Download Medication Assisted Treatment Why Treat Addiction with Medication?

James J. Nocon, M.D., J.D.
I have no commercial
interests to disclose.
Other than my USC Rugby
Jersey.
And, the HS team I coach,
North Central, won the
Indiana State HS Rugby
Championship.
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Understand Addiction Theory, Opioid
Pathophysiology and Pharmacology
Define treatment success:
 Remission, recovery, cure.
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Compare abstinence approach to MAT.
Consider duration of MAT
Dealing with Diversion
Future Challenges
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“The vast majority of people in need of addiction treatment
do not receive anything that approximates evidence-based
care.”
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http://www.centeronaddiction.org/addiction-research/reports/addictionmedicine
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No experimental studies unequivocally demonstrated the
effectiveness of AA or [12-step] approaches for reducing
alcohol dependence or problems.
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http://www.theatlantic.com/magazine/archive/2015/04/theirrationality-of-alcoholics-anonymous/386255/
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Common Sense dictates that there is no “one size fits all” effective
treatment for addiction.
1800-2000
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Cocaine – the 7% solution
Cannabis (THC)
Laudanum – tincture of opium;
Morphine – from the Civil War
Methadone – developed in Nazi
Germany prior to WWII
Alcohol –how the West was won
Amphetamine -1887; used
extensively in WWII, Korea, Viet
Nam, Iraq to keep soldiers alert;
Methamphetamine -1893
Methylenedioxymethamphetamine (MDMA)
Developed by Merck in 1912 as
an appetite suppressant; today
it’s called ecstasy
2002-2007
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Cocaine
52
Cocaine and THC 59
THC
49
Methadone
42
Other Opiates
27
Alcohol
10
Other Combinations 48
(opiates/amphetamines)
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Based on 287 consecutive
pregnant patients treated from
2002 to 2007.
1784: Dr. Benjamin Rush's Inquiry into the Effects of Ardent
Spirits on the Human Mind and Body, catalogues the
consequence of chronic drunkenness and argues that this
condition is a disease that physicians should be treating.
2000: Drs. McLellan, Lewis, O'Brien, and Kleber call for the
re-conceptualization and treatment of addiction as a
chronic relapsing medical illness.
McLellen AT, Lewis DC, O’Brien CP, Kleber HD. Drug dependence, a
chronic medical illness: implications for treatment, insurance and
outcomes evaluation. JAMA 2000;284:1689-1695.
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1879: Dr. Leslie Keeley opens more than 120
Keeley Institutes across the U.S,
 Franchised, private, for-profit addiction treatment
institutes/sanatoria.
 Keeley’s treatment included “elixirs” containing
alcohol and marijuana among other substances.
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Freud and many physicians advocate cocaine
in the treatment of alcoholism and morphine
addiction.
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1950: Disulferam
1972: Methadone approved by FDA
1996: Buprenorphine approved in France for
opioid treatment
2002: Buprenorphine approved in US
2004-5: Buprenorphine and
buprenorphine/naloxone available in US.
Others - Naltrexone
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Addiction is a relationship to a substance or
a process, which is mind altering, used to
excess and has life-damaging
consequences.
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Note the definition refers to a substance or
process.
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Or both.
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Substance Addictions:
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Process Addictions:
 Alcohol
 Love
 Recreational Drugs
 Sex
 Prescription Drugs
 Romance
 Caffeine,
 Relationship
 Nicotine
 Co-dependence
 Foods (especially sugar)
 Work
 Even decaffeinated
 Gambling
coffee!
 Spending
 Geographic fix
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What alters the mind is the release of the
neurotransmitter DOPAMINE in the brain in
response to the substance or process.
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Dopamine creates the “BUZZ”
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This occurs in the “reward center” of the brain
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The depletion of Dopamine has even more
profound effects – systemic withdrawal.
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Ventral Tegmental Area
(VTA)
 Nucleus Accumbens –
dopamine rich center in the
limbic area: the buzz
 Prefrontal Cortex – short
term memory: “what was I
going to do?”
 Amygdala – moderates
emotional influences on
memory & fear response
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These are the primary centers
involved in pleasurable
sensations.
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Nicotine activates the nucleus accumbens: releases
dopamine – you get a mild buzz; dopamine is depleted.
Antidepressants that are dopamine reuptake inhibitors
are effective in stabilizing dopamine levels
 Blocking or blunting the effect of nicotine,
 Decreasing the cravings, and
 Enhancing smoking cessation.
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Similar antidepressants have also been used in
methamphetamine treatment with good results.
