Opioid Dependence: Treatment Options

Walter Ling MDIntegrated Substance Abuse Programs(ISAP)

UCLA

Suboxone Advisory Board MeetingKaohsiung, TaiwanNovember 4, 2007

lwalter@ucla.eduwww.uclaisap.org

Treating Opioid Addiction: Aims

• Getting off opioids: detoxification– Agonist opioid based detoxification– Non-opioid based detoxification– Antagonist based detoxification

• Staying of opioids: relapse prevention– Agonist maintenance: methadone/others– Antagonist maintenance: naltrexone– Partial agonist maintenance: buprenorphine

• Changing life style

Phases of Opioid Withdrawal1. Anticipatory withdrawal (3-4 hrs)

Fear of withdrawalAnxietyDrug seeking

2. Early Withdrawal (8-10 hrs)

Anxiety

Restlessness

Nausea

Nasal stuffiness

Abdominal cramps

Drug seeking

Hypertension

Tachycardia

Yawning

Sweating

Rhinorrhea

Lacrimation

Dilated pupils

3. Fully Developed Withdrawal3. Fully Developed Withdrawal(1-3 days)

Severe anxiety

Restlessness

Muscle spasm

Elevated BP

Fever/Chills

Drug seeking

Tremor Piloerection

Vomiting

Diarrhea

Tachycardia

4. Protracted Abstinence4. Protracted Abstinence (up to 6 mos.)

Hypotension

Bradycardia

Insomnia

Loss of appetiteLoss of energyCue induced craving

Determinants of Withdrawal Severity• Triggers and intensity of withdrawal

– Amount and regularity of use – Rate of withdrawal– Patient physical & psychological

condition and expectation• Settings and the severity of withdrawal

– Presence of opiates vs absence – Treatment setting and environment – Physician confidence and attitude – Medications for symptom relief and general nutrition

Detoxification

• Relieve Symptoms of withdrawal

• Reverse neuro-adaptation from chronic heroin use

• Reduce degree of physical dependence

• Promote long term treatment leading to life style changes

• Transitional treatment strategy

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Methods and Medications• Methadone and buprenorphine

– Opioids agonist and partial agonist

– Short and long term

• Clonidine and Lofexidine– Non-opioids; alpha adrenergic

agonists

• Antagonists assisted – Naloxone /Naltrexone

– Rapid and ultra-rapid detoxifications

Detoxification• The most common

outcome of detoxification, by whatever means and for however long, is relapse. “Detoxification may be good for a lot of things; staying off drugs is not one of them”

0

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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

4-6MonthsLater

45.5%

57.6%

72.7%

82.1%

7-9Months

Later

10-12MonthsLater

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

Pe

rce

nt

IV U

se

rs

Relapse to IV Drug Use After Termination of Methadone Maintenance Treatment

Clonidine for Opioid Withdrawal -2 adrenergic agonist binds to

pre-synaptic autoreceptors on adrenergic neurons– In Locus Coeruleus– Possibly in A1 and A2 cell groups

of the caudal medulla that project to BNST (extended amygdala)

• FDA approved for hypertension– Limiting side effect: hypotension

• Reduces W/D signs and sx:– Significantly better than placebo– Nearly comparable to slow

methadone taper

• Doses: 0.1 mg tid to 0.4 mg tid

• Push dose until withdrawal sx abate or diastolic BP <60

• Use adjunctive benzodiazepines, anti-emetics, anti-diarrheals

Rapid &Ultra Rapid Opioid Withdrawal

• Patient placed under deep sedation or general anesthesia • Administer opioid antagonists to provoke W/D

• Manage emergent sx with:– Clonidine/ Lofexidine

– Benzodiazepines

– Antiemetics

– Antidiarrheals

• W/D essentially resolved in 12-24 hours (ultra rapid) or 2-3 days (rapid) with patient ± on full dose of antagonist (naltrexone)

