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Using Suboxone and Methadone to Treat Opiate

Dependence

Karen Miotto, M.D.UCLA Addiction Medicine Service

kmiotto@ucla.edu

Scope of this Talk

• Epidemiology of heroin and prescription drug dependence

• Pharmacology, side effects and safety of methadone and buprenorphine (Suboxone® and Subutex®)

• Patient selection, monitoring and counseling

• The role of counseling in opioid treatment

Opioid addiction spread in last half of 19th century via:

• • Medical administration • Doctors injected morphine to treat casual

complaints as well as serious problems

• • Civil War • Morphine widely used for Civil War

injuries

• • Self-administration via patent medicines

No requirements for safety, efficacy

Anyone could produce, sell “medicines” – Unsafe– Ineffective– Made curative claims without benefit of

scientific proof

By early 1900s, medical consensus developed:

Opiates, other drugs overly prescribed Sold to unsuspecting customers & produced

addiction Worthless patent “medicines” being sold Harrison Act of 1914

Federal Pure Food and Drug Act of 1906

(& subsequent amendments)

Food, drugs pure Contents labeled Drugs must be safe and effective Food and Drug Administration

Harrison Act of 1914(& subsequent laws)

• • First law to control opiates, cocaine, other drugs• • Subsequent laws attempt to balance

– Use in medicine with potential for abuse

• • Marijuana Tax Act of 1937– Adds cannabis

The 1960 and 1970s

In 2005, for 12-17 year olds:

Current users of illicit drugs: 9.9%

Used Rx drugs non-medically: 3.3%

In 2005 for 18-25 year olds:

Current users of illicit drugs: 20.1%

Used Rx drugs non-medically: 6.3%

2005 National Survey on Drug Use and Health (NSDUH)

Prevalence of any illicit drug use

In 2005, for 12-17 year olds:

Ever used: 13.4%

Used in past year: 4.9%

In 2005, for 18-25 year olds:

Ever used: 25.5%

Used in past year: 12.4%

2005 National Survey on Drug Use and Health (NSDUH)

Prevalence of non-medical use of an Rx pain reliever

In 2005, for 12-17 year olds:

Past year Dependence or Abuse: 1.1% (275,000 persons)

In 2005, for 18-25 year olds:

Past year Dependence or Abuse: 1.7% (541,000 persons)

2005 National Survey on Drug Use and Health (NSDUH)

Prevalence of non-medical use of an Rx pain reliever

In 2005, for 12-17 year olds:

Past year use: 0.2% (60,000 persons)

Abuse or Dependence: 0.0% (9,000 persons)

In 2005, for 18-25 year olds:

Past year use: 1.5% (496,000 persons)

Abuse or Dependence: 0.3% (89,000 persons)

2005 National Survey on Drug Use and Health (NSDUH)

Prevalence of heroin use

Opioid Emergency Department Mentions 2004

0

20,000

40,000

60,000

80,000

100,000

120,000

140,000

160,000

180,000

Heroin Opioid Analgesics

Hydrocodone

Oxycodone

Seeking Detox

Trends In Emergency Department Mentions2004-2005

0 100,000 200,000

2004

2005

Heroin Rx Opioids

SOURCE: SAMHSA Drug Abuse Warning Network, 2007

Heroin Purity

Average Purity of Retail HeroinStreet Samples in U.S

0

5

10

15

20

25

30

35

40

1980's 1991 2000

Source: DEA, 2002

Types of Opioid Types of Opioid ReceptorsReceptors

-10 -9 -8 -7 -6 -5 -40

10

20

30

40

50

60

70

80

90

100

Intrinsic Activity

Log Dose of Opioid

Full Agonist(Methadone)

Partial Agonist(Buprenorphine)

Antagonist (Naloxone)

Intrinsic Activity: Full Agonist (Methadone), Partial Agonist (Buprenorphine), Antagonist (Naloxone)

OPIOID CNS EFFECTS

EFFECTS Analgesia Sedation Euphoria Body Temperature

Changes Miosis Respiratory

Depression

WITHDRAWAL Muscle Pain,

Cramping Insomnia Dysphoria Chills, Piloerection Mydriasis Yawning, Sneezing,

Rhinorrhea

THE BASICS: THE BASICS:

HOW IT HOW IT

WORKS WORKS 23

Opioid Maintenance Pharmacotherapy - A Course for Clinicians

GOALS FOR PHARMACOTHERAPY

• Prevention or reduction of withdrawal symptoms

• Prevention or reduction of drug craving

• Prevention of relapse to use of addictive drug

• Restoration to or toward normalcy of any physiological function disrupted by drug abuse

Source: MJ Kreek, Rationale for Maintenance Pharmacotherapy of Opiate Dependence, 1992

24

PROFILE FOR POTENTIAL PSYCHOTHERAPEUTIC AGENT

• Effective after oral administration

• Long biological half-life (>24 hours)

• Minimal side effects during chronic

administration

• Safe, no true toxic or serious adverse effects

• Efficacious for a substantial % of persons with

the disorder

Opioid Maintenance Pharmacotherapy - A Course for Clinicians

Source: MJ Kreek, Rationale for Maintenance Pharmacotherapy of Opiate Dependence, 1992

25

On/Off - Non-Tolerant Drug StatesOn/Off - Non-Tolerant Drug StatesM

oo

d/E

ffe

ct

Sc

ale “ON”

Drug Effect

“OFF”

No Drug Effect;

“Normal”

Overdose

Intoxication

Euphoria

“Normophoria”

Dysphoria

Opioid Maintenance Pharmacotherapy - A Course for Clinicians26

Opioid Maintenance Pharmacotherapy - A Course for Clinicians

Dru

g E

ffec

t S

cale

Time

“Loaded”

“High”

Normal Range“Comfort Zone”

“Sick”

Tolerant/Dependent Drug States

28

Do

se R

esp

on

se

Time

“Loaded” “High”

Normal Range“Comfort Zone”

“Sick”

Heroin Simulated 24 Hr. Dose/Response

With established heroin tolerance/dependence

0 hrs.

24 hrs.

“Abnormal Normality”

Subjective w/d

Objective w/d

Opioid Maintenance Pharmacotherapy - A Course for Clinicians29

Do

se R

esp

on

se

Time

“Loaded” “High”

Normal Range“Comfort Zone”

“Sick”

Methadone Simulated 24 Hr. Dose/ResponseAt steady-state in tolerant patient

0 hrs.

24 hrs.

“Abnormal Normality”

Subjective w/d

Objective w/d

Opioid Maintenance Pharmacotherapy - A Course for Clinicians

30

What Does Opioid What Does Opioid Maintenance Treatment Maintenance Treatment

DO?DO?

Impact of Impact of Treatment!Treatment! 31

Impact of Maintenance Treatment

Reduction death rates (Grondblah, ‘90)

Reduction IVDU (Ball & Ross, ‘91)

Reduction crime days (Ball & Ross)

Reduction rate of HIV seroconversion

(Bourne, ‘88; Novick ‘90,; Metzger ‘93)

Reduction relapse to IVDU (Ball & Ross)

Improved employment, health, & social

function32

J. Thomas Payte, MD – Colonial Management Group, LP

Patients are 6.7 times more likely to die

during induction than untreated heroin

addicts (Caplehorn & Drummer, 1999).

42% of drug-related deaths occurred during

the first week of OMT (Zador & Sunjic, 2000).

10 OMT deaths are reported ― All 10 had

been in treatment less than 7 days

(Drummer, Opeskin, Syrjanen & Cordner,

1992). 33

SAFE SAFE

INDUCTION INDUCTION

TECHNIQUESTECHNIQUES34

Initial Dose

Degree of Tolerance

Dose Range

Non-Tolerant

10 mg +/- 5

Unknown Tolerance

20 mg +/- 5

Known Tolerance

20-40 mg

Payte

Opioid Maintenance Pharmacotherapy - A Course for Clinicians

35

Early Induction

Early dose adjustments to reach the “Therapeutic Window” as determined by established opioid tolerance.

