Download Section 34_Addiction Medications 2_68 slides

Section 34:
Addiction Medications
Richard A. Rawson, Ph.D., Professor
Semel Institute for Neuroscience and Human Behavior
David Geffen School of Medicine
University of California at Los Angeles
Opiate Agonist and
Partial Agonist Therapy
Methadone and Buprenorphine
Global Abuse of Opiates
Overview:



Sixteen million (0.4%) of
world’s population age
15-64 abuse opiates
Heroin abusers make up
about 71% of opiate
abusers
Opiates accounts for 2/3
of all treatment demands
in Asia and 60% of
treatment demand in
Europe
Regional Breakdown of Opiate Abusers
Africa Oceania
6%
1%
Americas
14%
Asia
54%
Europe
25%
Sources: UNODC, Annual Reports Questionnaire Data,
Govt. reports, reports of regional bodies, UNODC
estimates.
3
Opioids
Opiate (n)
an unlocked door
in the prison
of identity.
It leads to the
jail yard.
Ambrose, Bierce (1906)
The Devil’s Dictionary
4
Opioid-related Problems
 Most
prominent problems are associated
with heroin dependence
 Not
all users of heroin develop
dependence. Between 1:4 to 1:3 regular
users develop dependence
 Development
of heroin dependence
usually requires regular use over months
(or longer where use is more irregular).
5
The Revolving Door

Heroin dependence is a chronic relapsing
disorder. It is a dependency which is very
difficult to resolve
 Relapse is extremely common. It is part of the
process of resolving the dependence – much
like giving up tobacco
 A principal health care objective is to get the
patient into treatment, help keep them in
treatment and to return them to treatment when
relapse occurs.
6
Classification of Opioids
Pure Opioid Agonists
opium
papaverine
morphine
codeine
heroin
buprenorphine
hydromorphone
oxycodone
Partial Agonists/Antagonists
naltrexone
buprenorphine
LAAM
Synthetic
LAAM
fentanyl
meperidine
hydrocodone
methadone
pentazocine
pethidine
7
Opioids: Long-term Effects (1)


Little evidence of long-term direct toxic
effects on the CNS from opioid use
Long-term health-related complications
may result from:
–
–
–
–
–
dependence
antisocial behaviour
poor general self-care
imprisonment
drug impurities or contaminants, BBV.
8
Opioids: Considerations for
assessment
 Pregnancy
 BBV
 Polydrug
dependence
 Opioid related overdose
 Major or pre-existing medical conditions
(e.g. liver, cardiac)
 Major psychiatric/mental health issues
(e.g. psychosis, depression, suicide).
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Opioid Withdrawal







Signs
Yawning
Lacrimation, mydriasis
Diaphoresis
Rhinorrhoea, sneezing
Tremor
Piloerection
Diarrhoea and
vomiting.







Symptoms
Anorexia and nausea
Abdominal pain or
cramps
Hot and cold flushes
Joint and muscle pain or
twitching
Insomnia
Drug cravings
Restlessness/anxiety.
10
Progress of the Acute Phase of
Opioid Withdrawal Since Last Dose
Severity of signs and symptoms
Withdrawal from heroin
Onset: 6–24 hrs
Duration: 4–10 days
0
Withdrawal from methadone
Onset: 24–48 hrs, sometimes more
Duration: 10–20 days,
sometimes more
10
Days
deCrespigny & Cusack (2003)
Adapted from NSW Health Detoxification Clinical Practice Guidelines (2000-2003)
20
11
Predictors of Withdrawal Severity

Main predictors
–
Greater regular dose
–
Rapidity with which drug is withdrawn.
 Also consider
}
–
–
–
Greater
withdrawal
severity
Type of opioid used, dose, pattern and duration of use
Prior withdrawal experience, expectancy, settings for
withdrawal
Physical condition (poor self-care, poor nutritional status,
track marks)
–
Intense sadness (dysthymia, depression)
–
Constipation or ‘Narcotic Bowel Syndrome’
–
Impotence (M) or menstrual irregularities (F).
Opioids
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Opioid Withdrawal Treatment
Involves:





reassurance and supportive care
information
hydration and nutrition
medications to reduce severity of somatic
complaints (analgesics, antiemetics, clonidine,
benzodiazepines, antispasmodics)
opioid pharmacotherapies
(e.g. methadone, buprenorphine, naltrexone).
Opioids
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Opioid Withdrawal Complications






