Opioid Dependence: Highlighting Buprenorphine Treatment

1
Opioid Dependence Highlighting Buprenorphine
Treatment

• Tony Tommasello, Pharmacist, PhDAssociate
  ProfessorUM School of Pharmacy
• Office of Substance Abuse Studies515 West
  Lombard Street 263 410 706-7513
• atommase_at_rx.umaryland.edu

ACPE Universal Program Number 025-999-06-054-X01
2
Learning Objectives

• At the conclusion of this program participants
  will be better able to
• 1. Describe the forces that are driving the
  current increase in opioid abuse in the U.S.
• 2. Explain the need for non-pharmacological
  interventions for addicted patients
• 3. List therapeutic outcomes for addiction
  treatment
• 4. Distinguish medical withdrawal and medical
  maintenance
• 5. Explain the pharmacological basis for
  medical maintenance
• 6. Describe differences between methadone,
  buprenorphine, and naltrexone pharmacotherapy
• 7. List policy changes relative to opioid
  addiction treatment in America

3
Dynamics of a Heroin Epidemic
Input
Input
Narcotic Addiction
Recovery
Input

• 2.4 million users
• 0.5 to 1 million addicts
• 150 to 200,000 new users each year

• Broad-based screening
• Addiction Severity Index
• Treatment on demand

4
Number of US Narcotic Analgesic-Related ED
Visits, 1994-2001
Source www.samhsa.gov/oas/2k3/pain/dawnpain.pdf.
5
Teen Abuse of Rx DrugsNational Figures
Curran JJ. Prescription for Disaster The
growing problem of prescription drug abuse in
Maryland. September 2005.
6
Access to Treatment Is Limited

• Of the estimated 810,000 opioid-dependent
  persons in the United States, only 170,000
  maintenancetreatment slots exist

7
Aspects of Addiction
Chronic Incurable but manageable
Primary Not relieved by treating a suspected causative condition
Progressive Gets worse if untreated
Relapsing Prone to recurrence if untreated
Fatal Premature death in untreated individuals
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9
The Memory of Drugs
10
Opioid Addiction Effects on the Body

• Opioids activate receptors in the central nervous
  system (CNS) and the gastrointestinal (GI) track
• CNS stimulation provides pleasurable feelings
  while GI stimulation produces constipation
• Other CNS effects include miosis, respiratory
  depression, drop in blood pressure

11
Why Treatment?
Rewards

• Dysfunctional lifestyle of opioid addiction makes
  treatment a desired alternative
• Oral methadone and buprenorphine sublingual
  tablets are approved for both medical withdrawal
  and medical maintenance

Negative Consequences
Utility Theory
12
Addiction Treatment

• Optimal treatment combines pharmacological and
  nonpharmacological therapies for successful
  management of those addictions for which
  pharmacotherapy has been approved (opioid,
  alcohol, nicotine)

13
Primary Treatments Are Nonpharmacological

• Individual and/or group cognitive behavioral
  therapy
• Urine monitoring for drugs of abuse (also sweat,
  saliva, and blood)
• Support group participation
• Narcotics Anonymous
• Alcoholics Anonymous

14
Patient Response to Addiction Treatment Will Vary

• Patient characteristicsage, employment
  experiences, concurrent illnesses, family support
• Patient historypast treatment experiences,
  duration and level of drug use
• Patient motivation
• Length of time in treatment

15
Opioid Addiction Pharmacotherapy Enhances
Treatment Outcomes

• Medical Withdrawal Remove the opioid from the
  body and remain free of future opioid use
• Maintenance Therapy Use a substitute opioid
  (agonist), satisfy narcotic hunger, eliminate
  craving
• Buprenorphine approved for both approaches

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Pharmacology of Opioids

• Affinity The strength with which a drug binds to
  its receptor
• Dissociation The speed at which a drug uncouples
  from its receptor
• Efficacy The percent of maximal response that a
  drug generates when it binds to the receptor

17
Full Agonists

• Bind to and activate receptor site
• As dose is increased, effect is increased until a
  maximum response is attained
• Examples
• Heroin
• Oxycodone
• Methadone

18
Antagonists

• Bind to the receptor without causing activity
• An antagonist can block the receptor from being
  activated by partial or full agonist
• Examples
• Naloxone
• Naltrexone

19
Partial Agonists

• Bind to receptor and excite the receptor
• Activity reaches a plateau at which an increase
  in dose does not result in increased activity
• Examples
• Buprenorphine (also a kappa antagonist)
• Pentazocine

20
Comparative Efficacies
Conceptual Representation of Opioid Effect
Versus Log Dose for Opioid Full Agonists, Partial
Agonists, and Antagonists
Full Agonist (Methadone)
Partial Agonist (Buprenorphine)
Antagonist (Naloxone)
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Pharmacokinetic Distinctions

