diagnosis and treatment of opioid dependence matthew a. torrington, md aafp asam medical director,...

Diagnosis and Treatment of Opioid Dependence

• Matthew A. Torrington, MD AAFP ASAM• Medical Director, Matrix Institute Narcotic Treatment Program

• Clinical Research Physician, UCLA Integrated Substance Abuse Programs• Medical Director, Prometa Center, Los Angeles

AAPainMed,APainS, ASAMdefined ADDICTON in 2001

• Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving

• Savage et al., 2001

DSM 4 criteria for drug abuse

• Significant impairment or distress resulting from use

• Failure to fulfill roles at work, home, or school • Persistent use in physically hazardous

situations • Recurrent legal problems related to use • Continued use despite interpersonal problems

DSM 4 criteria for drug Dependence≥ 3 of the following occurring in the same 12- month period

1. Desire or unsuccessful efforts to cut down on use2. Large amount of time spent obtaining drugs, using drugs,

or recovering from drug effects3. Social, occupational, or recreational activities reduced

because of drug use4. Drug use continued despite knowledge that a physical or

psychological problem is being caused or exacerbated by use

5. Use of drug in larger amounts or for longer periods of time than originally anticipated

6. Tolerance• Need for increased amounts of drugs to

achieve desired effect; or• Diminished effect with continued use of the

same amount of drug

• Tolerance develops normally with repeated use of some drugs

7. Withdrawal

withdrawal syndrome with cessation of use, reduction of use, or use of an antagonist

Drugs or related substances

taken to relieve or avoid withdrawal symptoms

Addiction is NOT:

• Physical dependence - characteristic withdrawal syndrome emerges upon decreased blood levels of substance or antagonist administration

• Tolerance - increasing amount of drug needed over time to induce the same effect

Both are neuroadaptive states resulting from chronic drug administration

Pseudoaddiction

• operationally defined as aberrant drug-related behaviors that make patients with chronic pain look like addicts.

• these behaviors stop if opioid doses are increased and pain improves (Weissman and Haddox, 1989).

• This indicates that the aberrant drug-related behaviors were actually a search for relief

• Little data on the subject, but evidence in rats

Substance Dependence A Multifactorial Brain Disease

Genetic

BiologicalDysregulation

Social Cultural

Psychological Environmental

WHO. Neuroscience of Psychoactive Substance Use and Dependence. 2004.

Substance Dependence

Substance Dependence Is a Disease

Disease• An interruption, cessation, or disorder of bodily

function, system, or organ; When something is wrong with a bodily function.1

• Determinants include environment and genetics (nature and nurture).

Substance Dependence• A disorder of the normal biological regulation of brain

chemicals, specifically the GABA system in the brain. • Determinants include environment and genetics

1. Stedman’s Medical Dictionary. Baltimore, Md: Williams & Wilkins; 2000.

Substance-related disorders

• Intoxication – use of substance resulting in maladaptive behavior

Withdrawal negative reactions that occur when use is discontinued or drastically reduced

Delirium Dementia Psychosis Mood disorder Anxiety Sexual dysfunction Sleep disorder

Opiates

• OxyContin– long acting oral

• Propoxyphene– (Darvon)

• Hydrocodone– (Vicodin)

• Hydromorphone– (Dilaudid)

• Meperidine– (Demerol),

• Diphenoxylate (Lomotil)• Codeine

http://www.chemheritage.org/EducationalServices/pharm/asp/images/heroin.gif

Opiate Abuse• Total number of drug mentions in drug abuse-

related emergency department episodes, by type of drug, 1997-00

•    •   Cocaine Heroin

Marijuana • ---------------------------------------------------------------------

---

•        • 1997 161,083 70,712 64,720• 1998 172,011 75,688 76,842• 1999 168,751 82,192 87,068• 2000 174,881 94,804 96,426

• Source: U. S. Department of Health and Human Services, SAMHSA, Office of Applied Studies, Emergency Department Trends from the Drug Abuse Warning Network Preliminary Estimates January - June 2001 with Revised Estimates 1994-2000, February 2002.

http://www.nrc.nl/W2/Lab/Profiel/Drugs/

Heroin Prevalence

• Across years and across cultures, prevalence of heroin abuse is fairly stable at about 1.5% of the adult population.– Social upheaval linked to increases in heroin

abuse (Afghanistan, Iraq, Russia)

Heroin

• Heroin is processed from morphine (diacetylmorphine)

• Morphine is a naturally occurring substance extracted from the seedpod of the Asian poppy plant.

