of an opioid antagonist to a person physically dependent upon mu agonist opioids - Is qualitatively similar to spontaneous withdrawal but faster onset - Duration depends upon half life of antagonist

10 Repeated Administration and Withdrawal Precipitated Withdrawal (continued) - While the most common situation is for an antagonist such as naloxone or naltrexone to precipitate withdrawal, it is possible for a partial agonist such as buprenorphine to precipitate withdrawal under proper circumstances - A partial agonist displaces a full agonist, but only partially activates the receptor (a net decrease in activation)

11 Repeated Administration and Withdrawal Precipitated Withdrawal (continued) - Withdrawal precipitated by a partial agonist is more likely if there is: - High level of physical dependence - Short time interval between administration of full agonist and partial agonist - High dose of partial agonist

12 Differences in Precipitated Syndromes Buprenorphine will precipitate withdrawal only when it displaces a full agonist off the mu receptors - Buprenorphine only partially activates the receptors, therefore a net decrease in activation occurs and withdrawal develops % 50 Mu Receptor 40 Intrinsic 30 Activity no drug low dose DRUG DOSE high dose Full Agonist Partial Agonist (e.g. heroin) A Net Decrease in Receptor Activity if a Partial Agonist displaces Full Agonist (e.g. buprenorphine)

13 Before Buprenorphine Induction Clinical Opioid Withdrawal Scale (COWS) score should be in the moderate withdrawal range (13-24) or greater before starting buprenorphine, to avoid precipitated withdrawal Estimated time after last dose of opioid agonist before starting Buprenorphine: Heroin, Oxycodone IR, other short-acting opioids: hours Fentanyl patches, Oxycodone SR, other sustained release opioids: hours Methadone: hours

14 Clinical Opioid Withdrawal Scale (COWS) Ling and Wesson Withdrawal scoring: 5-12=Mild 13-24=Moderate 25-36=Moderately severe >36=Severe

15 Buprenorphine Induction Overview: Goal of induction To find the dose of buprenorphine at which the patient: discontinues or markedly reduces use of other opioids, experiences no cravings, has no opioid withdrawal symptoms, and has minimal/no side effects

16 Buprenorphine Induction Overview: Practical Issues with Induction As part of the physician s preparation for office-based buprenorphine treatment, he/she will need to decide whether to keep a supply of medication in the office for induction administration, or to have the patient fill a prescription for the first day s dose and bring the medication to the office where it will be administered. There are advantages and disadvantages to each approach.

17 Buprenorphine Induction Overview: Practical Issues with Induction (continued) Keeping a supply of buprenorphine tablets in the office means the physician must keep the records required by federal and state law for maintaining supplies of controlled substances for administration or dispensing. Those records may be audited by the DEA. [Assume the records will be audited by the DEA.]

18 Buprenorphine Induction Overview: Practical Issues with Induction (continued) Giving the patient a prescription for the first day s doses, and having the patient fill the prescription and bring the tablets back to the office means there would be a delay with the first day s dosing and a risk that a patient might not return with the filled prescription.

19 Buprenorphine Induction Day 1 Patients dependent on short-acting opioids Instruct patients to abstain from any opioid use for hours (so they are in mild-moderate withdrawal at time of first buprenorphine dose) Can use an opioid withdrawal scale to assess severity of withdrawal when the patient arrives at the office and to track the patient's response to first day s dose For withdrawal scales, see Appendix B of CSAT Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction 2004

20 Buprenorphine Induction Day 1 Patients dependent on short-acting opioids (continued) 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 until evidence of withdrawal is seen [Or do home induction]

21 Buprenorphine Induction Day 1 Patients dependent on short-acting opioids (continued) First dose: 2/0.5-4/1 mg sublingual buprenorphine/naloxone Monitor in office for up to 2 hours after first dose The length of time the patient is monitored in the office can vary depending upon the clinician s familiarity with the patient, and the clinician s familiarity with using buprenorphine.

