Buprenorphine/Naloxone Training Workshop for Medical Practitioners

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1 Buprenorphine/Naloxone Training Workshop for Medical Practitioners Program developed by Dr Nicholas Lintzeris MBBS, PhD, FAChAM (RACP) Turning Point Alcohol and Drug Centre, Melbourne, Australia Federation of Private Medical Practitioners Associations, Malaysia Ministry of Health Malaysia

2 Workshop Overview Module 1 Working with heroin users» Drugs, dependence and harms» Overview of services» Clinical assessment of drug users Module 2 Treatment with Suboxone (Buprenorphine-naloxone)» Clinical Pharmacology» Therapeutic guidelines Module 3 Addressing co-morbidity» BPN abuse» Polydrug use» Psychiatric comorbidity» Medical comorbidity 2

3 Module 2 Prescribing Buprenorphine / Naloxone Clinical Pharmacology & Therapeutic Guidelines

4 Learning Objectives 1. To understand the rationale, goals, potential benefits and problems associated with Suboxone treatment 2. To understand and communicate the pharmacology of Suboxone treatment 3. To be able to safely initiate and stabilise patients in Suboxone treatment 4. To be familiar with the components of effective maintenance treatment 5. To be familiar with the processes for discontinuing Suboxone treatment 4

5 Overview of substitution maintenance treatment Provision of a long acting opioid (e.g. methadone, buprenorphine) enables patient to cease / reduce their heroin use and related behaviours Long term treatment approach: provides opportunity for patients to distance themselves from drug-using lifestyle Combines medication with psychosocial services 5

6 Rationale for Substitution Treatment 6

7 SUBOXONE Buprenorphine naloxone Clinical Pharmacology

8 Classification of Opioids 100 Full Agonists: Heroin, morphine, methadone, codeine Size of Opiate Agonist Effect 0 Threshold for respiratory depression Drug Dose Partial Agonists: Buprenorphine Antagonists: Naltrexone, naloxone 8

9 Buprenorphine Partial agonist at the μ opiate receptor - Low intrinsic activity only partially activates receptors High affinity for the μ receptor - Binds more tightly to receptors than other opiates 9

10 Buprenorphine: Pharmacological & Clinical Properties Pharmacological property Clinical implication Substitutes for heroin Mild opiate-like effects Blocks other opiates due to high affinity Long duration of action Ceiling effects Prevents withdrawal Reduces cravings & increases treatment retention Reduces heroin use Daily (or alternate day) dosing Greater safety profile 10

11 Buprenorphine: Safety Aspects Less risk of overdose c/w full opiate agonists Less respiratory depression & sedation than methadone BPN tolerated by individuals with low levels of opiate dependence Potential concerns re: safety BPN-related deaths reported in combination with other sedatives (alcohol, BZDs) Some respiratory depression seen in opiate naïve individuals Safety concerns are much less than methadone 11

12 BPN effects in ex-opiate addicts (Walsh et al 1994) 12

13 Respiratory depression in non-opiate users Dose peak ventilatory depression relationships for (A) IV fentanyl and (B) IV buprenorphine in opiate naïve healthy volunteers. Dahan et al British Journal of Anaesthesia

14 Buprenorphine: Clinical Pharmacology Sublingual tablets (30-40% bioavailability) 2 & 8 mg tablets available 3 to 10 minutes to dissolve Time course Onset: min; peak effects: 1 4 hours Duration of action: dose related (4 hrs to 3 days) Side Effects Typical for opioid class Withdrawal syndrome Milder than full agonists 14

15 Buprenorphine: Common Side Effects Side effects occur early & then usually subside Headache Constipation Nausea Drowsiness, sedation Tiredness, lethargy Sleep disturbances Sweating Precipitated withdrawal on commencing buprenorphine 15

16 Understanding Precipitated Withdrawal BPN competes with and displaces full opioid agonists (heroin, methadone) from receptors BPN has lower intrinsic opioid activity than full agonists Reduction in opioid activity experienced as withdrawal Only likely to occur if first dose of BPN is given whilst patient is experiencing effects of other opiates 16

17 Precipitated Withdrawal Profile More common features include: Autonomic withdrawal features, such as sweating, anxiety, GI symptoms (cramps, diarrhoea, nausea) If not aware of risks: confusion, disillusionment Symptoms related to peak effects of BPN Start ~30 60 min after first BPN dose Peak within 1½-2 hrs after first dose, then subside Induction treatment procedures aim to avoid precipitated withdrawal 17

