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PHARMACOTHERAPY IN ALCOHOL AND OPIOID USE DISORDERS
DOMENIC A CIRAULO MD
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MEDICATION INTEGRATED TREATMENT OF ALCOHOLISM
SEE TIPS #49 Download from
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EVERYTHING OLD IS NEW AGAIN (SORT OF)
• SELF MEDICATION HYPOTHESIS • TENSION REDUCTION HYPOTHESIS • STRESS, COMORBIDITY, GENETICS, ENVIRONMENT,
NEUROPLASTIC CHANGES, REPEATED EPISODES OF DRINKING, RELAPSE, SENSITVITY, KINDLING, AND ALLSOSTATIC LOAD
• SLEEP STRUCTURE CHANGES (Knapp, Ciraulo, Datta 2014) • CIRCADIAN ALTERATIONS (for review see Oldham and Ciraulo
2014), Clock. Per2 genes (Ozburn et al 2013, Huang et al 2010, and other labs)
• PRODUCTION OF AN “ALCOHOLIC BRAIN” – See Breese, Sinha, and Heilig 2011, Alcohol kindling see
Ballenger and Post 1978, Self-Medication Khantzian1970s through 2014 3
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ALLOSTATIC LOAD
• Stress induces (increased) SNS (decreased) PNS imbalance (HRV)
• Altered neurotransmitter balance, with primary decline in GABA
• Increased HPA stress and alterations in several pathways and neuroreceptors (E.G., SEROTONIN, NE)
• Biological, psychological, and ancient healing practices (e.g., yoga)produce brain neuromodulatory changes that counteract stress and depression (MRS GABA INCREASES, See Streeter et al)
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BRAIN STRESS SYSTEMS (Koob 2013)
• STRESS SYSTEMS – GLUCOCORTICOID SYSTEM, INCLUDING
CORTICOTROPIN RELEASING HORMONE – NOREPINEPHRINE – DYNORPHIN (MAY BE CRH MEDIATED)
• OPPOSITIONAL SYSTEMS TO STRESS SYSTEMS – Neuropeptide Y – Nociceptin – Endocannabinoids – Oxytocin??
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BRAIN REWARD PATHWAYS
• Complex brain circuitry underlies the rewarding properties of abused drugs
• As allostatic load (stress) increases, the reward pathway becomes less active (there is a new higher set point) while negative emotional areas of brain have lower set points
• Koob has called this “the dark side” when drinking for pleasurable effects changes to drinking to ward off neuroplastic changes that have produced negative affect
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STRESS, ANXIETY, HPA AXIS, DEPRESSION AND ALCOHOLISM
• RELATIONSHIP COMPLEX • ACUTE STRESS ACTIVATES HPA WITH RELEASE OF CRF,
ACTH, CORTISOL • CHRONIC STRESS ADAPTIVE CHANGES OCCUR • FEEDBACK INHIBITION OF GLUCOCORTICOID RECEPTORS
DOWNREGULATE CRH RELEASE IN HYPOTHALAMUS BUT NOT IN CENTRAL AMYGDALA, CRH CONTINUES TO DRIVE ETOH CONSUMPTION. MEDIAL PFC ALSO INVOLVED
• DOWNREGULATION OF POSTSYNAPTIC NE RECEPTORS AND UPREGULATION OF INHIBITORY AUTORECEPTORS AND HETERORECEPTORS ON PRESYNAPTIC NE NEURONS
• HIPPOCAMPAL SIGNS OF OXIDATIVE STRESS, INFLAMMATION CELL DEATH
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HPA, STRESS, CRH
• HPA IS PRIMARY NEUROENDOCRINE STRUCTURE MEDIATING STRESS RESPONSE
• CRH (ALSO CALLED CRF) IS PRODUCED IN THE PVN OF THE HYPOTHALAMUS AND AMYGDALA
• CRH ACTS ON CRF-1 AND CRF-2 RECEPTORS IN CNS AND ANTERIOR PITUITARY
• VASOPRESSIN 1B ANTAGONISTS MAY HAVE THERAPEUTIC EFFECT IN STRESS BY ACTIONS AT AMYGDALA, ACTING ALONE OR IN CONJUNCTION WITH CRH
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THE ROLES OF CRF 1 AND 2
• CRF-1 MEDIATES ANXIETY, DEPRESSION, AND STRESS RESPONSE
• ROLE OF CRF-2 IS NOT FULLY ELUCIDATED. SOME BELIEVE IT a) COUNTERACTS ROLE OF CRF-1 OR b) CRF-2 IS ACTIVATED BY INESCAPABLE STRESSORS WHILE CRF-1 IS ACTIVATED BY ESCAPABLE STRESSORS
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DOWNSTREAM EFFECTS
• CRF IS A MAJOR REGULATOR OF BASAL AND STRESS INDUCED POMC AND POMC-INDUCED PEPTIDES (BETA ENDORPHIN AND ACTH) FROM ANTERIOR PITUITARY
• ACTH ACTS ON ADRENAL CORTEX TO PROMOTE SYNTHESIS AND RELEASE OF CORTISOL AND OTHER GLUCOCORTICOIDS
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BIOLOGICAL CHANGES FROM ALCOHOL
• TWO LEADING GROUPS INFLUENCED RESEARCH AGENDA – Ballenger and Post lab developed kindling hypothesis
which explained increased severity of alcohol withdrawal symptoms over repeated bouts of intoxication and abstinence
– Koob laboratory proposed that prolonged excessive alcohol intake led to allostatic changes
– The two concepts are related---a negative state results from chronic drinking and withdrawal. Negative emotion results and leads to “relief drinking”
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Caveats About Treatment
• Addiction treatment is not one size fits all. There are many options—use them
• Compliance with treatment is important. Continually support treatment
• Treatment is not a “carve out” available only in select settings
• While abstinence is often the goal, it is not the only goal
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SPECIFIC MEDICATIONS USED TREAT ALCOHOLISM: RELAPSE PREVENTION
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FDA approved medication for alcohol dependence treatment
• Disulfiram • Oral naltrexone • Acamprosate • Extended release Naltrexone
• ANY OTHER MEDICATIONS DISCUSSED IN THIS
PRESENTATION ARE NOT APPROVED BY THE US FDA FOR THE TREATMENT OF ALCOHOLISM
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SOME CLINICAL APPLICATIONS
• Alcohol Dependence – Naltrexone – Acamprosate – Ondansetron – Disulfiram – Anticonvulsants: gabapentin, topiramate,
zonisamide, carbamazepine – Orexin antagonists – Atypical Antipsychotics – Medications for comorbidity
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DISULFIRAM Interferes with metabolism of ethanol by inhibiting acetaldehyde dehydrogenase
Acetaldehyde accumulates and causes increased heart rate and blood pressure, chills, nausea, vomiting. Severe cases result in hypotension, myocardial infarction, and stroke. Death can occur.
