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Viral Hepatitis and Addictions
Therapeutic Update in Addictions & Alcohol
2015
Arturo G. Lerner, MD
Dual Disorders Ward
Lev-Hasharon Mental Health Medical Center
Netanya
Israel
050-626-7912
State of Israel
Ministry of Health
Lev-Hasharon
Mental Health Medical Center
Affiliated to
Sackler School of Medicine
Tel-Aviv University
Israel
Alcohol
Management of craving and substance seeking behaviour
Disclosure
Reckitt Benckiser
Lundbeck
Janssen
Eli Lilly
Sanofi
Personal fees and financial support
2
Affiliations
1. Lev- HaSharon Mental Health Medical Center, Netanya,
Israel
2. Israel Association of Addiction Medicine (ILSAM)
3. Israel Dual Disorders Forum
4. Israel Psychiatric Association
1. Affiliated to Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel
2. Affiliated to International Association of Addiction Medicine
3. Affiliated to International Dual Disorders Section, World Psychiatric
Association
Substances and Mechanism of Action
� This talk will cover and analyze some, but not all the aspects of the topic.
� This conversation will probably place and produce more questions than answers.
Substances and Mechanism of Action
GHB� γ-Hydroxybutyric acid (GHB) is a naturally occurring substance found in the human CNS. It is illegal
in many countries.
� Xyrem is used to treat cataplexy and excessive daytime sleepiness in patients with narcolepsy. GHB has been used in a medical setting as a general anesthetic.
� GHB has at least two distinct binding sites in the central nervous system. GHB is an agonist at the GHB receptor (a G protein-coupled receptor) which is excitatory and it is a weak agonist at the GABAB receptor, which is inhibitory.
� GHB is a naturally occurring agent. GHB is probably synthesized from GABA in GABAergic neurons, and released when the neurons fire. Activation of both the GHB receptor and GABA(B) is responsible for the addictive profile of GHB. GHB's effect on dopamine release is biphasic (may release or inhibit).
� Amisulpride binds GHB receptor. It has a safer profile in the treatment of alcoholics because of its minimal impact on liver function.
� Hormesis is a term used by toxicologists to refer to a biphasic dose–response to an environmental agent characterized by a low dose stimulation or beneficial effect and a high dose inhibitory or toxic effect. In the fields of biology and medicine hormesis is defined as an adaptive response of cells and organisms to a moderate (usually intermittent) stress. Examples include ischemic preconditioning, exercise, dietary energy restriction and exposures to low doses of certain phytochemicals.
� Galloway GP, Frederick-Osborne SL, Seymour R, Contini SE, Smith DE (2000). "Abuse and therapeutic potential of gamma-hydroxybutyric acid". Alcohol 20 : 263–9
� Zvosec DL, Smith SW, Porrata T, Strobl AQ, Dyer JE (2011). "Case series of 226 gamma-hydroxybutyrate-associated deaths: lethal toxicity and trauma". The American Journal of Emergency Medicine 29: 319–32
Substances and Mechanism of Action
LSD
� The psychedelic effects of LSD are attributed to its strong partial agonist effects at post-synaptic 5-HT2A receptors.
� Specific 5-HT2A agonists are psychedelics and 5-HT2A specific antagonists block the psychedelic activity of LSD.
� LSD additionally binds to most serotonin receptor subtypes except for 5-HT3 and 5-HT4.
� LSD also binds and activates D2 receptors .
� It is an D2 agonist. This fact may explain LSD induced psychotic episodes or its triggering effect in predisposed individuals.
� it is thought that LSD increases glutamate release in the cerebral cortex and thus excitation in this area, specifically in layers IV and V.
� LSD has been shown to activate DARPP-32-related pathways.(Dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32).
� Nichols, David E. (2004). "Psychotropics". Pharmacology & Therapeutics 101 (2): 131–81.
� Jump up Marona-Lewicka, D.; Thisted, R. A.; Nichols, D. E. (2005). "Distinct temporal phases in the behavioral pharmacology of LSD: Dopamine D2 receptor-mediated effects in the rat and implications for psychosis". Psychopharmacology 180 (3): 427–435.