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Elkashef AM, et al. Bupropion for the Treatment of Methamphetamine Dependence.
Neuropsychopharmacology 2007, 1-9.
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Tolerance: Increased dosage and/or increased frequency
to get the same effect.
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Withdrawal: The onset of a predictable constellation of
signs and symptoms after the abrupt discontinuation of
or a rapid decrease in dosage of a psychoactive
substance.
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Dependence: removal of the substance or behavior will
have some degree of withdrawal.
 Physical
 Psychological
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Great question. Like obscenity, hard to
define but, “I know it when I see it.”
Empirical definition:
 “There comes a point when the affected
person becomes an addict, as if a switch in
the brain is flipped, and the person no longer
has the ability to make free choices about the
continued use of the drug.” (or process)
 Leshner AI. Addiction is a brain disease, and it matters. Science
1997;278:45-47
All those addicted to
alcohol, tobacco and
other drugs are
dependent on those
drugs.
 BUT, not all those
dependent on such
substances are
addicted.
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Entitlement/Despair: I’m
entitled to feel good, or
things are horrible and I
need something to help
me feel good.
Despair: the effect
wears off
Preparation: obsessing
on how to feel good;
what to use or do.
Acting out: Using or
doing, or both.
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Alcohol Metabolism: alcohol dehydrogenase
Impulsivity Disorders: ADHD
Low Level of Response
Independent Psychiatric Disorders
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Bipolar
Panic Disorder
Schizophrenia
Social Phobia
Depression
Module 1 draft
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Bind to receptors
 Mu: analgesia; euphoria, respiratory depression,
constipation, sedation, miosis
 Kappa: dysphoria, sedation, psychotomimetic
 Delta: unknown
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Rate of Excretion faster than withdrawal
 Morphine excreted within 72 hours
 Methadone takes 4-5 days.
 Clinical relevance is patient in withdrawal may have negative
UDS.
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Withdrawal in Adult: 6-24 hours from last dose
 Morphine: 3-7 days duration
 Methadone: 10-20 days or more
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Morphine/Codeine/Dilaudid and
Derivatives
 Metabolized by liver
 ½ life 2-4 hours
 90% excreted in urine/24 hrs
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Methadone
 90% bound to protein
 ½ life 20-40 hours
 Slow release into blood
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Naloxone - Narcan
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Very strong affinity for Mu receptor
Rapid competitive antagonist – 2-4 minutes
Lasts about 45 minutes
“Jump starts” withdrawal
Naltrexone - Vivitrol
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Binds more slowly
½ life 4 hours
Used in alcohol and opiate treatment.
Blocks effects and dampens cravings.
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Nalbuphine (Nubain)
 10 mg. IV or IM q. 3 hours ; onset 2-3 min IV
 Neonatal half life: 4.1 hours
 A favorite of OB nurses – less nausea
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Butorphanol (Stadol)
 1-2 mg. IV or IM every 4 h; onset 1-2 min IV
 Neonatal half life unknown
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Buprenorphine (Subutex/Suboxone)
 Long acting; long half life - up to 36-48 hours
 Potent agonist
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Buprenorphine
 A partial agonist at mu and kappa opioid
receptors – potent analgesia
 Antagonist at delta receptors: “ceiling” effects.
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Buprenorphine/naloxone: Naloxone is a
potent antagonist at mu-opioid receptors.
Metabolized and eliminated in urine and
feces.
Replacing methadone as drug of choice for
managing opioid addiction.
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But first, a review of the manner in which
addiction, to either a substance or process,
alters the brain and neural pathways.
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And most importantly, the role of adult brain
stem cells in repairing the damage.
It’s all in your head !!!
Well, most of it is
Addiction is a “double whammy.”
1.
Tolerance - The brain needs
more and more of the drug in
order to get the same effect.
And in this process, the brain
cells are actually altered.
2.
Drugs reduce fear response
in Amygdala and Prefrontal
cortex – person uses more
drug with less fear of
consequences.
McCann UD, Szabo Z, Scheffel U,
Dannals RF, Ricaurte GA. Positron
emission tomographic evidence of toxic
effect of MDMA ("Ecstasy") on brain
serotonin neurons in human beings.
Lancet 1998 Oct 31;352(9138):1433-7.
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Loss of neurons, e.g., ETOH toxicity
Alteration in structure and function
Neurotransmitters depleted (dopamine)
Signaling pathways disrupted (neural
circuitry) – results in abnormal behaviors.
DNA transcriptions – making new proteins
diminished or inhibited.
