PHARMACOLOGIC TREATMENT OF

OPIATE DEPENDENCE

Paula Colescott MD

Diplomat of The American Board of Addiction Medicine

Board Certification in Internal Medicine

Objectives

The student will understand:

• The Brain changes in the addict

• The Historical Approaches of Treatment

• Agonist Treatment

• Blockade of the Opiate Receptor

• Those who qualify for Buprenorphine/Naltrexone

• The Clitheroe Protocol

In Reflection

• 25 yo Native Female, IV heroin user ,being released from Hiland Prison. She is tremulous as she tells me she doesn’t think she can stay clean.

• 30 yo white female, narcotic/heroin user, who is in RSAT @ Hiland Prison. She confides to me that despite treatment she fears her inability to resist relapse.

WHY

OPIUM

1898

18041832

OPIATESDerived from extracts of the juice of opium poppy.

OPIOIDSAny exogenous substance that acts as an agonist at any of

several receptors

Neurobiology of Addiction

George F. Koob

Take a Drug Change Your Brain

DRUG ADDICTION IS A COMPLEX ILLNESSDRUG ADDICTION IS A COMPLEX ILLNESS

www.drugabuse.gov

Steward, 1987, p. 166

“It’s staying off that is the hard part. It

takes a lot of willpower. But seeing

smack eats away at your willpower; it

makes it very hard. When I stop I just

feel vacant with no direction or

energy and that lasts for months.’

Behavioral Mechanisms of Addiction

“The special role the drug comes to play in the personality organization of these patients. They have not successfully established familiar defensive, neurotic, characterological or other common adaptive mechanisms as a way of dealing with their distress. Instead, they have resorted to the use of opioids as a way of coping with a range of problems including ordinary human pain, disappointment, anxiety, loss, anguish, sexual frustration, and other suffering”

Opioids relieve emotional painand this is one of the behavioral mechanisms implicated in the

addiction cycle (Khantzian, 1985, 1990, 1997)

Opioid Intoxication

1st Profound euphoria the rush Visceral sensations, a facial flush, deepening of the voice. The

rush is resistant to tolerance.

2nd The High feeling of well-being over several hours, no tolerance

3rd The Nod state of escape from reality ranging

from sleepiness to virtual unconsciousness

4th Being Straight User no longer experiencing the rush or nod or high, but also not in withdrawal. This can

last up to 8 h following an injection or smoking of heroin.

NATURAL REWARDS DISPLACED

SPIRITUALLY

PHYSICALLY

SOCIALLY

INTELLECTUALLY

EMOTIONALLY

Salient

Substance Dependence (brief)

• Organization around acquisition, use, recovery from effects, of the drug—behavior is rewarding

• Dosage and frequency not the issue

• Consequences are the issue

• Adaptation and deterioration are hallmarks

• Ambivalence is the psychodynamic

– Loss of CONROL

WITHDRAWAL

Acute Withdrawal5-7 Days

• Runny nose, sneezing,

• Sweating, yawning

• Restless, insomnia

• Piloerection, myalgia

• Twitching, arthralgia

• Abd. Cramps, diarrhea

• Vomiting, dehydration

• Tachycardia, HBP, Fever

• Psychosis

• Autonomic rebound locus ceruleus

•

Protracted (1-12 months) Abstinence

• Anergia, Anhedonia

• Sleep disturbance

• Poor appetite

• Emotional lability/dysphoria

• Stress incompetence

• Drug craving, obsession

• Muscle aches and pains

• Reduced libido, impotence

• Dopaminergic deficiency,

nucleus accumbens, VTA

WHY TREAT OPIOID DEPENDENCE WITH OPIOID AGONISTS?

Repeated Exposure

Neuronal Adaptation

Tolerance, physical dependence, craving

Chronic relapsing nature of opioid dependence

Natural History of Narcotic Addiction: Male Heroin Addicts

• Hser et al.,2001

Therapeutic Options Available to Benjamin Rush, MD

Coming in For Treatment

Medical Withdrawal from Opioids

1. Cold Turkey

2. Symptomatic Medications/Social SupportClonidine, ibuprofen, hydoxyzine, methocambanol, loperamide…

3. Taper ( Goodman & Gilman: 20-50% decrease/day)

4. Federally regulated methadone clinic

5. Ultra-Rapid Opioid Detox (UROD), Rapid Opioid Detox

6. Buprenorphine –(suboxone/subutex)

7. Blockade of the Opiate Receptor ?

Medical Withdrawal or “Detox” is not treatment

OPIATES

Just Detox Alone

And then

Aftercare??