Opioid Substitution or Maintenance Therapy

• Reduce symptoms & signs of withdrawal

• Reduce or eliminate craving

• Blocks effects of illicit opioids

• Restored normal physiology

• Promote psychosocial rehabilitation and non-drug life style

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Maintenance Medications:• Methadone maintenance

(agonist)• Naltrexone (antagonist)• Buprenorphine (partial

agonist)– Buprenorphine (Subutex)

– Buprenorphine-naloxone (Suboxone)

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Methadone: Clinical Properties

Orally active synthetic μ opioid agonist with morphine-like properties

Action—CNS depressant/ Analgesic

Quick absorption, slow elimination, long half-life

Effects last 24 hours; once daily dosing maintains constant blood level

Prevent withdrawal, reduce craving and use

Long term treatment normalize physiological function

Facilitates rehabilitation

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Methadone Pharmacokinetics•Good oral bioavailability; fast and complete absorption•Peak plasma concentration 21/2 hrs (liquid), 31/2 hrs (tablet); mean half-life 24 hrs, steady state 3-10 days•96% plasma protein bound•Variable bioavailability (40%-99%);genetic variations in protein binding, oxidative metabolism and GI (majority) and renal (minor) excretion, capacity limited clearance•Onset of analgesia 15-20 min; difficult to predict initial dose and dosing frequency.•Metabolism mediated via P450 cytochrome, primarily

•CYP3A4, but also CYP2D6, CYP1A2, CYP2C9 CYP2C19

Clinically significant drug/drug interactions

Methadone and CYP3A4 Enzyme

• CYP3A4: Inducible enzyme– Methadone induces its own metabolism; levels vary

over time; 3.5 fold increase in clearance between induction and steady state

• Increases metabolism of certain drugs:– Dilantin, Tegretol, Barbiturates, Rifampin, Cypro,

Verapamil, Zidovudine, amitryptyline, spinololactone, and others

• Decrease metabolism of certain other drugs:– Fluvoxamine, Nefazedone, Omeprazole, Indinavir, Nelfinavir, Ritonavir, Fluoxetine, Saquinavir, other

SSRI’s

Pharmacodynamics• Full agonist; receptor affinity lower than Ms

– Main action on mu receptors• inhibit adenyl cyclase = cAMP potasium channel opening calcium channel opening

– also inhibit serotonin reuptake– also non competitive antagonist NMDA receptor

• No known active metabolites; limited toxicity– No significant cognitive impairment with chronic use– No organ toxicity with chronic use

Equianalgesic dose references

• Pereira J et al Equianalgesic dose ratio for opioids: a critical review and proposals for long-term dosing. J. Pain Symptom Management 2001 22(2) p. 672-687

• Anderson R, et al Accuracy in equianalgesic dosing conversion dilemmas J Pain Symptom Management 2001 21(5) p.397-406

Phases of Treatment: • Assessments:

– Agreed treatment goals– Level of tolerance and dependence– Use/dependence on other drugs – Co-existing conditions– What social support systems

• Initial Treatment Phase– Adequacy of dosing; clinic

visits & dose changes – S&S of withdrawal– Side effects and toxicity– Drug/drug interactions

• On going Management:– Co-occurring disorders – Smoking, alcohol & other drugs – Adequate pain management – Dose and duration of treatment – Ancillary services &social support – Quality of therapeutic relationship

• Life Changes:– Experience creates memory– Memory leads to protein synthesis– Protein synthesis alters gene

expression– Gene expression creates new

behavior– New behavior leads to life changes

“You can change a man’s life by altering his genes; but you can also do that by paying off his credit card”—James Watson

Methadone Maintenance

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

Annu

al R

ate

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 47%

23%

17%

12.5%

6%0%

10%20%30%40%50%

Not in Tx

Currently in TxIn Tx 5 years

C&D

No needle

use since admission to TxA B C D

HIV Rates

Naltrexone: The Perfect Drug

• Orally Effective

• Rapid onset of action

• Long duration of action

• Safe

• Few side effects

• Blocks effects of heroin

• Non-addicting One reason not to take

• No tolerance naltrexone: can’t get high

• No dependence “It’s like taking nothing”

