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USING MEDICATIONS IN ADDICTION TREATMENT:

A Clinical Perspective

Marvin D. Seppala, MD Chief Medical Officer Hazelden Foundation

  Advances in Neurobiology of Addiction

  Recognition of Benefits

  Commitment to Our Clients

  Assisting Abstinence Long Enough for People to Get into Recovery

Drugs for Drug Addiction!? Prevalence of Alcohol Use

NIAAA=National Institute on Alcohol Abuse and Alcoholism. Grant BF et al (2004).

NIAAA – National Epidemiologic Survey on Alcohol and Related Conditions (NESARC)

  Medications used as an adjunct to psychosocial treatments

  Solid research basis established

  FDA approval and/or strong research basis and community standard for treatment of addiction

  Use of medications to address high risk periods in addiction treatment

  Do what’s best for addicts and alcoholics

  Do no harm

  Use of medications requires that the individual desires abstinence

Principles for Pharmacologic Interventions

  Research reveals shortcomings of medications used without other treatments

  Pharmaceutical industry recommends use only with other treatments

  Our goal should be to provide the best opportunity for lifelong recovery

  People need recovery, not just abstinence

Medications Alone Will Not Be of Much Benefit

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  Cortex: Judgment, Decision Making – Site for psychotherapy

  Mesolimbic System: Reward Center – Site for medications

Medications and Psychotherapy

  All rewarding activities cause an increase in dopamine in the brain’s reward center

  This increase signals the salience of the stimuli

  All drugs of abuse cause supraphysiologic increases in dopamine within the reward center

Dopamine and Addiction

© 2004 Terese Winslow Scientific American March 2004

  Psychosocial treatments help many alcoholics reduce their drinking or achieve abstinence. –  40% to 70% relapse within 1 year (Swift 1999)

  Neuroscientific advances suggest the possibility of developing medications to enhance the effectiveness of psychosocial treatments (Litten et al 1996).

  These medications target neurotransmitter systems that mediate alcohol reward and/or ameliorate neurochemical dysfunction in those with a biological predisposition to the disease.

Alcohol Dependence Treatment: Overview

  Disulfiram (Antabuse®)

  Naltrexone (oral, Vivitrol®)

  Acamprosate (Campral®)

FDA Approved Medications for Alcohol Dependence

Antabuse®; Florham Park, NJ: Odyssey Pharmaceuticals, Inc. Campral®; St. Louis, MO: Forest Pharmaceuticals, Inc. Vivitrol®; Cambridge, MA: Alkermes, Inc.

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Disulfiram Blocks Alcohol Metabolism:

Ethanol ↓ ← alcohol dehydrogenase Acetaldehyde ↓ ← aldehyde dehydrogenase (blocked

by disulfiram) Acetate (Acetyle co-enzyme A) ↓ Carbon Dioxide and water

Opioid (NMDA) Antagonists: Basic Science

FH+=positive family history. 1. Herz A (1997). 2. Swift RM (1999). 3. Boyle AE et al (1998). 4. Giannoulakis C et al (1996).

5. King AC et al (1997).

  Alcohol consumption affects the production, release, and activity of opioid peptides1

  Opioid peptides mediate some of alcohol’s rewarding effects by enhancing midbrain DA release

  Opioid antagonists suppress alcohol-induced reward2 and general consummatory behaviors3

  Genetic high-risk/FH+ individuals have an exaggerated alcohol-induced rise in β-endorphin level, and are more responsive to naltrexone treatment4,5

Embellished from Gianoulakis (1998).

Dopamine

β-endorphin pathways from the nucleus arcuatus

GABA

VTA NAC

  FDA approved for treatment of alcohol dependence in 1994

  Initial results were positive with evidence that fewer people on naltrexone drank and those that did, drank less

  More studies have been positive resulting in acceptance as an adjunctive treatment for alcohol dependence

  Compliance with medication is an ongoing problem, partially solved by Vivitrol, an IM injection that lasts a month

Naltrexone

  The patient is willing to take a medicine to help with alcohol dependence

  The patient is opioid free for 7-10 days

  The patient does not have severe or active liver or kidney problems (Typical guidelines suggest liver function tests no greater than 3 times the upper limits of normal, and bilirubin normal.)