-- The “Comfort Zone” –

Increase dose daily until pt. comfortable during methadone peak levels (3-5 hours after dose) then;

Hold dose for 3-5 days to reach steady-state before further dose adjustments.

REMEMBER STEADY-STATE PHARMACOLOGY!

Payte

Opioid Maintenance Pharmacotherapy - A Course for Clinicians 36

Induction Simulation – Low Dose/Low Tolerance with failure to reduce dose on day 2 or 3

0

50

100

150

200

250

300

350

400

450

1 2 3 4 5 6 7 8

ng/ml

mg/day

Time in DaysDose remains constant to steady-state in toxic

rangeOpioid Maintenance Pharmacotherapy - A Course for Clinicians

IntoxicationPotential OD

TherapeuticWindow

37

Induction Simulation – Low Dose/Low Tolerance with reduced dose on day 3 & 4

0

50

100

150

200

250

300

1 2 3 4 5 6 7 8

ng/ml

mg/day

Time in Days = Dose Reduction

Opioid Maintenance Pharmacotherapy - A Course for Clinicians

Intoxication,Potential OD

TherapeuticWindow

38

Induction Simulation – Low to Moderate Tolerance

050

100150200

250300350400

450500

1 2 3 4 5 6 7 8 9 10

ng/ml

mg/day

Days/Half-Lives =Dose Increase

Opioid Maintenance Pharmacotherapy - A Course for Clinicians

Therapeutic

Window

39

Issues in Issues in Maintenance:Maintenance:

HOW MUCH?HOW MUCH?

&&

HOW LONG?HOW LONG?Opioid Agonist Treatment of Addiction - Payte - 1998

40

. . . As long as patient desires and benefits from continued treatment

Opioid Agonist Treatment of Addiction - Payte - 1998

41

Recovery is a process, not an event!

P

ER

CE

NT

IV

US

ER

S

0

100

LA

ST

AD

DIC

TIO

N P

ER

IOD

AD

MIS

SIO

N

100%

81.4%

Pre- | 1st Year | 2nd Year | 3rd Year | 4th Year Admission

*

*

63.3%

41.7%

28.9%

Adapted from Ball & Ross - The Effectiveness of Methadone Maintenance Treatment, 1991 Opioid Agonist Treatment of Addiction - Payte - 1998

Opioid Maintenance Pharmacotherapy - A Course for Clinicians

OPTIMAL RESPONSE FROM OPIOID AGONIST IN MAINTENANCE

TREATMENT

Prevention of onset of withdrawal syndrome for 24 hours or more

Reduction or elimination of drug hunger or craving

“Blockade” of euphoric effects of illicit self-administered opioids

Kreek, 1987 – title change by Payte, 2001

Opioid Agonist Treatment of Addiction - 200144

Optimal Vs. Desired Response

The clinician and the patient must speak the same language to ensure realistic expectations and goals of OAT. A pattern of dose escalation in pursuit of the elusive state of “abnormal normality” must be recognized by the patient and the clinician.

Opioid Agonist Treatment of Addiction - Payte - 2001

45

Edwin A. Salsitz, MD

Cytochrome P-450 Enzyme ActivityDrug Interactions - Methadone

Induction Rifampin Phenytoin Ethyl Alcohol Barbiturates Carbamazepine Nevirapine (Viramune)

Opioid Maintenance Pharmacotherapy - A Course for Clinicians

Cytochrome P-450 Enzyme ActivityDrug Interactions - Methadone

Inhibition

Fluconazole

Cimetidine

Erythromycin

Fluvoxamine (Luvox)

Ketoconazole

Nefazodone (Serzone)

Ritonavir (Norvir)

Opioid Maintenance Pharmacotherapy - A Course for Clinicians

Methadone Death

Overdose, overmedication or drug-drug interaction?

