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