Treatment Overview of Opioid Dependence

DEATH

HARM REDUCTION

OPIOID

REPLACEMENT

Methadone or buprenorphine

ABSTINENCE

< 20% CAN ACHIEVE THIS

Naltrexone

Needle Exchange Program

Is Clean & Sober too Much to ask with Opiates??

OpioidReplacement

Methadone=76% Buprenorphine=?

Abstinence Detox only

3% @ 1 yr

MJ Kreek<20% in

lifetime

WA state MDs85% @ 10 yrs.

New History

1960-70s Dole, Nyswander, and Kreek• Proposed addiction to be a change in brain from

prolonged exposure to opiates

• Started evaluating methadone in the early 1960s

• Methadone for dependence/addiction Rx in special clinics

Buprenorphine

(Subutex)

Orphan drug developed by NIDA and private

pharmaceutical interest over 25 years

2000 Drug Addiction Treatment Act• Addiction is a chronic disease

• Physicians may offer buprenorphine treatment, as a

replacement therapy in their office “OBOT” –Office Based

Opioid Therapy (need 8h CME)

• PCP knows the patient, the family, “the story”

• Reduces stigma, increases access to care

• Aligns addiction with other chronic relapsing conditions

(asthma, HBP, DM, Obesity, depression, mental illness, etc.)

Cognitive Behavioral TherapiesSubstance abuse is related to maladaptive

social learning/adverse life situations.

• Improve interpersonal &Coping skills

– Evaluating feelings, thoughts

• Self-efficacy

– Teach problem solving

Reduce risk of relapse

– Triggers, cues

– Coping with urges

“As a Man thinks, so is he”

Solomon

Is Buprenorphine an Opioid?

Yes

Is Buprenorphine an Analgesic?

• Yes• 20-40 X as potent as morphine

• Analgesic in US, Buprenex (IV/IM), for decades

• Worldwide use for pain as Temgesic

• There is no FDA approval for pain(SL), but it is prescribed to pain patients “off-label”

[problematic]

Opioid Receptors and Effect of Agonist

Mu1 (μ1) analgesia, euphoria

Mu2 (μ2) constipation, respiratory depression

Kappa spinal analgesia, dysphoria

Delta unknown

Receptor Binding at Mu receptor

Agonist

Partial Agonist

Antagonists

Morphine-like effect, increasing dose increases effect

Morphine-like effect with strong receptor affinity, slow dissociation, ceiling effect (bup)

No effect in absence of an opiate or opiate dependence (e.g., naltrexone)

Function at Receptors: Full Agonists

Mureceptor

Full agonist binding …

activates the mu receptor at higher levels with higher doses

is highly reinforcing

is the most abused opioid type

includes, oxycodone, morphine,methadone, others

Slide Courtesy of John T. Pichot, MD

Opioid Receptor Partial Agonists

Mureceptor

activates the receptor at lower levels but plateaus at lower levels

is relatively less reinforcing

is a less abused opioid type

includes buprenorphine

Partial agonist binding …

Slide Courtesy of John T. Pichot, MD

Full Agonist Bound to Receptor

Bup affinity is higher

Therefore Full Agonist is displaced

Partial Agonist (Bup) Receptor Affinity

MuReceptor

• Strength: Drug physically binds to a receptor

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

Can precipitate withdrawal

Slide Courtesy of John T. Pichot, MD

Receptor Dissociation

• Speed (slow or fast) of disengagement or uncoupling of a drug from the receptor

• Buprenorphine’s dissociation is slow – Blocks other opioids (ie morphine) from binding

– Prolonged therapeutic effect (> 24 hours)

MuReceptor

Bup dissociation is slow

Therefore Full Agonists can’t bind

Slide Courtesy of John T. Pichot, MD

0

10

20

30

40

50

60

70

80

90

100

2 mg 16 mg 32 mg

Dose

% R

ecep

tor

Occ

up

an

cy

Source: Greenwald, MK et al, Neuropsychopharmacology 28, 2000-2009, 2003.