18 Buprenorphine: Drug Interactions Sedatives - In combination with alcohol, BZDs can produce respiratory depression, heavy sedation, coma, death Opioid agonists Will reduce the effects of other opioids used for analgesia Hepatic CYP 450 enzyme inhibitors / inducers Fewer interactions with CYP450 related drugs than methadone (HAART, HCV & TB treatment, anticonvulsants). Usually not clinically relevant with BPN 18

19 Buprenorphine Abuse: Injecting BPN (like all opioids) is subject to abuse by injecting Laboratory data indicates IV BPN greater euphoria, sedation and drug liking than SL Epidemiological data indicates BPN injecting linked to Low levels of supervised consumption Small doses of BPN prescribed Erratic / poor availability of other opioids Local cultural variations 19

20 Concerns with Buprenorphine Injecting IV BPN combined with CNS depressants (e.g. benzodiazepines) may be associated with respiratory depression and death Localised injecting problems (abscesses, thrombosis, etc..) Systemic fungal infections HIV/HCV if shared equipment Cytolytic hepatitis: rare Bad reputation for treatment 20

21 SUBOXONE

22 Why was Suboxone developed? Developed in response to reports of BPN injecting Aim of introducing BPN treatment outside of clinic based system in USA with little capacity for supervised dispensing Designed to decrease BPN s injectable abuse potential 22

23 Suboxone: Combination Medication Buprenorphine : naloxone 4:1 ratio Preparations 2 mg BPN:0.5 mg NLX 8 mg BPN:2 mg NLX 23

24 Naloxone Short acting opioid antagonist: will reverse opioid agonist effects Clinical applications reversing opiate overdoses: 0.8 to 2mg IV/IM naloxone challenge tests: mg IV/IM Duration of effect: ~30-60 minutes (t 1/2 ~70 min) Poor sublingual absorption (<10%) Naloxone has comparable receptor affinity to BPN 24

25 Rationale for Suboxone Combination buprenorphine - naloxone tablet Pharmacology If taken sublingually: naloxone poorly absorbed, so get BPN effects only & no naloxone effect If injected by heroin user, naloxone produces antagonist effect (severe withdrawal) & deterrent to further injecting 25

26 Suboxone Value of a Dose in Dollars Dollars (USD) MS BUP Bup 2:1 4:1 8:1 Minutes MS 4.1 PBO 2:1 Plac 8:1 Subjects stabilized on 60 mg/day i.m. morphine and given IV doses of BPN (2 mg), MS (morphine sulfate, 15 mg); 8:1 (BPN, 2 mg; NLX, 0.25 mg); 4:1 (BPN, 2 mg; NLX, 0.5 mg); 2:1 (BPN, 2 mg; NLX, 1 mg) and Placebo. (Mendelson et al 1996) Left: Observer rating of antagonist effects (CINA Scale) Right: Subjective ratings (willingness to pay) 26

27 Will Suboxone stop all injecting? No. Suboxone patients can still inject Suboxone Naloxone has comparable receptor affinity to BPN If already on BPN, then IV naloxone unlikely to displace BPN and cause severe antagonist effects Variable effects of injecting Suboxone will blunt or reduce the euphoric effects of IV use may cause minor antagonist effects Makes Suboxone injecting less pleasurable & less sought after than Subutex / heroin injecting 27

28 Comparing Subutex and Suboxone effects in different groups SL BPN IV BPN Abuse potential Subutex SL BPN-NLX IV BPN-NLX Abuse potential Suboxone Opiate naive LOW LOW Opiate abuser HIGH MOD Heroin addict / HIGH Methadone patient LOW BPN patient HIGH / V.LOW V.LOW MOD 28

29 Why prescribe Suboxone? Reduces likelihood that medication will be injected Fewer risks of overdose, injecting problems Reduces street value of diverted medication Greater adherence to medication regime Greater confidence in providing take-away doses Better reputation for treatment 29

30 Are there any patients who should not be prescribed Suboxone? Pregnant women (Category C drug) Allergy or sensitivity to naloxone (rare) Patients transferring from high dose methadone Use Subutex for the first 2-3 days, then Suboxone 30

