NALTREXONE

PRESENTED BY:
PRAG G.K. SUBEDI
INTERN( DEPARTMENT OF PSYCHIATRY)
HISTORY:
• Naltrexone was first synthesized in 1963 by Metossian at Endo
Laboratories, a small pharmaceutical company in New York City.

• It was characterized by Blumberg, Dayton, and Wolf in 1965 and was

found to be an orally active, long-acting, and very potent opioid
antagonist.

• The drug showed advantages over earlier opioid antagonists such as

cyclazocine, nalorphine, and naloxone, including its oral activity and a
long duration of action allowing for once-daily administration.
• The drug was approved by the FDA for the oral treatment of opioid
dependence in 1984.

• And for the oral treatment of alcohol dependence in 1995.

• A depot formulation for intramuscular injection was approved by the

FDA for alcohol dependence in 2006 and for opioid dependence in
2010.
CHEMISTRY:
• Naltrexone, also known as N-cyclopropylmethylnoroxymorphone, is a
derivative of oxymorphone (14-hydroxydihydromorphinone).

• It is specifically the derivative of oxymorphone in which the tertiary

amine methyl substituent is replaced with methylcyclopropane.
PHARMACOKINETICS:
ABSORPTION:
• Absorption after oral administration is rapid.

• 96%(i.e nearly complete absorption) absorbed from gastrointestinal

tract, but because of first-pass metabolism, only 5-40% reaches
systemic circulation.

• So bioavailability is 5-40%.

• Onset: 15-30 min

• Duration: 24 hr

• Peak plasma time: PO tablet, 1 hr; PO solution, 0.6 hr

• Peak plasma concentration (50-mg dose): Naltrexone, 10.6-13.7 ng/mL;

6-β-naltrexol, 109-139 ng/mL

DISTRIBUTION:

• Plasma protein binding of naltrexone is 21 to 28%.

• volume of distribution of naltrexone is 1350 L

METABOLISM:
• Naltrexone is metabolized in the liver mainly by dihydrodiol
dehydrogenases into 6β-naltrexol (6β-hydroxynaltrexone).

• Levels of 6β-naltrexol are 10- to 30-fold higher than those of

naltrexone with oral administration due to extensive first-pass
metabolism

• 6β-Naltrexol is an opioid receptor antagonist similarly to naltrexone

and shows a comparable binding profile to the opioid receptors.

• However, 6β-naltrexol is peripherally selective and crosses into the

brain much less readily than does naltrexone.
• In any case, 6β-naltrexol does still show some central activity and may
contribute significantly to the central actions of oral naltrexone.

• Other metabolites of naltrexone include 2-hydroxy-3-methoxy-6β-

naltrexol and 2-hydroxy-3-methoxynaltrexone.

• Following their formation, the metabolites of naltrexone are further

metabolized by conjugation with glucuronic acid to form
glucuronides.

• Naltrexone is not metabolized by the cytochrome P450 system and

has low potential for drug interactions.
EXCRETION:
• Half lives of oral naltrexone and the metabolite 6β-naltrexol are 4
hours and 13 hours respectively.

• Half life for both naltrexone and the metabolite 6β-naltrexol given in
once monthly im injection form is 5 to 10 days.

• Naltrexone and its metabolites are excreted in urine.

PHARMACODYNAMICS AND MOA:
• Naltrexone and its active metabolite 6β-naltrexol are competitive
antagonists of the opioid receptors.

• Naltrexone is specifically an antagonist preferentially of the μ-opioid

receptor (MOR), to a lesser extent of the κ-opioid receptor (KOR), and to a
much lesser extent of the δ-opioid receptor (DOR).

• However, naltrexone is not actually a silent antagonist of these receptors

but instead acts as a weak partial agonist, with Emax values of 14 to 29% at
the MOR, 16 to 39% at the KOR, and 14 to 25% at the DOR in different
studies.
• In accordance with its partial agonism, although naltrexone is
described as a pure opioid receptor antagonist, it has shown some
evidence of weak opioid effects in clinical and preclinical studies.

• By itself, naltrexone acts as an antagonist or weak partial agonist of

the opioid receptors.

• In combination with agonists of the MOR such as morphine however,

naltrexone appears to become an inverse agonist of the MOR.
• Conversely, naltrexone remains a neutral antagonist (or weak partial
agonist) of the KOR and DOR.

• In contrast to naltrexone, 6β-naltrexol is purely a neutral antagonist of

the opioid receptors.

• The MOR inverse agonism of naltrexone when it is co-present with

MOR agonists(Eg. Morphine) may in part underlie its ability to
precipitate withdrawal in opioid-dependent individuals.