• No withdrawal

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Buprenorphine: Pharmacological Characteristics

Partial Agonist (ceiling effect)

• high safety profile

• low dependence

Tight Receptor Binding• long duration of action

• slow onset mild abstinence

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p 1 2 4 8 16 32

Buprenorphine (mg)

Bre

ath

s/m

inu

te

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100

p 0.5 2 8 16 32

Buprenorphine (mg)

Peak

Sco

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3.75 15 60

Methadone (mg)

Study # 999A: Buprenorphine’sEffect on Opiate Use

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0102030405060708090

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

Day

Perc

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Placebo (n=60)2 mg (n=60)8 mg (n=30)

Dose change option in effect

Percent Patients on Initial Dose Johnson et al., 1998

Study 1008: Suboxone

Study #1008 Buprenorphine

4/76 15/85 22/77

Mono

% o

f G

oo

d O

utc

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Number of Good Patients/TotalPBO = 5.26 Combo = 17.65 Mono = 28.57 Statistics Value ProbChi-Square 13.641 0.001Mantel-Haenszel 13.591 0.001

*

(8 Urines)

30

05

10152025

PBO

Combo*

• 16mg mono SL tablets (Subutex) and 16mg/4mg combo SL (Suboxone) are equally efficacious.

• Most reported adverse effects were those commonly seen in patients treated with opioids.

Buprenorphine and Methadone dose responsesfrom four studies using “Joint Probability”

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Join

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Week 8 Week 17

Schottenfeld, et al. 1997 -4 mg

Johnson et al. 1992 - 8 mg

Ling et al. 1996- 8 mg

Strain et al. 1994 (8 variable)

Schottenfeld et al. 1997 -12 mg

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Week 8 Week 17

ARC 20 mg

Schottenfeld 20 mg

LA 30 mg

Strain (50 variable)

ARC 60 mg

Schottenfeld 65 mg

LA 80 mg

N remaining in treatmentX

Total N of subjects

N giving clean urinesN remaining in treatment

Joint Probability

Opiate Agonist Measures VAS Good Drug Effect (0-100)

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25

50

0 15 30 45 60Minutes

buprenorphine (2mg)buprenorphine (2mg) and naloxone (1 mg)buprenorphine (2 mg) and naloxone (0.5 mg)buprenorphine (2 mg) and nalxone (0.25 mg)morphine (15 mg)placebo

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Bup

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Adding Naloxone to Buprenorphine

Value of a Dose in Dollars

Dol

lars

Minutes

• Naloxone not absorbed sufficiently to interfere with buprenorphine when the combination is taken sublingually

• Sublingual absorption of buprenorphine @ 70%; naloxone @ 10%

• If injected, BUP/NX will precipitate withdrawal in a moderately to severely dependent addict

Suboxone vs Clonidine

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Day 3 or 4 Day 7 or 8 Day 10 or 11 Day 13 or 14

ClonidineBup/Nx

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Day 3 or 4 Day 7 or 8 Day 10 or 11 Day 13 or 14

ClonidineBup/Nx

Percent Present and CleanCTN 0001 (Inpatient)

Percent Present and Clean0002 (Outpatient)

NNT: Number Needed to TreatNNT for Bup/Nx 77/59 = 1.31 NNT for Clonidine 36/8 = 4.5NNT Clonidine : BupNx = 3.44

NNT:Number Needed to TreatNNT for Bup/Nx: 157/46 = 3.4 NNT for Clonidine: 74/4 = 18.5 NNT Clonidine : Bup/Nx = 5.44

In Conclusion• Opioid addiction is a serious chronic

relapsing but treatable disorder• Treatment must be sustained, detoxification

alone insufficient for long term outcome• Treatment must address both disordered

physiology and disrupted lives• There are no right or wrong medications,

only the right and wrong ways to use them.

• Medications can only change physiology, but new behavior can change lives

Thank you

Thank you Thank you