Alcohol
Management of craving and substance seeking behaviour
Modulation of Dopamine Reward System
� Endocannabinoids may increase DA release
� Block CB1 receptorTaranabant (Merck)
SLV319 (Solvay)
CP-945598 (Pfizer)
� Endogenous opioids
� Block μ-opioid receptorNalmefene & Naltrexone (Antagonist or best defined “inverse agonist”)
Buprenorphine + Naloxone (Partial μ agonist & κ antagonist)
Consumption of BZ leads to endorphin release, inhibition of GABA in the VTA
which allows dopamine release in the terminal areas of the NAc
Heilig et al. Nat Rev Neurosci 2011;12(11):670–684 (review); Clapp et al. Alcohol Res Health 2008;31(4):310–339 (review)
Endorphin
Dopamine
GABA
Nucleus accumbens
(NAc)
Ventral tegmental area
(VTA)
•Acute alcohol consumption induces endorphin release, resulting in inhibition of GABA release in the VTA and removal of
the inhibitory tone from the dopamine cells
•This ultimately results in increased dopamine release in the terminal areas in the NAc
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GABA release from GABAergic neurones is under negative regulation by the
µ-opioid receptor
Dopaminergic VTA neurones that project to the NAc (i.e. mesolimbic neurons) are under tonic inhibition by GABAergic interneurones within the VTA
Support for scientific statement 1.2.3
Opioids antagonists
� Antagonists – bind to the µ receptor but do not produce a biological response and are able to block agonist effects: naloxone, naltrexone, nalmefene
Nalmefene is an opioid receptor antagonist (inverse agonist) and used primarily in the management of alcohol dependence, and also has been investigated for the treatment of other addictions such as pathological gambling and shopping.
� All of the opioid antagonists used in medicine are non-selective, either blocking all three opioid receptors, or blocking the mu-opioid receptor but activating the kappa receptor.
� Highly selective antagonists:
� Cyprodime is a selective mu opioid receptor antagonist
� Naltrindole is a selective delta opioid receptor antagonist
� Norbinaltorphimine is a selective kappa opioid receptor antagonist
� Mu-opioid receptor specific antagonist cyprodime: characterization by in vitro radioligand and [35S] GTP gammaS binding assays. Márki A et al.
European Journal of Pharmacology (1999) 383:209
� Naltrindole, a highly selective and potent non-peptide delta opioid receptor antagonist. Portoghese PS et al.
European Journal of Pharmacology (1988) 146:185-6.
� Binaltorphimine and nor-binaltorphimine, potent and selective kappa-opioid receptor antagonists. Portoghese
PS et al.
Life Sciences (1987) 40:1287-92.
Opioids antagonists
Nalmefene
� Nalmefene is a full opioid “universal” competitive receptor antagonist used primarily in the management of alcohol and opioid dependence. It has been also used in Gambling and Shopping Disorder.
� It is marketed under the trade name Selincro 18 mg.
� Mechanism of action:
� Primarily, Nalmefene blocks opioid receptors, impeding narcotic (opioid and opiates) access
� to these receptors thus producing extinction response.
� Secondarily, Nalmefene modulates dopaminergic mesolimbic pathway which may reduce
craving.
Mu antagonist: b-endorphins
Delta antagonist: enkephalins
Kappa partial agonis: dynorphins
� Alcohol causes the release of B-endorphins which reduces the inhibition produced by GABA interneurons on Dopamine release in VTA (increase DA release) projecting to NAs.
� Naltrexone & Nalmefene block opioid receptors.
� Advantages of Nalmefene over naltrexone may include:
Longer half-life: 11 + - 5 Hours
Greater oral bioavailability
No observed dose-dependent liver toxicity
(Longer, greater and no)
Nalmefene
Nalmefene (Selincro 18 mg)
� Nalmefene administration: mild & moderate: “as needed”
� Nalmefene administration: severe: on a daily basis
Mechanisms of action associated to acute dopamine increase
� Substances may be classified by at least, four cellular mechanisms of action that have been described to cause an acute dopamine increase (representative, not exhaustive list).
� Group I consists of opioids , cannabinoids and γ-hydroxybutyrate (GHB). They decrease the release of GABA from VTA interneurons and thereby remove the inhibitory transmission “brake” onto DA neurons. This indirect increase of DA cells’ activity is known as dis-inhibition, and is possible due to either cell-type specific expression of their respective receptor to the substance like in opioids, cannabinoids or higher affinity of the drug for the receptor located on GABA neurons (GHB).
� Group II consists of Nicotine which directly activates DA neurons.
� Group III consists of stimulants like cocaine and amphetamines which target and perturb the DA transporter (DAT) either by blocking it (cocaine) or reversing its activity (amphetamines).
� Group IV consists of alcohol which release B-endorphins that reduces the inhibitory effect on VTA allowing DA release.
� Arnaud L. Lalive, Uwe Rudolph, Christian Lüscher, Kelly R. Tan.