Permanent defects in cellular regulation
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Repeated drug use and behaviors deplete
dopamine and serotonin and norepinephrine.
Neurons and axons contract.
Circuitry shrinks
Brain gets smaller
Stereotypical behaviors emerge.
Liu X, Matochik JA, Cadet J-L, and London ED. Smaller volume of
prefrontal lobe in polysubstance users; a magnetic resonance imaging
study. Neuropsychopharmacology; 18:243-252. 1998
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The physical alterations of addiction show
commonly observed changes in cognitive
thinking, behavior and emotions, typically:
 Denial and Lying (even when they don’t need to)
 Reduced fear of consequences
 Grandiosity
 Withdrawal and Isolation
 Responsibilities slip; loss of interest job, hobbies, etc.
 Marked changes in daily habits.
Adult brain stem cells can generate new cells:
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Neurons, astrocytes and oilgodendrocytes.
Most adult stem cells in the brain are in the exact
area directly affected by substances and processes.
 (this is not a coincidence – DNA is programmed to do this)
 They “migrate” to repair damaged areas and circuitry.
 They do better when the addiction is no longer active, that
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is, when the offending stimulus is removed.
This data is 25 years old.
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http://stemcells.nih.gov/info/basics/pages/basics4.aspx
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Three critical factors stimulate adult stem cells
to repair and rebuild neuro-circuitry:
1. Nutrition and exercise:
Note: Exercise increases serotonin, dopamine and
norepinephrine release in the brain and can be an
addictive process.
2. Folic acid (prevents CNS defects in fetus)
3. Reading is critical to rebuilding new circuitry.
AA says to read the “Big Book,” over and over.
Stem cell repair in the brain is a slow process
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It takes 8-12 months for stem cells to make “effective”
repairs.
Repairs may take years to decades and is continuous.
Therefore, treatment may take years to decades.
Relapse:
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Return of the manifestations of a disease after an interval
of apparent cessation.
Clinical relevance:
Relapse in the first 3 months is high in abstinence
based treatment – up to 90%
Relapse after 9 months is less than 10%.
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Based on removing the offending stimulus
 The degree of damage; Etoh destr0ys neurons
 Nutrition: folic acid
 The ability of the body to heal; stem cells
▪ Immune competence; genetics
▪ Other diseases: hypertension, diabetes.
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Co-morbid psychiatric disorders.
Luck (no kidding).
And many other factors: social, cultural,
spiritual, gender, etc.
All of the above is the “short list.”
Complete remission: undetectable disease
Partial Remission: still detectable but much less
effect, aka: “controlled” or “stable” remissions.
 Partial response: a remission where disease, e.g.
cancer, is 50% less for at least 1 month.
 Relapsing-remitting: sometimes worse,
sometimes better – this best describes
addiction.
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A remission is NOT a Cure.
Generally: RELAPSE is the return of the
manifestations of a disease after an interval of
apparent cessation.
 Remission has little meaning in addiction, which is a
chronic relapsing disease.
 Clinical relevance:
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30 y/o “oxy” withdrawal triggers psychotic episode
Bipolar – on meds – chronic pain improves, stops opioids
Is this remission?
1 year – stops bipolar meds
1 mo dies of heroin overdose – relapse?
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Distress - most common cause of relapse.
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Three choices for distress
 Talk to peers – call the sponsor!
 Deep Relaxation - prayer and meditation (12
Steps; yoga)
 Exercise (as effective as antidepressants in
mild to moderate depression)
 Brosse, et al. Sports Med 2002:32;741-760
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Addiction recovery requires, at the least:
 Abstinence – remove or reduce the offending substance or
process
 A change in behavior.
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Cognitive behavioral therapy and Motivational
Intervention are two successful approaches, which
support abstinence and behavioral change.
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What is a cure?
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https://www.drugabuse.gov/publications/drugfacts/treatmentapproaches-drug-addiction
Many addicts “in recovery” believe they will always be
in recovery.
 AA Big Book says, “we shall be recovered.”
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Like most issues, there is little evidence to support
“cure” in addiction.
 What would “cure” mean in a chronic relapsing
disease?
 A remission of relapses?
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And there are many who have “cured” their Type 2
Diabetes with changes in dietary habits and behavior.
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Availability of medication is the most
significant factor in treatment success.
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A study of heroin-overdose deaths in Baltimore
between 1995 and 2009 found an association
between the increasing availability of
methadone and buprenorphine and an
approximately 50% decrease in the number of
fatal overdoses.
