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Dr. Naila AbrarDr. Naila Abrar
OPIOID ANALGESICSOPIOID ANALGESICS
LEARNING OBJECTIVESLEARNING OBJECTIVES
After this session, you should be able to:After this session, you should be able to: Classify opioidsClassify opioids Describe opioid receptor distribution and Describe opioid receptor distribution and
the mechanism of action of opioid the mechanism of action of opioid analgesicsanalgesics
Discuss pharmacological effects, adverse Discuss pharmacological effects, adverse effects and contraindications of opioidseffects and contraindications of opioids
Outline salient features of various opioid Outline salient features of various opioid agonists, partial agonists and opioid agonists, partial agonists and opioid antagonist.antagonist.
TERMINOLOGIESTERMINOLOGIES
SOURCESOURCE
OPIUMOPIUM PoppyPoppy Papaver somniferum Papaver somniferum P albumP album Prototype: MorphinePrototype: Morphine
OPIUM
“Among the remedies which it
has pleased Almighty God to give to man to
relieve his sufferings, none is so universal
and so efficacious as opium”
CHEMISTRY of OPIUM CHEMISTRY of OPIUM ALKALOIDSALKALOIDS
Phenanthrene der.– Morphine– Codiene – Thebaine
Benzylisoquinoline der.– Papaverine– Noscapine
CLASSIFICATION (Based on source)
Naturally Occurring Opium Alkaloids: Morphine, Codeine
Semisynthetic Derivatives: Diamorphine (Heroin), Etorphine,
Buprenorphine, Hydromorphone, Oxymorphone, Hydrocodone, Oxycodone
(phenanthrenes)
Synthetic Morphine Substitutes: Phenylpiperidine series:
• Pethidine• Fentanyl, sufentanil, alfentanil, remifentanil• Diphenoxylate, Loperamide
Phenylheptylamines• Methadone, d– Propoxyphene
Morphinans• Levorphanol, levallorphan
Benzomorphan compounds• Pentazocine, Cyclazocine
Terminology (recall)Terminology (recall)
Pure Agonist: has affinity for binding plus efficacy
Pure Antagonist: has affinity for binding but no efficacy; blocks action of endogenous and exogenous ligands
Mixed Agonist-Antagonist: produces an agonist effect at one receptor and an antagonist effect at another
Partial Agonist: has affinity for binding but low efficacy
CLASSIFICATION OF CLASSIFICATION OF OPIOID ANALGESICSOPIOID ANALGESICS
OPIOID AGONISTS- Morphine- Methadone- Levorphanol- Fentanyl gp- sufentanil, remifentanil- Hydromorphone- Meperidine - Tramadol
PARTIAL AGONIST/weak agonist- Codeine- Oxycodone - Hydrocodone- Propoxyphene- Dextropropoxyphene - Diphenoxylate
MIXED AGONIST-ANTAGONIST- Nalbuphine- Nalorphine - Butorphenol- Pentazocine- Buprenorphine
ANTAGONISTS- Naloxone - Naltrexone- Nalmefene
Opioid alkaloids produce analgesia through actions at regions in the brain that contain
peptides which have opioid-like pharmacologic properties
ENDOGENOUS OPIOID PEPTIDESNaturally occurring ligands for opioid receptors (endorphins)(endorphins)
– Pentapeptides met-enkephalin & leu–
enkephalinThese endogenous opioid peptides are derived from three precursor proteins
PRECURSOR PROTIENS1. Pre-proopiomelanocortin
(POMC) Met-enkephalin sequence, B-
endorphin, ACTH, B-lipotropin& MSH2. Preproenkephalin Six copies of met-enkephalin & one
copy of leu- enkephalin3. Preprodynorphin Dynorphin A, dynorphin B, alpha &
beta neoendorphinsEndomorphins
PHARMACOKINETICSABSORPTION – Well absorbed– First-pass metabolism oral
dose higher than parenteral dose
DISTRIBUTION– Bind to plasma proteins but rapidly
leave the blood and localize in highest concentrations in tissues that are highly perfused
METABOLISM– Polar metabolites excreted by kidneys– Morphine conjugated to morphine-3-
glucuronide (neuroexcitatory)– 10% metabolized to morphine-6-
glucoronide(more potent analgesic)– Esters hydrolyzed by
common tissue esterase– Heroin hydrolyzed by common tissue
esterases to monoacetylmorphine
(contd.)