Disulfiram is considered an “alcohol deterrent” or “aversive” treatment----it reduces drinking because people fear the reaction
Most effective when used in a contract with family member
Monitor for hepatic toxicity
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DISULFIRAM
• Inhibits acetaldehyde dehydrogenase to cause aversive response to alcohol
• NEW FINDINGS: – Reduces craving by inhibiting dopamine beta
hydroxylase thus interfering with metabolism of dopamine to NE
– Its major metabolite is an NMDA ANTAGONIST
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Disulfiram and Behavioral Treatment
• The effectiveness of disulfiram increases with behavioral treatment
• A therapeutic contract with person who would be substantially and negatively affected by resumption of drinking, e.g. spouse, family member) is the most effective
• Person should observe patient taking medication and have contact with therapist/prescriber
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Naltrexone long-acting injection in Alcohol Dependent Adults: Efficacy and Tolerability
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NALTREXONE AND ALCOHOLISM
• The largest, best designed studies demonstrate naltrexone is effective and safe
• Most information is for 12 week efficacy, and when medication is stopped, relapse likely
• An important exception is the multisite study in the VA that did not show efficacy (Krystal et al NEJM)
• We still do not know the predictors of good outcome, but FHP, CRAVING, GENETICS OF MU RECEPTOR have support in studies
• Medication Adherence critical
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NTX PREDICTORS OF RESPONSE
• CUE REACTIVITY AND fMRI in ventral striatum pre-treatment predicted response to NTX (Mann et al 2014)
• OPRM1 A118G genotype, better outcomes in in G-allele carriers than homozygous A-allele carriers (Oslin et al 2003, Heilig et al 2011)
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The Product
– Sophisticated, easy-to-use product
– Specially designed diluent for tolerability and ease of administration
Dry Powder Microspheres Diluent
Microsphere Suspension
Hypodermic Needle
IM
Once Monthly Dosing
+
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Summary of Depot NTX
Pharmacokinetics • Therapeutic concentrations reached with
first injection (therapeutic effects within 2 days Ciraulo et al 2008)
• Extended and sustained naltrexone concentrations for one month – Repeat dose concentration-time profile
similar to single dose – No accumulation of naltrexone or 6β-naltrexol
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Results: Median Heavy Drinking Days
Baseline Placebo Depot NTX 190 mg Depot 380 mg
Med
ian
Hea
vy D
rinki
ng
Day
s pe
r Mon
th
0
5
10
15
20
25
30
n = 624
19.3
3.1
6.0 4.5
48% p < 0.002
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Effect of Depot NTX in Maintenance of Abstinence
0 10 20 30 40 50 60 70 80 90
100
Perc
ent A
bstin
ent
p < 0.025
Placebo (n = 28) DEPOT NTX 380mg (n = 28)
Subjects with 4 day lead in abstinence
1 2 3 5 4 6 7 8 10 9 11 12 13 15 14 16 17 18 20 19 21 22 23 25 24 26 27 28 30 29 31
Weeks
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Most Common AEs (%)
Placebo 190 mg 380 mg Nausea 11 25* 33*† Headache 16 16 22 Fatigue 11 16 20*
Insomnia 12 13 14 Vomiting 6 11 14* Appetite Decreased 1 6* 13*†
Diarrhea 9 11 13 Dizziness 4 11* 13* Injection Site Pain 6 9 12*
Nasopharyngitis 11 15 11 Upper Resp Tract Infection 9 7 10
*P < 0.05 vs. placebo † P < 0.05 vs. naltrexone 190 mg Garbutt et al. JAMA. 2005;293:1617-1625.
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Safety Data Liver Function Tests — ALT, AST
Placebo 190 mg 380 mg
ALT Baseline 33.9 ± 21.9 33.1 ± 20.3 32.0 ± 19.4
Last visit 31.5 ± 22.5 29.7 ± 20.0 32.0 ± 30.3
AST Baseline 31.8 ± 17.8 32.8 ± 17.1 29.9 ± 13.3
Last visit 30.9 ± 20.1 29.9 ± 20.9 30.0 ± 21.0
Subjects with > 3X elevated AST or ALT 13 (6.6%) 9 (4.9%) 9 (4.7%)
Discontinued for LFT abnormality 1 (0.5%) 3 (1.4%) 1 (0.5%)
Garbutt et al. JAMA. 2005;293:1617-1625. 28
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Safety Data Liver Function Tests — GGT (U/L)
Placebo 190 mg 380 mg
Baseline 73.9 ± 113.0 74.3 ± 87.0 60.2 ± 62.8
Last visit 72.5 ± 139.6 62.3 ± 79.7 55.7 ± 85.0
Garbutt et al. JAMA. 2005;293:1617-1625.