• This may be due to suppression of basal MOR signaling via inverse

agonism.
CLINICAL USES:
• For the management of alcohol dependence.

• Blockade of effects of exogenously administered opioids (oral).

• Prevention of relapse to opioid dependence (injection).

• Naltrexone has also been under investigation for reducing behavioral

addictions such as gambling or kleptomania as well as compulsive sexual
behaviors.

• Low dose naltrexone(Daily dose of 1 to 5 mg) is used in chronic

autoimmune disorders like MS, Fibromyalgia, SLE etc. to reduce the pain
and neurological symptoms.
SIDE EFFECTS:
• Nausea, vomiting, decreased appetite.

• Dizziness, dysphoria, anxiety.

• Injection site reactions in case of im naltrexone (pain, tenderness,

pruritus, induration, swelling, erythema, or bruising); in some cases
injection site reactions may be very severe and may require surgery.

• Eosinophilic pneumonia
• Hepatocellular injury (at excessive doses i.e 100 to 300 mg daily)

• Weight Gain(Reported but not expected)

• Sedation(Occurs in significant minority)

CONTRAINDICATIONS:
• If patient is taking opioid analgesics.

• If patient is currently dependent on opioids or is in acute opiate withdrawal.

• If patient has failed the naloxone challenge test or has a positive urine
screen for opioids.

• Patients with an anticipated future need for opiates (such as those

expecting to undergo elective surgery) may not be good candidates for
naltrexone.
• If patient has acute hepatitis or liver failure.

• If there is a proven allergy to naltrexone.

• If there is a proven allergy to polylactideco-glycolide (PLG),

arboxymethylcellulose, or any other components of the diluent ( in
case of injection).
NALOXONE VS NALTREXONE:
NALOXONE NALTREXONE
Silent antagonist of opioid Not a silent antagonist( can act as
receptors( Thats why given in competitive antagonist, partial
opioid poisoning). agonist and inverse agonist).

Available in only injectable form as Available in both oral and im

oral bioavailability is only 2%. injection form.
Reaches peak concentration in 10 Reaches peak concentration in 1 to
mins(Thats why given in opiod 2 hours.
poisoning).
Half life is 30 to 81 mins. Half life ; Oral: 4 hrs and IM: 5-10
days
Duration of action is 1 to 4 hrs. Duration of action is up to 24
hrs( so used in mx of alcohol and
opiod dependence)

Hepatic metabolism. Hepatic metabolism.

Renal and biliary excretion. Only renal excretion.
MOA: Immediately knocks opiate Attaches to the opioid receptors in
drug off the opioid receptors in the the brain and prevents cravings for
brain and reverses the effect of these drugs.
opioid overdose.

No hepatotoxicity seen. May cause hepatotoxicity at higher

doses.
The Dopamine Theory of Addiction: The Mesolimbic
Dopamine Circuit as the Final Common Pathway of
Reward
• Dopamine is central to reward.

• Dopamine (DA), and specifically the mesolimbic pathway from the

ventral tegmental area (VTA) to the nucleus accumbens, has long been
recognized as a major player in the regulation of reinforcement and
reward.

• Naturally rewarding activities, such as achieving major accomplishments,

can cause fast and robust increase in DA in the mesolimbic pathway.

• Drugs of abuse also cause DA release in the mesolimbic pathway, and can
often increase DA in a manner that is more explosive and pleasurable
than that which occurs naturally.
• The mesolimbic dopamine pathway is modulated by many naturally
occurring substances in the brain in order to deliver normal
reinforcement to adaptive behaviors (such as eating, drinking, sex)
and thus to produce “natural highs,” such as feelings of joy or
accomplishment.

• These neurotransmitter inputs to the reward system include the

brain’s own morphine/heroin (endorphins), the brain’s own
cannabis/marijuana (endocannabinoids such as anandamide), the
brain’s own nicotine (acetylcholine [ACh]), and the brain’s own
cocaine/amphetamine (dopamine [DA] itself), among others.
• The numerous psychotropic drugs of abuse that occur in nature
bypass the brain’s own neurotransmitters and directly stimulate the
brain’s receptors in the reward system, causing dopamine release and
a consequent “artificial high.”

• Thus, alcohol, opioids, stimulants, marijuana, benzodiazepines,

sedative hypnotics, hallucinogens, and nicotine all affect this
mesolimbic dopaminergic system.
• When an alcohol-dependent person consumes alcohol, dopamine is
elevated in the nucleus accumbens.