– Phenylpiperidines hepatic oxidative metabolism
– Meperidine is demethylated to normeperidine (seizures in high conc.)
– Codiene-CYP2D6 (genetic polymorphism)
EXCRETION– Polar metabolites, including
glucuronide conjugates are excreted mainly in the urine
PHARMACODYNAMICS
MECHANISM OF ACTION– Opioid agonists produce analgesia
by binding to specific GPCRs– Located primarily in brain & spinal
cord regions involved in the transmission and modulation of pain
Mechanism of action Activation of peripheral nociceptive fibers-
release of substance P and other pain-signaling neurotransmitters from nerve terminals in the dorsal horn of the spinal cord
Release of pain-signaling neurotransmitters is regulated by endogenous endorphins or by exogenous opioid agonists by acting presynaptically to inhibit substance P release, causing analgesia
CELLULAR EFFECTS of Opioid CELLULAR EFFECTS of Opioid Receptor ActivationReceptor Activation
Inhibition of neurotransmission due to opioid-induced presynaptic inhibition of neurotransmitter release
Involves changes in transmembrane ion conductance
1. Close voltage-gated Ca2+ channels on pre-synaptic nerve terminals reduce transmitter release
2. Open K+ channels thus hyperpolarize and inhibit postsynaptic neurons
RECEPTOR TYPES
Three major classes
1. mu () 2. kappa (k)3. delta (d)
GPCRs
Majority of the opioid analgesics act primarily at the receptors
Analgesia, euphoria, respiratory depression & physical dependence properties of morphine result principally from actions at the receptor
Endogenous opioid peptides have more affinity for the & receptors
Reduced incidence for respiratory depression and addiction & dependence with k receptors but dysphoric effects
RECEPTOR DISTRIBUTION
– Dorsal horn of the spinal cord
– Receptors present both on:
spinal cord pain transmission neurons &
primary afferents that relay the pain message to them
NEUROANATOMY OF NEUROANATOMY OF PPAINAIN
1. Afferent pathways a) nociceptors (pain receptors)
b) afferent nerve fibresc) spinal cord network
2. CNS-limbic system, reticular formation,
thalamus, hypothalamus and cortex
3. Efferent pathways- fibres connecting
the reticular formation, midbrain & substantia gelatinosa (responsible for pain modulation)
Theory of Theory of ppain ain productionproduction and and
modulationmodulation Gate control theory (created by
Melzack and Wall) Nociceptive impulses are transmitted
to the spinal cord through large A- delta & small C- fibers
Synapses in the SG Cells in this structure function as a
gate, regulating transmission of impulses to CNS
Theory of pain production and modulation (contd.)
Stimulation of larger nerve fibers (A, A) causes the cells in SG to "close the gate“
A closed gate decreases stimulation of 2nd afferent neuron, which decreases the transmission of impulses, & diminishes pain perception
Theory of pain production and modulation (contd.)
Stimulation of small fiber input inhibits cells in SG and "open the gate".
An open gate increases the stimulation of 2nd order neuron cells & increases transmission of impulses and enhances pain perception
In addition to gate control through large and small fibers stimulation, the CNS, through efferent pathways, may close, partially close, or open gate
Cognitive functioning may thus modulate pain perception
NEURAL MECHANISM OF ANALGESIA
– Opioid agonists inhibit the release of excitatory transmitters from the primary afferents that relay the pain message to them
– They directly inhibit the dorsal horn pain transmission neurons
– Thus opioids exert a powerful analgesic effect directly on the spinal cord
(contd.)(contd.)