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NTX AND HEP-C HIV (Mitchel et al 2012)
• HEP-C INCREASINGLY COMMON IN PATIENTS WHO COULD BENEFIT FROM DEPOT NTX
• HEP-C NATURAL COURSE IS CHARACTERIZED BY ELEVATIONS IN LIVER ENZYMES WHICH COMPLICATES ATTRIBUTION TO NTX
• CONSENSUS IS THAT LFT ABNORMALITIES SHOULD NOT BE SOLE DETERMINANT OF CONTINUED TREATMENT
• PHYSICAL SIGNS: JAUNDICE, MALAISE, NAUSEA, VOMITING, ABDOMINAL PAIN ARE BEST INDICATORS OF LIVER TOXICITY
• REQUIRES CONSULTATION AND EDUCATION OF PRIMARY CARE CLINICIANS, OR HEPATOLOGIST
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Summary
• Clinical study of naltrexone long-acting injection 380 mg demonstrated – Significant reduction in event rate of heavy drinking
days relative to placebo (p < 0.03) – ~50% reduction in median heavy drinking days
• Baseline: 19.3, Placebo: 6.0, 380 mg: 3.1 – Reduction in heavy drinking days observed in both
actively drinking and abstinent patients
Garbutt et al. JAMA. 2005;293:1617-1625.
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PRAZOSIN AND NTX
• MAY HAVE ADDITIVE EFFECTS IN REDUCING ALCOHOL CONSUMPTION COMPARED TO NTX ALONE
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NALMEFENE
• NOT IDENTICAL TO NALTREXONE • NALMEFENE IS ALSO A PARTIAL AGONIST AT KAPPA RECEPTOR • THE ROLE OF THE KAPPA/DYNORPHIN SYSTEM IN
ALCOHOLISM NOT FULLY UNDERSTOOD • THE RATIONALE IS THAT ALCOHOL RELEASES DYNORPHIN,
WHICH IS THE LIGAND OF THE KAPPA RECEPTOR. • THIS COULD PRODUCE DYSPHORIA AND ANHEDONIA, WHICH
IN TURN LEADS TO INCREASED • NALMEFENE AS A PARTIAL AGONIST REDUCES THIS EFFECT
AND ALCOHOL CONSUMPTION • KEY USA INVESTIGATORS INCLUDE B MASON ET AL 1994 AND
OTHERS, ANTON ET AL ) • APPROVED BY EUROPEAN MEDICINES AGENCY BASED ON
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ACAMPROSATE IN ALCOHOL DEPENDENCE
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ACAMPROSATE
• Efficacy demonstrated in European trials • US multisite trial was equivocal • Subjects are not directly comparable (e.g.,
European subjects were abstinent, 50% of US sample was drinking)
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ACAMPROSATE
• Other differences in studies – Alcoholism severity – Pattern: episodic or continuous drinkers – How was drinking data obtained (diaries, self
report, biological markers) – Time that medication was started: early or late
abstinence? – Other: motivation, psychosocial, drop-out
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ACAMPROSATE DOSING
• 2-3 grams in three divided doses • Adverse effects increase with dose • Optimal dosing period unknown
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Acamprosate (calcium acetylhomotaurinate)
• May act by reducing conditioned alcohol withdrawal induced craving
• No sedative or anxiolytic effect • No abuse potential • Does not interact with ethanol • Most common side effect is diarrhea. Also rash, pruritis, sexual
disturbance reported • No sleep or EEG changes • NEW FINDINGS—GENETIC INFLUENCE???The minor GRIN2B A
allele associated with greater abstinence rs2058878 SNP may be involved in GRIN2Bwhich encodes for the GluN2B, which increases expression in chronic ethanol consumption
• CALCIUM LOADING??? (See Spanagel et al 2014, with editorial comment by Heilig)
• Craving, length of abstinence predicts positive response to acamprosate
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Acamprosate Findings: Continuous Abstinence (% Subjects)
05
1015202530354045
Paille6m
Paille1yr
Sass48wk
Whit1yr
Pelc 90d
Acam 1.3Acam 2.0PlaceboAc_both doses
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ACAMPROSATE, PSYCHOPATHOLOGY, AND OUTCOMES
• PREDICTORS OF POSITIVE RESPONSE – MOTIVATION TO ACHIEVE ABSTINENCE – LOWER PRE-TREATMENT DRINKING INTENSITY – LONGER PERIOD OF ABSTINENCE BEFORE ACAMPROSATE
IS STARTED • PREDICTORS OF NEGATIVE RESPONSE
– HIGH CRAVING AT BASELINE – HIGH DEPRESSION AT BASELINE
• FINDINGS FROM DIFFERENT STUDIES ARE CONTRADICTORY
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ACAMPROSATE AND NTX
• ARE THEY MORE EFFECTIVE IN SUBGROUPS OF ALCOHOLICS (MAISEL et a 2013)
• META-ANALYSIS SUGGESTED – A>N FOR MAINTENANCE OF ABSTINENCE – N>A FOR REDUCTION OF HEAVY DRINKING AND
CRAVING – REQUIRING ABSTINENCE BEFORE INITIATION OF N
PRODUCED LARGER EFFECT SIZES FOR ABSTINENCE EFFECT SIZE AND REDUCTION IN HEAVY DRINKING
– FOR A, REQUIRING DETOXIFICATION PRIOR TO ADMINISTRATION WAS ASSOCIATED WITH BETTER ABSTINENCE OUTCOMES
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NEUROTRANSMITTER SYSTEMS
• OPIOID • GABA • GLUTAMATE • DOPAMINE • SEROTONIN • ADENOSINE • NPY • NOREPINEPHRINE • CANNABINOID
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OPIOID SYSTEM AND ALCOHOLISM • ALCOHOL STIMULATES RELEASE OF BETA ENDORPHINS • LOWER LEVELS OF BETA ENDORPHINS IN PLASMA AND
CSF OF ALCOHOLICS • ETHANOL CHALLENGES IN NON-DRINKING CHILDREN OF
ALCOHOLICS PRODUCED GREATER INCREASES IN BETA ENDORPHIN THAN CONTROLS
• ANIMAL STUDIES SUPPORT ROLE OF OPIOID SYSTEM IN ETHANOL REWARD
• ASP40 ALLELE OF MU OPIATE RECEPTOR AND POSITIVE NTX RESPONSE
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The Relationship of GABA and Benzodiazepines (BZs) to Alcoholism
• Acute low doses of ethanol increase GABA activity and may contribute to its rewarding properties
• Cross tolerance; BZs treat withdrawal • Chronic ethanol is associated with decreased
BZ/GABA-A receptors in some brain regions • Some effects of ethanol and GABA-A positive
modulators are decreased in alcoholics, while reinforcing effects are increased (using ARCI scales, but not POMS)
• Alcoholics have lower brain and cerebrospinal fluid GABA levels
GABA=gamma aminobutyric acid; ARCI=Addiction Research Center Inventory; POMS=Profile of Mood States.
