BACLOFEN

PRESENTED BY:
KRISHNA GHIMIRE
INTERN
 INTRODUCTION:
• Baclofen is the centrally acting muscle relaxant.

• It is an analogue of the inhibitory neurotransmitter GABA ie;gamma

amino butyric acid.

• It is a GABA receptor agonist,more accurately GABAB

receptor agonist.

• It reduces the skeletal muscle tone by selective action in the

cerebrospinal axis without altering consciuosness.
• The volume of distribution of baclofen is 0.7 L/kg.As baclofen is
mainly water-soluble, it does not readily cross the blood-brain barrier.
Drug concentrations of baclofen in the cerebrospinal fluid are
approximately 8.5 times lower than in the plasma

• The protein binding is approximately 30%.

• Approximately 15% of the oral dose is metabolized in the liver, mainly

by deamination.Deamination yields the main metabolite, β-(p-
chlorophenyl)-4-hydroxybutyric acid, which is pharmacologically
inactive.
 GABA receptor
• They are divided into,

GABAA receptor
Intrinsic ion channel receptor
increases chloride conductance
blocked by Bicuculine
facilitated by benzodiazipine
 GABAB receptor

• G-protein coupled receptor

• Hyperpolarize neurones by increasing k+ conductance and

decreasing Ca++

• GABAB stimulate the opening of K+ channels, specifically GIRKs, which

brings the neuron closer to the equilibrium potential of K+.

• This reduces the frequency of action potentials which reduces

neurotransmitter release.Thus GABAB receptors are inhibitory receptors.
• The primary site of action of Baclofen is in the spinal cord where it
depressed both monosynaptic and polysypnatic reflex.As such,it does
produce muscle weakness
• Less sedative than Diazepam
• It reduces spasticity in many neurological disorder like multiple
sclerosis,spinal injuries
• Baclofen is well absorbed orally and is primarily excreted unchanged
in urine .
• Half life is about 3-4 hours.
 MECHANISM OF ACTION:

• The exact mechanism of action of baclofen is unclear.

• Baclofen is an agonist at the beta subunit of gamma-aminobutyric

acid (GABA) receptors expressed on pre- and post-synaptic neurons.

• Upon binding to GABAB, baclofen causes an influx of potassium into

the neuron, leading to hyperpolarization of the neuronal membrane
and decreased calcium influx at presynaptic nerve terminals.
• This results in a decreased rate of action potential threshold being reached
by presynaptic neurons.

• It reduceas action potential of postsynaptic motor neurons that innervate

the muscle spindles.

• Baclofen thereby inhibits the transmission of both mono- and polysynaptic

reflexes at the spinal cord, relaxing spasticity.

• Baclofen may act on some voltage-gated calcium channels; however, the

clinical significance of this is unclear.
GABA binds to GABA-B

decrease in CAMP formation

inhibition of adenyl cyclase

inhibiton of IP3-DAG system

decrease in ca++ release from ER

inhibitory response(decrease spasticity)

 USES OF BACLOFEN
oral baclofen
• To treat the spasticity resulting from multiple sclerosis
• For the relief of flexor spasm and concomitant pain,clonus and
moscular rigidity.
• To treat patient of spinal cord diseases.

intrathecal baclofen
• Management of severe spasticity especially of cerebral origin
• If patients unresponsive to oral therapy
• Spasticity due to traumatic brain injury
Baclofen in psychiatric cases

• ALCOHOL ADDICTED PATIENTS

used as Anti-craving agent
anxiolytic agent

• POST TRAUMATIC STRESS DISORDER(PTSD)

 USE IN ALCOHOL USE DISORDER
• Baclofen is a structural analogue of gamma-aminobutyric
acid (GABA). It has an anti-spasticity effect by acting in the
spinal cord.
• It slows down the transmission of reflexes/spasms by
stimulating the GABA-B receptors in the spinal cord. The key
role of the GABA-B receptor in the causation of addictions
has been demonstrated.
• GABA-B receptor dysfunction has been documented in
alcohol dependence, and may also be responsible for the
comorbid anxiety in people with AUD and in relapse into
drinking.
• The GABA-B receptors are found
in the reward pathway of the
brain, the mesolimbic
dopaminergic (MLD) pathway, on
the pre-synaptic side of the
dopaminergic neurons. When
activated, the GABA-B receptors
decrease the release of dopamine
into the synapse.
• The GABA-B receptor agonists,
like baclofen, cause a particularly
marked decrease in the release of
dopamine in two parts of the
MLD pathway, the nucleus
accumbens and ventral tegmental
area.
• Baclofen action in addiction is therefore a combination of its Anticraving
effect ie a control to the compulsion to drink, with an indefferences to the
effect of alcohol and the context of drinking behaviour and an anti anxiety
effect which reduces the risk of relapse.

• Baclofen reduces the releases of excitatory neurotransmitter in pre-

synaptic area and stimulates the releases of inhibitory neurotransmitter in
the post synaptic neurons.

• Alternatively, GABA-B receptor agonists which attach to the pre-synaptic

part of glutamatergic neurons in the limbic system can change the
conditioned response to pleasant or unpleasant experiences, important in
addiction.
 The Hypothesis of Professor Olivier Ameisen

• Olivier Ameisen was a brilliant cardiologist suffering from an Alcohol Use

Disorder (AUD), refractory to all alcohol dependence treatments. For him,
alcohol dependence was a neurological disease: the symptoms of cravings
and loss over control over drinking were due to abnormalities in brain
functioning.

• Treating alcohol cravings with medication targeting the brain networks

involved would treat the disease of alcohol dependence.
• The conventional treatments for alcohol dependence could diminish but not
eradicate cravings. When Ameisen looked at animal models of alcohol
dependence, he found that baclofen was the only pharmaceutical agent
capable of completely extinguishing cravings for alcohol. The effect of
baclofen on cravings increases with increasing doses and the extinction of
cravings happens at doses of around 3mg/kg.

