Buprenorphine in the treatment of Opioid Dependence

1
Buprenorphine in the treatment of Opioid
Dependence
Dr Tommie M Richardson MD, CAS
Addiction doesnt come heralded by a brass
band, it sneaks up on you, and sometimes with
extraordinary speed C. Everett Koop
(former US Surgeon General), 2003
2
The American story

• 2.3 million Americans reported using heroin ?
  once (1998)
• 149,000 new users (1999)
• 980,000 persons using at least weekly (1998)
• 810,0001 million chronic users of heroin
• Only 170,000200,000 receiving treatment

(National Household Survey on Drug Abuse, 1999
Office of National Drug Control Policy, 1997
SAMHSA, Office of Applied Studies, National
Household Survey on Drug Abuse, 2000 and 2001)
3
Worrying trends with prescription opioids

• Abuse of prescription painkillers has risen
  rapidly in the US
• OxyContin, Vicodin, Demerol
• Dramatic press coverage fueled demand
• Rx narcotics causing Emergency Department visits
  19942001
• 41,687?90,232 (117 increase)
• Significant diversion and abuse of methadone

4
Abuse of prescription opioids a growing problem
Non-medical OxyContin use 2002
2000000
1800000
1600000
1400000
1200000
1000000
800000
600000
400000
200000
0
1997
2000
2001
2002
Prescription drug monitoring American Society of
Interventional Pain Physicians, 2002
5
What is the cost to society?

• 20 billion per year total cost of heroin abuse
  (Harwood et al, 1998)
• The economic cost of drug use and dependence
  estimated to be 98 billion (Harwood et al, 1998)
  
• Figures do not take into account social impact of
  drug addiction
• Crime / legal costs
• Absenteeism from work / unemployment
• Welfare / medical costs

6
Choosing to use?

• A non-dependent user controls his/her use
• A dependent person is controlled by his/her
  addiction
• People suffering from addiction often seek
  treatment because they want their life back
• Addiction doesnt come heralded by a band, it
  sneaks up on you, and sometimes with
  extraordinary speed
• Koop, 2003

7
Are opioid-dependent individuals bad or sick?

• Opioid dependence has several features in common
  with diabetes and hypertension
• Chronic, relapsing nature
• Genetic vulnerability
• Physiologic brain changes
• Responds to chronic disease management
  strategies, not short-term symptomatic relief

8
Diagnosing addiction?

• More than 3 of the following during last 12
  months
• Tolerance
• Withdrawal syndrome
• Use of the drug to avoid/reverse withdrawal
  symptoms
• Compulsion to use drug, especially when trying to
  stop
• Narrowed repertoire of behaviors associated with
  drug use
• Drug-related behaviors more important than other
  previously more important activities/behaviors
• Early relapse after withdrawal

World Health Organization
9
What are the usual signs and symptoms?

• Sweating
• Yawning
• Anxiety
• Increased BP and respiratory rate
• Cravings
• Lacrimation
• Piloerection
• Rhinitis
• Gastrointestinal symptoms
• Abdominal cramps
• Diarrhea

10
Once addicted, why isnt it easy to stop?

• Withdrawal from opioids is associated with an
  extremely unpleasant syndrome
• Physical pain (muscle aches, cramps)
• Nausea and vomiting
• Diarrhea
• Dysphoria
• Depression
• Irritability and anxiety
• Dysregulation of brain reward systems
• Pharmacologic intervention proven to help relieve
  symptoms of withdrawal

11
Cost-effectiveness of treatment

• Treatment saves society money in costs of
  dependence eg,
• Emergency admissions from overdose
• Treatment of BBVs
• Costs of crime etc
• ? treatment access ? savings for society
• Potential for substantial net cost savings in
• Patients involved in extensive criminal activity
• Patients who undergo multiple detoxifications
  each year

12
OPIOID RECEPTORS Activity determined by -

• Affinity - how tight does the drug bind to the
  receptor
• Intrinsic Activity - how much does the drug
  stimulate the receptor
• Dissociation - how fast does the drug leave the
  receptor