31 Transferring Patients from Subutex to Suboxone Use equivalent doses (e.g. 8mg Subutex = 8/2mg Suboxone) In context where transfer is involuntary proportion of patients report side effects (anxiety, nausea, headache, fatigue), which tend to subside with time In context where transfer voluntary few reports of adverse events & few difficulties Patients complaining of intolerance of Suboxone often expectancy issues may be attempt to continue Subutex injecting should be referred to a specialist clinic for further assessment 31

32 Therapeutic Guidelines Induction procedures, maintenance and withdrawal

33 Eligibility for Suboxone Treatment Opiate dependent + informed consent Precautions for primary care settings: High risk polydrug use Low-level physical dependence <18 y.o.a Severe active psychiatric conditions Medical (severe hepatic / respiratory) disease) Chronic pain 33

34 Goals of Treatment Induction To initiate patient into appropriate treatment To minimise adverse events Opioid side effects Avoid toxicity with methadone Avoid precipitated withdrawal with BPN Stabilise dose and patient so that not in withdrawal/intoxicated To retain patient in treatment 34

35 Principles of Safe Induction I. Comprehensive assessment Establish opioid dependence & tolerance history presence of withdrawal features examination of injecting sites urine drug screen Identify risk factors use of sedative drugs (e.g. alcohol, BZDs, TCAs) medical (severe liver / respiratory disease, current infections) / psychiatric (depression) comorbidity 35 DO NOT RUSH THE ASSESSMENT DO NOT CUT CORNERS

36 Principles of Safe Induction II. Patient Information Inform patient of process of treatment Inform patient of potential side effects Warn against additional drug use Warn against driving, operating machinery Inform patient of the rules (e.g. missed doses, intoxicated presentations, appointments) Informed consent 36

37 Principles of Safe Induction III. Initiate BPN dosing safely & effectively 1. Commence BPN 2. Avoid adverse effects precipitated withdrawal 3. Increase dose quickly to achieve target dose not in withdrawal/intoxicated to retain patient in treatment 37

38 Buprenorphine Partial agonist at the μ opiate receptor - Low intrinsic activity only partially activates receptors High affinity for the μ receptor - Binds more tightly to receptors than other opiates 38

39 Understanding precipitated withdrawal BPN competes with and displaces full opioid agonists (heroin, methadone) from receptors BPN has lower intrinsic opioid activity than full agonists Reduction in opioid activity experienced as withdrawal Only likely to occur if first dose of BPN is given whilst patient is experiencing effects of other opiates 39

40 Precipitated withdrawal profile More common features include: Autonomic withdrawal features, such as sweating, anxiety, GI symptoms (cramps, diarrhoea, nausea) If not aware of risks: confusion, disillusionment Symptoms related to peak effects of BPN Start ~30 60 min after first BPN dose Peak within 1½-2 hrs after first dose, then subside Precipitated withdrawal profile 40

41 Factors impacting precipitated withdrawal Amount of opioid agonist in system: Dose & duration of action of opioid used Heroin use Low methadone doses (e.g. <40mg) Higher methadone doses / Size first BPN dose greater precipitated withdrawal with higher first dose Patient expectancy 41

42 Factors impacting precipitated withdrawal Methadone to BPN (Strain et al, 1992, 1994) 42

43 Principles of Buprenorphine Induction Day 1 BPN dosing 1. Assessment & prepare the patient (information) 2. Avoid precipitated withdrawal Delay first BPN dose until patient in mild-opiate withdrawal* >6 8 hrs after last use of heroin >24 hrs after low methadone dose (<40 mg) >36 48 hrs after medium methadone dose (40 60 mg) First BPN dose = 2 4 mg as test dose Dose with more BPN >2 hrs after first dose Aim for at least 8 mg total dose day 1 If patient in significant opiate withdrawal and no concurrent sedative intoxication, can dose with 8mg start dose 43 * Role of dispensing clinician

44 After day 1 Once concerns re: precipitated withdrawal abated, aim to achieve target dose ASAP Maintenance Rx: 8 16mg by days 2-3 Detox treatment: dose required to minimise withdrawal & stop heroin use (at least 4-8mg in most patients) 44

45 Examples of induction doses (heroin users) Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 A B C

46 Faster Buprenorphine Induction Improves Early Treatment Retention Kakko et al Fudala et al Ortner et al Amadi et al Fischer et al Gerra et al Petitjean et al Pani et al Krook et al % retained at 4 weeks Time (days) to at least 8 mg Subutex 46