μEffects of Buprenorphine Maintenance Dose on

Mu Opioid Receptor Availability

27 to 47%

85 to 92%94 to 98%

Benefits of Buprenorphine• Mild withdrawal syndrome

• Prolonged therapeutic effect

• Safe and effective as an analgesic

• Blockade of “illicit” opioids

• Greater safety margin compared to methadone

• Decreased risk of abuse and diversion with combination tablet

• Efficacy comparable to methadone

“Normal”

Withdrawal

Effects of IV Heroin without Buprenorphine

High

Opiate

Effects

Rush

Usual Effect of Buprenorphine Induction in an Opiate Dependent Patient

“Normal”

Withdrawal

High

Opiate

Effects

“Normal”

Withdrawal

Effects of Using Heroin while on Buprenorphine

High

Attenuated

rushOpiate

effects

CESAR FAXU n i v e r s i t y o f M a r y l a n d , C o l l e g e P a r k

A Weekly FAX from the Center for Substance Abuse Research

April 9, 2012

Vol. 21, Issue 14

Northeastern and Southern Regions of Country Account for Largest Increases in Buprenorphine Found in Law Enforcement Drug Seizures

2003 2004 2005 2006 2007 2008 2009 2010

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

831

1,689

4,161

3,856

West

Midwest

Northeast

South

Estimated Number of Buprenorphine Reports,

U.S. Law Enforcement-Seized Drug Exhibits Analyzed by Forensic Laboratories,

by U.S. Census Region*, 2003-2010

*Northeast: CT, MA, ME, NH, NJ, NY, PA, RI, VT

South: AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA WV

Midwest: IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, WI

West: AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, WY

Buprenorphine estimates for the South and West regions do not meet the DEA’s standard of precision and reliability.

Who is Appropriate for Buprenorphine Treatment?

Patient Selection: 10 Assessment Questions

• Is the patient dependent/addicted to opioids?

• Does the Client live in Anchorage?

• Is the patient aware of other available treatment options?

• Does the patient understand the risks, benefits, and limitations of buprenorphine treatment?

• Is the patient expected to be reasonably compliant, with all treatment modalities?

• Is the patient able to follow safety procedures?

Patient Selection: 10 Assessment Questions

• Is the patient psychiatrically stable?

• Is the patient taking other medications that may interact with buprenorphine?

• Are the psychosocial circumstances of the patient stable and supportive?

• Is the patient interested in office-based buprenorphine treatment?

• Are there resources available in the office to provide appropriate treatment, and support?

• Do they have a means of paying for the Suboxone?

Less Likely to be an Appropriate Candidate:

• High BNZ doses, alcohol, other CNS depressants• Significant psychiatric co-morbidity• Multiple addiction treatment episodes (+ -??)• Actively or chronic suicidal or homicidal ideation• Needs that cannot be addressed with existing office-

based resources or through referrals

• High daily doses of methadone ( 40mg+/day)

• Poor social support system—Cannot be living with IV opiate user . Cannot be employed by Business linked to drug use

How do you determine Dependence?

DSM-IV requirements:3 or more needed x 12 months– Tolerance– Withdrawal– Larger amt. longer period than intended – Any unsuccessful effort / persistent desire to cut down

/control substance use – A lot of time spent obtaining / recovering– Important social, occupational, or recreational

activities given up / reduced– Continuation despite consequences caused or

exacerbated by the substance

Narcotic / Alcohol Dependent

• Do CIWA and COWS scale

• Treat according to the CIWA/ETOH protocol

• This patient is NOT a candidate for suboxone

• This patient is a good candidate for NALTREXONE maintenance once they finish withdrawing from ETOH.

• They can be made comfortable with BZDs, clonidine, phenergan or zofran

The Narcotic/Alcohol Dependent

• Suboxone possible If – they contract to remain in residential treatment for

90 days– Their counselors confirm their investment in recovery– They have no underlying psych co-morbidity– Upon release they have a stable living situation – Upon release they remain in IOP– Upon release they have the finances to obtain

suboxone consistently.– They agree to be on a monitored ANTABUSE

PROGRAM

$$

Subutex: 2 mg: $14.49.

#30 $173.49

8mg: $20.99

#30 $317.49

CARRS—6/2010