13
OPIOID RECEPTOR PHARMACOLOGY
Agonists, antagonists, and partial
agonists Agonists substances that bind to the
receptor and produces a full biological
response Antagonists substances that bind to
the receptor and do not produce a biological
response Partial agonists substances that
bind to the receptor and produce a limited
response less than the full response produced
an agonist
14
AGONIST
DECREASED
MAXIMAL
EFFECT
PARTIAL
AGONIST
EFFECT
Antagonist
LOG DOSE
15
What is DATA (Drug Alcohol Treatment Act) 2000?
Provisions An Amendment to the Controlled
Substances Act that allows certified physicians
to prescribe and dispense Schedule III, IV, and V
narcotic drugs that have been approved by the
Food and Drug Administration for use in addiction
treatment (i.e., maintenance or medical
withdrawal (detoxification))
16
Limitations

• The total number of patients for a practitioner
  or group practice to 30
• Secretary of HHS may change this number by
  regulation (group practice number is currently
  under review)

17
Enter buprenorphine

• Effective treatment option for opioid dependence
  (Ling et al 1998)
• Reduces morbidity and mortality (Auriacombe et al
  1998)
• Improves quality of life (Giacomuzzi, et al 2003,
  Anisse, 2001)

18
Buprenorphine

• A synthetic opioid
• Partial agonist at the ? receptor
• - Low intrinsic activity only partially
  activating opiate receptors
• - Exhibits ceiling effects on respiratory
  depression
• High affinity for the ? receptor
• - Binds more tightly to opiate receptors than
  other opiates or opiate antagonists
• Slow dissociation from the receptor
• milder withdrawal

19
Buprenorphine preparations

• Subutex Suboxone registered as
• Schedule III narcotic
• sublingual tablet registered for treatment of
  opioid dependence
• - 2mg/0.5mg (2 mg)
• - 8 mg/2mg (8mg)
• Typical doses 4 to 32 mg per day
• Buprenorphine preparations also registered for
  analgesia (Buprenex)

20
Duration of effects

• Rapid onset of action 30 60 minutes (after S/L
  administration)
• Peak effects 1 4 hours
• Duration of action is dose related
• low dose 4 12 hrs
• med dose 24 hrs
• high dose 2 3 days
• Elimination half-life 24 to 36 hours

21
Pharmacological Clinical Properties
22
Drug Interactions Pharmacokinetic
Metabolic interactions (CYP P450
3A4) Inhibitor Inducer Pharmacodynamic
interactions CNS depressants Benzodiazepines
23
Interactions with other opioids?

• Opioid antagonists
• Incomplete reversal by naloxone
• Opioid agonists
• Blockade effect, limiting the effects of
  additional opioid use
• Potential for precipitated withdrawal when taken
  too soon after a full agonist

24
Side-effects

• All opioids have a qualitatively similar profile
  of side-effects
• Side-effects generally transient
• Experience of side-effects variable
• A client may experience side-effect to one opioid
  but not to another
• Not all symptoms are necessarily side-effects
  consider other causes

25
Why Suboxone? Limit misuse, abuse and diversion
of buprenorphine Reduce potential Public
Health problem ? allowing for changes in
treatment delivery
26

• How does Suboxone work?
• Buprenorphine works when placed under tongue
• very little naloxone absorbed
• Naloxone works when injected
• it gets to the receptor faster than
  buprenorphine
• naloxone has poor sublingual absorption but high
  IV absorption
• Buprenorphine suppress withdrawal and craving
• Naloxone causes withdrawal when injected by an
  opioid-dependent person

27
Parenteral and sublingual Suboxonechallenge in
hydromorphone-maintained subjects
100
Bad effects
60
50
Mean peak rating
40
30
20
10
0
16/4
1/.25
2/.5
4/1
8/2
1/.25
2/.5
4/1
8/2
16/4
Buprenorphine/ naloxone (mg/mg, IM)
Buprenorphine/ naloxone (mg/mg, SL)
Adapted from Stoller et al, 2001
28
Safety of sublingual Suboxone

• Well tolerated
• No apparent adverse clinical effects attributable
  to naloxone, even during induction
• No safety concerns following administration of
  246 mg for up to a year
• Naloxone does not appear to interfere with the
  sublingual absorption of buprenorphine

Mendelson et al., 1996
29
Common side-effects to Suboxone

• Headache
• Constipation
• Nausea
• Drowsiness, sedation
• Tiredness, lethargy
• Sleep disturbances
• Sweating
• Precipitated withdrawal on commencing
  buprenorphine

30
Understanding Precipitated Withdrawal (1)

• Buprenorphine (high affinity) competes with
  displaces full opioid agonists from receptors
• Buprenorphine has lower intrinsic opioid activity
  than full agonists
• Reduction in intrinsic opioid activity
  experienced by clients as opiate withdrawal