47 Transferring from Methadone to Buprenorphine (M to B) Individual variation Why transfer? side effects, rapid metabolisers, drug interactions Common difficulties with methadone Rx reluctance to be on effective methadone doses convenience & safety of take-away BPN doses convenience of primary care setting Patient request curiosity, stigma, expectancy Ease of withdrawal attempt to withdraw from maintenance treatment 47

48 Minimising precipitated withdrawal in M to B Educate the patient Reduce methadone dose as far as possible Below 40mg if possible Transfers can be done from higher doses (40-80mg) Delay time interval between last methadone dose & first BPN dose Wait for patient to be in early-mod withdrawal hrs Initial test dose of 2 4mg BPN & then add more BPN doses >1 2 hrs after test dose Aim for at least 8mg day 1 48

49 Follow-up after Transfers Review patients regularly in first 1 2 weeks on BPN Common for side effects during this time Sleep problems Dysphoria, anxiety Flooded with emotions Most difficulties with BPN settle within this time Some patients will want to transfer back to methadone 49

50 Maintenance & Treatment Cessation

51 Principles of Effective Treatment Dose Duration of treatment Quality of therapeutic relationship Regular review & monitoring Participating in psychosocial services Structured dispensing arrangements Bio-psycho-social model for chronic condition 51

52 Maintenance Dosing What is the correct BPN dose? The correct dose is as much as required to Stop withdrawal symptoms Achieve treatment goals (stop heroin use) Avoid side effects (of too little / too much medication) Most patients need 8-16mg to achieve this e.g. blockade effects at>8mg BPN Continued heroin use is usually an indication for a dose increase. 52

53 Efficacy of Buprenorphine & Methadone for maintenance treatment High dose MMT (> 80 mg) better than Medium dose MMT(40-80mg) = Medium dose BMT (8-12mg) better than Low dose MMT (< 40 mg) = Low dose BMT (< 8 mg) Note: No RCTs of high dose BMT ( 16mg) to high dose MMT 53

54 Alternate Day Dispensing Safety of Suboxone allows for alternate day & 3-day dosing Reduces inconvenience of daily dispensing without takeaway risks Can be initiated once dose stable (> 2 weeks) Alternate (2) day dosing = 2 x daily dose e.g. daily dose 8/2mg = ADD of 16/4mg Three day dosing = 3 x daily dose e.g. daily dose of 8/2mg = 3 day dose of 24/6mg Not all patients stabilise on 2 or 3 day dosing Withdrawal features, increased cravings, poor sleep on non-dispensed days 54

55 Responding to continued drug use Must review: drug use, risk practices, medical, psychiatric, social circumstances patient goals of treatment & drug use frequency of reviews and monitoring (urine tests) medication regimes Suboxone dose take-aways patient adherence (missed doses) other prescribed drugs psychosocial interventions and supports precipitants to continued drug use 55

56 Counseling Approaches Early phase of treatment (first 1-3 months): Focus on ongoing assessment, providing information & developing rapport Motivational & supportive counselling approaches Stabilising drug use & unstable social / medical issues Avoiding drug related harms (overdoses, needle sharing) Once stability achieved: (+2 months) Relapse prevention strategies Address medical, psychiatric, social & relationship issues Long-term patients (>12 months) referral for insight oriented therapy? discussions of withdrawal from maintenance 56

57 When should we stop treatment? Chronic condition needs long term treatment Premature cessation of treatment usually results in relapse to dependent heroin use Consider ending treatment when no illicit drug use for months / years stable social environment stable medical / psychiatric conditions patient has a life that does not revolve around drugs patient informed consent Trial of reduction 57

58 Withdrawal Procedures Withdrawal severity greatest in 1-2 weeks after stopping BPN Strategy is to reduce dose slowly (e.g. 2mg every 2-4 weeks), review often & reassess treatment plans frequently High risk of relapse to heroin / other drug use If patient not coping (severe cravings / withdrawal, drug use), then slow down or cease reduction. Try again at later stage, or under different circumstances Limit other medications until final stages of withdrawal, or else tolerance to their effects Beware BZD use beyond 1-2 weeks 58