• Methadone
• Slowly absorbed from the gut reaching peak blood
  level in 45 to 90 minutes
• Half-life in maintenance patient is 24 hours
• Allows once-daily dosing

• Buprenorphine
• Sublingual tablets must be held under the tongue
  for 4 to 8 minutes for absorption
• Peak blood level in 60 minutes
• Half-life is 32 hours
• Allows once-daily or every-other-day dosing

Chiang CN, Hawks RL. Pharmacokinetics of the
combination tablet of buprenorphine and naloxone.
Drug Alcohol Depend. 200370(suppl 2)S39-S47.
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Other Distinctions

• Buprenorphine has greater opioid receptor
  affinity and slower receptor dissociation than
  methadone
• Buprenorphine will displace a full agonist
  (methadone) and dock at the receptor, thus
  blocking other full agonists from attaching there
• Patients switching from methadone to
  buprenorphine may experience withdrawal distress
  and are advised to complete a reduction process
  before starting buprenorphine

23
Buprenorphine/Naloxone Combination and
Buprenorphine Alone

• Two dosages
• Buprenorphine 2 mg with naloxone 0.5 mg
• Buprenorphine 8 mg with naloxone 2 mg
• Two dosages
• Buprenorphine 2 mg
• Buprenorphine 8 mg

SUBOXONE SUBUTEX
Tablet(s) should be held under the tongue until
completely dissolved.
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Medical Withdrawal With Buprenorphine

• Opioid-dependent individuals are treated with the
  goal of achieving a smooth transition to being
  substance free in a short period of time
• Dose-tapering patients should be engaged in
  counseling and have counseling continued after
  medical withdrawal is complete
• MDs and pharmacists should continue to reinforce
  to patients the importance of counseling after
  withdrawal

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Induction Dosing Guidelines Buprenorphine for
Non-Methadone Patients

• Give the first dose after discontinuing opioids
  and some withdrawal symptoms are evident
• Precipitated withdrawal is avoided by giving the
  first dose of buprenorphine after withdrawal
  symptoms are displayed

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Titrate to Stability
Withdrawal
Intoxication
Withdrawal
Intoxication
Insufficient Opioid
Excessive Opioid
Withdrawal
Intoxication
Stabilization
27
Staging and Grading Systems of Opioid Withdrawal
(TIP 40)
Stage Grade Physical Signs/Symptoms
Early Withdrawal (824 hours after last use) Grade 1 Lacrimation and/or rhinorrhea Diaphoresis Yawning, restlessness, insomnia
Early Withdrawal (824 hours after last use) Grade 2 Dilated pupils Piloerection Muscle twitching, myalgia and arthralgia Abdominal pain
Fully Developed Withdrawal (13 days after last use) Grade 3 Tachycardia, tachypnea Hypertension Fever Anorexia or nausea Extreme restlessness
Fully Developed Withdrawal (13 days after last use) Grade 4 Diarrhea and/or vomiting Dehydration Hyperglycemia Hypotension Curled-up (fetal) position
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Signs of Opioid Intoxication and Overdose (TIP
40)

• Opioid Intoxication
• Conscious
• Sedated, drowsy
• Slurred speech
• Nodding or intermittently dozing
• Memory impairment
• Mood normal to euphoric
• Pupillary constriction

• Opioid Overdose
• Unconscious
• Pinpoint pupils
• Slow, shallow respirations respirations below
  10 per minute
• Pulse rate below 40 per minute
• Overdose triad apnea, coma, pinpoint pupils
  (with terminal anoxia fixed and dilated
  pupils)

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Medical Withdrawal Dosing Buprenorphine for
Non-Methadone Patients

• A maximum dose of 8 mg can be administered on the
  first day as Subutex or as Suboxone
• Patients who still have withdrawal distress
  should be treated symptomatically and have their
  doses increased to a maximum of 16 mg for Day 2
• Stabilize for 2 days before tapering, then taper
  2 mg/day every 2 to 3 days

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Model Prescription Medical Withdrawal
Physician name, address, DEA and waiver number
Ralph Amado, M.D. 3862 North Hampton
Lane Rudolph, PA 38216
AA620395 XA620395
Patient
Patient name and address
Roger Bacon 1063 Eastlight Dr. Essex, PA 38604
Drug name and strength Dosage form and quantity
Suboxone 2/0.5 Tablets 42 (forty-two)
SIG for opioid withdrawal
Day of tx 3 4 5 6 7 8 9 10 11 12 13
date 5/25 5/26 5/27 5/28 5/29 5/30 5/31 6/1 6/2 6/3 6/4
tabs 8 7 6 5 4 3 3 2 2 1 1
Treatment on days 1 and 2 were done in the
physicians office
Refill x 0 (zero)
Physician signature Ralph Amado
Date issued 5/24/03
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Medical Withdrawal

• Withdrawal services are essentially acute
  services with short-term outcomes, whereas heroin
  dependence is a chronic relapsing condition, and
  positive long-term outcomes are more often
  associated with longer participation in
  treatment.