Anxiety and agitation
Low tolerance to discomfort and dysphoria
Drug-seeking behaviour (requesting or
seeking medication to reduce symptom
severity)
Muscle cramps
Abdominal cramps
Insomnia.
Opioids
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Heroin Withdrawal

Non-life threatening
 Commences 6–24+ hours after last use
 Peaks at around 24–48 hours after use
 Resolves after 5–7 days.
Increasing recognition of the existence of a
protracted phase of withdrawal lasting some
weeks or months, characterised by reduced
feelings of wellbeing, insomnia, dysthymia,
and cravings.
Opioids
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15
General Principles of Pharmacotherapies
Pharmacodynamics:

Agonists
–

Partial agonists
–

directly activate opioid receptors
(e.g. morphine, methadone)
unable to fully activate opioid receptors even with
very large doses (e.g. buprenorphine)
Antagonists
–
occupy but do not activate receptors, hence
blocking agonist effects (e.g. naloxone).
Opioids
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Maintenance Pharmacotherapies





Methadone
Buprenorphine
Naltrexone
LAAM
Slow-release morphine.
Opioids
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17
Key Outcomes of Maintenance
Pharmacotherapy Programs

 Retention in treatment

Facilitates reduction/cessation of opioid use

Reduces risky behaviours associated with opioid use

Enables opportunity to engage in harm reduction
measures

 Mortality and morbidity

 Psychological, emotional and physical wellbeing of
patients

 Social costs associated with illicit drug use

 Crime.
Opioids
18
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Methadone: Clinical Properties
The ‘Gold Standard’ Treatment






Synthetic opioid with a long half-life
μ agonist with morphine-like properties and actions
Action – CNS depressant
Effects usually last about 24 hours
Daily dosing (same time, daily) maintains constant
blood levels and facilitates normal everyday activity
Adequate dosage prevents opioid withdrawal
(without intoxication).
Opioids
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19
Rationale for opioid agonist
treatment (1)
Advantages of opioid agonist medication
over heroin:
Non-parenteral administration
Known composition
Gradual onset and offset
Long-acting
Mildly reinforcing
Medically supervised
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20
Rationale for opioid agonist
treatment (2)
Opioid agonist treatment:

Most effective treatment for opioid
dependence

Controlled studies have shown that with long
term maintenance treatment using
appropriate doses, there are significant:
 Decreases in illicit opioid use
 Decreases in other drug use
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21
Rationale for opioid agonist
treatment (3)
Opioid agonist treatment (continued):




Decreases in criminal activity
Decreases in needle sharing and HIV
transmission
Improvements in prosocial activities
Improvements in mental health
22
22
The global response: UN support for
good treatment
WHO/UNODC/UNAIDS position paper: Substitution
maintenance therapy in the management of opioid
dependence and HIV/AIDS prevention
“Substitution maintenance treatment is an effective,
safe and cost-effective modality for the management
of opioid dependence. Repeated rigorous evaluation
has demonstrated that such treatment is a valuable
and critical component of the effective management
of opioid dependence and the prevention of HIV
among IDUs.”
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Safety Overview

Safe medication (acute and chronic dosing)
 Primary side effects: like other mu agonist opioids
(e.g., nausea, constipation), but may be less
severe
 No evidence of significant disruption in cognitive
or psychomotor performance with Methadone
maintenance
 No evidence of organ damage with chronic dosing
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Methadone: Advantages of Treatment

Suppresses opioid withdrawal
 Pure – no ‘cutting agents’ present
 Oral administration (syrup or tablet forms used)
 Once daily doses enable lifestyle changes
 Slow reduction and withdrawal can be negotiated with
minimal discomfort
 Counselling and support assists long-term lifestyle
changes
 Legal and affordable – reduced participation in crime
 Few long-term side-effects.
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Methadone: Disadvantages of Treatment








Initial discomfort to be expected during
stabilisation phase
Opioid dependence is maintained
Slow withdrawal (preferably) negotiated and
undertaken over a period of months
Protracted withdrawal symptoms
Can overdose, particularly with polydrug use
Daily travel and time commitment
Variable duration of action
Diversion
26
26
To Maximize Treatment Adherence
 Address
psychosocial issues as first
priority




emotional stability
"chaotic" drug use
accommodation
income
 Opioid


agonist pharmacotherapy can:
address psychosocial instability
increase opportunities to directly observe the
administration of various HIV therapies
27
27
Drug Use History

Primary drug







Average daily use (quantity/duration)
Time last used
Route of administration
Age commenced, periods of abstinence
Severity of dependence
Previous treatment(s)
Other drugs


Current and previous
dependence
28
28
Medical and Psychiatric
 HIV/HCV
 Pregnancy
 Other