Inhibit neurons in pain- modulating descending pathways
Inhibition of inhibitory neurons in several location
Neurons that send processes to the spinal cord & inhibit pain transmission are activated
ORGAN SYSTEM EFFECTS OF MORPHINE & ITS SURROGATES
CNS EFFECTS– Principal effects of opioid
analgesics with affinity for receptors are on CNS
– Analgesia, euphoria, sedation & respiratory depression, cough suppression, miosis, truncal rigidity, nausea vomiting, temperature
MIOSIS– Valuable in the diagnosis of opioid
overdose (no tolerance)
– Can be blocked by opioid antagonists
– Mediated in part by parasympathetic pathways
TRUNCAL RIGIDITY– Increase in tone of the large trunk
muscles
– Reduces thoracic compliance & thus interferes with ventilation
– Prevented by concomitant use of neuromuscular blocking agents
NAUSEA & vomiting– Activate brainstem CTZ
TEMPERATURE - Homeostatic regulation of body
temperature is mediated in part by endogenous opioid peptides
– Hypothermia
PERIPHERAL EFFECTSCARDIOVASCULAR SYSTEM– No significant direct effect on the heart
& cardiac rhythm except bradycardia– Meperidine may result in tachycardia
due to its antimuscarinic action– Blood pressure is usually well
maintained unless the CVS is stressed, in which case hypotension may occur (due to peripheral arterial & venous dilation)
GASTROINTESTINAL TRACT
– Constipation– Tolerance does not develop – Opioid receptors present in high
density – Stomach motility decreases but tone
increases– Nonpropulsive contractions of
intestine– Delayed passage of fecal mass
BILIARY TRACT
– Constrict biliary smooth muscle, which may result in biliary colic
– Sphincter of Oddi may constrict, resulting in reflux of biliary & pancreatic secretions and elevated plasma amylase & lipase levels
RENAL
– Renal function is depressed– Due to decreased renal plasma flow– Opioids have an anti-diuretic effect– Enhance renal tubular sodium
absorption– Ureteral & bladder tone are
increased– Increased sphincter tone
UTERUS– May prolong labor
NEUROENDOCRINE– Stimulate release of ADH, prolactin, &
somatotropin– Inhibit release of LH
PRURITIS– Flushing & warming of the skin
accompanied sometimes by sweating & itching
MISCELLANEOUS– Modulate the actions of the immune
system– Natural killer cell cytolytic activity &
lymphocyte proliferative responses usually inhibited
– Mediated by the sympathetic NS in acute administration & by the hypothalamic-pituitary-adrenal system in prolonged administration
CLINICAL USE OF OPIOID ANALGESICS
A.Analgesia– Severe, constant pain– Sharp, intermittent pain is not as
effectively controlled– Useful in the management of pain
associated with cancer & other terminal illnesses
– Used during obstetric labor (meperidine)
B.Acute pulmonary edema– Remarkable relief in dyspnea from
pulmonary edema associated with left ventricular failure
– Involves reduced perception of shortness of breath & reduced patient anxiety as well as reduced cardiac preload (reduced venous return) and afterload (decreased peripheral resistance)
– Useful in treating painful myocardial ischemia with pulmonary edema
– morphine
Relief of anxiety & apprehension in pts Relief of anxiety & apprehension in pts with MI, internal bleeding with MI, internal bleeding They are NOT anxiolytics or hypnoticsThey are NOT anxiolytics or hypnotics
CARDIAC ASTHMA OR acute LVFCARDIAC ASTHMA OR acute LVFReduce preload & after load – VD Reduce preload & after load – VD Shift blood from pulm to systemic circuitShift blood from pulm to systemic circuitRelieves air hunger by depressing resp Relieves air hunger by depressing resp centrecentreCalms pt - decreases symp response – Calms pt - decreases symp response – decrease workloaddecrease workload
C.Cough– Suppression of cough (obtained at doses
lower than those needed for analgesia)– Both central & peripheral effects– Codeine, dextromethorphan,
levopropoxyphene, noscapine
D.Diarrhea– Diarrhea from any cause– Crude opium preparations used in the
past– Synthetic surrogates with more selective
GI effects & few or no CNS effects are used (diphenoxylate, loperamide)
E.Anesthesia– Frequently used as preanesthetic
medication because of their sedative, anxiolytic, and analgesic properties
– Also used intra-operatively both as adjuncts to other anesthetic agents and in high doses
– Fentanyl, as a primary component of anesthetic regimen, most commonly in cardiovascular surgery
– Neuroleptanesthesia( contd. )( contd. )
– Used as regional analgesics due to their direct action on the neurons of the spinal cord dorsal horn- epidural or subarachnoid space
– Morphine is most frequently used– Adverse effects are less common– Respiratory depression, pruritis,
nausea & vomiting may occur and can be reversed with naloxone
– Fentanyl + LA- pain management– Post op shivering-meperidine
used
PATIENT CONTROL PATIENT CONTROL ANALGESIA (PCA)ANALGESIA (PCA)
Parenteral infusion device Parenteral infusion device controlled by the patient by controlled by the patient by pressing a button to deliver a pressing a button to deliver a programmed dose of the desired programmed dose of the desired opioid analgesicopioid analgesic
TOXICITY & UNDESIRED TOXICITY & UNDESIRED EFFECTSEFFECTS
Direct toxic effects are extensions of their pharmacologic actions
Include respiratory depression, nausea, vomiting & constipation
Tolerance & dependence Overdosage ( diagnosis &
treatment) Contraindications
Stupor------- comaStupor------- coma RR low------- apnea, cyanosisRR low------- apnea, cyanosis HypotensionHypotension Pinpoint pupilPinpoint pupil HypothermiaHypothermia Death due to resp. failureDeath due to resp. failure TRIAD of pinpoint pupils, coma & resp. TRIAD of pinpoint pupils, coma & resp.
