Fighting Fire With Fire?

(1)

Why Would Anyone Treat

Drug Addiction With Drugs?

Methadone Maintenance Treatment: Methadone Maintenance Treatment:

Fighting Fire With Fire?

Mark Stanford, Ph.D.

Sangeetha Raghuraman, M.D.

SCVHHS Dept Alcohol & Drug Svcs Addiction Medicine Div.

(2)

Case Presentation

• 50 yr old with poorly controlled diabetes. • Despite patients best efforts to control his

blood sugars, he continues to run high. • Patient has voiced concerns to his

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Case Presentation (cont.)

• His physician’s response was…

“You’re just substituting an addiction to

sugar with an addiction to insulin. You just need to make a choice to eat the right

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Case Presentation (cont.)

• When the patient objected, arguing that he needed his insulin to control his diabetes, the physician relented, but informed the patient that he was only going to prescribe insulin for a few weeks and then he would gradually reduce the dose until it was

(5)

Methadone Maintenance:

History

• 1950’s-1960’s: NYC epidemic heroin use • By 1961 death related to heroin injection

became #1 cause of death in 15-35 yr old age group

• Cost to health care system of 100 billion/yr • Treatment options: incarceration, “civil

commitment,” and “therapeutic communities” • Methadone for detox in the 1950’s, but relapse

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Methadone Maintenance:

History

• 1964: Dole and Nyswander (Rockefeller

University) pilot study with 6 long term addicts. – Morphine failed as a maintenance medication – Methadone successfully treated drug craving – Eventually all 6 patients stabilized and were

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Methadone Maintenance:

History

• 1964…6 patients

• 1971: Returning Vietnam veterans with heroin addiction led Nixon to establish “Special Office for Drug Abuse Prevention”

• 1998…179,000 MM patients nationwide

• 1995 IOM report estimated 500,000 to 1 million heroin users in U.S. = only 19-36% of heroin

(8)

30 years of independent research

shows that . . .

.

The success of MMT in

reducing crime, death, disease

and drug use is well

documented.

-Death rates among persons on MM 30% less than for those not on treatment

(9)

581 Male Heroin Addicts Followed for 33 Years

(10)

Methadone Maintenance

• “Since the mid-1960’s, methadone

maintenance has been the gold standard for the treatment of opioid dependence.”

(11)

DADS Addiction Medicine

Division

3 clinics:

Central Valley Clinic (on the VMC campus) East Valley Clinic (East San Jose at Alexian) South County Clinic (San Martin)

571 patients:

510 maintenance

50 medically managed withdrawal

7 Suboxone (buprenorphine) patients 4 Perinatal patients

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Based on the science, how is

addiction currently defined?

• A brain disease expressed as a compulsive behavior

• The continued abuse of drugs despite negative consequences

• A chronic, potentially relapsing disorder

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ADDICTION AS A CHRONIC

ILLNESS

Chronic relapsing condition which

untreated may lead to severe complications

and death.

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ADDICTION AS A CHRONIC

ILLNESS

• It is treatable but not curable.

• Adjustment to diagnosis is part of patient’s task.

• There is a wide spectrum of severity. • Retention in treatment is key.

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Addiction is a Chronic Illness Because:

9 It has both a genetic and environmental basis influencing its development and manifestation

9Recovery from it is often a long-term process requiring repeated treatments

9 Relapses can occur during or after successful treatment episodes

9 Participation in self-help support programs during and following treatment can be helpful in sustaining long-term recovery

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Addiction Diagnosed

DSM-IV Dependence

Any 3 of:

• tolerance

• withdrawal

• uses more or longer than intended

• unable to cut down

• use consumes a great deal of time

• important social/work activities given up

• continued use despite

mental or health problems known to be caused by substance

DSM-IV Abuse

Any 1 of:

• recurrent use causing failure to fulfill major role obligations at

work/home/school

• recurrent use when physically hazardous

• recurrent substance-related legal problems

• continued use despite persistent

social/interpersonal

problems due to substance use

(17)

Stabilization

When a patient is on a stabilized dose

of methadone, they no longer meet the

DSM IV diagnostic criteria for opioid

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Signs of Stabilization

• abstinence from opioids

• no switching to other depressants

(benzos alcohol, etc)

• participation in counseling treatment

• disassociation from drug-using friends

and family members

• involvement with healthy people and

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What is Methadone?

• a long-acting opiate with a slow onset of action…no rush…not particularly addicting

– opiate addicts experience gradual relief from symptoms of withdrawal

– opiate naïve users experience slow onset of sedation

• produces/perpetuates physical dependence

(20)

Why use Methadone?