Liver
Cardiac
 Major

major medical conditions
psychiatric conditions
Depression, suicide, psychosis
 Opioid
related overdose
29
29
Induction Stabilization Phase

Dose adequacy and drug interactions




signs intoxication/withdrawal
frequency of drug use
frequency of sharing
Case coordination and management




psychological
social
medical
health/welfare system interaction
30
30
Safe Initial Dose
 20
- 30mg methadone is generally safe
 Deaths have occurred with higher
starting doses or poly-drug use
 Opioid-dependent polydrug users may
be safer to start as inpatients
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31
Resting Pulse Rate: _______ beats/minute
Measured after patient is sitting or lying for one minute
0 pulse rate 80 or below
1 pulse rate 83-100
2 pulse rate 101-120
4 pulse rate greater than 120
Sweating: over past ½ hour not accounted for by room
temperature or patient activity
0 no report of chills or flushing
1 Subjectie report of chills or flushing
2 flushed or observable moistness on face
3 beads of sweat on brow or face
4 sweat streaming off face
GI Upset: over last ½ hr
0 no GI symptoms
1 stomach cramps
2 nausea or loose stool
3 vomiting or diarrhoea
3 multiple episodes of diarrhoea or vomiting
Restlessness Observation during assessment
0 able to sit still
1 reports difficulty sitting still but is able to do so
3 frequent shifting or extraneous movements of legs/arms
5 unable to sit still for more than a few seconds
Yawning Observation during assessment
0 no yawning
1 yawning once or twice during assessment
2 yawning three or more times during assessment
4 yawning several times/minute
Pupil Size
0 pupils pinned or normal size for room light
1 pupils possibly larger than normal for room light
2 pupils moderately dilated
5 pupils so dilated that only the rim of the iris is visible
Anxiety or Irritability
0 none
1 patient reports increasing irritability or anxiousness
2 patient obviously irritable or anxious
4 patient so irritable or anxious that participation in the
assessment is difficult
Bone or Joint aches If patient was having pain previously,
only the additional component attributed to opiates
withdrawal is scored
0 not present
1 mild diffuse discomfort
2 patient reports severe diffuse aching of joints/muscles
4 patient is rubbing joints or muscles and is unable to sit still
because of discomfort
Runny nose or tearing Not accounted for by cold
symptoms or allergies
0 not present
1 nasal stuffiness or unusually moist eyes
2 nose running or tearing
4 nose constantly running or tears streaming down cheeks
Gooseflesh skin
0 skin is smooth
3 piloerection of skin can be felt or hairs standing up on
arms
5 prominent piloerection
Tremor observation of outstretched hands
0 no tremor
1 tremor can be felt but not observed
2 slight tremor observable
4 gross tremor or muscle twitching
Total Score _______
The total score is the sum of all 11 items
Initials of persons
Completing assessment ___________________
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Relationship between methadone dose and heroin use
% of clients using heroin (last 30 days)
(adapted from Ball and Ross, 1991)
Methadone Dose (MG)
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Stabilisation
FREQUENCY OF APPOINTMENTS
 First 5 -7 days - see every 1-2 days
 Write prescription till next appointment
only
 Always see the patient before increasing
the dose
 Continue the assessment process, build
the therapeutic relationship
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34
Effective Programs
 Longer
duration (2-4 years).
 Higher doses - > 60mg methadone.
 Accessible prescriber and dispenser.
 Ancillary services.
 Quality of therapeutic relationship.
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35
Opioids: Other Drug Interactions
Respiratory
depression
Toxicity/
Hypotension Coma
risk of death
CNS
Depressants