Is there a way to curb benzodiazepine addiction?
Swiss Med Wkly. 2011;141:w13277
Nalmefene
� Selincro is to be taken as-needed: on each day the patient perceives a risk of
drinking alcohol, one tablet should be taken, preferably 1-2 hours prior to the
anticipated time of drinking.
� If the patient has started drinking alcohol without taking Selincro, the patient
should take one tablet as soon as possible.
� The maximum dose of Selincro is one tablet per day.
� Selincro can be taken with or without food.
Nalmefene
Contraindications
� Hypersensitivity to the active substance or to any of the excipients.
� Patients taking opioid analgesics.
� Patients with current or recent opioid addiction.
� Patients with acute symptoms of opioid withdrawal.
� Patients for whom recent use of opioids is suspected.
� Patients with severe hepatic impairment (Child-Pugh classification).
� Patients with severe renal impairment.
� Patients with a recent history of acute alcohol withdrawal syndrome including
Seizures and delirium tremens.
Nalmefene
Selincro is not recommended for patients for whom
the treatment goal is immediate abstinence.
Reduction of alcohol consumption may be an
intermediate goal on the way to abstinence.
Nalmefene
Interactions
No clinically relevant interactions between nalmefene, or its metabolites, and
concomitantly administered medicinal products metabolized by the most common
CYP450 and UGT enzymes or membrane transporters are anticipated.
Co-administration with medicinal products that are potent inhibitors of the UGT2B7
enzyme (for example, diclofenac, fluconazole, medroxyprogesterone
acetate, meclofenamic acid) may significantly increase the exposure to nalmefene.
This is unlikely to present a problem with occasional use, but if long-term concurrent
treatment with a potent UGT2B7 inhibitor is initiated, a potential for an increase in
nalmefene exposure cannot be excluded
Nalmefene
� Conversely, concomitant administration with a UGT (uridine diphosphate
glucuronyltransferase) inducer (for example, dexamethasone, phenobarbital,
rifampicin, omeprazole) may potentially lead to sub-therapeutic nalmefene
plasma concentrations.
� If Selincro is taken concomitantly with opioid agonists (for example, certain types
of cough and cold medicinal products, certain antidiarrheal medicinal products,
and opioid analgesics), the patient may not benefit from the opioid agonist.
� There is no clinically relevant pharmacokinetic drug-drug interaction between
nalmefene and alcohol.
� There seems to be a small impairment in cognitive and psychomotor
performance after administration of nalmefene.
� However, the effect of nalmefene and alcohol in combination did not exceed the
sum of the effects of each substance when taken alone.
� Simultaneous intake of alcohol and Selincro does not prevent the intoxicating
effects of alcohol.
Nalmefene
Pregnancy
� There are no or limited data (fewer than 300 pregnancy outcomes) from the use
of nalmefene in pregnant women.
� Animal studies have shown reproductive toxicity. Selincro is not recommended
during pregnancy.
Breast-feeding
� Available pharmacodynamic/toxicological data in animals have shown excretion of
nalmefene/metabolites in milk. It is unknown whether nalmefene is excreted in
human milk. A risk to newborns/infants cannot be excluded.A decision must be
made whether to discontinue breast-feeding or to discontinue/abstain from
Selincro therapy, taking into account the benefit of breast-feeding to the child and
the benefit of therapy to the woman.
Fertility
� In fertility studies in rats, no effects were observed for nalmefene on fertility,
mating, pregnancy, or sperm parameters.
Nalmefene
Side Effects
� The most common adverse reactions were nausea, dizziness, insomnia, and
headache. The majority of these reactions were mild or moderate, associated with
treatment initiation, and of short duration.
� Confusional state and, rarely, hallucinations and dissociation were reported in the
clinical studies. The majority of these reactions were mild or moderate, associated
with treatment initiation, and of short duration (a few hours to a few days). Most
of these adverse reactions resolved during continued treatment and did not recur
upon repeated administration.
� While these events were generally short lasting, they could represent alcoholic
psychosis, alcohol withdrawal syndrome, or comorbid psychiatric disease.
Nalmefene
Overdose
� In a study in patients diagnosed with pathological gambling, doses of nalmefene up to 90 mg/day for 16
weeks were investigated.
� In a study in patients with interstitial cystitis, 20 patients received 108 mg/day of nalmefene for more
than 2 years.
� Intake of a single dose of 450 mg nalmefene has been reported without changes in blood pressure, heart
rate, respiration rate, or body temperature.