depression strongly suggests opioid depression strongly suggests opioid poisoningpoisoning
TOLERANCETOLERANCE– With frequently repeated administration of
therapeutic doses of morphine or its
surrogate, there is a gradual loss in
effectiveness– To reproduce the original response, a larger
dose must be administered– Develops most readily when large doses are
given at short intervals & is minimized by
giving small amounts of drug with longer
intervals between doses
– Opioid rotation– Receptor uncoupling
CROSS TOLERANCE– Patient tolerant to morphine show a
reduction in analgesic response to other agonist opioids
PHYSICAL DEPENDENCEPHYSICAL DEPENDENCE– Occurrence of a characteristic withdrawal
or abstinence syndrome when the drug is stopped or an antagonist is administered
– Signs & symptoms of withdrawal include rhinorrhea, lacrimation, yawning, chills, gooseflesh (piloerection), hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhea, anxiety & hostility
– Methadone is used in the detoxification of heroin addicts as the slower subsidence of effects is associated with a less intense immediate syndrome
– Buprenorphine+ naloxone also used in maintenance treatment plans
– Antagonist-precipitated withdrawal
PSYCHOLOGIC PSYCHOLOGIC DEPENDENCEDEPENDENCE
Compulsive use promoted due to:
– Euphoria– Indifference to stimuli– Sedation – Abdominal symptoms
DIAGNOSIS & TREATMENT OF DIAGNOSIS & TREATMENT OF OPIOID OVERDOSAGEOPIOID OVERDOSAGE
– Known addict, needle marks, miosis– Difficult to diagnose in comatose
patients– I/V injection of naloxone reverses
coma due to opioid overdose but not that due to other CNS depressants
Degrees of tolerance that may develop to some of the effects of
the opioid
High ModerateMinimal or
none
AnalgesiaEuphoria,dysphoriaMental cloudingSedationResp. depressionAntidiuresisNausea & vomitingCough suppression
Bradycardia MiosisConstipationConvulsions
CONTRAINDICATIONS & CAUTIONS IN THERAPY
1. Use of pure agonists with weak partial agonists
2. Use in patients with head injuries
3. Use in patients with endocrine disease
4. Use in patients with impaired pulmonary functions
5. Use in patients with impaired hepatic or renal function
6. Use during pregnancy Fetus may become physically dependent
in utero & manifest withdrawal symptoms in the early postpartum period
signs & symptoms of withdrawal syndrome in the infant include irritability, shrill crying, diarrhea or even seizures
treated with diazepam in mild withdrawal Camphorated tincture of opium is given
in severe withdrawal Oral methadone is also used
DRUG INTERACTIONSDRUG INTERACTIONS
Drug groupInteraction with opioids
Sedative-hypnotics
Increased CNS depression, particularly respiratory depression
Antipsychoti
cs
Increased sedationAccentuation of CVS effects
MAO inhibitors
Contraindicated because of high incidence of hyperpyrexic coma
METHADONEMETHADONE Long acting MOR agonistLong acting MOR agonist potent & clinically useful analgesic (oral BA
better than morphine) Relieves difficult to treat pain Used in the treatment of opioid abuse (long
t1/2) OPIOID ROTATION to methadone provides
superior analgesia For detoxification of a heroin-dependent
addict, low doses of methadone(5-10mg) are given two or three times daily for 2 to 3 days
FENTANYLFENTANYL SyntheticSynthetic Sufentanil > fentanyl >alfentanylSufentanil > fentanyl >alfentanyl Short time to peak analgesic effect, Short time to peak analgesic effect,
rapid termination, minimal direct rapid termination, minimal direct myocardium depressant effect, myocardium depressant effect, reduce dosing requirement for the reduce dosing requirement for the volatile agents– useful in anesthesiavolatile agents– useful in anesthesia