• The addicted patient benefits

– addicts are able to quit using heroin and remain abstinent

– a therapeutic dose enhances patients’

ability to pursue education or employment – a therapeutic dose enhances patients’

ability to regain/maintain family relationships

(21)

Why Use Methadone? (cont)

• Society benefits

– decreased transmission of HIV and hepatitis C – decreased criminal activity

– improved pregnancy outcome for opiate addicted patients

(22)

Characteristics of a Candidate

for Methadone Maintenance

Characteristics of a Candidate

for Methadone Maintenance

• moderate to severe addiction • demonstrated inability to

achieve/maintain abstinence with other treatment modalities

• physiological dependence on opiates for longer than one year

• OR any pregnant woman with evidence of physical dependence on opiates

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Methadone maintenance: an

evidence-based medical

treatment

• Stigmatized in spite of saving many lives and lots of money

• Urban legends persist, including ‘it’s just another drug’.

(24)

Four questions patients ask:

• Is methadone better than heroin?

• What is the right dose of methadone? • How long should patients stay on

methadone?

(25)

First question:

Is methadone better than heroin?

• Legal

• Avoids needles

• Known amount ingested

(this is what patients already know, but there is more to it…)

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

Dose Response “Loaded” “High” Normal Range “Comfort Zone” “Sick” Time Subjective w/d Objective w/d 0 hrs. 24 hrs.

(27)

Is methadone better than heroin?

• Legal

• Avoids needles

• Known amount ingested • Slow onset: no “rush”

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

(28)

Four questions patients ask:

second question

• What is the right dose of methadone?

• How long should patients stay on methadone? • What are the side effects of methadone?

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How Much????

“Enough!!!”

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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. (see stars on the next graph)

• Not over-sedated • Blocking dose

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

Dose Response “Loaded” “High” Normal Range “Comfort Zone” “Sick” Time “Abnormal Normality” Subjective w/d Objective w/d trough 0 hrs. 24 hrs.

(32)

A Non-therapeutic Dose

• Jeopardizes the success of treatment. • Sub-therapeutic dosing (under-dosing)

results in physical discomfort and ongoing use.

• Over-dosing causes physical discomfort and over-sedation.

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Adapted from V. Dole (1989) JAMA, 282, p. 1881

Effectiveness of Methadone

Treatment:

Dose Adequacy

0 10 20 30 40 50 60 70 80 90 10 20 30 40 50 60 70 80 90 100 Daily Methadone Dose (in mgs.)

Past month heroin use (%)

(34)

Methadone Is NOT

A Heroin Substitute

Methadone Is NOT

A Heroin Substitute

(35)

Methadone Pharmacology

• compared to heroin, the patient is stabilized

sick

normal

high Day 1 Day 2 Day 3 Day 1 Day 2 Day 3

(36)

Stabilization means…

• patient experiences no withdrawal between doses • cravings are minimized

• no drowsiness or sedation

• no euphoria if other opioids are used because the opioid receptors are blocked

• no medically significant or subjectively intolerable side effects

• no longer meets DSM IV diagnosis for opioid dependency

(37)

Four questions patients ask: third

question

• What is the right dose of methadone?

• How long should patients stay on

methadone?

(38)

How Long???

“Long Enough!!”

(39)

Adapted from: Ball & Ross, 1991.

Relapse to heroin use after MMT-105 patients who left treatment

% I V U S E R S 28.9% 82.1% 72.7% 57.6% 45.5% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% In Tx. 1 to 3 4 to 6 7 to 9 10 to 12

(40)

Adapted from: Ball & Ross, 1991.

How Long For Methadone Treatment?

8% 23% 97% 67% 0 20 40 60 80 100 120 P e r c e n t Pre-treatment Admission: < 6 months stay Average Stay: 6 to 54 months Long-term: > 54 months

(41)

Four questions patients ask:

fourth question

• What is the right dose of methadone?

• How long should patients stay on methadone?

• What are the side effects of

methadone?

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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

(43)

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

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What is the QT and Why Does It Matter?

When the heart contracts it emits an electrical signal, which can be recorded on an electrocardiogram (ECG). On a paper readout strip, the ECG produces a

characteristic waveform with the different parts designated by letters - such as Q, R, S, and T

The QT interval represents the time for electrical activation and relaxation of the ventricles, which is measured in fractions of a second, or milliseconds (msec). It is an indicator of either healthy or abnormal heart rhythm.

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What is the QT and Why Does It Matter?

When the QTc becomes significantly prolonged, the person may be at risk of developing a particularly rapid, abnormal heart

rhythm, called torsade de pointes, or TdP. This literally means 'twisting of the points' and is represented on the ECG by

undulating peaks twisting about a central axis.

This may signal convulsive twitching of heart muscle, or

ventricular fibrillation, which can cause death if emergency care is not provided [Leavitt and Krantz 2003].

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Case Reports Are Inadequate

There have been various case reports of QTc interval prolongation and serious arrhythmia, TdP, in patients prescribed methadone. These cases often, but not

always, appear to be more commonly associated with higher-dose treatment (> 200 mg/day)

[Pearson and Woosley 2005].