� No unusual pattern of adverse reactions was observed in these settings, but experience is limited.
� Management of an overdose should be observational and symptomatic.
Buprenorphine
Buprenorphine (Suboxone)
Indications
� Substitution or maintenance treatment (as a part of a Comprehensive Recovery Process) for patients suffering from dependence, abuse or addiction to natural-occurring or synthetic narcotics (DSM-IV-TR and DSM-5).
� Half-way medication between narcotic’s use (partial or full agonists) and total cessation.
� Pain management.
� Partial agonist
� “Ceiling or buffer” or Sub-maximal response� It will not lead to respiratory OD
� Safer profile than full agonist medications
� Compounds Possessing Morphine-Antagonising or Powerful Analgesic Properties.
Bentley KW et al. Nature (1965) 206:102-3.
Buprenorphine, take in mind…..
Opioid Receptors (17 types)
Buprenorphine
Opioid-Receptor Interaction Profile
� Mu partial agonist: “Ceiling Effect” & Analgesia
� NOP1 partial or full agonist: Nociception
� Delta partial or full agonist: Anti-depressant effect
� Kappa competitive antagonist: Unpleasant effect
� Epsilon antagonist: Analgesia
Full and partial opioid agonists
� Full agonist mainly binds to µ receptors producing an almost linear increase in physiological effect:
� Opium, morphine, codeine, heroin, methadone
� Partial agonist mainly binds to the µ receptor but have a linear ‘ceiling’ effect on receptor activation:
� Buprenorphine partial agonist’s effect (32 mg) linearly increases with increasing doses until it reaches a plateau and no longer continue to develop respiratory depression with further doses, meaning “ceiling effect”.
� A compound that has an affinity for & stimulates physiological activity at the same cell receptors as opioid agonists but that produces only a partial (i.e., submaximal) bodily response.
� Buprenorphine profile
� Mu partial opioid agonist
� NOP-1 (Nociceptin Receptor or Kappa Type 3) agonist
� Kappa antagonist
� Delta antagonists
� The anti-nociceptive effect of buprenorphine mediated primarily by the mu opioid receptor is attenuated by the ability of the drug to activate the NOP-1 receptor.
� Partial agonist effect at the mu opioid receptor and antagonism at the kappa or delta opioid receptor (“anti-physical dependence”) have been considered as possible underlying mechanisms for the ceiling effect.
Partial opioids
Combined agonist & antagonist effect
Buprenorphine + Naloxone (Suboxone)
Major Receptor binding profile
� Mu partial agonist
� Kappa antagonist
� Naloxone
• ineffective by oral use
• effective against OD by parenteral use
Buprenorphine/Naloxone
Rational
� A Buprenorphine - Naloxone combination
(Suboxone).
� Developed in response to previous reports
of opioid misuse and abuse.
� Designed specifically to decrease injectable
abuse potential of Buprenorphine.
Buprenorphine/Naloxone
Adherence
� Buprenorphine is clinically effective when taken sublingually.
� Negligible effect of naloxone via sublingual route.
� Suboxone is reported as identical to buprenorphine alone in opioid-
dependents.
Buprenorphine/Naloxone
Preparation
4 part buprenorphine: 1 part naloxone
BP 8mg / Nx 2mg
BP 2mg / Nx 05mg
The right balance between agonist and
antagonist effects
� Sublingual: Opiate agonist effect from buprenorphine
� Intravenous: Opiate antagonist effect from naloxone
Buprenorphine
Duration of effects
� Rapid onset of action: 30 – 60 minutes
� Peak effects: 1 – 4 hours
� Duration of action is dose related
� low dose : 4 – 12 hrs (2-4 mg)
� med dose : ~ 24 hrs (8-16 mg)
� high dose : 2 – 3 days (32 mg)
� Elimination half-life ~24 to 36 hours
� Steady state equilibrium achieved after 3 – 7 days
Buprenorphine/Naloxone
Suboxone may limit misuse
� Buprenorphine works when placed under tongue
� Naloxone works when injected
� Very low if any, sublingual/oral bioavailability
� Suboxone suppresses withdrawal and craving when taken
sublingually
� Suboxone precipitates withdrawal when injected by opioid-
dependent patients
Buprenorphine/Naloxone
Suboxone Safety
� Well tolerated
� No apparent adverse clinical effects attributable to naloxone, even during induction.
(induction, stabilization and maintenance)
� No safety concerns following administration of 24/6 mg for up to a year.
� Naloxone does not appear to interfere with the sublingual absorption of buprenorphine.