31
Understanding Precpted Withdrawal (2)

• Only likely to occur if first dose of
  buprenorphine is given whilst client experiencing
  effects of other opiates
• - Within hours of recent heroin use
• - Within 24 hours of patient on medium to high
  dose of methadone (e.g. 40 mg) or other long
  acting opiate
• Rule of Thumb
• wait until patient is feeling withdrawal
  symptoms coming on

32
Precipitated withdrawal or not enough
buprenorphine?
Adapted from Lintzeris et al., 2003
33
Indications contra-indications for treatment
with buprenorphine

• Indications
• - Opioid dependent (DSM-IV)
• Contra-indications
• - Severe side effects from previous exposure to
  buprenorphine
• - Hypersensitivity to naloxone

34
Suboxone Treatment pathways
35
Suboxone in Medical Withdrawal (Detox.)

• Minimal rebound withdrawal following short
  courses of buprenorphine
• Minimal other medication needed
• Post-withdrawal linkages
• - Maintenance substitution treatment
• - Naltrexone treatment
• - Psycho-social interventions
• Lintzeris et al, 2001

36
Objectives of medical withdrawal

• Short-term intervention
• To alleviate withdrawal discomfort
• To prevent complications
• To interrupt a pattern of heavy and regular
  opioid use
• To facilitate post-withdrawal treatment linkages
• Withdrawal is not a cure for opioid dependence

37
Examples of ?10 day inpatient medical withdrawal
schedules
Buprenorphine dose (mg) sublingual tablet
3-day schedule
Day
7-day schedule
10-day schedule
1
8
8
48
2
6
6
8
3
4
4
8
4
4
4
5
4
2
6
2
2
7
2
0
Adapted from Vignau, 1998
8
2
Adapted from Zhi-Min et al., 1997
9
2
Adapted from Cheskin et al., 1994
10
0
As seen in Drug and Alcohol Dependence
Supplement, Volume 70, Issue 2, Supplement S1-S104
38
Objectives of maintenance treatment

• To reduce mortality from overdose and infection
• To reduce opioid and other illicit drug use
• To reduce transmission of HIV, HBV / HCV
• To improve the general health and well-being of
  patients
• To reduce drug-related crime
• To improve social functioning and ability to stay
  in work

39

• Clinical guides for Maintenance treatment
• Dose to patient response
• Majority of patients respond to 4-24 mg daily
• No maximum recommended dose
• No maximum or minimum duration
• Provides opportunity for health care providers
  to address all aspects of needed care (e.g.
  psychosocial, medical, etc.)
• Variability between patients (e.g.,
  absorption, metabolism,elimination) requires
  individualized dosing

40
Maintenance With Buprenorphine - Retention
Johnson et al., NEJM 2000
41
Maintenance With Buprenorphine Self-Reported Use
(n220)
28
26
26
24
22
20
18
Mean Frequency/week
16
14
12
10
8
6
6
4
4
4
4
2
0
Baseline
LAAM
BUP
HDM
LDM
Johnson et al., NEJM 2000
Medication Group
42
Dose Ranges

• Most held 12-16mg
• Aim 10 mg
• Higher doses associated with better retention
  treatment success (12mg)

43
Buprenorphine in medical withdrawal and
maintenance
20
15
Buprenorphine
10
Number remaining in treatment
P0.0001
5
Control
0
0
250
200
150
100
50
300
350
Time from randomization (days)
Kaplan-Meier curve of cumulative retention in
treatment (Kakko et al, 2003)
44
Selecting treatment modalities

• Consider
• Patient expectations of treatment
• Patient goals
• Stages of change
• Current circumstances
• Available resources
• Past history of treatment outcome
• Evidence regarding safety, efficacy and
  effectiveness
• Informed consent

45
Getting started

• Engage the patient in the treatment process
• Ascertain valid information in order to identify
  most suitable treatment plan
• Diagnose dependence
• Determine suitability and gain patient consent
  for OBT with buprenorphine
• Create the treatment plan

46
The medical assessment

• Does this patient qualify for treatment?
• Drug use history
• Presenting problem
• Current and past drug use
• Quantity, frequency, duration
• All drug classes
• Assessment of dependence DSM IV
• Treatment history
• Motivation(s) and patient goals
• Previous attempts / treatment agents

47
Psychological assessment

• Psychiatric history and mental status examination
• ? Referral to specialist / psychiatrist
• Psychosocial circumstances
• Family history
• Medical history and physical examination
• Clinical lab tests (especially LFT and HCV
  testing)
• Discussion of treatment options
• Risks and benefits of treatment