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Schwartz RP, Gryczynski J, O'Grady KE, et al. Opioid agonist
treatments and heroin overdose deaths in Baltimore, Maryland,
1995-2009. Am J Public Health 2013;103:917-922
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States with medical cannabis laws had a 24.8% lower mean annual
opioid overdose mortality rate (95% CI, −37.5% to −9.5%; P = .003)
compared with states without medical cannabis laws.
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Examination of the association between medical cannabis laws and
opioid analgesic overdose mortality in each year after implementation of
the law showed that such laws were associated with a lower rate of
overdose mortality that (generally strengthened over time. (50%
reduction by 2010)
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Note: 25 States plus D.C consider marijuana a medicine
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Bachhuber MA; Saloner B, Cunningham CO, Barry CL. Medical Canabis Laws and
Opioid Analgesic Overdose Mortality in the US, 1999-2010.JAMA Intern
Med. 2014;174(10):1668-1673
40 patients (heroin addicts) randomized in
double blind study to buprenorphine or placebo
group for one year
 Buprenorphine dose was 16 mg daily
 All received behavioral therapy and individual
sessions for relapse prevention.
 Retention after 1 year
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 Buprenorphine
 Placebo
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75%
0%
Kakko, et al. Lancet 2003; 361: 662–68
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Patients who received placebo generally reported a massive
heroin craving that was triggered during sessions of relapseprevention, when trigger stimuli were discussed.
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This effect might have contributed to the decision to
discontinue treatment.
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In contrast, patients receiving active treatment did not
report excessive craving, and found the relapse-prevention
sessions useful for development of coping skills.
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Opioid substitution with buprenorphine can act as a
powerful reinforcer to treatment retention.
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The only other published randomized controlled trial
with buprenorphine lasting 1 year was a US trial which
obtained a 20% retention rate.
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The different retention rates could in part be an effect
of the buprenorphine dose: 16 mg in the Swedish trial
and 8 mg in the US study.
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Ling W, Wesson DR, Charuvastra C, Klett CJ. A controlled trialcomparing
buprenorphine and methadone maintenance in opioid dependence. Arch
Gen Psychiatry 1996; 53: 401–07.
Opioid Only (31) Opioid/Illicit Drugs (45)
Preterm Delivery:
LBW (<2500g):
Mean Birth Weight
Positive Meconium
NAS Treated
Mean Length of Stay
Failed to return PP
PP “negative”
4 (12.9%)
3
3085 g
0
1
3.3
3
23 (74.2%)
8 (17.7%)
8
2879g
12 (26.6%)
5
7.8
13
25 (55.5%)
p
NS
NS
NS
0.001
NS
0.01
0.01
NS
Incidence of NAS treated in all opioid dependent patients in Prenatal
Recovery Clinic: 6/76 or 7.8%
Preterm Delivery
LBW(<2500g)
Mean Birth Weight
NAS
NAS Treated
Mean Length of Stay
Failed to return PP
PP “negative”
Bup. (46)
Meth (90)
p
5 (10.9 %)
4
3079 g
8
6 (13%)
6.78 days
13 (28.8%)
29 (65.1%)
27 (30%)
26
2718g
89
80 (89%)
30.3 days
28 (31.1%)
59 (65.5%)
0.001
0.01
0.005
0.001
0.001
0.001
NS
NS
See also, Kakko J, Heilig M, Sarman I. Buprenorphine and methadone
treatment of opiate dependence during pregnancy: comparison of fetal
growth and neonatal outcomes in two consecutive case series. Drug
Alcohol Depend 2008 Jul 1;96(1-2):69-78.
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Study compares the health care expenditures between two groups with
opioid addiction:
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those receiving MAT (“MAT group”), specifically methadone or
buprenorphine,
 and those receiving non-medication treatment approaches ,such as
behavioral therapies alone (“non-MAT group”)
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The results indicated that the overall difference in annual average
expenditures was lower for the MAT group, even with the cost of MAT,
but not significantly lower.
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However, when opioid addiction treatment costs were removed, the
MAT group had substantial and statistically significant lower health care
costs overall compared to the non-MAT group.
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Reduction in cost was due, in part, to lower inpatient admissions and
outpatient hospital emergency department visits.
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Few studies of untreated mortality in heroin users:
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Kakko: heroin 20%; Buprenorphine 0%
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A larger Swedish study”
 Untreated 7.2%
 Methadone 1.4%
 Gronbladh L, Ohlund LS, Gunne L-M. Mortality in heroin treatment:
impact of methadone treatment. Acta Psychiat Scand 1990; 82: 223–27.