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GABA and Alcoholism
• Genetics may predispose to alcoholism via alterations at the GABA-A receptor
• The function and density of GABA-A receptors are altered by chronic alcohol exposure
• Positive modulators of the GABA-A receptor have effects in alcoholics that differ from nonalcoholics and low-risk subjects
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GLUTAMATE AND ALCOHOLISM
• System involved in learning and memory • Linked to dopamine and GABA systems • Blockade of NMDA glutamate receptors by ethanol • NMDA antagonists substitute for high doses of ethanol in
animals • Acamprosate may act through this system • Blunted response to NMDA antagonists in alcoholics and
high familial density
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CYTOKINES
• SOME PATIENTS WITH ALCOHOLISM HAVE INCREASED LEVELS OF INFLAMMATORY MARKERS IN BLOOD AND CSF
• IL-1, IL-6 TUMOR NECROSIS FACTOR-ALPHA, C-REACTIVE PROTEIN, CHEMOKINES
• CYTOKINES DECREASE NEUROTRANSMITTER FUNCTION (SEROTONIN), DECREASE GLUCOCORTICOID SENSITIVITY, BLOCK NEUROPLASTICITY. ALTER PERMEABILITY OF BBB, ALTER P-GLYCOPROTEIN TRANSPORT ACROSS BARRIER
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Increasing GABA
• Anticonvulsants hold greatest promise • Valproate and carbamazepine effective in
withdrawal, and some evidence for relapse prevention
• Valproate inhibits GABA metabolism and enhances synthesis, leading to higher brain GABA
• Carbamazepine and oxcarbazepine increase limbic GABA-B receptors, decrease GABA and dopamine turnover, and inhibit Ca influx via NMDA effect (among other actions)
• Liang and Olsen (2014) also suggest that kudzu and hovenia, ancient herbal remedies may be useful in alcohol withdrawal and cravings, but mechanisms not fully elucidated
• Hovenia may act at GABA-A receptors in brain (dihydromyricetin pharmacologically active
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GABA and Anticonvulsants
• Tiagabine increases GABA by reuptake inhibition by GABA transporter
• Topiramate increases GABA activity by binding to a novel site on the GABA-A receptor – It also antagonizes AMPA/kainate receptors and
modulates high voltage-activated Ca channels – Some evidence that the combination of effects increases
mesolimbic dopamine release – Carbonic anhydrase inhibitor – Properties may make it useful for treatment of
alcoholism
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GABA and BACLOFEN
• Preliminary data suggest that baclofen is efficacious in alcohol withdrawal and relapse prevention
• Acts at GABA-B receptors • Addolorato et al (2002) first RCT, 30 mg/d
baclofen v placebo May reduce w/d, increase abstinence, reduce drinking levels, decrease anxiety and lower craving
• Garbutt et al (2010) could not replicate these findings
• Leggio et al (2014) had mixed results in small RCT of alcoholic smokers
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GABA-B RECEPTORS
• GABA-B RECEPTORS ARE THOUGHT TO INHIBIT MESOLIMBIC DOPAMINE PATHWAYS TO REDUCE DRUG REWARD
• TEGMENTAL GABA-B ACTIVATION (BY AGONISTS OR PARTIAL AGONISTS) DECREASES DOPAMINE RELEASE IN VTA, NAc
• ANIMAL MODELS SHOW THESE DRUGS SUPPRESS COCAINE AND ALCOHOL SELF ADMINISTRATION
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SEROTONIN AND ALCOHOLISM
• Alcoholics have lower levels of serotonin • Serotonin plays a role in impulsivity and craving • Ethanol can increase brain serotonergic activity • 5-HT1A, 5-HT2 and 5-HT3 receptors have been
linked to alcoholism • CSF 5-HIAAA may be lower in alcoholics • 5-HTT receptor gene—LL/TT ondansetron
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DOPAMINE AND ALCOHOLISM
• Alcohol activates dopamine release at the nucleus accumbens and extended amygdala
• Dopamine thought to mediate craving • D2 receptors decreased in alcohol preferring
rates and human alcoholics • Possible relationship between alcoholism
(and other addictions) and the D2 receptor gene (DRD2 and its allele TaqI A1)
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Topiramate
A potential new medication treatment for alcoholism
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Topiramate
• Reduces craving for alcohol • May also reduce rewarding properties • Marketed as an anticonvulsant • Facilitates GABA, inhibits glutamate
AMPA/kainate, inhibits mesocorticolimbic dopamine release
• SNP in GRIK1, a C- to A- noncoding substitution; CC homozygotes better response to TOP (Kranzler et al, 2014a,b,c)