In the majority of those involving typical MMT doses, additional medications, illicit drug use, and/or clinical conditions such as low potassium levels were noted as contributing factors.

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Case Reports Are Inadequate

An examination of all methadone adverse-event cases

reported to the FDA spanning more than 3 decades found only a 0.29% incidence of QT prolongation and 0.79% incidence of TdP. [Pearson and Woosley 2005].

They conceded that it was impossible to be "absolutely certain if methadone caused or contributed to the

prolonged QT and TdP."

Therefore, while case reports can be of use in signaling a possible problem, in themselves they are weak evidence of methadone being a primary or even significant

(48)

Treatment 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

(49)

Outcomes

• Methadone Reduces:

– overall and overdose deaths – Illicit drug use

– criminal behavior

– spread of infectious diseases (HIV, HCV and TB)

(50)

HIV CONVERSION IN TREATMENT 0% 5% 10% 15% 20% 25% In Tx (N=95) Partial Tx (N=45) No Tx (N=55) Tx Status

Source: Metzger, D. et. al 18 month HIV conversion by treatment retention. J of AIDS 6:1993. p.1053

(51)

Methadone Treatment Reduces

Criminal Behavior

Drug offense arrests decline because MMT patients reduce or stop buying and using illegal drugs. Arrests for predatory crimes decline because MMT patients no

longer need to finance a costly heroin addiction, and because treatment allows many patients to stabilize their

lives and return to legitimate employment.

Hubbard, R.J. Treatment Outcomes Prospective Study, op. cit; J.C. Ball. The Criminal Justice System and Opiate Addiction. NUIDA Research Monograph 86.

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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 TX During TX

Crime Days Per Year

(53)

Pregnancy

• MMT treatment of choice for pregnant, opioid-abusing women.

• Efforts to avoid intra-uterine fetal withdrawal, including split dose.

• Neonatal withdrawal occurs within 72 hours, at least 45% need treatment.

• Breastfeeding recommended if not HIV positive.

(54)

Pain in patients on MMT

• Methadone is prescribed for pain

treatment in twice or three times daily doses.

• Up to 60% of MMT patients have chronic pain (Jamison 2000, Rosenblum 2003)

(55)

Methadone Treatment Is More

Effective With...

Methadone Treatment Is More

Effective With...

• counseling (individual/group) • urine testing

• involvement in community recovery groups

• lifestyle changes to support recovery • mental health evaluation/treatment • medical assessment/referral

(56)

Evidence for Counseling In

Methadone Maintenance

• The “dose” of these services can determine treatment outcomes

• McLellan et al., 1993:

– 6-month randomized clinical trial

– three levels of psychological services

• methadone alone

• methadone plus standard counseling services • methadone plus enhanced services (counseling,

(57)

Evidence for Counseling Services in

Methadone Maintenance

55%

28% 0% >16 consecutive weeks of (-) urines

81%

59% 31% Retention Methadone + Enhanced Counseling Methadone + Std. Counseling Methadone Outcome

(58)

A FEW WORDS ABOUT

BUPRENORPHINE

• “Ceiling effect” and safety

• Displaced other opiates: withdrawal on induction

• Sublingual tablet

• Schedule 3(methadone is 2)

• One form combined with naloxone • Office – based use available

(59)

(60)

(61)

Buprenorphine is a Partial Agonist

0 10 20 30 40 50 60 70 80 90 100 % Mu Receptor Intrinsic Activity Full Agonist (e.g. methadone) Partial Agonist (e.g. buprenorphine)

Antagonist (e.g. naloxone) no drug high dose

DRUG DOSE low dose

(62)

Differences in Precipitated Syndromes

Buprenorphine will precipitate withdrawal only when it displaces a full agonist off the mu receptors

0 10 20 30 40 50 60 70 80 90 100 % Mu Receptor Intrinsic Activity

no drug high dose DRUG DOSE low dose Full agonist (e.g. heroin) Partial agonist (e.g. buprenorphine)

A Net Decrease in Receptor Activity if a Partial Agonist displaces the Full Agonist

(63)

Receptor Affinity

Affinity is the strength with which a drug physically binds to a receptor

• Buprenorphine affinity is very strong and it will displace full agonists like heroin and methadone

• Note receptor binding strength (strong or weak) is NOT the same as receptor activation (agonist or antagonist)

Bup affinity is higher Mu

Receptor _{Bound to receptor}

Therefore, Full Agonist is displaced

(64)

Receptor Dissociation

Dissociation is the speed (slow or fast) of

disengagement or uncoupling of a drug from the receptor

• Buprenorphine’s dissociation is slow

• Therefore Buprenorphine stays on the receptor a long time and blocks heroin or methadone from binding

Bup dissociation is slow Mu

Receptor

Therefore, Full Agonists can’t bind

(65)

Buprenorphine, Methadone, LAAM: Treatment Retention Percent Retained 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