  The patient is not allergic to naltrexone

  Daily dose: 50 mg

Naltrexone Use

  Nausea (10%)   Headache (7%)   Dizziness (4%)   Nervousness (4%)   Fatigue (4%)   Insomnia (3%)   Vomiting (3%)   Anxiety (2%)   Somnolence (2%)

Naltrexone Side Effects

  Improved medication adherence

  Decreased side effects

  Improved outcomes

Naltrexone IM (Vivitrol)

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  Injection site reactions (3%)

  Nausea (2%)

  Headache (1%)

  Suicide-related events (0.3%)

Vivitrol Side Effects Glutamate Antagonist: Acamprosate

  Excitatory neurotransmitter N-methyl-D-aspartate (NMDA) contributes to alcohol’s intoxicating, cognitive, and dependence-forming effects

  NMDA antagonist acamprosate reduces the intensity of post-cessation alcohol craving on exposure to high-risk drinking situations

Embellished from Spanagel and Zieglgansberger (1997).

Spanagel and Zieglgansberger (1997).

  Approved for treatment of alcohol dependence in 29 countries

  Approved for treatment of alcohol dependence in the U.S. in July 2004

  Increased continuous abstinence rates

  Decreased frequency of drinking and amount of alcohol once a relapse occurred

  No predictors of a response to acamprosate have been found, including anxiety, physiologic dependence, family history, late age of onset, and gender

Acamprosate

Johnson et al (2003a); Mason et al (2002)

Acamprosate – Clinical Science

  Diarrhea 10%   Insomnia 9%   Anxiety 8%   Depression 8%   Asthenia 7%   Anorexia 5%

Acamprosate Side Effects The Combine Study

Nine Groups Combined Behavioral Intervention—No Pills

Medical Management with Pills

Placebo Acamprosate Naltrexone Acamprosate

& Naltrexone

Combined Behavioral Interventions & Medical Management with Pills

Placebo Acamprosate Naltrexone Acamprosate

& Naltrexone

JAMA May 3, 2006; vol. 295; No. 17

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  Patients receiving medical management and: –  Combined Behavioral Intervention (CBI) –  Naltrexone –  CBI and Naltrexone

Had improvement in drinking outcomes.

  Acamprosate (with or without CBI / naltrexone) Had no improvement.

JAMA 2006

Project COMBINE

JAMA 2006

Project COMBINE

The Combine Study

“Nevertheless, our data suggests that Naltrexone can be effective within the

context of medical management without specialist behavioral treatment.”

JAMA May 3, 2006; Vol. 295; No. 17

  Used to prevent nausea and vomiting from cancer chemotherapy and after anesthesia

  Serotonin antagonist

  Defined effectiveness in a subgroup of alcoholics (early onset alcoholics – Type B like alcoholics)

  Resulted in less days drinking and an increased percentage of days abstinent

  Suggested tailoring pharmacologic treatments for certain groups

Ondansetron (Zofran)

  Topiramate is used to treat seizures

  Topiramate is a glutamate antagonist

  Topiramate is an effective treatment for alcohol dependence –  Reduces heavy drinking –  Promotes abstinence –  Decreases alcohol-related psychosocial consequences

(Johnson et al 2004)

Topiramate

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  371 pts at multiple sites received topiramate 50-300 mg/d (tapered upward) or placebo x 14 wks

  Topiramate pts had better drinking outcomes, beginning at 100 mg   Fewer heavy drinking days   Greater likelihood of abstinence

(Johnson et al 2007)

Topiramate

Clinical Decision Making

  Willingness and knowledge of primary care physician

  Stage of change and willingness of patient

  Severity and chronicity of alcohol use disorder (ASAM criteria)

  Psychosocial support available within family and community

  Prior treatment response

  Availability of psychosocial and behavioral treatments

  Adherence to treatment plan

Is the Primary Care Office Appropriate for Addiction Treatment?

  Watch for evidence of alcohol and drug use   Ask about alcohol and drug use   Consider blood and urine testing (alcohol and drug screens,

biologic indicators-transaminase level)   Evaluate adherence to medication and all aspects

of treatment plan   Monitor Alcoholics Anonymous or other group attendance   Involve other care givers   Evaluate for ongoing psychiatric illness   Evaluate other stressors   Monitor side effects   Provide support

Monitoring Pharmacotherapy for Alcohol Dependence

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  Neurotransmitters and receptors –  Acetylcholine –  Adenosine (A1, A2 receptors) –  Cannabinoid receptors –  Dopamine D1, D2, D3, D4 –  Gamma-aminobutyric acid (GABA-A, GABA-B receptors) –  Glutamate (NMDA, AMPA, kainate receptors) –  Glycine –  Norepinephrine (alpha, beta receptors) –  Opioid peptides (mu, delta, kappa receptors) –  Other peptides (vasopressin, neuropeptide Y) –  Serotonin (5-HT) (several receptors, particularly 5-HT3)