Vorrath E (ed) (2001) National Clinical
Guidelines and Procedures for the use of
Buprenorphine in the Treatment of Heroin
Dependence (p.30). Available at
http//www.nationaldrugstrategy.gov.au/resources/p
ublications/buprenorphine_guide.pdf
32
Medical Withdrawal

• Overemphasis on the importance of being drug free
• Underestimates the challenges associated with
  addiction
• Nonpharmacological interventions are critical to
  recovery success

33
Sustaining Abstinence

• Naltrexone (Trexan) 50 mg/day is used to prevent
  opioid effects if a patient uses opioids during
  recovery
• Patient must be narcotic free 7 to 10 days before
  starting therapy
• Naltrexone blocks heroin high and other effects
• Noncompliance and low patient acceptance

34
Maintenance Treatment

• Patients consume a long-acting prescription
  opioid medication as a substitute for the illegal
  short-acting street opioid
• The most dramatic effect of this treatment has
  been the disappearance of narcotic hunger

Dole VP, Nyswander M. A medical treatment for
diacetylmorphine (heroin) addiction. JAMA.
1965193646-650.
35
Outcomes of Treatment

• Methadone is the standard pharmacotherapy for
  opioid addiction
• Two outcomes for treatment
• Reduction of illicit opioid abuse
• Retention in treatment
• Medical maintenance is the best treatment option
  in achieving these outcomes

36
Buprenorphine Trials Data (Retention)
37
Buprenorphine Trials Data (Opioid Abuse)
38
Buprenorphine Trials Data (Urine Tests)
39
Strain EC et al. Buprenorphine versus methadone
in the treatment of opioid dependence
self-reports, urinalysis, and Addiction Severity
Index. J Clin Psychopharmacol. 19951659-67.
40
Fudala PJ et al. Office-based treatment of opiate
addiction with a sublingual-tablet formulation of
buprenorphine and naloxone. N Engl J Med.
2003349949-958.
41
Adverse Events Reported by at Least 5 Percent of the Subjects in Any Treatment Group During the Double-Blind Trial Adverse Events Reported by at Least 5 Percent of the Subjects in Any Treatment Group During the Double-Blind Trial Adverse Events Reported by at Least 5 Percent of the Subjects in Any Treatment Group During the Double-Blind Trial Adverse Events Reported by at Least 5 Percent of the Subjects in Any Treatment Group During the Double-Blind Trial Adverse Events Reported by at Least 5 Percent of the Subjects in Any Treatment Group During the Double-Blind Trial
Adverse Event Buprenorphine and Naloxone (n107) Buprenorphine Alone(n103) Placebo(n107) PValue
No. of subjects () No. of subjects () No. of subjects ()
Headache 39 (36.4) 30 (29.1) 24 (22.4) 0.08
Withdrawal syndrome 27 (25.2) 19 (18.4) 40 (37.4) 0.008
Pain 24 (22.4) 19 (18.4) 20 (18.7) 0.74
Insomnia 15 (14.0) 22 (21.4) 17 (15.9) 0.37
Nausea 16 (15.0) 14 (13.6) 12 (11.2) 0.73
Sweating 15 (14.0) 13 (12.6) 11 (10.3) 0.70
Abdominal pain 12 (11.2) 12 (11.7) 7 (6.5) 0.37
Rhinitis 5 (4.7) 10 (9.7) 14 (13.1) 0.09
Diarrhea 4 (3.7) 5 (4.9) 16 (15.0) 0.005
Infection 6 (5.6) 12 (11.7) 7 (6.5) 0.24
Chills 8 (7.5) 8 (7.8) 8 (7.5) 1.0
Constipation 13 (12.1) 8 (7.8) 3 (2.8) 0.03
Back pain 4 (3.7) 8 (7.8) 12 (11.2) 0.12
Vasodilation or flushing 10 (9.3) 4 (3.9) 7 (6.5) 0.28
Vomiting 8 (7.5) 8 (7.8) 5 (4.7) 0.66
Weakness 7 (6.5) 5 (4.9) 7 (6.5) 0.87
Data were unavailable for two of the subjects in
each group. P values are for the overall
comparison among three groups. Fudala PJ et al.
Office-based treatment of opiate addiction with a
sublingual-tablet formulation of buprenorphine
and naloxone. N Engl J Med. 2003349949-958.
42
Model PrescriptionMaintenance Treatment
Physician name, address, DEA and waiver number
Ralph Amado, M.D. 3862 North Hampton
Lane Rudolph, PA 38216
AA620395 XA620395
Patient
Patient name and address
Roger Bacon 1063 Eastlight Dr. Essex, PA 38604
Drug name and strength Dosage form and quantity
Suboxone 8/2 Tablets 60 (sixty)
SIG for opioid maintenance take two tablets
daily dissolved under the tongue.
Refill x 5 (five)
Physician signature Ralph Amado
Date issued 5/24/03
43
Clinical Trials Dosing