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Topiramate in Alcohol Dependence (Johnson et al, Lancet 361:167-85, 2003)
• Double blind randomized controlled 12 week clinical trial in 150 individuals
• Topiramate in doses of 50-300 mg per day • Topiramate group did better on all alcohol
outcomes compared to placebo
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Topiramate
• Active drug produced following differences from placebo: – Drinks per day: -1.06 fewer – Drinks per drinking day: -1.20 fewer – % Heavy drinking days: -14.9 fewer – % Days abstinent: 11.62 more – Gamma glutamyl transferase: lower – Obsessive Compulsive Drinking Scale: lower
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ZONISAMIDE
• First studied for alcoholism in our animal lab and found to reduce self-administration in rodents
• We followed up with a human study of heavy drinkers in a laboratory study and when taking zonisamide compared to placebo they drank less
• Open trial, and later double blind suggests efficacy in reducing drinking
• Larger comparative study with zonisamide, levetiracetam (Keppra) and topiramate underway
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ZONISAMIDE HUMAN LAB
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ZONISAMIDE
• Arias was first to publish positive RCT in alcohol dependence (2010) about the same time Ciraulo et al were completing animal models, human lab studies, and open trials
• Rubio et al used ZON for alcohol withdrawal (2010) and a positive open trial in alcohol dependence
• Evidence very strong from 3 different labs, using a variety of screening models, provided support for a full RCT
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BLUE ARROWS SHOW ZON AND TOP GROUPS
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ANTICONVULSANTS AND CRAVING MEASURED BY OCDS
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OCDS HAS COMPONENT SUBSCALES
• ZONISAMIDE PREFERENTIALLY AFFECTED RESISTANCE/IMPULSIVITY COMPONENT
• SUGGESTS POTENTIAL PSYCHOLOGICAL MECHANISMS OF ACTION
• AND BRAIN NETWORKS THAT COULD BE EXAMINED FOR MEDICATION EFFECTS AND MEDICATION SCREENING
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NEUROPSYCHOLOGICAL TEST FINDING
• ZON AND TOP SHOWED MILD TO MODERATE PROBLEMS IN VERBAL FLUENCY, VERBAL MEMORY, VISUOSPATIAL MEMORY
• TESTS OF EXECUTIVE FUNCTION VARIED BY TEST BUT NEITHER PRODUCED CLINICALLY IMPORTANT DECREMENTS
• NEUROTOXICITY AB SCALE (commonly used in AED studies) showed significant TOP memory slowing (300 mg dose)
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GABAPENTIN (Mason et al 2013) • Gabapentin has uncertain mechanism—although a GABA
analogue, it does not have affinity for receptor. MRS studies show it produces increased brain GABA – Renewed interest after recent dose/response study of
Mason et al , positive antialcohol effect, improves mood and sleep
– Possible mechanisms include increased activity of glutamic acid decarboxylase, which converts glutamate to GABA, inhibition of GABA-transaminase, which metabolizes GABA, blocks specific subunit (alpha-2d) of voltage gated calcium channel modulating GABA, and decreases glutamate by inhibiting enzyme responsible for synthesis and activating enzyme that is responsible for metabolism
– Normalizes stress induced GABA activation in amygdala
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www.mghcme.org Date of download: 9/14/2014 Copyright © 2014 American Medical
Association. All rights reserved.
From: Gabapentin Treatment for Alcohol Dependence: A Randomized Clinical Trial
JAMA Intern Med. 2014;174(1):70-77. doi:10.1001/jamainternmed.2013.11950
Gabapentin Effects on Number of Drinks per Week and Number of Heavy Drinking Days per Week During the 12-Week Study in the Intention-to-Treat PopulationA, Number of drinks per week; B, number of heavy drinking days per week. Error bars indicate SEM (N = 150).
Figure Legend:
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Association. All rights reserved.
From: Gabapentin Treatment for Alcohol Dependence: A Randomized Clinical Trial
JAMA Intern Med. 2014;174(1):70-77. doi:10.1001/jamainternmed.2013.11950
Gabapentin Effects on Rates of No Heavy Drinking and Complete Abstinence During the 12-Week Study in the Intention-to-Treat Population A, No heavy drinking; B, complete abstinence. Error bars indicate 95% confidence intervals (N = 150).
