Section 34: Section 34: Addiction MedicationsAddiction Medications

Richard A. Rawson, Ph.D., ProfessorRichard A. Rawson, Ph.D., ProfessorSemel Institute for Neuroscience and Human BehaviorSemel Institute for Neuroscience and Human Behavior

David Geffen School of MedicineDavid Geffen School of MedicineUniversity of California at Los AngelesUniversity of California at Los Angeles

Opiate Agonist and Opiate Agonist and Partial Agonist TherapyPartial Agonist Therapy

Methadone and BuprenorphineMethadone and Buprenorphine

Global Abuse of OpiatesGlobal Abuse of Opiates

Overview:Overview: Sixteen million (0.4%) of Sixteen million (0.4%) of

world’s population age world’s population age 15-64 abuse opiates15-64 abuse opiates

Heroin abusers make up Heroin abusers make up about 71% of opiate about 71% of opiate abusersabusers

Opiates accounts for 2/3 Opiates accounts for 2/3 of all treatment demands of all treatment demands in Asia and 60% of in Asia and 60% of treatment demand in treatment demand in EuropeEurope

Asia54%

Europe25%

Africa6%

Americas14%

Oceania1%

Sources: UNODC, Annual Reports Questionnaire Data, Govt. reports, reports of regional bodies, UNODC estimates.

Regional Breakdown of Opiate Abusers

33

OpioidsOpioids

Opiate (n)Opiate (n)

an unlocked door an unlocked door in the prison in the prison of identity. of identity. It leads to the It leads to the jail yard.jail yard.Ambrose, Bierce (1906) Ambrose, Bierce (1906) The Devil’s DictionaryThe Devil’s Dictionary

44

Opioid-related ProblemsOpioid-related Problems

Most prominent problems are associated Most prominent problems are associated with heroin dependencewith heroin dependence

Not all users of heroin develop Not all users of heroin develop dependence. Between 1:4 to 1:3 regular dependence. Between 1:4 to 1:3 regular users develop dependenceusers develop dependence

Development of heroin dependence Development of heroin dependence usually requires regular use over months usually requires regular use over months (or longer where use is more irregular)(or longer where use is more irregular)..

55

The Revolving DoorThe Revolving Door

Heroin dependence is a chronic relapsing Heroin dependence is a chronic relapsing disorder. It is a dependency which is very disorder. It is a dependency which is very difficult to resolvedifficult to resolve

Relapse is extremely common. It is part of the Relapse is extremely common. It is part of the process of resolving the dependence process of resolving the dependence –– much much like giving up tobaccolike giving up tobacco

A principal health care objective is to get the A principal health care objective is to get the patient into treatment, help keep them in patient into treatment, help keep them in treatment and to return them to treatment when treatment and to return them to treatment when relapse occursrelapse occurs..

66

Classification of OpioidsClassification of Opioids

LAAMLAAMfentanylfentanyl

meperidinemeperidinehydrocodonehydrocodonemethadone methadone pentazocinepentazocine

pethidinepethidine

Syntheticheroinbuprenorphine

hydromorphoneoxycodone

Pure Opioid Agonists

opiumpapaverine morphinecodeine

naltrexone buprenorphine

LAAM

Partial Agonists/Antagonists

77

Opioids: Long-term EffectsOpioids: Long-term Effects (1)(1)

Little evidence of long-term direct toxic Little evidence of long-term direct toxic effects on the CNS from opioid useeffects on the CNS from opioid use

Long-term health-related complications Long-term health-related complications may result from:may result from:

– dependencedependence– antisocial behaviourantisocial behaviour– poor general self-carepoor general self-care– imprisonmentimprisonment– drug impurities or contaminants, BBVdrug impurities or contaminants, BBV..

88

Opioids: Considerations for Opioids: Considerations for assessmentassessment

PregnancyPregnancy BBVBBV Polydrug dependencePolydrug dependence Opioid related overdose Opioid related overdose Major or pre-existing medical conditions Major or pre-existing medical conditions

(e.g. liver, cardiac)(e.g. liver, cardiac) Major psychiatric/mental health issues Major psychiatric/mental health issues

(e.g. psychosis, depression, suicide).(e.g. psychosis, depression, suicide).

