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