48

• Induction
• Accurate history
• Objective signs of withdrawal
• Day 1
• Initial dose 4 mg
• Second dose of 4 mg after assessing initial
• response
• 4 mg take home dose has been given prn
• Day 2
• First days dose plus 24 mg as indicated by
• patients response
• Day 3
• Target 16 mg according to patients response

49
Always dose to desired clinical effect

• Variability in patient metabolism of
  buprenorphine requires individualized dosing
• Majority respond to 424 mg daily
• No maximum recommended dose
• Use of illicit opioids and treatment retention
  improves with increasing dose (Ling, Addiction
  1998)
• No maximum or minimum duration of treatment

50
Reviewing dose adequacy

• Intoxication.
• Adverse events.
• Cravings
• On-top use use of heroin/opiates
• Withdrawal.
• Urines

51
Finishing treatment with buprenorphine

• Buprenorphine binds tightly to the receptor and
  is stored in the body fat
• High affinity and slow dissociation from the
  receptor prolongs effects
• Slow release from body fat stores prolongs
  effects
• Gives rise to a smooth physiologic withdrawal
• Patients do better with comprehensive
  psychosocial, vocational, medical, psychiatric
  and behavioral therapy
• (McLellan et al, 1993 and 1994)

52
Web Resources

• http//buprenorphine.samhsa.gov/
• http//suboxone.com/Suboxone/
• Thank-you

53
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54
Additional Slides
55
Methadone?buprenorphine transfers generally
not recommended in stable patients
56
Reasons to transfer

• Patient preference
• Side effects from methadone
• Desire to stop additional heroin use
• Escalating doses of methadone
• Rapid metabolizers
• Tolerance
• Patient wishes to reach abstinence
• May be easier to stabilize on buprenorphine first
  and taper dose
• Ease of dosing, easier access to treatment

57
Transfer from ?30mg methadone considerations

• Be mindful of patient anxiety
• Develop trusting relationship with patient
• Explain potential issues related to the transfer
  and manage patient expectations
• Methadone is longer acting than heroin
• Greater risk of precipitated withdrawal

58
Avoiding precipitated withdrawal

• To reduce risk of precipitated withdrawal
• Transfer from doses of methadone
• Check patient has not used opioid since last
  methadone dose
• Commence with low dose of buprenorphine (4 mg)
• Delay first dose of buprenorphine until
  mild-moderate objective signs of opioid
  withdrawal are evident

59
How to transfer from methadone

• Reduce methadone dose as far as possible
• Many patients become unstable if they reduce
  their methadone dose too low
• Cease methadone and commence buprenorphine 24
  hrs after last methadone dose
• Always wait for objective signs of opioid
  withdrawal before 1st buprenorphine dose ( 4 mg)
• Review patient prior to dosing on following day
• Titrate dose according to response

60
Communication is key

• Discuss risks with patient, carers
• Develop emergency plan
• Possibility of being uncomfortable for several
  days (up to 2 weeks) after transfer
• Even without having experienced significant
  precipitated withdrawal

Lintzeris et al, Turning Point Buprenorphine
Training Package, Australia 2001
61
Managing the first day

• Review the patient 34 h after 1st dose
• Worsening of withdrawal
• Provide symptomatic withdrawal medication for
  remainder of day
• No worsening of withdrawal or improvement in
  withdrawal symptoms
• Further 24 mg of buprenorphine can be dispensed
  that afternoon / evening

Australian National Clinical Guidelines, 2001
62
After the first day

• Stabilization doesnt happen over night
• Patient may be uncomfortable for several days (up
  to 2 weeks) after transfer
• Even without significant precipitated withdrawal
• Frequent patient review is required over several
  weeks
• Increase dose only after reviewing patient
• Increments of 24 mg at a time
• Principles of dose titration, stabilization and
  maintenance prescribing as for heroin users

63
Pharmacological Effects following IV use
64
Must haves for medical withdrawal

• Assessment
• Supportive care
• Counseling
• Safe environment / patient trust
• Provision of patient information
• Monitoring
• Medications
• Post-withdrawal ongoing support
• Continuing counseling and psychosocial support
• Naltrexone treatment
• Maintenance treatment

65
Treatment planning

• Patient is dependent
• Patient is suitable for OBT with buprenorphine
• Treatment plan

Available resources including referral
availability
Patient needs identified from assessment
procedures