99

Opioid Withdrawal Opioid Withdrawal

SignsSigns YawningYawning Lacrimation, mydriasisLacrimation, mydriasis DiaphoresisDiaphoresis Rhinorrhoea, sneezingRhinorrhoea, sneezing TremorTremor PiloerectionPiloerection Diarrhoea and Diarrhoea and

vomitingvomiting..

SymptomsSymptoms Anorexia and nauseaAnorexia and nausea Abdominal pain or Abdominal pain or

crampscramps Hot and cold flushesHot and cold flushes Joint and muscle pain or Joint and muscle pain or

twitching twitching InsomniaInsomnia Drug cravingsDrug cravings Restlessness/anxiety.Restlessness/anxiety.

1010

Progress of the Acute Phase of Progress of the Acute Phase of Opioid Withdrawal Since Last DoseOpioid Withdrawal Since Last DoseWithdrawal from heroinWithdrawal from heroinOnset: 6Onset: 6––24 hrs24 hrsDuration: 4Duration: 4––10 days10 days

Withdrawal from methadoneWithdrawal from methadoneOnset: 24Onset: 24––48 hrs, sometimes more48 hrs, sometimes moreDuration: 10Duration: 10––20 days, 20 days,

sometimes moresometimes more

Seve

rity

of s

igns

and

sym

ptom

s

0 10 20 Days

deCrespigny & Cusack (2003)Adapted from NSW Health Detoxification Clinical Practice Guidelines (2000-2003) 1111

12

Main predictors – Greater regular dose – Rapidity with which drug is withdrawn.

Also consider– 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).

Predictors of Withdrawal Severity

Opioids

Greater withdrawal severity

}

1212

13

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).

Opioids1313

14

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.

Opioids1414

15

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.

Opioids1515

16

General Principles of PharmacotherapiesPharmacodynamics:

Agonists– directly activate opioid receptors

(e.g. morphine, methadone)

Partial agonists– 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).

Opioids1616

17

Maintenance Pharmacotherapies

Methadone Buprenorphine Naltrexone LAAM Slow-release morphine.

Opioids1717

18

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.

Opioids1818

19

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).

Opioids1919

20

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

2020

21

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

2121

22

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

2222

23

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.”

2323

24

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

Safety Overview

2424

25

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.

2525

26

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

2626

27

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

2727

28

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

2828

29

Medical and Psychiatric

HIV/HCV Pregnancy Other major medical conditions

Liver Cardiac

Major psychiatric conditions Depression, suicide, psychosis

Opioid related overdose

2929

30

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

3030

31

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

3131

Resting Pulse Rate: _______ beats/minuteMeasured after patient is sitting or lying for one minute0 pulse rate 80 or below1 pulse rate 83-1002 pulse rate 101-1204 pulse rate greater than 120

GI Upset: over last ½ hr0 no GI symptoms1 stomach cramps2 nausea or loose stool3 vomiting or diarrhoea3 multiple episodes of diarrhoea or vomiting

Sweating: over past ½ hour not accounted for by room temperature or patient activity0 no report of chills or flushing1 Subjectie report of chills or flushing2 flushed or observable moistness on face3 beads of sweat on brow or face4 sweat streaming off face

Tremor observation of outstretched hands0 no tremor1 tremor can be felt but not observed2 slight tremor observable4 gross tremor or muscle twitching

Restlessness Observation during assessment0 able to sit still1 reports difficulty sitting still but is able to do so3 frequent shifting or extraneous movements of legs/arms5 unable to sit still for more than a few seconds

Yawning Observation during assessment0 no yawning1 yawning once or twice during assessment2 yawning three or more times during assessment4 yawning several times/minute

Pupil Size0 pupils pinned or normal size for room light1 pupils possibly larger than normal for room light2 pupils moderately dilated5 pupils so dilated that only the rim of the iris is visible