Figure Legend:
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Ondansetron and Early Onset Alcoholics (Johnson et al 2000)
Variable
Ondansetron
Placebo
Drinks per day 1.56 3.30
% Days Abstinent 70 50
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Genotype Combinations Predict Positive Response to Ondansetron
• Polymorphisms of serotonin transporter: HTR3A and HTR3B genes regulate ondansetron binding 5-HT receptor;
• Previous studies of serotonin transporter gene also predicted POSITIVE response to ondansetron SLC6A4-LL/TT in earlier study (Johnson et al 2013)
• Kenna et al (2014) preliminary findings that sex differences influence genetic predictability and DRD4, which codes for dopamine receptor predicts response (NB study include sertraline and ondansetron)
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Atypical Antipsychotics
• Atypical antipsychotic (risperidone, olanzapine, aripiprazole, quetiapine, and others) may be safe and also reduce comorbid substance abuse
• May also have a direct effect on drug/alcohol intake (but quetiapine study negative)
• May have indirect effect by reducing anxiety symptoms and sleep disturbances, in addition to their antipsychotic effects
• Best evidence for PTSD/Alcoholism
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Buspirone, Anxiety and Alcohol (Kranzler et al 1994)
Variable Buspirone
Hydrochloride
Placebo
No. of drinking days during 12 week treatment period
3.6 (11.0) 9.6 (13.3)
No. of drinking days posttreatment period
9.5 (14.4) 24.8 (21.8)
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PAROXETINE FOR ANXIETY AND ALCOHOLISM
• MUSC RESEARCH GROUP (RANDALL ET AL) PROVIDE EVIDENCE THAT PAROXETINE MAY BE EFFECTIVE (but some patients have trouble in tapering of drug)
• OPEN STUDIES AND CLINICAL PRACTITIONERS USING MIRTAZEPINE, evidence anecdotal
• DON’T USE VENLAFAXINE---IT MAY INCREASE DRINKING AND COUNTERACT BEHAVIORAL INTERVENTIONS (CIRAULO, BARLOW ET AL 2013)
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NCIG PROGRAM
• NIAAA DIRECTED MULTISITE CLINICAL TRIALS AT 5 ACADEMIC CENTERS
• QUETIAPINE IN HEAVY DRINKERS NEGATIVE • LEVITRACETAM IN HEAVY DRINKERS NEGATIVE
BUT OTHER STUDIES CONFLICT • CHANTIX (VARENICLINE) POSITIVE EFFECT ON
REDUCING ALCOHOL CONSUMPTION • AGENTS THAT REDUCE AMYGDALA ACTIVITY
NOW UNDER STUDY
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GLUTAMATE AND ALCOHOLISM
• System involved in learning and memory • Linked to dopamine and GABA systems • Blockade of NMDA glutamate receptors by ethanol • NMDA antagonists substitute for high doses of ethanol in
animals • Acamprosate may act through this system • Blunted response to NMDA antagonists in alcoholics and
high familial density
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CYTOKINES
• SOME PATIENTS WITH ALCOHOLISM HAVE INCREASED LEVELS OF INFLAMMATORY MARKERS IN BLOOD AND CSF
• IL-1, IL-6 TUMOR NECROSIS FACTOR-ALPHA, C-REACTIVE PROTEIN, CHEMOKINES
• CYTOKINES DECREASE NEUROTRANSMITTER FUNCTION (SEROTONIN), DECREASE GLUCOCORTICOID SENSITIVITY, BLOCK NEUROPLASTICITY. ALTER PERMEABILITY OF BBB, ALTER P-GLYCOPROTEIN TRANSPORT ACROSS BARRIER
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OPIOID SYSTEM AND ALCOHOLISM • ALCOHOL STIMULATES RELEASE OF BETA ENDORPHINS • LOWER LEVELS OF BETA ENDORPHINS IN PLASMA AND
CSF OF ALCOHOLICS • ETHANOL CHALLENGES IN NON-DRINKING CHILDREN OF
ALCOHOLICS PRODUCED GREATER INCREASES IN BETA ENDORPHIN THAN CONTROLS
• ANIMAL STUDIES SUPPORT ROLE OF OPIOID SYSTEM IN ETHANOL REWARD
• ASP40 ALLELE OF MU OPIATE RECEPTOR AND POSITIVE NTX RESPONSE
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GABA and Alcoholism
• Genetics may predispose to alcoholism via alterations at the GABA-A receptor
• The function and density of GABA-A receptors are altered by chronic alcohol exposure
• Positive modulators of the GABA-A receptor have effects in alcoholics that differ from nonalcoholics and low-risk subjects
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HEROIN
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OPIUM
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PRESCRIPTIONS: HYDROCODONE & PERCODAN
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PAIN, SUFFERING, AND DRUG ABUSE
• FOR MANY YEARS CLINICIANS WERE TAUGHT THAT PATIENTS WITH LEGITIMATE MEDICAL ILLNESS CAUSING PAIN RARELY ABUSED OPIOID ANALGESICS
• RECENT EXPERIENCE HAS CHANGED RECOMMENDATIONS
• CHRONIC OPIOIDS CAN BE ABUSED BY ANY PATIENT DUE TO TOLERANCE OF ANALGESIA, HYPER ALGESIA (INCREASED SENSITIVITY TO PAIN)
• MANY ADDICTION EXPERTS HAVE EXPRESSED OPPOSITION TO THE INTRODUCTION OF ZOHYDRO AND OTHERS THAT ELIMINATE ACETAMINOPHEN, AN AGENT TOXIC TO THE LIVER
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OPIOID ADDICTION
• THERE ARE MANY PATHS TO ADDICTION TO OPIOID DRUGS – DIVERSION FROM PRESCRIPTIONS – CULTURAL PRESSURES – CHRONIC PAIN – GENETIC PREDISPOSITION – ENVIRONMENTAL/SOCIAL INFLUENCES
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OPIOID EPIDEMICS IN US
• OCCURRED AFTER WORLD WAR I, II, AND VIETNAM
• LATE 1990’S USE SKYROCKETED---NEW NON-MEDICAL USERS TRIPLED FROM 700,000 TO 800,000 TO 2.5 MILLION