• Heroin usually appears as a white or brown powder.

• Street names – "smack," "H," “horse,” "skag,"

and "junk" "Mexican black tar,” “China White”

• Originally produced by Bayer as a “non addictive” analgesic

www.thinkbigdesigns.com/ justin/Heroin.jpg

Opiate EFFECTS• Desirable

– Euphoria - heroin produces greater ‘rush’ than morphine due to lipophilicity

– Prolonged sense of contentment and well-being

• Undesirable– Nausea and vomiting – Respiratory depression – in sensitivity of respiratory centre to PCO2

– Constipation - tone + motility in GI tract• DON’T RX OPIATES WITHOUT CONSIDERING THIS

– Pupillary constriction - stimulation of oculomotor nucleus

MECHANISM OF ACTION• Heroin metabolites act on receptors on GABA neurons to uninhibit the

firing of dopaminergic neurons in VTA. • This results in DE release in Nacc.

Tolerance, Addiction, and Withdrawal

• With regular opiate use, tolerance develops.

• As higher doses are used over time, physical dependence develops.

• Withdrawal, which in regular abusers may occur as early as a few hours after the last administration

• drug craving, restlessness, muscle and bone pain, insomnia, diarrhea and vomiting, cold flashes with goose bumps ("cold turkey"), kicking movements ("kicking the habit"), etc.

www.naplesnews.com/cgi-bin/ sendto.pl?location=specials

Opiate withdrawal

• Major withdrawal symptoms peak between 48 and 72 hours after the last dose

• Duration and intensity dependent on quantity and half live of opiates being used

• Heroin WD usually subsides after about a week.

• Methadone WD can last weeks• RX OPIATES CAUSE

WITHDRAWAL TOO

http://www.heroinaddiction.com/Pictures/withdrawal.jpg

SYMPTOMS OF WITHDRAWAL

Picture from: www.schoolscience.co.uk/.../4/ biology/medicines/drugs4.html

MOA Withdrawal• On cessation of heroin excessive cAMP

production occurs causing withdrawal symptoms

Opiate Overdose Treatment

• Respiratory depression, CNS depression, Myosis, signs of drug abuse, history

• R/O hypoglycemia, acidemia, fluid and electrolyte abnormalities

• Support: airway, ventilation, cardiac function, • Naloxone HCL 0.4-0.8mg initially;• repeat PRN

Treatment of opiate dependence

• Comprehensive treatment gives best chance of long lasting remission– Opiate replacement or pharmacologic support

of withdraw symptoms– Cognitive Behavioral Treatment: matrix,

counseling, etc.– 12 step work– CAN NOT RX OPIATES FOR OPIATE WD

Relapse curves for heroin, tobacco and alcohol addiction

0

20

40

60

80

100

0 3 6 12

months

% a

bst

ain

ers

herointobaccoalcohol

Effect of Common Opiates at mu receptor

• Heroin, morphine, methadone

• Buprenorphine• ? tramadol

• Naltrexone (Revia, Vixo)• Nalmefene• naloxone

Full Agonist

Partial Agonist

Antagonist

Receptor Binding at Mu receptor

Agonist

Opens door

Partial AgonistOpens door with safety

chain

AntagonistsDummy key

Morphine like effect

Weak morphine like effects with strong receptor affinity

No effect in absence of an opiate or opiate dependence

Agonist Therapy

• Methadone is the gold standard– Must be administered in setting of OTP, Opiate

Treatment Program– Highly regulated– Can be used for pain

• Legislation prevents the use of agonists specifically for the treatment of opiate dependence outside the setting of OTP

THE DOSING WINDOW

How is methadone better than heroin?