• Amiesen hypothesized that the effect in rats might also happen in humans
so he treated himself with similar doses of baclofen. At a dose of 270mg/day,
Ameisen became “indifferent” to alcohol.

• After having published a case report of his own experience in 2005 , Ameisen
proceeded to publish a book about baclofen treatment for AUD “The End of
My Addiction” , first in France in 2008 then worldwide.
DR. OLIVIER AMEISEN
 The Concept of Indifference

• The aim of baclofen treatment is to render the patient “indifferent” to

alcohol. Baclofen is the only current AUD treatment capable of
producing this effect.

• “Indifference” is a new concept in Addiction Medicine, described for

the first time by Olivier Ameisen as “bottles of alcohol don’t talk to me
anymore” and is often not really understood.
• It is characterized by a complete eradication of obsessional thoughts
about alcohol and, as a consequence, a drinking pattern that becomes
effortlessly moderated to reasonable levels or to an abstinence which
is freely chosen. As Ameisen described, “I am not forcing myself to
remain abstinent, I just don’t feel like drinking anymore”.

• Indifferent AUD patients don’t need to work at reducing their alcohol

consumption. Quite simply, they no longer feel the urge to drink: their
addiction has disappeared.
 Indication

• Baclofen is indicated for all forms of alcohol use disorder, whichever

its form, abuse or dependence, occasional or continuous.

• Baclofen is indicated whether the aim of the patient is a complete

abstinence or a simple reduction of alcohol consumption.

• Baclofen is also indicated in all medical illnesses resulting from

chronic alcohol overconsumption, such as cirrhosis.
 CONTRAINDICATION

• Baclofen has no absolute contraindications except true allergy.

• Baclofen treatment is not recommended in patients with certain rare

inherited diseases of the carbohydrate molecules, glucose and
galactose or in patients with lactase deficiency or intolerance to
galactose.

• Besides, there are a number of clinical conditions, e.g. obstructive sleep

apnoea and renal insufficiency, that must be thoroughly evaluated with
the patient before treatment initiation, in order to minimize the risk of
adverse events and medical morbidity.
 TITRATION
• The titration of baclofen involves increasing the dose slowly and
progressively. The pattern of dose increases will vary between
baclofen prescribers who will have their own ways of doing the
titration and will vary between individual patients: how
independently they normally function, how much they want to guide
their own treatment and what other health problems they already
have.

• The titration regime continues by continuing additions of 10mg to the

total daily dose until the effective dose for that individual is reached.
This is the dose at which there is a complete suppression of cravings,
i.e. “indifference”. The patient will recognize when the effective dose
has been reached.
 MOST COMMON SIDE EFFECT
• Sleepiness
• Fatigue
• paradoxical insomnia
• Nausea,Vomiting and Digestive problem
• Dizzines
• memory problem or trouble concentrating
• Sensory disorders;parasthesia,tinnitus,pain,hallucination etc
• blunting of emotion
• muscle weakness
LESS FREQUENT SIDE EFFECT
• sleep apnoea
• depression
• hypomania and mania
• confusional state
• others;oedema,excessive salivation,tremors,irritability,speech
disturbances
 OVERDOS
E
The sign of overdose are,,

• Increasing loss of consciousness up to coma.

• Weakness or hypotonicity of muscles which can last up to 72 hours

and can affect the respiratory muscles.

• Other symptoms such as confusion, hallucinations, vertigo, nausea,

vomiting, excessive salivation, seizures, bradycardia, hypotension and
hypothermia.
 Management
There is no antidote to baclofen,,
• stop the baclofen treatment
• Transfer immediately to hospital.
• Full supportive care which may include intubation.
• Hemodialysis can be used in cases of severe baclofen toxicity to
decrease clinical manifestations and shorten the treatment time
required.
• Seizures are treated with IV benzodiazepines e.g. midazolam.
 INTERACTIONS
• It may be necessary to adjust the dose of baclofen if other
medications are taken such as:
• Sedative medications which calm the activity of the brain such as
antipsychotic medications, benzodiazepines (eg valium), sleeping
tablets.
• Tricyclic antidepressants which can increase muscle hypotonicity.
• Medications used to treat high blood pressure: baclofen may increase
their effect on lowering blood pressure.
• Levodopa
• Medications which can cause postural hypotension i.e. large drops in
blood pressure when standing up.
 BACLOFEN IN PTSD
• As one of the primary neurotransmitters in the brain, GABA is an inhibitory (vs.
excitatory) chemical responsible for creating the calming, rhythmic electrical
impulses in the brain. It elevates the production of alpha waves associated
with feeling relaxed (without drowsiness) and boosts mental alertness. GABA
lowers beta waves, impulses that contribute to a state of nervousness, racing
thoughts and hyperactivity.

• While a balanced brain receives regular, smooth electrical impulses, a GABA

deficient one receives them in spurts. As a result, the brain experiences
arrhythmia, or dysrhythmia which directly affects overall emotional well-being.

• .Researchers believe GABA levels can be low in PTSD survivors, which means
there is less nerve transmission inhibition leading to increased levels of anxiety
 MY REFERENCES
• K.D TRIPATHI

• A prescription guide for baclofen in Alcohol Use Disorder- For use by

physicians and patients,Sylvie Imbert1, Samuel Blaise2, Jacques
Bérard3, Renaud de Beaurepaire4*, Amanda Stafford5 and Philippe
Jaury6

• Baclofen Treatment for Chronic Posttraumatic Stress Disorder,Roger G

Drake, Lori L Davis, […], and Joette S Lowe+3View all authors and
affiliations
THANK YOU.