• IN 2011 THERE WERE MORE THAN 1.8 MILLION NEW USERS OF OPIOID PAIN RELIEVERS. THE SECOND MOST COMMON NEW DRUG OF ABUSE (GREATER THAN MARIJUANA)
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OXYCONTIN—THE BEGINNING OF THE CRISIS
• IN 1996 OXYCONTIN WAS INTRODUCED AS A LONG ACTING, TIME RELEASE FORMULA OF OXYCODONE
• HOWEVER THE TIME RELEASE FORMULATION COULD BE CIRCUMVENTED BY CRUSHING OR CHEWING. THIS ALLOWED RAPID RELEASE OF THE DOSE THAT WAS INTENDED AS A SLOW RELEASE AGENT
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SYNTHETIC OPIOIDS AND HEROIN
• LOCAL AVAILABILITY AND PRICES DETERMINE CHOICE OF DRUG
• THIS REMAINS PRIMARILY A DISEASE OF YOUNG ADULTS
• SWITCHING FROM SYNTHETIC OPIOIDS TO HEROIN IS PREDICTED BY LOCAL SUPPLY NETWORKS
• EITHER DRUG RESULTS IN OVERDOSES, EMERGENCY ROOM VISITS, AND DEATH
• NALOXONE AVAILABILITY HAS ICREASED TO REDUCE DEATHS, BUT LONG TERM TREATMENT AND FREQUENT RELAPSES REMAIN A SERIOUS PROBLEM
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THE DILEMMA OF PAIN TREATMENT WITH OPIOIDS
• IN 2011 THE INSTITUTE OF MEDICINE REPORTED THAT PAIN IN THE US REMAINED UNDERTREATED
• RECOMMENDATIONS INCLUDED APPROPRIATE ASSESSMENT OF PAIN AND TREATMENT REGIMENS THAT AVOIDED POTENTIAL OF DEPENDENCE
• THIS REMAINS A SERIOUS AND UNRESOLVED PROBLEM IN CHRONIC PAIN PATIENTS
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OPIOID TREATMENT
THE ROLE OF MEDICATIONS IN THE TREATMENT OF OPIOID USE DISODERS
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MEDICATIONS USED IN OPIOID ADDICTS
• SAFE AND COMFORTABLE WITHDRAWAL IN ACUTE
PHASE IS PRIMARY GOAL • FOLLOWED BY SAFE TRANSITION TO OUTPATIENT
TREATMENT • SUBSTITUTION:
– METHADONE – BUPRENORPHINE (SUBOXONE, SUBUTEX)
• BLOCKADE: – NALTREXONE (VIVITROL IS EXTENDED RELEASE
NALTREXONE) – NALOXONE (NARCAN) IN OVERDOSES
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WITHDRAWAL SYMPTOMS Early Middle Late Lacrimation Restless sleep Increased severity of earlier symptoms Yawning Dilated pupils Tachycardia Rhinorrhea Anorexia Nausea Sweating Gooseflesh Vomiting Restlessness Diarrhea Irritability Abdominal cramps Tremor Increased blood pressure Mood liability Depression Muscle spasms Weakness Bone Pain
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OPIOID WITHDRAWAL TREATMENT
• INPATIENT VS OUTPATIENT? • USE OF COMFORT MEDICATION PROTOCOL,
BUPRENORPHINE PROTOCOL, OR COMBINATION? • WHAT IS LONG TERM GOAL—SHORT-TERM OR
LONG-TERM MANTENANCE WITH BUPRENORPHINE OR NALTREXONE EXTENDED RELEASE INJECTIONS?
• ULTRA LOW DOSE NALTREXONE HAS BEEN USED AS A KAPPA ANTAGONIST TO SHORTEN TIME NEEDED TO SWITCH FROM BUP TO NTX-ER
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COMFORT MEDICATIONS
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TREATMENT OF OPIOID WITHDRAWAL (from Sigmon SC et al Am J Drug Alc Abuse 38: 187-199, 2012, copyright do not duplicate without
permission)
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OPIOID WITHDRAWAL OUTPATIENT
• DETERMINE SEVERITY OF DEPENDENCE (AMOUNT OF OPIOID USE)
• DETERMINE USE OF OTHER DRUGS AND ALCOHOL FROM WHICH PATIENT MAY REQUIRE MEDICATION TREATMENT OF WITHDRAWAL SYNDROME
• INQUIRE ABOUT SAFETY OF LIVING SITUATION AND PRESENCE OF PERSON TO SUPPORT PATIENT
• TRANSPORTATION AVAILABLE FOR DAILY VISITS • DETERMINE PRESENCE OF ACTIVE PSYCHIATRIC OR
MEDICAL CONDITIONS THAT REQUIRE TREATMENT
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SUBSTITUTION
• METHADONE WAS USED IN PAST TO DETOXIFY FROM OPIATES AND AS MAINTNENANCE THERAPY
• SUCCESSFUL IN DECREASING OPIOID USE, DECREASING CRIMINAL BEHAVIOR, AND IMPROVING QUALITY OF LIFE
• NEGATIVE ASPECTS WERE CLINICS THAT MAINTAINED ADDICT CULTURE, DIFFICULTY WITHDRAWING FROM LONG TERM USE, ESP AT HIGH DOSES
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BUPRENORPHINE-NX (SUBOXONE) BUPRENORPHINE ALONE (SUBUTEX)
• SUBUTEX ONLY FOR PREGNANT WOMEN • ALLOWS TREATMENT IN PRIVATE OFFICES
(BUT LEVEL OF DIVERSION IS RAISING CONCERNS ABOUT THIS PRACTICE SETTING)
• ALSO CONCERNS ABOUT MONITORING APPROPRIATENESS OF SOME PRESCRIBERS
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ADMINISTRATION OF SUBOXONE
• SUBOXONE INDUCTION – PREPARE PATIENT, MUST BE IN WITHDRAWAL OR
SUBOXONE WILL CAUSE WITHDRAWAL – IT IS A PARTIAL AGONIST (IT CAN ACT AS AN
ANTAGONIST IS PERSON IS TAKING OPIOID) – IT HAS A CEILING EFFECT, MAKING IT SAFER THAN
METHADONE – SUBLINGUAL TABLETS NOT ABSORBED WELL
FROM GUT – MONITOR SYMPTOMS WITH “COWS” OR”SOWS”
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A COMMON PROTOCOL FOR INDUCTION
Patient Type: Not currently dependent
Day 1 _____________ Day 2 First Dose Supplemental Dose 2/0.5mg none 4/1 mg * Dose amounts consist of buprenorphrine dose (the number before the slash) and the naltrexone dose (the number after the slash)
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A COMMON PROTOCOL FOR INDUCTION
• Patient Type: Dependent on heroin or pain medications Day 1 Day 2 First dose Supplemental dose 2/0.5 to 4/1mg Redose every 1-2 hrs, If the patient is still if withdrawal continues, in withdrawal, give up to a total of 8/2mg first day dosage plus 2/0.5mg to 4/1mg **Do not begin buprenorphine until patient shows evidence of opioid withdrawal.