MAOIs



TCAs


Betablockers
BZDs


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36
Efficacy of Methadone Concurrent
Control Studies
100 male narcotic addicts randomized to methadone or
placebo in a treatment setting
Both groups initially stabilized on 60 mg methadone per
day. Both groups had dosing adjustments:
 Methadone could go up or down
 Placebo – 1 mg per day tapered withdrawal
Outcome measures: treatment retention and
imprisonment
Follow-up
Time
2 years
Percent DrugFree
"Methadone
Group"
12/17
Percent DrugFree
“No Methadone
Group"
1/17
Imprisonment rate: twice as great for placebo group
37
37
Efficacy of Methadone Concurrent
Control Studies
34 patients assigned to methadone or no
methadone at one clinic
Outcomes: percent drug free
Follow-up
Time
2
years
Percent DrugFree
"Methadone
Group"
12/17
Percent DrugFree
“No Methadone
Group"
1/17
Five year follow-up: No methadone group offered methadone
Those choosing methadone: 8/9
Those not choosing methadone: 1/8
5 Died of ODs, 2 Imprisoned
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38
Evidence for the Efficacy of Methadone
Dose Response Studies
 Dose
Response Trials
 Retention and illicit opiate use
N
212
Methadone
Doses
0,20,50 mg
Results
50 mg  20 mg  0
Strain, E., et al. Ann. Int. Med. 119:23-27, 1993
N
162
Methadone
Doses
20, 60 mg
Results
60 mg >20 mg
Johnson RE, Jaffe J, Fudala PJ, JAMA, 267(20), 1992
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39
Evidence for the Efficacy of Methadone
Dose Response Studies
Outcomes: Retention and illicit opiate use
N
225
Methadone
Doses
30 and 80 mg
Results
80  30 mg
Ling et al, Arch Gen Psych, 53(5), 1996
N
140
Methadone
Doses
20 and 65 mg
Results
65  20 mg
Schottenfeld R, et al., 1993
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40
% I.V. Drug Use
Heroin Abuse Frequency Vs.
Methadone Dose
80
60
40
20
0
10 20
30 40 50 60 70 80 90 100
Daily Dose In MGS.
V.P. Dole, JAMA, VOL. 282, 1989, p. 1881
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Evidence for the Efficacy of
Methadone
N
4,776
Treatment
Untreated
Annual Death Rate
7.0
100
109
3,000
368
Treated
Detox
MM
MM
3.4
8.3
0.8
1.4
Age Adjusted
Control
0.6 1
0.3
2
3
3
0.17
4
1 Prescore MJ, US Public Health Report, Suppl 170, 1943
2 Valliant GE, Addictive States, 1992
¾ Gearing MF, Neurotoxicology, 1977
4 Grondblah L, ACTA Psych Scand, 82, 1990
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42
Death Rates in Treated and
Untreated Heroin Addicts
Annual Rate
8
6.91
7.20
6
4
1.65
2
0.85
0.15
0
Matched
Cohort
Methadone Voluntary Involuntary Untreated
Discharge Discharge
43
Compare the Costs
25,000
No Treatment
$21,500
$20,000
Costs are for a 6 month
period, per person
20,000
15,000
10,000
In Treatment Program
$9,825
$8,250
5,000
$1,750
$1,575
0
Untreated Incarceration Adolescent Adult
Residential
Methadone Drug Free
Outpatient
44
Relapse to IV Drug Use After Termination
of Methadone Maintenance Treatment
Percent IV Users
100
82.1%
80
72.7%
57.6%
60
45.5%
40
20
0
28.9%
In
Treatment
Rate
1-3
Months
Later
1 2 3
4-6
Months
Later
10-12
Months
Later
7-9
Months
Later
Months Since Drop Out
4 5 6
7 8 9
10 11 12
Ball, JC, Ross A. The Effectiveness of Methadone Maintenance Treatment, Springer-Verlag, New York, 1991
45
Naltrexone

Morphine antagonist, true blockade

No psychoactive effect

Prevents euphoria from opioid use therefore
‘drug money spent = money wasted’

Prevents reinstatement of opioid dependence, although
does not reinforce compliance

No withdrawal experienced upon cessation

Reported to reduce cravings in some people.
Opioids
46
46
Naltrexone: Indications for Use
 Prescribed
for the management of opioid
dependence by registered prescribers
 Primary role = relapse prevention
 Abstinence-based treatment option
 Non-dependence inducing
 Commenced at least a week after
cessation of heroin use.
Opioids
47
47
Opiate Addiction Treatment with
Buprenorphine
48
48
Overview

Buprenorphine is a thebaine derivative (classified in
the law as a narcotic)

High potency

Produces sufficient agonist effects to be detected by
the patient

Available as a parenteral analgesic (typically 0.3-0.6
mg im or iv every 6 or more hours)