59 Managing Heroin Detox with Suboxone

60 Objectives of Detoxification Detox is not a cure for heroin dependence Most heroin users relapse after withdrawal Need long-term treatment to achieve long-term changes Short-term intervention that aims to: Interrupt a pattern of heavy & regular drug use Alleviate withdrawal discomfort Prevent complications of withdrawal Facilitate post-withdrawal treatment linkages

61 Components of Detox Program Supportive care safe environment (inpatient / outpatient) patient information & supportive counselling regular monitoring Medication Buprenorphine is preferred medication Avoid benzodiazepines in outpatient settings Limit access to medications (supervised, daily) Post-withdrawal linkages Counselling, rehab, naltrexone, self-help groups, community supports 61

62 Buprenorphine for Detoxification Short inpatient / outpatient regimes (3-14 days) BPN reduces main heroin withdrawal features minimal rebound withdrawal on stopping BPN Example short regime Day 1: 8mg Day 2: 8mg Day 3: 6mg Day 4: 4mg Day 5: 2mg Gradual outpatient regimes (1 6months) allows more time for stability to be achieved greater withdrawal rebound on stopping BPN no / minimal other medication required Example Stabilise on 8mg / day. After 1 month reduce by 2mg every 2-4 weeks 62

63 Case Studies

64 Exercise: Induction Dose 1. New patient, states injecting 2 times / day for past 3/12; 5 yrs regular heroin use; occasional binge BZD 10 tabs at a time. HCV+(ve). States last used 3 hrs ago. O/E ++ injection marks; no intoxication or withdrawal. No significant medical conditions. 2. Patient with past Subutex treatment. Reports using heroin 4 to 5 times / day until went into inpatient detox, where lasted 6 days before leaving yesterday. States used heroin only once since leaving detox. Pupils 2 mm, quiet demeanor. 3. Patient discharged from government clinic for ongoing benzo & heroin use. Was on methadone 40mg/day, last methadone dose 2 days ago (confirmed with clinic). Presents anxious, sweaty, piloerection, pupils 5mm and wants treatment. How would you induct each patient onto Suboxone (include doses)? 64

65 Case Study: Sue Sue, a 27-year old presents to your practice for the first time. She states that she has been using heroin for the past 4 years - in recent months has been using 2 to 3 times a day, and recently started injecting (to get more effects). Her boyfriend also injects heroin. She wants treatment to stop using heroin. What further assessment do you do? 65

66 Case Study: Sue (2) Full drug history: Syabu (smoked) once every 2 weeks. Last used 5 days ago Diazepam 5-20mg once a week when heroin not available or after syabu use. Last used 2 days ago. Irregular alcohol /cannabis use reported No prior addiction treatment Nil significant medical / psychiatric history. Uncertain HIV/HBV/HCV. Irregular menstrual periods LMP?10/52 ago Lived with boyfriend (heroin user), who was recently arrested & in prison. Not working, occasional sex-work. O/E: anxious, sweaty, pupils 4mm, new & old injection marks Urine screen: opiate, BZD, amphetamines, cannabis positive She requests outpatient treatment. How do you respond & commence treatment? 66

67 Case Study: Sue (3) Discuss Suboxone treatment & get informed consent. You suggest 4/1mg Suboxone as starting dose AND for her to present later in day for?additional dose She does not return that day, but attends next day stating that was OK until 2 am then experienced stomach cramps, sweats, bone aches. She states that she is worried that Suboxone not working. Could she also have some diazepam to help her sleep tonight? How do you respond? What other issues do you want to address with Sue? 67

68 Case Study: Sue (4) Increase Suboxone dose to 8/2mg Avoid diazepam and educate that best way to respond to opiate withdrawal is with adequate Suboxone dose. Continue with daily supervised dispensing Review regularly & regular UDS Need to address Contraception / Pregnancy test HIV/HCV/HBV testing Safe sex & injecting practices if continues these 68

69 Case Study: Steven A 29 yr old with 10 yr history heroin dependence in treatment on BPN last 18/12. Initially was injecting heroin 1-2 times / week whilst on 4mg BPN. After 6/12 in treatment, increased dose to 8mg & subsequent cessation heroin use. Clean UDS for next 9 months & started work again with his parent s business. Reduced BPN dispensing from daily to two times / week (5 TA s / week). He presents 2 days late for his medical review. You see that he has missed his last 2 appointments with his worker, and no UDS in past 2/12. He is looking well but says he cannot stay long as he has to get back to work. Everything is fine can you sign my prescription as I need my dose What do you do? 69