• One mechanism of this elevation is the release of β-endorphin, which

stimulates dopamine release either directly (in the nucleus
accumbens) or indirectly (in the ventral tegmental area) by inhibiting
the activity of γ-aminobutyric acid (GABA) neurons, thereby
alleviating the blockade on dopamine cells. Naltrexone reverses both
of these actions.

• Acute alcohol use stimulates neurons in the ventral tegmental area of

the brain, inducing the release of dopamine in the nucleus
accumbens, an area of the brain that mediates reward,and pleasure.
• Low doses of alcohol stimulate the glutamate system, which enhances
dopaminergic activity and leads to arousal and increased energy.

• In contrast, higher doses of alcohol inhibit glutamate and augment

GABA neurotransmission, suppressing dopaminergic activity and
leading to sedation, among other effects.

• These pathways are further modulated by endogenous opioid-like

protein neurotransmitters, enkephalins and β-endorphin .

• Such “endogenous opioids” are thought to be released during alcohol

intoxication and may contribute to alcohol addiction by inhibiting
GABA pathways and enhancing dopaminergic signaling.
NALTREXONE IN MANAGEMENT OF
ALCOHOL DEPENDENCE:
• Naltrexone is an agent that blocks opioid receptors, particularly the μ-
opioid receptor.

• Use of this agent in leads to a reduction of dopamine levels in the

nucleus accumbens and a reduction in alcohol intake.

• The effect of environmental cues and associated alcohol craving can

also be blocked by pretreatment with opioid-receptor antagonists.
• In clinical laboratory settings, naltrexone has been shown to decrease
alcohol use as well.

• The confluence of these data has suggested that blocking opioid

receptors with naltrexone might be one potential treatment approach
to reduce alcohol use (by reducing the reward or pleasure of drinking)
and to maintain abstinence (by reducing craving induced by
environmental stimuli).
• The ideal patient for naltrexone therapy would be a person who has
moderate-to-severe alcohol dependence — for example, a person
who drinks on more than 50% of days, consumes more than five
drinks a day, and has alcohol-related problems.

• Such a person has probably failed in attempts to quit drinking but has
a relatively high motivation to be abstinent or at least to try
abstinence for a while.

• A good indication of this motivation is the ability to abstain from

drinking for several days before starting naltrexone.

• The patient should always be asked to attempt to abstain for several

days or be withdrawn from alcohol with medical assistance
(benzodiazepines or anticonvulsants) before the drug is prescribed.
• It is imperative that hepatic-enzyme tests (and perhaps tests of γ-
glutamyltransferase and carbohydrate-deficient transferrin, if
available)be obtained to establish baseline biomarker levels of
drinking, along with urine screening for drugs of abuse, before the
initiation of naltrexone treatment.

• Naltrexone is relatively contraindicated in patients who have liver-

enzyme levels that are four to five times above the upper limit of the
normal range.

• In addition, naltrexone, due to its blockade of brain opiate receptors,

should not be used in patients who are dependent on opiates or
those needing opiates for relief of chronic pain.
• The typical starting dose of naltrexone is 25 mg for several days, with
a subsequent increase to 50 mg per day over approximately 1 week.

• The drug should be taken after a meal, since nausea and vomiting are
more likely to occur if the drug is taken while fasting.

• If abdominal symptoms occur, a reduction in the dose or

maintenance of a lower dose with symptomatic treatment (e.g., with
bismuth subsalicylate) may be effective.
• Tests of hepatic enzymes (and possibly of γ-glutamyltransferase and
carbohydrate-deficient transferrin) should be obtained about a month
after the initiation of treatment.

• Such tests can be repeated monthly during a 4-month course of

treatment with naltrexone.

• Common adverse events are nausea, vomiting, headache, and fatigue.

• Most side effects are mild and self-limiting and usually occur only
during initial therapy.
• Treatment with daily oral naltrexone should last for at least 3 to 4
months.

• If the patient becomes completely abstinent during the last several

months of treatment, naltrexone can be stopped, and monthly
monitoring should continue during the next 4 to 6 months.

• If an increase in craving occurs or drinking resumes, naltrexone can

be restarted.

• If sporadic heavy drinking occurs during the first 3 to 4 months of

treatment, then continued naltrexone treatment for a prolonged
period (chronic treatment model) should be considered.
• If the patient continues to drink heavily in the face of naltrexone
treatment, the dose can be increased to 100 mg, or the use of long-
acting injectable naltrexone (380 mg administered intramuscularly
once every month) can be considered to rule out noncompliance as a
cause of treatment failure.

• In such cases, long-term use of oral or injectable naltrexone should

be prescribed and administered, and consultation with an alcohol-
treatment specialist should be considered.