22 Buprenorphine Induction Day 1 Patients dependent on short-acting opioids (continued) If opioid withdrawal appears (worsens) shortly after the first dose, it suggests that the buprenorphine may have precipitated a withdrawal syndrome Clinical experience suggests the period of greatest severity of buprenorphine-related precipitated withdrawal occurs in the first few hours (1-4) after a dose, with a decreasing (but still present) set of withdrawal symptoms over subsequent hours

23 Buprenorphine Induction Day 1 Patients dependent on short-acting opioids (continued) If a patient has precipitated withdrawal consider: giving another dose of buprenorphine, attempting to provide enough agonist effect from buprenorphine to suppress the withdrawal, or stopping the induction, provide symptomatic treatments for the withdrawal symptoms, and have patient return the next day. Since the latter would risk loss of the patient, the first option should be considered.

24 Buprenorphine Induction Day 1 Patients dependent on short-acting opioids (continued) Can re-dose if needed (every 2-4 hours, if opioid withdrawal subsides then reappears) Maximum first day dose of 8/2 mg buprenorphine/naloxone

25 Induction: Patient Physically Dependent on Short-acting Opioids, Day 1 Patient dependent on short-acting opioids? Yes Withdrawal symptoms present hrs after last use of opioids? Yes Give buprenorphine/naloxone 2/0.5--4/1 mg, observe No Stop; Reevaluate suitability for induction Withdrawal symptoms continue or return? No Withdrawal symptoms return? No Daily dose established. Yes Repeat dose up to maximum 8/2 mg for first day Yes Withdrawal symptoms relieved? Yes No Manage withdrawal symptomatically Daily dose established. Return next day for continued induction.

26 Buprenorphine Induction Day 1 Patients dependent on short-acting opioids (continued) Can initiate therapy starting with buprenorphine/naloxone combination tablets If beginning with buprenorphine monotherapy tablets, then switch to buprenorphine/naloxone combination tablets after 2-3 days [can usually switch after 1 day without problems] When switching to combination tablets, switch directly to same dose of buprenorphine (i.e., from 8 mg daily go to 8/2 mg daily)

27 Buprenorphine Induction Day 1 Patients dependent on long-acting opioids Patients should have dose decreases until they are down to 40 mg/d of methadone or the equivalent [e.g mg of LAAM, no longer available] Begin induction hours after last dose of methadone. [Can bridge with tramadol.] [Old recommendations: hours after last dose of methadone, at least 48 hours after last dose of LAAM] Give no further methadone once buprenorphine induction is started

28 Buprenorphine Induction Day 1 Patients dependent on long-acting opioids (continued) Use similar procedure as that described for short acting opioids Expect total first day dose of up to 8/2 mg sublingual buprenorphine/naloxone

29 Induction: Patient Physically Dependent on Long-acting Opioids, Day 1 Patient dependent on long-acting opioids? If LAAM, taper to mg for Monday/Wednesday dose Yes If methadone, taper to 40 mg per day hrs after last dose, give buprenorphine 2/0.5-4/1 mg hrs after last dose, give buprenorphine 2/0.5-4/1 mg Withdrawal symptoms present? Yes Give buprenorphine 2/0.5-4/1 mg Withdrawal symptoms continue? Yes Repeat dose up to maximum 8/2 mg/24 hrs Withdrawal symptoms relieved? Yes Daily dose established No No No Daily dose established Manage withdrawal symptomatically GO TO INDUCTION FOR PATIENT PHYSICALLY DEPENDENT

30 Buprenorphine Home Induction In-office induction is the current standard of care; however, other protocols are being studied. Home Buprenorphine/Naloxone Induction in Primary Care Lee et al., 2008 Dec 17, J Gen Intern Med. Home buprenorphine induction was feasible and appeared safe. Induction complications (Buprenorphine-prompted withdrawal and prolonged unrelieved withdrawal symptoms) occurred at expected rates and were not associated with short-term treatment drop-out. Problem: Difficulty staying off opioids long enough to start withdrawal and induction