70 Case Study: Steven (2) On enquiry, he denies any illicit drug use & states that he just went to the toilet before coming to the clinic so he cannot give a UDS. On examination you notice 3-4 recent injection marks. He then admits to having used IV heroin 3 to 5 days ago (a friend dropped by), and he did not take his BPN for 3 days. Took 8mg BPN yesterday & now has run out. Adamant that he will not be using heroin again. How do you respond? 70

71 Case Study: Steven (3) Concerns that recent lapse may become more prolonged relapse Schedule regular reviews & UDS Counselling to address relapse prevention Review take-away doses. Either Provide clean UDS to avoid losing take-aways; or stop take-aways & get them back when clean UDS 71

72 Self Assessment of Learning

73 1. Which of the following statement(s) is/are TRUE? A. The general principle of Suboxone treatment is to withdraw Suboxone after the patient has achieved a 1 to 2 month period without heroin use. B. Suboxone treatment is generally most effective when patients remain in treatment for several years. treatment is generally most effective in reducing e with doses in the range of 2 to 4mg per day. ion in Suboxone treatment should only be allowed if the nt participates in regular counselling. l, patients who continue to use heroin during the Suboxone program should have their dose reduced. 73

74 2. How do you commence treatment? Alex is a 32 year old presenting for Suboxone treatment. In recent weeks he describes injecting either heroin three times a day, or 3 x 30 mg morphine ampoules (obtained from his sick aunt). He has no major medical problems, and says he last used heroin 4 hours ago. He has a runny nose, dilated pupils and is sweating profusely during the interview. A. Delay Suboxone for a further 2 hours (at least 6 hours since last use) B. Start with 2mg, and review tomorrow. C. Start with 4mg and a further 4 mg after 2 hours D. Start with 8mg and review tomorrow E. Start with 8mg and a further 8mg after 2 hours. 74

75 3. Which of the following strategies are appropriate courses of management? James, a 27 year old commenced Suboxone three days ago an a dose of 4/1 mg. He now presents complaining of poor sleep, mild nausea and withdrawal discomfort each morning before his next dose. He reports using heroin once since starting treatment. A. Prescribe metoclopramide 10 mg tds prn for nausea B. Prescribe mg diazepam to help with sleep and withdrawal discomfort C. Increase the Suboxone dose to 8/2mg D. Increase the Suboxone dose to 16/4mg E. Reassure the patient that these are common side effects that usually subside within a few days 75

76 1. Which of the following statement(s) is/are TRUE? A. The general principle of Suboxone treatment is to withdraw Suboxone after the patient has achieved a 1 to 2 month period without heroin use. B. Suboxone treatment is generally most effective when patients remain in treatment for several years. C. Suboxone treatment is generally most effective in reducing heroin use with doses in the range of 2 to 4mg per day. D. Continuation in Suboxone treatment should only be allowed if the patient participates in regular counselling. E. In general, patients who continue to use heroin during the Suboxone program should have their dose reduced. 76

77 2. How do you commence treatment? Alex is a 32 year old presenting for Suboxone treatment. In recent weeks he describes injecting either heroin three times a day, or 3 x 30 mg morphine ampoules (obtained from his sick aunt). He has no major medical problems, and says he last used heroin 4 hours ago. He has a runny nose, dilated pupils and is sweating profusely during the interview. A. Delay Suboxone for a further 2 hours (at least 6 hours since last use) B. Start with 2mg, and review tomorrow. C. Start with 4mg and a further 4 mg after 2 hours D.Start with 8mg and review tomorrow E. Start with 8mg and a further 8mg after 2 hours. 77

78 3. Which of the following strategies are appropriate courses of management? James, a 27 year old commenced Suboxone three days ago an a dose of 4/1 mg. He now presents complaining of poor sleep, mild nausea and withdrawal discomfort each morning before his next dose. He reports using heroin once since starting treatment. A. Prescribe metoclopramide 10 mg tds prn for nausea B. Prescribe mg diazepam to help with sleep and withdrawal discomfort C. Increase the Suboxone dose to 8/2mg D. Increase the Suboxone dose to 16/4mg E. Reassure the patient that these are common side effects that usually subside within a few days 78

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