• Naltrexone should not be prescribed without some sort of supportive

counseling or medical management.
• The regimen includes an emphasis on alcohol education, motivation
toward abstinence, referral to Alcoholics Anonymous if such
attendance is acceptable to the patient, assessment of medication
adherence, review of side effects, and laboratory testing

• Failure of this approach would trigger a referral to specialized alcohol

counseling.
COMPARISON WITH ACAMPROSATE IN
MANAGEMENT OF ALCOHIOL DEPENDENCE:

• It is a weak NMDA-receptor antagonist and a GABA-A receptor

activator.Because withdrawal of alcohol following chronic
administration can lead to excessive glutamate activity and deficient
GABA activity,acamprosate can act as “artificial alcohol” to mitigate
these effects.

• Acamprosate is an effective alternative to naltrexone and is the first

choice in patients with contraindications to naltrexone, including
those who are using opioids or prescribed opioids, or in those with
advanced liver disease.
• For patients who have minimal to no response to naltrexone as first line of
treatment, naltrexone is stopped and treated with acamprosate as second
choice (unless contraindicated i.e in individuals with severe renal dysfunction
(creatinine clearance ≤30 mL/min).

• In individuals with a partial or insufficient response to naltrexone augment

with acamprosate.

• Treatment with acamprosate is started when abstinence is achieved. The

usual dose for acamprosate is 666 mg three times daily.

• However, in individuals with moderate renal dysfunction (creatinine

clearance 30 to 50 mL/min) an initial dose of 333 mg three times daily is
recommended.

• Additionally, in individuals with a body weight <60 kg initiate treatment at a

NALTREXONE IN MANAGEMENT OF
OPIOID DEPENDENCE:
• Treatment of opioid addiction begins with managing withdrawal.

• Way to do this is to substitute a prescribed opioid at known dose and

avoid intravenous administration. There are two options: methadone or
buprenorphine.

• Methadone is a full agonist at μ-opioid receptors and can suppress

withdrawal symptoms completely when given orally and is usually
administered daily at ward.

• Buprenorphine is a μ-opioid partial agonist ,has less powerful agonist

effects, yet can suppress withdrawal symptoms especially when mild
withdrawal has already begun after stopping abused opioids.
• Although tapering off methadone or buprenorphine directly to a state
of opioid abstinence is theoretically possible, it is rarely successful
long term as stopping both of these can lead to withdrawl symptoms
(less intense and longer duration with methadone and less intense
and short duration withdrawl with buprenorphine) and hence to
avoid these withdrawl symptoms patient can go for street opioids and
hence relapse.

• So, intensity but not the duration of withdrawal of both methadone

and buprenorphine can be reduced by the addition of an α2A agonist

• Both clonidine and lofexidine are α2-adrenergic agonists that reduce

signs of autonomic hyperactivity during withdrawal and aid in the
detoxification process.
• And finally, in an attempt to enhance successful long-term abstinence,
opioid addicts may be transitioned not to abstinence but to
maintenance on a long-acting injectable opioid antagonist like
naltrexone.

• In the short run, naltrexone shortens the withdrawal time of an α2

agonist administered either with methadone or with buprenorphine.

• The advantages of giving naltrexone long term are having the drug
present at therapeutic levels all day long, in contrast to administering
naltrexone orally.

• Furthermore, with naltrexone monthly injections the opioid-abstinent

person now only has to make a decision to take medication once every
30 days instead of 30 times in 30 days. Even better, an impulsive patient
Figure showing fluctuating, dose dependent plasma concentration with oral
naltrexone and increased and consistent plasma concentration with im
naltrexone.
REFERENCES:
• STAHL’S ESSENTIAL PSYCHOPHARMACOLOGY[ Prescriber’s Guide ] 7th
EDITION BY STEPHEN M. STAHL
•STAHL’S ESSENTIAL PSYCHOPHARMACOLOGY[Neuroscientific Basis and
Practical Applications ] 5th EDITION BY STEPHEN M. STAHL
•BASIC AND CLINICAL PHARMACOLOGY 15 TH EDITION BY BETRAM G.
KATZUNG.
•ESSENTIALS OF MEDICAL PHARMACOLOGY 8TH EDITION BY KD
TRIPATHI.
• NALTREXONE FOR THE MANAGEMENT OF ALCOHOL DEPENDENCE:
Raymond F. Anton, M.D.[AUGUST 14 , 2008]
•KAPLAN & SADOCK'S SYNOPSIS OF PSYCHIATRY, 12th EDITION.
THANK YOU !