• Legal

• Avoids needles

• Known amount ingested

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 Agonist Treatment of Addiction - Payte - 1998

How is methadone better than heroin?

• Legal

• Avoids needles

• Known amount ingested

• Slow onset: no “rush”

• Long acting: can maintain “comfort” or normal brain function

• Stabilized physiology, hormones, tolerance

Four questions patients ask:

• How is methadone better for me than heroin?

• What is the right dose of methadone for me?

• How long should I stay on methadone?

• What are the side effects of methadone?

What is the right dose?

• Eliminate physical withdrawal

• Eliminate ‘craving’

• Comfort/function: usually trough is 400-600 ng/ml, peak no more than twice the trough.

• Not over-sedated

• Blocking dose

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 Agonist Treatment of Addiction - Payte - 1998

trough

Recent Heroin Use by Current Methadone Dose

0

20

40

60

80

100

0 10 20 30 40 50 60 70 80 90 100

Methadone Dose, in mg.

% H

eroi

n U

se

Ref: J. C. Ball, November 18, 1988Slide adapted from Tom Payte

“How Much????

Enough!!!”Tom Payte, MD

Four questions patients ask:

• How is methadone better for me than heroin?

• What is the right dose of methadone for me?

• How long should I stay on methadone?

• What are the side effects of methadone?

Relapse to IV drug use after MMT105 male patients who left treatment

28.9

45.5

57.6

72.2

82.1

0

20

40

60

80

100

IN 1 to 3 4 to 6 7 to 9 10 to 12

Pe

rce

nt

IV U

se

rs

Treatment Months Since Stopping Treatment

Opioid Agonist Treatment of Addiction - Payte - 1998

Adapted from Ball & Ross - The Effectiveness of Methadone Maintenance Treatment, 1991

“How Long???

Long Enough!!”Tom Payte, MD

Four questions patients ask:

• How is methadone better for me than heroin?

• What is the right dose of methadone for me?

• How long should I stay on methadone?

• What are the side effects of methadone?

Opiate effects, physical

• Predictable physical effects of administering opiates:– Tolerance: the body becomes efficient in

processing the drug and requires ever higher doses to produce the desired effect.

– Dependence: when the drug is discontinued there are typical withdrawal signs and symptoms.

Side effects of methadone:

• General opiate effects: – Sedation/stimulation– Maintained phys. dependence (stable)– hypogonadism (not as severe as with heroin, may be dose

dependent)

• Constipation• Slight QTc prolongation on ECG (Martell etal)• Sweating• Methadone treatment tied to regulated clinic

Treatment Outcome DataTreatment Outcome Data

• 4-5 fold reduction in death rate

• reduction of drug use

• reduction of criminal activity

• engagement in socially productive roles

• reduced spread of HIV

• excellent retention(see: Joseph et al, 2000, Mt. Sinai J.Med., vol67, # 5, 6)

Crime among 491 patients before and during MMT at 6 programs

0

50

100

150

200

250

300

A B C D E F

Before TXDuring TX

Adapted from Ball & Ross - The Effectiveness of Methadone Maintenance Treatment, 1991

Cri

me

Day

s P

er Y

ear

Opioid Agonist Treatment of Addiction - Payte - 1998

HIV CONVERSION IN TREATMENT

0%

5%

10%

15%

20%

25%

30%

35%

Base line 6 Month 12 Month 18 Month

ITOT

HIV infection rates by baseline treatment status. In treatment (IT) n=138, not in treatment (OT) n=88Source: Metzger, D. et. al. J of AIDS 6:1993. p.1052

Opioid Maintenance Pharmacotherapy - A Course for Clinicians - 1997

Buprenorphine

Buprenorphine for Opiate Dependence:

• Suppresses withdrawal

• Substitutes for street opiates

• Blocks subsequently administered opiates

• Safety in long term use

Buprenorphine pharmacology contd.