Long duration of action when used for the treatment of
opioid dependence contrasts with its relatively short
analgesic effects
49
49
Affinity and Dissociation
 Buprenorphine


has:
A high affinity for mu opioid receptor competes with other opioids and blocks
their effects
A slow dissociation from mu opioid
receptor –
prolonged therapeutic effect for opioid
dependence treatment (contrasts to its
relatively short analgesic effects)
50
50
Mu efficacy and opiate addiction
Full agonist -
Super agonist fentanyl
morphine/heroin
hydromorphone
Positive
effect
=
Potentially lethal dose
Agonist + partial agonist
addictive
potential
Partial agonist
- buprenorphine
Antagonist - naltrexone
dose
Negative
effect
Antagonist + agonist/partial agonist
51
Buprenorphine: Clinical
Pharmacology
Partial Agonist

high safety profile/ceiling effect
 low dependence
Tight Receptor Binding

long duration of action
 slow onset mild abstinence
52
52
Intensity of abstinence
Buprenorphine
Himmelsbach scores
60
Morphine
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Days after drug withdrawal
53
53
Buprenorphine Stabilization /
Maintenance
 Stabilize
on daily sublingual dose
 Expect average daily dose will be
somewhere between 8/2 and 32/8 mg of
buprenorphine/naloxone
 Higher daily doses more tolerable if tablets
are taken sequentially rather than all at
once
54
54
Maintenance Treatment Using
Buprenorphine
Studies conclude:
Buprenorphine more effective than placebo
Buprenorphine equally effective as moderate
doses of methadone (e.g., 60 mg per day)
Not clear if buprenorphine can be as effective
as higher doses of methadone (e.g., 80-100
mg or more per day), and therefore may not
be the treatment of choice for some patients
with higher levels of physical dependence
55
55
Buprenorphine
Maintenance/Withdrawal
Comparison of buprenorphine maintenance
vs. withdrawal:
Shows both the efficacy of maintenance
treatment, and the poor outcomes
associated with withdrawal (even when
provided within the context of a
relatively rich set of psychosocial
treatments including hospitalization and
cognitive behavioral therapy)
56
56
Precipitated Withdrawal
Buprenorphine-precipitated withdrawal seen
in controlled studies has been mild in
intensity and of short duration
The likelihood for buprenorphineprecipitated withdrawal is low, and even
when it does occur, it is mild in intensity
and short in duration
57
57
Overdose with Buprenorphine

Low risk of clinically significant problems
 No reports of respiratory depression in
clinical trials comparing buprenorphine to
methadone
 Buprenorphine’s ceiling effect means it is
less likely to produce clinically significant
respiratory depression. However,
overdose in which buprenorphine is
combined with other CNS depressants
may be fatal (reviewed later in this section)
58
58
Drug Interactions with
Buprenorphine
1. Benzodiazepines and other sedating
drugs
2. Medications metabolized by cytochrome
P450 3A4
3. Opioid antagonists
4. Opioid agonists
59
59
Diversion and Misuse
Four possible groups that might attempt to divert
and abuse buprenorphine/naloxone
parenterally:
1. Persons physically dependent on illicit
opioids
2. Persons on prescribed opioids (e.g.,
methadone)
3. Persons maintained on
buprenorphine/naloxone
4. Persons abusing, but not physically
dependent on opioids
60
60
Combination of Buprenorphine plus
Naloxone
 Combination
tablet containing
buprenorphine with naloxone – if taken
under tongue, predominant
buprenorphine effect
 If opioid dependent person dissolves and
injects buprenorphine/naloxone tablet –
predominant naloxone effect (and
precipitated withdrawal)
61
61
Maintenance Treatment Using
Buprenorphine
Following slides briefly review
representative studies:



Comparison of different doses of
sublingual buprenorphine
Buprenorphine-methadone flexible
dose comparison
Buprenorphine, methadone, LAAM
comparison
62
62
Different Doses of Buprenorphine: Opiate Use
% Ss With 13 Consecutive
Opiate Free Urines
25
20
1
15
4
8
10
16
5
0
Buprenorphine dose (mg)
(Ling et al., 1998)
63
Buprenorphine – methadone:
treatment retention
100
90
80
Percent
70
60
50
40
Buprenorphine
30
Methadone
20
10
0
1
2
4
6
8
10
12
14
16
Week
(Strain et al., 1994)
64
Buprenorphine, Methadone,
LAAM:Treatment Retention
Percent Retained
100
80
73% Hi Meth
60
58% Bup
40
53% LAAM
20
20% Lo Meth
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Study Week
(Johnson et al., 2000)
65
Remaining in treatment (nr)
Buprenorphine
Maintenance/Withdrawal: Retention
20
15
10
Detox/placebo
5
Buprenorphine
0
0
50
100
150
200
250
Treatment duration (days)
300
350
(Kakko et al., 2003)
66
Buprenorphine
Maintenance/Withdrawal: Mortality
Detox/Placebo Buprenorphine Cox regression
Dead
4/20 (20%)
0/20 (0%)
c2=5.9; p=0.015
(Kakko et al., 2003)
67
Questions?
Comments?
68