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NALTREXONE EXTENDED RELEASE INJECTION
• PURPOSE IS TO BLOCK OPIOID EFFECTS FOR PEOPLE WHO WANT TO LIVE AN OPIOID FREE LIFE
• AFTER SOMEONE IS OPIOID FREE EITHER BY NARCAN CHALLENGE OR QUANTITATIVE TOX SCREEN, NALTREXONE IS ADMINISTERED
• USUALLY GIVEN ORALLY AT FIRST TO TEST SENSITIVITY AND THEN INJECTION
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A COMMON PROTOCOL FOR INDUCTION
Patient type: Dependent on methadone (< 30mg/day) Day 1 Day 2 First dose Supplemental dose 2/0.5mg** Redose every 1-2 hours, if If patient is still in withdrawal continues, up withdrawal, give first-day to a total of 8/2mg dosage plus 2/0.5 to 4/1mg; if oversedated, give <8/2mg
**Do not begin buprenorphine until patient shows evidence of opioid withdrawal.
Source: Adapted from McNichols and Howell 2000
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NTX-XR Microspheres
• Size: ~100 µM • Formulation:
– Polylactide-co-glycolide matrix • Common biodegradable medical polymer • Other uses: absorbable sutures, Risperdal Consta1,
Lupron2, others • Metabolized to CO2 and H20 1 Trademark Johnson & Johnson
2 Trademark TAP Pharmaceuticals 104
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Vivitrol (NTX-ER)
– Slide provided by Alkermes
Dry Powder Microspheres Diluent
Microsphere Suspension
Hypodermic Needle
IM
Once Monthly Dosing
+
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Mean Naltrexone Concentration Following 50 mg Oral Naltrexone
Time (Hours) 0 4 8 12 16 24
Nal
trex
one
(ng/
mL)
0
5
10
15
20
25
Single Dose (n = 28) Multiple Dose (n = 14)
20
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Mean 6β-Naltrexol Concentration Following 50 mg Oral Naltrexone
Time (Hours) 0 12 24 36 48
6β
-Nal
trex
ol (n
g/m
L)
0
20
40
60
80
100
120
140
160
180
Single Dose (n = 28) Multiple Dose (n = 14)
Alkermes, Data on File 107
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Summary of Vivitrol® (NTX-ER)
Pharmacokinetics • Therapeutic concentrations reached with
first injection • Dose proportionality between Vivitrol NTX-ER IM
190 mg and 380 mg • Extended and sustained naltrexone concentrations for one
month – Repeat dose concentration-time profile was
similar to single dose – No accumulation of naltrexone or 6β-naltrexol
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Tiny Needles Prepare Skin for Patch Medication: A microneedle array (left) is a small rectangle of 50 tiny needles, each 620 microns in length and thinner than a human hair. Tiny, painless epidermal punctures created by pressing the needles against the skin act as conduits for medication to flow evenly from a skin patch into dermal capillaries and the bloodstream (NIDA)
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ADVERSE EVENTS NTX-ER
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NTX-ER in Opioid Dependence: SUMMARY
• 380MG NTX-XR is safe and effective in opioid dependent patients who have completed detoxification and have documented abstinence from opioids by quantitative assay or Narcan challenge
• Convenient monthly injections with good patient acceptance • Studies show that treatment produces greater abstinence, more opioid
free days, and decreased craving compared to placebo injections • Should be administered as part of complete treatment program of
behavioral (counseling, individual or group, mutual support groups, family therapy and others)
• Few adverse effects that lead to dropout • Be sure you address “Urban Myths”. Patients in group or inpatient
treatment centers may try to discourage others from taking it. This must be addressed by staff. Sexual desire NOT commonly affected, pleasure center is not turned off, depression is RARE
• Headache, and GI more common especially at initiation, especially in patients with incomplete detoxification from alcohol, benzodiazepines,
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Narcan (Naloxone)
• Short acting opioid antagonist • Administered
– parenterally (subcutaneous injection) in Emergency Departments in opioid overdoses
– Intranasal “on street” – Nebulizer in hospital or ED – May be used as a challenge to determine opioid
sensitivity prior to starting oral or long-acting injectable naltrexone (Vivitrol)
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NEBULIZED NALOXONE
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Narcan Ampule
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Narcan Syringe
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NALOXONE INJECTABLE
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Psychopharmacology Friday, September 28 – Sunday, September 30, 2012
The Westin Copley Place
39th Annual Psychopharmacology Conference Thursday – Sunday, October 22– 25, 2015
The Westin Copley Place MGHCME.ORG
Massachusetts General Hospital Department of Psychiatry
Presents
39th Annual Psychopharmacology
Conference
THURSDAY-SUNDAY, OCTOBER 22-25, 2015 THE WESTIN COPLEY PLACE
BOSTON, MA