Anxiety or Irritability0 none1 patient reports increasing irritability or anxiousness2 patient obviously irritable or anxious4 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 scored0 not present1 mild diffuse discomfort2 patient reports severe diffuse aching of joints/muscles4 patient is rubbing joints or muscles and is unable to sit still because of discomfort

Gooseflesh skin0 skin is smooth3 piloerection of skin can be felt or hairs standing up on arms5 prominent piloerection

Runny nose or tearing Not accounted for by cold symptoms or allergies0 not present1 nasal stuffiness or unusually moist eyes2 nose running or tearing4 nose constantly running or tears streaming down cheeks

Total Score _______

The total score is the sum of all 11 items

Initials of persons

Completing assessment ___________________

3232

33

Relationship between methadone dose and heroin use (adapted from Ball and Ross, 1991)

Methadone Dose (MG)% o

f cl

ien

ts u

sin

g h

eroi

n (

last

30

day

s)

3333

34

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

3434

35

Effective Programs

Longer duration (2-4 years). Higher doses - > 60mg methadone. Accessible prescriber and dispenser. Ancillary services. Quality of therapeutic relationship.

3535

36

Opioids: Other Drug Interactions Respiratory

depression Toxicity/ risk of death

Hypotension Coma

CNS Depressants

MAOIs

TCAs

Betablockers

BZDs

3636

37

Efficacy of Methadone Concurrent Control Studies

100 male narcotic addicts randomized to methadone or placebo in a treatment settingBoth 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 withdrawalOutcome measures: treatment retention and imprisonment

Imprisonment rate: twice as great for placebo group

Follow-up Time

Percent Drug Free

"Methadone Group"

Percent Drug Free

“No Methadone Group"2 years

12/17 1/17

3737

38

Efficacy of Methadone Concurrent Control Studies

34 patients assigned to methadone or no methadone at one clinic

Outcomes: percent drug free

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

Follow-up Time

Percent Drug Free "Methadone

Group"

Percent Drug Free “No Methadone

Group"2 years 12/17 1/17

3838

39

Evidence for the Efficacy of Methadone Dose Response Studies

Dose Response Trials Retention and illicit opiate use

N Methadone Doses

Results212

0,20,50 mg50 mg 20 mg 0

Strain, E., et al. Ann. Int. Med. 119:23-27, 1993

N Methadone Doses

Results

16220, 60 mg

60 mg >20 mg

Johnson RE, Jaffe J, Fudala PJ, JAMA, 267(20), 1992

3939

40

Evidence for the Efficacy of Methadone Dose Response Studies

Outcomes: Retention and illicit opiate use

Ling et al, Arch Gen Psych, 53(5), 1996

NMethadone

DosesResults

22530 and 80 mg

80 30 mg

NMethadone

DosesResults

14020 and 65 mg 65 20 mg

Schottenfeld R, et al., 1993

4040

0

20

40

60

80

10 20 30 40 50 60 70 80 90 100

Daily Dose In MGS.

% I.V

. D

rug

Use

Heroin Abuse Frequency Vs. Methadone Dose

V.P. Dole, JAMA, VOL. 282, 1989, p. 1881

4141

42

Evidence for the Efficacy of Methadone

N Treatment Annual Death RateAge Adjusted Control

4,776 Untreated 7.0 0.6

100 Treated 3.4 0.3109 Detox 8.3

3,000 MM 0.8368 MM 1.4 0.17

1 Prescore MJ, US Public Health Report, Suppl 170, 19432 Valliant GE, Addictive States, 1992¾ Gearing MF, Neurotoxicology, 19774 Grondblah L, ACTA Psych Scand, 82, 1990

