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

alerner@lev-hasharon.co.il

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

Israeli Society of Addiction Medicine

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

9

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.

Nalmefene

Thanks for your attention