Remifentanyl – ester – short tRemifentanyl – ester – short t1/2, 1/2, more more rapid onset, 1-1.5 mins after I/V – rapid onset, 1-1.5 mins after I/V –
CODEINECODEINE Semisynthetic opioid - Methyl morphineSemisynthetic opioid - Methyl morphine Converted to morphine by CYP2D6 which Converted to morphine by CYP2D6 which
is responsible for analgesic actionis responsible for analgesic action Used in coughUsed in cough Less efficacious than morphine & Less efficacious than morphine &
adverse effects limit doseadverse effects limit dose Oxycodone more potent – prescribed in Oxycodone more potent – prescribed in
higher doses - abusehigher doses - abuse
HEROIN HEROIN DiacetylmorphineDiacetylmorphine Hydrolyzed to 6-Hydrolyzed to 6-
monoacetylmorphine monoacetylmorphine
cross into CNScross into CNS morphinemorphine
Excreted in urine as free and Excreted in urine as free and conjugated morphineconjugated morphine
MEPERIDINE (Pethedine)
Potent MOR agonist – strong analgesic effects
Antimuscarinic effects Inhibits catecholamine re-uptakeContraindicated with tachycardiaNegative inotropic effect on the heartSeizures with normeperidineSerotonin syndrome with MAO inhibitorsUsed in post anesthetic shivering
DIPHENOXYLATE & DIPHENOXYLATE & LOPERAMIDELOPERAMIDE
NOT for analgesia NOT for analgesia TREATMENT of DIARRHEATREATMENT of DIARRHEA Diphenoxylate – metabolite difenoxinDiphenoxylate – metabolite difenoxin Poorly soluble (even salts are insoluble in Poorly soluble (even salts are insoluble in
aqueous solution) so parenteral use is aqueous solution) so parenteral use is limitedlimited
+ atropine to reduce likelihood of abuse+ atropine to reduce likelihood of abuse Loperamide – limited access to brain so Loperamide – limited access to brain so
abuse potential very lowabuse potential very low
OPIOID OPIOID AGONIST/ANTAGONIST & AGONIST/ANTAGONIST &
PARTIAL AGONISTSPARTIAL AGONISTS
PentazocinePentazocine NalbuphineNalbuphine ButorphanolButorphanol BuprenorphineBuprenorphine partial partial
agonistagonist
competitive MOR
antagonist but KOR agonist
PENTAZOCINEPENTAZOCINE
KOR agonistKOR agonist Weak MOR antagonist or partial agonistWeak MOR antagonist or partial agonist Orally or parenterally but causes Orally or parenterally but causes
irritation so not used S/Cirritation so not used S/C Morphine like CNS effects - analgesia, Morphine like CNS effects - analgesia,
sedation, respiratory depression.sedation, respiratory depression. High dose – dysphoric effectsHigh dose – dysphoric effects CVS increase BP & HRCVS increase BP & HR
NALBUPHINENALBUPHINE Strong KOP agonistStrong KOP agonist MOR antagonistMOR antagonist Less likely to produce dysphoric effects Less likely to produce dysphoric effects
otherwise similar to pentazocineotherwise similar to pentazocine Ceiling effect- increases in dose beyond Ceiling effect- increases in dose beyond
30mg produces no further respiratory 30mg produces no further respiratory depression or analgesiadepression or analgesia
Safer in patients with cardiac disease Safer in patients with cardiac disease than pentazocinethan pentazocine
Precipitates abstinence syndrome in Precipitates abstinence syndrome in subjects dependent on low doses of subjects dependent on low doses of morphine morphine
Prolonged use can produce physical Prolonged use can produce physical dependencedependence
Parenteral onlyParenteral only
BUPRENORPHINEBUPRENORPHINE Buprenorphine- potent long acting Buprenorphine- potent long acting
partial MOR agonist and KOR antagonistpartial MOR agonist and KOR antagonist 25-50X more potent than morphine]25-50X more potent than morphine] 0.4mg = 10mg morphine0.4mg = 10mg morphine S/L to avoid 1S/L to avoid 1stst pass pass Resistant to naloxone reversalResistant to naloxone reversal Opioid dependenceOpioid dependence Slow dissociation from receptorsSlow dissociation from receptors