  Neurotransmitter transporters –  Adenosine, dopamine, 5-HT, norepinephrine

  Voltage-gated ion channels –  L-type, N-type calcium channels; sodium channels

  Second messengers –  G-proteins, phospholipases, protein kinases, neurosteroids, hormones

Adapted with courtesy of Anton & Swift (2003) and Litten et al (2005)

Neuropharmacological Targets for Treating Alcohol Dependence

  Medications are beginning to play an important role in the treatment of addiction

  Three medications have been approved by the FDA for the treatment of alcohol dependence—Antabuse, naltrexone, and acamprosate

  Pharmacologic interventions in combination with psychosocial treatments will help more people stay sober and enter into recovery

Pharmacologic Interventions Summary

Pharmacologic Interventions for Opioid Dependence

  Morphine in its natural form, obtained from poppy plants, has been used for over 8000 years

  Opium and opiate preparations widely available in U.S. with little control, throughout the 1800’s

  1804 - Morphine isolated (Morpheus-Greek god of dreams)   Mid 1800’s - Hypodermic syringe invented   1874 - Heroin synthesized   1898 - Heroin introduced by Bayer Company   1906 - Pure Food and Drug Act: Required accurate labeling of

patent medicines

History

  1909 - Importation of smoking opium outlawed in U.S.   1914 - Harrison Act: restricted importation of crude opium

to medicinal use   1919 - First Supreme Court decision forbidding physicians

prescription of opiates for the maintenance of addiction   1937 - Marijuana Tax Act   1970 - Drug Abuse Prevention and Control Act; established

Federal oversight   Late 1960’s, early 1970’s - Methadone maintenance initiated

History

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The Pharmacology of Opioids 1.  Opioid- an inclusive term for natural opiates and man-made

medications with morphine-like effects.

2.  Opium- derived from ‘juice’ of papaver somniferum

3.  Narcotic- great stupor; any drug which induces sleep

4.  Opiates- drugs derived from opium or thebaine with morphine-like effects.

Terminology

Terminology

Natural Semi-synthetic Synthetic

Morphine

Codeine

Thebaine

Papaverine

Heroin

Hydrocodone Oxycodone

Buprenorphine

Methadone

Demerol

Propoxyphene

Fentanyl

By 1970s Neurophysiologic Evidence:

  Analgesia produced by electrical stimulation of certain brain regions was reversed by Naloxone. (Akil 1972)

  Membrane associated opiate binding sites (receptors were demonstrated using radio ligand assays on brain tissue). (1973)

  Hughes et al (1975) identified an endogenous opiate.

Endogenous Opioid System

  Ligands: endorphins, enkephalins, dynorphins, endomorphins

  Receptors: mu, kappa, delta

  Agonist: binds to receptor and activates

  Partial Agonist: only partially activates

  Antagonist: binds to receptor and inhibits activation

Endogenous Opioids and Receptors

  Mu: supraspinal analgesia, respiratory depression, constipation, sedation, euphoria, miosis

  Kappa: spinal anesthesia, sedation, dysphoria, psychotomimetic

  Delta: unclear, analgesia

Opioid Receptors

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  Analgesia   Respiratory depression   Suppressed cough reflex   Decreased gastrointestinal activity-constipation   Nausea/emesis   Miosis

Effects of Opioids

  Peripheral vasodilation-hypotension   Increased sphincter tone   Urinary retention   Perspiration   Histamine release: pruritis & hypotension   Convulsions: meperidine and propoxyphene in high dose

Effects of Opioids

  Drowsiness/sedation   Euphoria   Mood changes   Mental clouding   Decreased libido   Psychotomimesis (kappa)

Effects of Opioids

  Mu receptor activation by agonist in ventral tegmental area

  Inhibition of GABA neurons results in disinhibition   Activation of dopamine neurons extending to nucleus

accumbens

Mechanism of Action

© 2004 Terese Winslow Scientific American March 2004

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  Diacetyl morphine   Rapid onset of action and T ½ ~ 3 min (I.V.)   I.V., I.M., and intranasal use ( purity)   Lipid soluble, lacks intrinsic opioid activity   Metabolized to monoacetylmorphine (T1/2 ~ 1 hour) and to

morphine   Not available for medicinal use in U.S.

Heroin

  2 – 3 times as potent as morphine in terms of behavioral and physiologic effect

  Heroin and morphine have limited oral bioavailability   Intranasal use produces peak blood level in 5 min

(comparable to I.M.) but half the potency of I.V.