HARMDHelping America Reduce

Methadone Deaths

• “Helping America Reduce Methadone Deaths”• http://www.harmd.org/

Edwin A. Salsitz, MD

THE DOSING WINDOW

Edwin A. Salsitz, MD

Edwin A. Salsitz, MD

Edwin A. Salsitz, MD

Edwin A. Salsitz, MD

Subutex® and Suboxone®

• Two, schedule III, sublingual buprenorphine tablet formulations (2 mg and 8 mg) approved for US use:• Subutex® (buprenorphine alone)• Suboxone® (buprenorphine + naloxone)

• In contrast, methadone is a schedule II drug

• Partial mu-opioid agonists• Suboxone® is the focus of US

marketing efforts

Combination of Buprenorphineplus Naloxone

Addition of naloxone to buprenorphine may decrease the abuse potential of tablets

If an opioid/heroin user injects Suboxone the naloxone will be active and cause withdrawal

Buprenorphine plus naloxone = Suboxone

Buprenorphine without naloxone = Subutex

1/8/06, Anaheim, ASAM physician buprenorphine training

1/8/06, Anaheim, ASAM physician buprenorphine training

333333333333

Edwin A. Salsitz, MD

2005 Anaheim, ASAM buprenorphine training

Phone screening

Patient agreements

Monitor progress Referrals

MEDICATION/PSYCHOSOCIAL

1/8/06, Anaheim, ASAM physician buprenorphine training

DATA 2000 restrictions:number of patients

• Solo practice: 30 patients• Unless doctors request increase to 100 patients

2005 Anaheim, ASAM buprenorphine training

Examples of Patient agreements:

• To take the medication only as prescribed

• To notify the clinic immediately in case of lost or stolen medication

• To comply with the required pill counts and urine tests

• Enter counseling or a treatment program

2005 Anaheim, ASAM buprenorphine training

Elements of periodic

monitoring

• Tox screens

• Medication compliance

• Health and wellbeing

• Counseling

2005 Anaheim, ASAM buprenorphine training

Are you going to watch?

2005 Anaheim, ASAM buprenorphine training

Whizmaster KitWhizmaster Kit

2005 Anaheim, ASAM buprenorphine training

Example of tox screen protocol: Urine On -Site at each visit, discussed right away

- Send -away initial and yearly and any positives

- Random call twice a year - Temperature testing at each collection

Breathalyzer: initial, then individualized

2005 Anaheim, ASAM buprenorphine training

Medication compliance

• Observed dosing early on, potential for observed dosing at pharmacy or periodically.

• Pill counts with random callbacks.

• Use urine test for buprenorphine – they are available!

2005 Anaheim, ASAM buprenorphine training

THREATS TO STABILITY

Other drug abuse or positive screensMedical problemsLife changes: moves, divorce, new

jobDropping out of counseling, mutual

support meetings

2005 Anaheim, ASAM buprenorphine training

RED FLAGS CHECKLIST

• Missing appointments

• Running out of medication too soon

• Taking medication off schedule

• Not responding to phone calls

• Refusing urine or breath testing

• Neglecting to mention new medications or outside treatment

2005 Anaheim, ASAM buprenorphine training

RED FLAGS CHECKILST,cont.

• Appearing intoxicated or disheveled • Frequent or urgent inappropriate phone

calls• Neglecting to mention change in address,

work, or home situation• Inappropriate outbursts of anger• Lost or stolen medication• Frequent physical injuries or accidents

RESPONSE TO RED FLAGS

• Address red flags as soon as possible

• Ask for patient generated plan

• Coordinate care with the counselor or treatment program

• Increase the level of care or frequency of meetings

• Formalize the plan in the office

2005 Anaheim, ASAM buprenorphine training

MONITORING: SUMMARY

Regular follow-up visits

Regular and random testing and pill counts

Address red flag behavior promptly

Adjust structure according to progress

What you are doing should make sense

$ Cost $

Referral and discontinuation

• Cost may prohibit treatment – TAR possible

• Methadone treatment cost less –Drug MediCal

• Taper for administrative non-compliance

• (clear guidelines important)

• Higher level of care needed

• Immediate dismissal for behavior

Summary• Increasing rates of prescription drug

dependence

• Pharmacology, side effects and safety Methadone - risk of drug interaction and overdose

• Buprenorphine – compliance and diversion

• Patient selection, monitoring and counseling

• Essential role of counseling

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