BUTORPHANOLBUTORPHANOL Similar to pentazocine & nalbuphineSimilar to pentazocine & nalbuphine Predominantly KOR agonistPredominantly KOR agonist MOR antagonistMOR antagonist Used for relief of acute post-op pain Used for relief of acute post-op pain Equal analgesia as nalbuphine but more Equal analgesia as nalbuphine but more
sedationsedation Increase BP & HRIncrease BP & HR incidence of psychotomimetic effects incidence of psychotomimetic effects
lower than pentazocine but still presentlower than pentazocine but still present
TRAMADOL & TRAMADOL & TRAPENTADOLTRAPENTADOL
Synthetic codeine analogSynthetic codeine analog Weak MOR agonistWeak MOR agonist Analgesic effect predominantly due to Analgesic effect predominantly due to
inhibition of reuptake of NE & 5HTinhibition of reuptake of NE & 5HT As effective as morphine & meperidine in As effective as morphine & meperidine in
mild to moderate painmild to moderate pain Oral & I/MOral & I/M Active metabolite formed in liver by Active metabolite formed in liver by
CYP2D6CYP2D6 tt1/21/2= 6-8hrs= 6-8hrs Max dose 400mgMax dose 400mg
Adverse effects:Adverse effects: Nausea, vomiting, dizziness, dry mouth, Nausea, vomiting, dizziness, dry mouth,
sedation and headachesedation and headache SeizuresSeizures Respiratory depression but less than Respiratory depression but less than
morphinemorphine Not to be used in patients taking MAO Not to be used in patients taking MAO
inhibitors, SSRIs or drugs that lower inhibitors, SSRIs or drugs that lower seizure thresholdseizure threshold
OPIOID ANTAGONISTSOPIOID ANTAGONISTS
PURE OPIOID PURE OPIOID ANTAGONISTANTAGONIST
NALOXONE, NALTREXONE, NALMEFENE Pure antagonistsPure antagonists
Morphine derivatives with Morphine derivatives with bulkier substituents at Nbulkier substituents at N17 17
High affinity for High affinity for -opioid -opioid binding sites binding sites
Naloxone – I/V, short tNaloxone – I/V, short t1/21/2 1-2hrs 1-2hrs Naltrexone – oral, tNaltrexone – oral, t1/21/2 10hrs 10hrs Nalmefene – only I/V, tNalmefene – only I/V, t1/21/2 10hrs 10hrs
Absence of an agonist – inert Absence of an agonist – inert completely reverse opioid effects in completely reverse opioid effects in 1-3 mins1-3 mins
Acute overdose – Normalizes Acute overdose – Normalizes respiration, level of consciousness, respiration, level of consciousness, pupil size, bowel activity, & pupil size, bowel activity, & awareness of painawareness of pain
Dependent subjects – precipitate Dependent subjects – precipitate abstinence syndrome abstinence syndrome
Treatment of acute opioid overdoseTreatment of acute opioid overdose 1 mg naloxone = 25mg heroin1 mg naloxone = 25mg heroin Keep in mind the short duration of actionKeep in mind the short duration of action Initial dose is 0.1-0.4 mg I/V (neonates Initial dose is 0.1-0.4 mg I/V (neonates
10ug/kg)10ug/kg) Maintenance with 0.4-0.8 mg I/V repeat as Maintenance with 0.4-0.8 mg I/V repeat as
requiredrequired Low dose 0.04 mg – treatment of adverse Low dose 0.04 mg – treatment of adverse
effects associated with I/V or epidural opioidseffects associated with I/V or epidural opioids Methylnaltrexone & alvimopan Methylnaltrexone & alvimopan
NALTREXONE NALTREXONE – maintenance drug for – maintenance drug for addictsaddicts
Decreases alcohol craving in chronic Decreases alcohol craving in chronic alcoholics by increasing baseline alcoholics by increasing baseline --endorphinsendorphins
Facilitates abstinence from nicotine Facilitates abstinence from nicotine with reduced weight gainwith reduced weight gain