Indiana: MAT OB patients (4/600) 0.67%
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3 methadone
1 buprenorphine
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This simple fact has drastically changed the
“abstinence only” treatment community.
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Most have accepted a “both/and” approach.
Hazeldon shifted in 2012 to include MAT
 There are still some holdouts, e.g., the AbstinenceBased Treatment Alliance.
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https://www.yahoo.com/news/abstinence-v--medication-traditional-12-step-programs-embrace-new-treatment202359290.html?ref=gs
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Data: it takes at least 8-12 months for
damaged neurons and circuitry to be repaired
Once stabilized, evidence clearly reveals
best outcomes if medications continue at
the maintenance dose for at least one year.
Relapse, after one year is low.
It is reasonable to consider lowering the dose
 Very, very gradually over a long time (“2 mg wall”)
 Every 2 years? 5Years?
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Like diabetes, hypertension and asthma,
addiction is a chronic relapsing disease.
There is no real evidence to support the
notion that MAT:
 Must be limited to a specific length of time.
 Must be tapered for patients to wean off.
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Thus, medication assisted treatment is best
tailored to the patient for as long as it works.
Because it saves lives.
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The Standard: what is expected of the
average competent physician in like or similar
circumstances.
MAT save lives.
Given the above:
 The failure to offer MAT to an opioid dependent
patient is both unethical and a deviation from the
standard of care.
 It’s only a matter of time…
“Uh, someone broke into my car and stole my
prescription”
 Or, “Can I get an early refill?”
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"'Drug diversion' is best defined as the diversion of
licit drugs for illicit purposes.
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The diversion of drugs from legal and medically
necessary uses towards uses that are illegal and
typically not medically authorized or necessary.
"Drug Diversion in the Medicaid Program: State Strategies for Reducing
Prescription Drug Diversion in Medicaid," Centers for Medicare & Medicaid
Services (Baltimore, MD: January 2012), p. 1.
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Major cause is lack of access to
buprenorphine treatment in the community
Areas with least access - most diversion.
Health Insurance : Payer Policies
 Receive only a certain number of months of
buprenorphine treatment for a lifetime disease.
 Payer may require a tapering of the dose, which
we don’t do for other chronic diseases.
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Spouses, Partners, Loved Ones
Hated Ones; Feared Ones
Family & Friends
To anyone who pays.
Buprenorphine diversion is lowest among all
prescription opioids.
Stable since 2007 and follows trend of other
opioids.
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Treatment Agreement
Recovery Plan (Stages of Change)
Quantitative urine screen specific for
buprenorphine products
State Prescription Monitoring Program
Attitude (yours) is critical
Do you “fire” offenders?
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Excellent ASAM treatment guideline for MAT in
opioid treatment promotes high standards of care.
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Physical exam required for opioid treatment.
 Many with buprenorphine waivers are
psychiatrists – practice where PE cannot readily
be performed.
 Need flexibility to allow PE after admission and
induction.
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ASAM guideline asserts doing a multidimensional
assessment prior to starting treatment.
 Many practices do not have time or personnel to do this
 No evidence reveals such assessments lead to a better
outcome.
 No evidence indicates better outcomes when behavioral
health providers are involved in treatment planning.

Flexible approach is to acknowledge the many
perspectives for psychosocial support.
 (Saxon and Mc Cance-Katz)
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ASAM summary guideline recommends, when
inducting patients onto methadone, dose should
not be raised more frequently than 7 days.
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Clinical Reality:
 Most reach steady state in 4-5 days
 If properly evaluated at 3-4 hours after dose,
 Can have dosage safely increased in that interval.
 Saxon and McCance-Katz
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“Addiction should be considered a bio-psychosocial-spiritual illness…where medication is only
one component.”
 ASAM summary guideline, opioid treatment
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“Unequivocal evidence shows for opioid use
disorder, MAT is overwhelmingly the
essential component, not merely one
component.” Saxon and McCance-Katz
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Addiction is a chronic relapsing disease.
MAT saves lives.
Treatment may last indefinitely.
Buprenorphine/naloxone is the MAT of choice
for opioid addiction.
A positive attitude and the ability to “roll with
the resistance” are the hallmarks of
successful addiction treatment.
So is a good sense of humor.
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When things become so serious and so sacred
that we can't laugh about them anymore, it
means that we have elevated the profane to
the realm of the sacred and misplaced the
sacred in the process.
 Anonymous M.D. in a 12 Step Recovery Group for Men, 1997
Module 1 draft
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