Heroin

  Largely selective for mu opioid receptor   Morphine metabolized mostly by the liver   Oral is 1/3 as potent as I.V.   T ½ 2-4 hrs   Prolonged elimination (T ½) with cirrhosis   90% of morphine excreted in the urine/24hr.   Caution with renal disease (unlike methadone)   Aging effects morphine pharmacokinetics

Morphine

  Synthesized in 1930’s for chronic pain   Long T ½ (20-40 hrs)   Peak plasma levels achieved at 2-4 hours and maintained

over 24 hours   Stored and accumulated in liver; slow release   Metabolized by the liver; slowed in liver disease   Long T ½ can result in dangerous accumulation when

initiated, with resulting respiratory depression and death

Methadone

  Introduced in 1995   Controlled release form of oxycodone; for chronic pain   OxyContin has a much larger amount of opioid than

other available oral medications   Initially described as “less addicting” due to slow release

mechanism.   By 2000 it was the 18th best selling medication and the

#1 opioid pain relieving medicine in the U.S.   Schedule II

OxyContin

  Designed to provide controlled delivery over 12 hours   Pain relief begins within one hour   Tablets can be manipulated (crushed) to eliminate the

controlled release mechanism resulting in a rapid opioid intoxication

  Expensive street drug: 50¢ to $1.00 per mg (comes in 10, 15, 20, 40, 80, 160 mg tablets)

  New forms that are “abuse resistant” are being developed

OxyContin

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  5 mg Hydrocodone and 500 mg Acetaminophen (Tylenol)   Maximum blood levels reached in 1.3 hours   T ½ ~3.8 hours   Commonly prescribed for acute and chronic pain   Referenced in popular media   Common drug of abuse among physicians   Schedule III

Vicodin

Solutions

  Chronic opioid addiction affects ~ 1 million people in the U.S.

  Less than 25% seek treatment   Most treatment is with methadone   Continued attempts to offer alternative maintenance

treatments resulted in investigation into the use of Buprenorphine

Solutions

  Limited to the treatment of opioid addiction   Use medications within the same class as the addicting

drug to: –  Prevent intoxication/euphoria –  Prevent craving, withdrawal and protracted abstinence

syndrome –  Prevent illicit use/relapse

Maintenance Therapies

  Very effective in: –  Eliminating use of heroin –  Reducing psychosocial and legal problems –  Reducing medical problems (Hep C, HIV…)

Methadone Maintenance Therapy

  Remarkable regulatory requirements inhibit availability of methadone

  Significant stigma remains associated with methadone maintenance

  Very difficult treatment system; daily visits for months to years

Methadone Maintenance Therapy

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  A long acting opioid antagonist   Reinforcing properties of opioids are blocked   Poor treatment retention rates (20-30% over six months)   Effective as adjunctive treatment for health care

professionals, also shown to be helpful for business executives and probation referrals.

  Studies underway using Vivitrol

Naltrexone

  Available as an injectable pain medication since the early 1980’s

  Semi-synthetic opioid   Partial agonist/mixed agonist-antagonist   Ceiling effect   25-40 times more potent than morphine   ½ life 24-60 hours   High affinity for mu receptors   Absorption: Oral intake - poor

Sublingual - moderate   Equivalent to moderate doses of methadone

Buprenorphine

  Allowed for qualified physicians to prescribe certain narcotics in their offices for the maintenance treatment of opiate addiction

  DEA approval of Buprenorphine in the form of Subutex and Suboxone occurred in October, 2002

  Subutex and Suboxone were made available in U.S. pharmacies in January 2003

Drug Addiction Treatment Act of 2000

  Safe and effective   Convenient: by prescription   Privacy: obtained in a doctor’s office

Buprenorphine Summary

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  Higher cost then methadone   Lower dose equivalent compared to methadone,

therefore not as effective for those with high opioid tolerance

  MD’s are currently limited to 100 clients

Buprenorphine

  Low toxicity, even at high doses   Very low risk of overdose   Relatively quick detox (5-12 days)   Long duration of action   More comfort than other methods   Higher retention rates

Advantages for Detoxification with Buprenorphine

  Assessment   Outpatient Addiction treatment   Length of treatment   Recovery issues   Problems with detoxification

Buprenorphine Maintenance

  Vaccines   Pharmacogenetic Treatments   Rimonabant

What’s New

  Nicotine   Cocaine

Vaccines

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  Heroin use has slowly increased since the mid 1990’s   Prescribed opioids are more commonly abused than

heroin   We may be witnessing another opioid epidemic in the

U.S.   Although treatment options are the same for heroin and

prescribed opioids, research has yet to distinguish which treatment is best for whom

  Buprenorphine maintenance is effective and has provided an important treatment option

Summary