31 Buprenorphine Induction Day 2+ Patients dependent on short- or long-acting opioids After the first day of buprenorphine induction for patients who are dependent on either short-acting or long acting opioids, the procedures are essentially the same

32 Buprenorphine Induction Day 2 Patients dependent on short- or long-acting opioids (continued) On Day 2, have the patient return to the office, if possible, for assessment and Day 2 dosing Adjust dose according to the patient s experiences on first day

33 Buprenorphine Induction Day 2 Patients dependent on short- or long-acting opioids (continued) Adjust dose according to the patient s experiences: lower dose if patient was over-medicated at end of Day 1 higher dose if there were withdrawal symptoms after leaving your office and/or if patient used opioid agonists Don t assume abstinence after the first day s dose

34 Buprenorphine Induction Day 2 Patients dependent on short- or long-acting opioids (continued) Continue adjusting dose by 2/0.5-4/1 mg increments until an initial target dose of 12/3-16/4 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 24/6 mg per day [Old Recommendation: with a maximum daily dose of 32/8 mg]

35 Induction: Patient Physically Dependent on Short- or Long-acting Opioids, Days 2+ Patient returns to office on up to 8/2 mg Yes Withdrawal symptoms present since last dose? Yes Increase buprenorphine/naloxone dose to 12/3-16/4 mg No Maintain patient on 8/2 mg per day. Withdrawal symptoms continue? Yes No Withdrawal symptoms return? No Daily dose established. Administer 4/1 mg doses up to maximum 16/4 mg (total) for second day Withdrawal symptoms relieved? Yes No Manage withdrawal symptomatically Return next day for continued induction; start with day 2 total dose and increase by 2/0.5-4/1 mg increments. Maximum daily dose: 24/6 mg Daily dose established.

36 Buprenorphine Induction Patients not physically dependent on opioids Examples: - A patient at high risk for relapse to opioid use, such as a person who had been incarcerated and was recently released - A patient whose use of illicit opioids has not reached the level that meets the DSM IV criteria for dependence but meets the criteria for abuse and is at risk for development of dependence

37 Buprenorphine Induction Patients not physically dependent on opioids (continued) First dose: 2/0.5 mg sublingual buprenorphine/naloxone Monitor in office after first dose The length of time the patient is monitored in the office can vary depending upon the clinician s familiarity with the patient, and the clinician s familiarity with using buprenorphine. [Patient can have significant sedation if non-tolerant] Gradually increase dose over days; increase in increments of 2/0.5 mg

38 Buprenorphine Induction Conversion to buprenorphine/naloxone In virtually all circumstances, induction can (and should) begin with the combination tablet For pregnant patients for whom buprenorphine is being used, induction and maintenance should be with monotherapy tablets If induction was begun with monotherapy tablets, switch to combination tablets after no more than 2-3 days (unless pregnant)

39 Buprenorphine Stabilization / Maintenance Stabilize on daily sublingual dose Expect average daily dose will be somewhere between 8/2 and 16/4 mg of buprenorphine/naloxone [old recommendations were up to 32/8, but this has been revised down to maximum of 24/6 mg] Higher daily doses more tolerable if tablets are taken sequentially rather than all at once

40 Stabilization / Maintenance No Induction phase completed? Yes Continued illicit opioid use? No Withdrawal symptoms present? No Compulsion to use, cravings present? No Daily dose established Yes Yes Yes Continue adjusting dose up to 24/6 mg per day Continued illicit opioid use despite maximum dose? Yes No Daily dose established Maintain on buprenorphine/naloxone dose, increase intensity of non-pharmacological treatments, consider if methadone transfer indicated

41 Dosing for Buprenorphine Maintenance Titrate to response: decreased craving, decreased to no drug use, improved functioning Individualize to patient response Most patients will respond to 8 to 16 mg per day May need higher doses with pain, increased psychiatric acuity, drug interactions, etc. May need higher initial dose, less as time goes on Increase dose with increased stress (and increased craving); may only be temporary increase Red Flag: Not all patients should be on same dose or in the same dose range