1

2

33

4

4242

0

2

4

6

8

MatchedCohort

Methadone VoluntaryDischarge

InvoluntaryDischarge

Untreated

0.150.85

1.65

6.91 7.20

Death Rates in Treated and Untreated Heroin Addicts

An

nu

al R

ate

4343

0

5,000

10,000

15,000

20,000

25,000

Untreated Incarceration Adolescent Adult Methadone Drug Free

Residential Outpatient

$1,575$1,750

$8,250$9,825

$20,000$21,500No Treatment

In Treatment Program

Compare the CostsCosts are for a 6 month

period, per person

4444

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12

In Treatment

Rate

28.9%

Months Since Drop Out

1-3Months

Later

4-6Months

Later

45.5%

57.6%

72.7%

82.1%

7-9Months

Later

10-12Months

Later

Ball, JC, Ross A. The Effectiveness of Methadone Maintenance Treatment, Springer-Verlag, New York, 1991

Pe

rce

nt

IV U

se

rsRelapse to IV Drug Use After Termination

of Methadone Maintenance Treatment

4545

46

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. Opioids4646

47

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.

Opioids4747

48

Opiate Addiction Treatment with Buprenorphine

4848

49

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

Overview

4949

50

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)

Affinity and Dissociation

5050

Potentially lethal dosePositive effect

=

addictive

potential

Negative effect

Full agonist -morphine/heroin

hydromorphone

Antagonist - naltrexone

dose

Antagonist + agonist/partial agonist

Agonist + partial agonist

Super agonist -fentanyl

Partial agonist - buprenorphine

Mu efficacy and opiate addiction

5151

52

Buprenorphine: Clinical Pharmacology

Partial Agonist high safety profile/ceiling effect low dependence

Tight Receptor Binding long duration of action slow onset mild abstinence

5252

53

Intensity of abstinence

60

50

40

30

20

10

0

Him

mel

sbac

h s

core

s

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Buprenorphine

Morphine

Days after drug withdrawal

5353

54

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

5454

55

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

Maintenance Treatment Using Buprenorphine

5555

56

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)

Buprenorphine Maintenance/Withdrawal

5656

57

Buprenorphine-precipitated withdrawal seen in controlled studies has been mild in intensity and of short duration

The likelihood for buprenorphine-precipitated withdrawal is low, and even when it does occur, it is mild in intensity and short in duration

Precipitated Withdrawal

5757

58

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)

Overdose with Buprenorphine

5858

59

1. Benzodiazepines and other sedating drugs

2. Medications metabolized by cytochrome P450 3A4

3. Opioid antagonists

4. Opioid agonists

Drug Interactions with Buprenorphine

5959

60

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

Diversion and Misuse

6060

61

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)

Combination of Buprenorphine plus Naloxone

6161

62

Following slides briefly review representative studies: Comparison of different doses of

sublingual buprenorphine Buprenorphine-methadone flexible

dose comparison Buprenorphine, methadone, LAAM

comparison

Maintenance Treatment Using Buprenorphine

6262

Different Doses of Buprenorphine: Opiate Use

0

5

10

15

20

25

% S

s W

ith

13 C

onse

cuti

ve

Opi

ate

Fre

e U

rine

s

Buprenorphine dose (mg)

1

4

8

16

(Ling et al., 1998)6363

Buprenorphine – methadone: treatment retention

Methadone

Buprenorphine

0

10

20

30

40

50

60

70

80

90

100

Week

Pe

rce

nt

1614121086421

(Strain et al., 1994)6464

Buprenorphine, Methadone, LAAM:Treatment Retention

Per

cent

Ret

aine

d

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

20% Lo Meth

58% Bup

73% Hi Meth

53% LAAM

Study Week (Johnson et al., 2000)6565

Treatment duration (days)

Rem

aini

ng in

tre

atm

ent

(nr

)

0

5

10

15

20

0 50 100 150 200 250 300 350

Detox/placebo

Buprenorphine

Buprenorphine Maintenance/Withdrawal: Retention

(Kakko et al., 2003)6666

2=5.9; p=0.0150/20 (0%)4/20 (20%)Dead

Cox regressionBuprenorphineDetox/Placebo

Buprenorphine Maintenance/Withdrawal: Mortality

(Kakko et al., 2003)6767

Questions?Questions?

Comments?Comments?6868