• Sublingual buprenorphine daily doses of 8 to16 mg
  has been shown to be equally effective to oral
  methadone daily doses of 80 to 120 mg
• Buprenorphine maintenance is ideal for people
  abusing illegal opiates and for those who want to
  switch from methadone to buprenorphine
• Protocols for treatment can be found in the
  manual Clinical Guidelines for the Use of
  Buprenorphine in the Treatment of Opioid
  Addiction a Treatment Improvement Protocol (TIP)
  40. Available at www.samhsa.gov/centers/csat/csat
  .html

44
Drug Interactions

• Benzodiazepinesrespiratory depression and
  cardiovascular collapse are possible when high
  doses are taken of both drugs. Patients must be
  closely monitored
• Other depressants produce additive effects on the
  CNS and may create interactive effects for
  patients operating motor vehicles or heavy
  machinery

• Buprenorphine given to tolerant physically
  dependent opiate addicts may produce withdrawal
  symptoms
• Buprenorphine is metabolized by the cytochrome
  p450 3A4 pathway. Drugs metabolized by the same
  pathway could result in higher than normal levels
  of either drug. Patients who are on both
  buprenorphine and one of these drugs need to be
  monitored closely

45
DATA (Drug Addiction Treatment Act)New
PolicyNew Practice
The Childrens Health Act of 2000
46
Provisions of DATA

• An amendment to the Controlled Substances Act
• Allows certain physicians to prescribe and
  dispense for up to 30 patients Schedule III, IV,
  and V narcotic drugs that have been approved by
  the Food and Drug Administration for use in
  maintenance or detoxification treatment
• An authorized physician, one year after his or
  her initial notification, may petition to
  increase up to 100 the number of patients s/he
  will treat

Changed by public law 109-56 on 8-2-2005
47
Authorized Buprenorphine Prescribers in the
United States

• http//buprenorphine.samhsa.gov/
• Physician locator selection provides map. Click
  on your state for physician listing

48
List of Drugs Approved by FDA for Use Under DATA

• Only buprenorphine formulated for sublingual use
  has been approved
• Approved on October 8, 2002
• Two formulations, Subutex and Suboxone are
  available
• No other medications are approved for use under
  DATA

49
Expanded Access to Care

• One public health goal is to make opioid
  addiction treatment available on demand
• Methadone treatment clinics are operating at
  full capacity
• The Drug Addiction Treatment Act, if widely
  implemented, will offer numerous points of entry
  into opioid addiction treatment

50
Pharmacists Roles

• Case finding through screening
• Dispense buprenorphine sublingual tablets in
  accordance with the law
• Patient education on proper sublingual use
• Counsel patients regarding drug interactions
• Advise counseling interventions and help
  patients locate appropriate therapists
• Manage refill regularity

51
Code of Federal Regulation Title 42 Part 2

• Protects the confidentiality of alcohol and drug
  abuse patients and their medical records
• Is different from HIPAA
• Restricts disclosure of patient information and
  any patient identifying information
• Requires consent for ANY information to be
  disclosed

52
Practice Implications

• Pharmacists need to practice diligence when
  counseling patients
• Pharmacists need to train their staff on the
  importance of not disclosing information on a
  patient receiving treatment
• Pharmacists must limit the information they
  provide to others

53
Initial Reports Are Favorable

• Pharmacists involved in early trials with
  buprenorphine sublingual pharmacotherapy
  generally found the experience to be clinically
  rewarding
• Few expressed concerns about dangers associated
  with this treatment ofopioid addiction

Raisch DW et al. J Am Pharm Assoc.
20054523-32.
54
Summary

• Buprenorphineeffective pharmacotherapy for
  opioid addiction
• Knowledgeable pharmacists can effectively counsel
  patients undergoing treatment with this
  medication
• Pharmacists will be increasingly expected to
  dispense buprenorphine prescriptions and provide
  associated services

55
Opioid Dependence Highlighting Buprenorphine
Treatment

• Tony Tommasello, Pharmacist, PhDAssociate
  ProfessorUM School of Pharmacy
• Office of Substance Abuse Studies515 West
  Lombard Street 263 410 706-7513
• atommase_at_rx.umaryland.edu