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43 Buprenorphine Stabilization / Maintenance The patient should receive a daily dose until stabilized Once stabilized, the patient can be shifted to alternate day dosing (e.g., every other day, MWF, or every third day, MTh for IOP/monitored dosing) Increase dose on dosing day by amount not received on other days (e.g., if on 8 mg/d, switch to 16/16/24 mg MWF) (note: daily dosing is recommended, but alternate day dosing may be useful for those attending treatment programs where medication is administered or for those not wanting to take medication daily)

44 Maintenance Treatment Using Buprenorphine Numerous outpatient clinical trials comparing efficacy of daily buprenorphine to placebo, and to methadone. These studies conclude: Buprenorphine more effective than placebo Buprenorphine equally effective as moderate doses of methadone (e.g., 60 mg per day)

45 Duration of Treatment Excluding those with short-term habits, the best outcome occurs with long-term maintenance on methadone or buprenorphine accompanied by appropriate psychosocial interventions. Those with strong external motivation may do well on the antagonist naltrexone. Currently, optimum duration of maintenance on either is unclear. Better agents are needed to impact the brain changes related to addiction. Kleber HD, 2007: Pharmacologic treatments for opioid dependence: detoxification and maintenance options. Dialogues Clin Neurosci, 9,

46 How long should treatment last with Buprenorphine? Varies with different treatment options: Detoxification only Stabilization and brief taper Stabilization and slow taper Stabilization and brief maintenance Stabilization and long maintenance Stabilization and indefinite maintenance Extenuating circumstances Court-imposed detoxification Medical complications

47 How long should treatment last with Buprenorphine? Consider: Length of addiction Severity of addiction Medical complications Co-occurring psychiatric disorders Pain conditions Consequences of potential relapse Psychosocial supports, recovery environment Treatment program requirements Functional improvement

48 Withdrawal Using Buprenorphine WITHDRAWAL IN </= 3 DAYS (rapid) Withdrawal over 4 to 30 days (moderate period) Withdrawal over more than 30 days (long term)

49 Withdrawal Using Buprenorphine Withdrawal in </= 3 days (rapid) Reports show buprenorphine suppresses opioid withdrawal signs and symptoms (better than clonidine) Using sublingual tablets or film: First day: 8/2-12/3 mg SL Second day: 8/2-12/3 mg SL Third (last) day: 6/1.5 mg SL

50 Withdrawal Using Buprenorphine Withdrawal in </= 3 days (continued) Buprenorphine is effective in suppressing opioid withdrawal symptoms Long-term efficacy is not known, and is likely limited Studies of other withdrawal modalities have shown that such brief withdrawal periods are unlikely to result in long-term abstinence

51 Withdrawal Using Buprenorphine Withdrawal over 4-30 days (Moderate period) Although there are few studies of buprenorphine for such time periods, buprenorphine has been shown more effective than clonidine over this time period However, outcomes not as good as for longer periods of buprenorphine withdrawal treatment (longer than 30 days)

52 CTN Buprenorphine Withdrawal Protocol Study Day Buprenorphine-Naloxone Dose (mg) additional 4 as needed

53 Withdrawal Using Buprenorphine Withdrawal over >30 day (long term) Not a well studied topic Literature on opioid withdrawal can provide guidance; suggests longer, gradual withdrawal more effective than shorter withdrawal Tapering schedule: 50% daily to 8 mg; then slower taper depending on clinical judgment Many iterations of above are effective Medical withdrawal from buprenorphine associated with much milder withdrawal than for full mu agonists

54 Summary Buprenorphine is effective and safe when used for maintenance treatment of opioid dependence Monitor patient during induction with buprenorphine; best to keep patient at office after first dose to gauge effectiveness Efficacy of buprenorphine in management of withdrawal not well determined, but withdrawal from buprenorphine may be milder than withdrawal from other opioids; probably best if conducted over longer periods