Treatment of Opioid Dependence with Buprenorphine/Naloxone (Suboxone )

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Cory McGee
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1 Treatment of Opioid Dependence with Buprenorphine/Naloxone (Suboxone ) Elinore F. McCance-Katz, M.D., Ph.D. Professor and Chair, Addiction Psychiatry Virginia Commonwealth University

2 Neurobiology of Opiate Addiction

3 Neurobiology of Opiate Addiction Opiates bind to opiate receptors in the nucleus accumbens: : increased dopamine release

4 Neurobiology of Opiate Addiction The reward pathway: Opiates activate receptor sites in the Ventral Tegmentum which in turn causes dopamine release by the NA. This is associated with intense euphoria. The memory of the experience is maintained in the hippocampus and other areas of the brain as well.

release by the NA. This is associated with intense euphoria.

5 Neurobiology of Opiate Addiction The Locus Ceruleus: Neurons produce Norepinephrine (NE) and opioids suppress the release of NE leading to respiratory depression and drowsiness. During withdrawal there is rebound NE release by these neurons causing anxiety, tremor, hypertension, tachycardia, and other withdrawal symptoms.

6 Buprenorphine Opioid partial agonist Schedule III (vs. methadone: Schedule II) Treatment modalities for buprenorphine: Office based treatment Primary Care Specialty (e.g.: Infectious Disease, GI, Psychiatry) Substance abuse treatment clinics Methadone maintenance programs

Office based treatment Primary Care Specialty (e.g.

7 How Does Buprenorphine Work? 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 Therefore Full Agonist is displaced

affinity is very strong and it will displace full agonists like heroin and methadone Note

8 How Does Buprenorphine Work? 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 t bind

from the receptor Buprenorphine s dissociation is slow Therefore buprenorphine stays

9 Clinical Forms of Buprenorphine Parenteral form for treatment of moderate to severe pain Sublingual forms for treatment of opioid dependence Combo buprenorphine or Suboxone Bup 2mg/naloxone 0.5mg or Bup 8mg/naloxone 2mg Developed to decrease diversion to i.v.. use Preferred form for maintenance therapy Precipitated withdrawal if injected Mono sublingual form = Subutex Bup 2mg or Bup 8 mg Use in pregnancy

10 Buprenorphine Dosing Sublingual administration Tablet under tongue Dissolves in minutes Taste is generally well tolerated Very few will complain about taste Have patient drink something before tablet to help with tablet dissolution Two-three tablets at once is limit

few will complain about taste Have patient drink something before

11 Buprenorphine: Side Effects Nausea/vomiting (consider precipitated withdrawal) Constipation Sedation (use of other sedating drugs or in those not currently dependent, but eligible for buprenorphine treatment by history) Elevations in liver transaminases (Hep C at higher risk)

those not currently dependent, but eligible for buprenorphine

12 Buprenorphine: Abuse Potential Abuse potential of buprenorphine varies as function of: level of physical dependence Lower opioid physical dependence time interval between last dose of opioid agonist and buprenorphine ingestion Longer it has been since the last use of opioid the more likely buprenorphine can be abused Naloxone may diminish opioid effect

dose of opioid agonist and buprenorphine ingestion Longer it has been since the last use

13 Buprenorphine: Abuse Potential Buprenorphine in all forms (SL, SQ, IM, IV) Has relatively lower abuse risk than full agonists (e.g. methadone), but can be abused Parenteral buprenorphine is abused Epidemiological studies Human laboratory studies: injected buprenorphine produces high,, is reinforcing Diversion less likely given study design

14 Buprenorphine Treatment Maintenance Medical Withdrawal

15 Buprenorphine Maintenance Numerous outpatient clinical trials in people with Opioid Dependence Disorder compared efficacy with: Methadone Maintenance Placebo Maintenance These trials reliably demonstrated that, in preventing relapse to heroin: Buprenorphine Maintenance is more effective than placebo Buprenorphine Maintenance is equally effective as moderate doses of methadone (e.g., 60 mg per day)

demonstrated that, in preventing relapse to heroin: Buprenorphine Maintenance is more effective

16 Induction for Patient Physically Dependent On Short-acting Opioids (For Substitution or Withdrawal) No opioids at least 8 hours before induction Observe withdrawal before dosing COWS > 5; objective, not just subjective! First dose: mg SL Monitor 2 hours Second dose mg; generally < 8 mg Day 1 Day 2: may increase by up to 8 mg Average maintenance dose: 16 mg daily

17 Buprenorphine Induction Most patients do well on 16 mg daily; some need less (e.g.: 12 mg), some more (e.g.: 24 mg daily) Do not exceed 32 mg daily Give patients a few days to stabilize following Day 2 increase to 16 mg before deciding to increase dose

18 Buprenorphine Induction Precipitated Withdrawal Occurs if buprenorphine is administered before withdrawal onset in person physically dependent on opioids Can be characterized by severe withdrawal (N/V, cramps, diarrhea, chills, myalgia) ) within approx minutes of buprenorphine dose Check time of last use Consider medications for withdrawal symptoms or Monitor and re-dose with buprenorphine after several hours (i.e.: continue induction) Opiate withdrawal is generally not life threatening in those without comorbid medical illness

of buprenorphine dose Check time of last use Consider medications for withdrawal symptoms or Monitor and re-dose with buprenorphine

19 Buprenorphine Substitution Once stabilized buprenorphine can block opiate effects (affinity/dissociation concepts) Thrice weekly dosing (32/32/48 mg) What is an effective dose? Discontinuation of opiate use Treatment retention Craving resolves Reduction/cessation of high risk, drug-related related activities

20 Buprenorphine: Medical Withdrawal Buprenorphine can be substituted for heroin and used as a withdrawal agent Repeated administration of buprenorphine produces or maintains physical dependence Degree of physical dependence is less than that produced by full agonist opioids Withdrawal syndrome less severe for buprenorphine than for heroin (or methadone)

physical dependence Degree of physical dependence is less than that produced by full

21 Buprenorphine: Medical Withdrawal Protocol: up to 19 day withdrawal period Stabilize over 3 days; On day 4 start withdrawal, decrease by 2 mg daily Most will stabilize on 16 mg; so withdrawal will be complete by Day 11 Withdrawal symptoms may not occur until completely off drug for days Treat withdrawal symptoms with as needed medications

22 Buprenorphine-Methadone Comparison Buprenorphine Methadone Regulation/ Diversion Dose/side Effects Ease of Use Drug Interactions Partial agonist Combined with naloxone Limited diversion Less regulation OBOT Preferred is combo: bup/nlx Side effects minor Precipitated withdrawal potential Induction requires clinical monitoring Available by prescription Withdrawal easily tolerated No clinically significant with HIV meds; BZD Full agonist May be diverted Toxicity risk greater Specialized treatment centers required Relatively high dose required for tolerance induction; continued opiate effects, sedation Induction and dosing straightforward Withdrawal challenging; patients c/o significant discomfort Numerous, especially HIV meds

23 Buprenorphine: Summary Opioid partial agonist: less opioid effects than heroin or methadone; less potential for toxicity Induction requires clinical observation Withdrawal is better tolerated than for other opioids Suboxone will cause precipitated withdrawal in physically dependent person if administered following recent opiate use or injected

Update on Buprenorphine: Induction and Ongoing Care

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