• “Less bounce to the ounce”

• Ceiling effect on respiratory depression

• Less physical dependence capacity

• Blunts effect of subsequently administered full agonists

• Precipitates withdrawal in moderate to severely dependent people

Buprenorphine: Clinical Pharmacology

Tight Receptor Binding• long duration of action• slow onset mild abstinence• long t 1/2 for tx of opiate dependence

– 37.5 hours • shorter t 1/2 for analgesia

– 3-6 hours

Good Effect

0

20

40

60

80

100

p 0.5 2 8 16 32

Buprenorphine (mg)

Pea

k S

core

3.75 15 60

Methadone (mg)

Respiration

02468

1012141618

p 1 2 4 8 16 32

Buprenorphine (mg)

Bre

ath

s/m

inu

te

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

Buprenorphine/Naloxone combo SUBOXONE

4 part buprenorphine: 1 part naloxone

Sublingual: Opiate agonist effect from buprenorphine

Intravenous: Opiate antagonist effect from naloxone

Addition of Naloxone Reduces Abuse Potential

• Naloxone will block buprenorphine’s effects by the IV but not the sublingual route

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

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

A Sequential Pharmacological Intervention Model for Opiate Dependence

OpiateDependent

DailyBuprenorphine

Successful

Unsuccessful

Naltrexone

Buprenorphine maint.

Medication-free

Methadone

Overview to theDrug Addiction Treatment Act

of 2000 – An Amendment

to the Controlled Substances Act

(October, 2000)

Narcotic drug:

Approved by the FDA for use in maintenance or detoxification treatment of opioid dependence

Schedule III, IV, or V

Drugs or combinations of drugs

Amended Controlled Substances Act

Practitioner requirements:“Qualifying physician”

Has capacity to refer patients for appropriate counseling and ancillary services

No more than 30 patients (individual or group practice)

Amended Controlled Substances Act

“Qualifying physician”:A licensed physician who meets one or more of the

following:

1. Board certified in Addiction Psychiatry

2. Certified in Addiction Medicine by ASAM

3. Certified in Addiction Medicine by AOA

4. Investigator in buprenorphine clinical trials

Amended Controlled Substances Act

“Qualifying physician” (continued):

Meets one or more of the following:

5. Has completed 8 hours training provided by ASAM, AAAP, AMA, AOA, APA (or other organizations which may be designated by HHS)

6. Training/experience as determined by state medical licensing board

7. Other criteria established through regulation by the Secretary of Health and Human Services

Amended Controlled Substances Act

Buprenorphine: Potent Analgesic

• 20-50 times potency of morphine

• Available worldwide for pain treatment

• Injectable formulation available in U.S.

• Usual analgesic dose: .2-.4 mg sl

• Higher dose for opiate dependence

Buprenorphine and Pain

• Animal data don’t predict human data• Good potent analgesic• Mild CVS effect, mild G-I effect• Ceiling effect on respiratory depression • Analgesia not compromised by ceiling.• Effective for long term use mos. to yrs.

Buprenorphine: Analgesic Profile

Rapid onset of action

Long duration of peak effect (60-120 min)

Long half life (3.5 hrs)

Analgesic action up to 8 hrs.

No apparent analgesic ceiling effect at doses below 300 mg Ms equivalent; no inverted U

Ceiling effect on respiratory depression

Low physical dependence profile

References

• Tomkins DN, Sellers EM (2001) Addiction and the brain: the role of neurotransmitters in the cause and treatment of drug dependence. Canadian Medical Association Journal 164 817-821

• O’Connor P, Fiellin DA. (2000) Pharmacological Treatment of Heroin-Dependent Patients Annals of Internal Medicine 133 40-54

• Sneader W. (1998)The Discovery of Heroin. Lancet 352 (9141) 1697-1699

• Rang HP, Dale MM, Ritter JM (1999). Pharmacology 4th ed. Edinburgh : Churchill Livingstone

• Wills S (1997) Drugs of abuse. London : Pharmaceutical Press

• Steve Shoptaw, Presentation, UCLA Addiction Clinic Course, 2005, with permission

• Judith Martin, Presentation, COMP Lecture, 2005 with permission