Baclofen (brand names Kemstro, Lioresal, and Gablofen) is a derivative of gamma-aminobutyric acid (GABA). It is
primarily used to treat spasticity and is under investigation for the
treatment of alcoholism.
It is an agonist for the GABAB receptors.[1][2] Its
beneficial effects in spasticity result from actions at spinal and supraspinal sites. Baclofen can also be used to
treathiccups, and has been shown to prevent rises in body temperature induced
by the drug MDMA in rats.[3]
In addition,
research has shown baclofen to be effective in the treatment of alcohol dependence and withdrawal,
by inhibiting both withdrawal symptoms andcravings.[4][5]
A very
beneficial property of baclofen is that tolerance does not seem to occur to any significant
degree — baclofen retains its therapeutic anti-spasmodic effects even after
many years of continued use.[6] However, oral dosage must be carefully
regulated; significantly high doses of the drug, particularly 80 milligrams per
day or higher, can cause excessive drowsiness that can interfere with daily function
Baclofen is widely used for the treatment of spastic
movement disorders, especially in
instances of spinal cord injury, spastic
diplegia cerebral palsy, multiple
sclerosis,amyotrophic lateral
sclerosis (Lou Gehrig's disease), peripheral
neuropathy and trigeminal and glossopharyngeal neuralgias.[citation needed]
Baclofen is often the primary, or at least
preliminary, drug treatment for spastic diplegia and more
general spasticity-based mobility
impairments. Research has not, however,
shown it to be consistently effective in improving function for people with
these issues.[7][8] Sometimes,
effects are immediate and clear; other times, effects may be mild, vague, or
nonexistent. What is known for sure is that, for unknown reasons, in about 5%
of the spastic cerebral palsy people who try intrathecally-administered baclofen, the drug has no
effect whatsoever on the person's spasticity. It does appear that intrathecal baclofen may be more effective than oral baclofen, but
some believe the long-term risks of an intrathecal pump (including potential
sudden infection, sudden malfunction leading to coma and death, etc.) outweigh
the potential benefits. Many clinicians and/or patients choose not to
administer baclofen intrathecally at all for such reasons. (Most manufacturers
of intrathecal pumps strongly disagree with the belief that an intrathecal pump
carries with it a significant or even remote risk of serious complication, despite
such things having occurred often enough to warrant concern.) Manufacturers
argue that a pump that fails shuts down, but this does not itself mean that a
suddenly punctured or similarly compromised pump would not pose a deathly risk
to its wearer.
Intrathecal pumps are much more commonly used
for the delivery of morphine than baclofen alone, although a mixture of both
for chronic pain sufferers is common. A failure of the type alleged with an
intrathecal pump with morphine would be fatal if it occurred when the pump was
full or near to full where even a small amount suddenly was released into the
Cerebral Spinal Fluid. It would likely be fatal if released into the abdominal
cavity. Similar circumstances are used as arguments against intrathecal baclofen.
Baclofen has been shown to be as effective as diazepam in uncomplicated alcohol withdrawal
syndrome.[4] An Italian study showed that it was effective in
promoting alcohol abstinence in patients with severe livercirrhosis.[9]
Due to its phenethylamine structure and properties, baclofen is useful in the
treatment of tardive dyskinesia.[10]
Oral baclofen, taken as needed, can be used to
alleviate painful low back spasms in patients with spinal abnormalities. It is
generally seen, for this use, as more effective than medications such as cyclobenzaprinee.g. Flexeril and Metaxalone e.g. Skelaxin but not as strong (or abusable) as carisoprodol e.g. Soma
Mechanism of action
Baclofen
produces its effects by modulating the GABAB receptor, similar to the drug GHB which
also activates this receptor and shares some of its effects. However, baclofen
does not have significant affinity for theGHB receptor, and has no known abuse
potential.[11][12] The modulation of the GABAB receptor is what produces baclofen's
range of therapeutic properties.
[edit]History
Historically
baclofen was designed to be a drug for epilepsy. It was synthesized for the
first time in Ciba-Geigy by the Swiss chemist Heinrich Keberle in 1962.[13] The effect on epilepsy was
disappointing but it was found that in certain patients spasticity decreased.
Baclofen was and is still given orally with variable effects. In severely
affected children, the oral dose is so high that side effects appear and the treatment
loses its benefit. How and when baclofen came to be used in the spinal sac is
not really clear but this is now an established method for the treatment of
spasticity in many conditions.
[edit]As a treatment for alcohol and other
addictions
Dr. Olivier Ameisen, a French-American
associate professor of medicine and a cardiologist at Weill Cornell Medical College of
Cornell University, reported in 2004 that he successfully used baclofen to
completely suppress his own alcohol addiction.[14] Ameisen called for randomized trials
of high-dose baclofen to be conducted to test the therapeutic model he had
proposed.[15] Ameisen believes, based on his own
experience and other anecdotal evidence, that baclofen acts on some mechanism
within the brains of addicts to suppress cravings brought on by addiction to
various substances such as alcohol, cocaine, and heroin.[15] However,
a few randomized clinical trials have shown mixed results to date.[15] A
more extensive clinical trial will take place starting in 2011.[15]
Ameisen authored Le Dernier Verre (The Last Glass,
titled The End of My Addiction and Heal
Thyself in English) to inform
public opinion and physicians.[16][17]
Based on
Ameisen's therapeutic model, some trials have been conducted in using baclofen
to treat cocaine addiction. In 2007, an Italian team
demonstrated the effectiveness and the safety of baclofen as a treatment for
alcohol addiction[5] There is also a report that baclofen
has beneficial role in the management of reflux disease.[18]
Inspired by
reading Olivier Ameisen’s The
End of My Addiction, a person who wishes to remain anonymous donated
$750,000 to the University of Amsterdam (UvA) in the Netherlands to initiate
the clinical trial of high-dose baclofen Ameisen had called for since 2004.[15] The
trial is scheduled to start in January 2011 and will be led by the team of Pr.
Dr. Reinout Wiers. Ameisen has been contacted by the team.[19] In May 2011 a Scottish team from
Glasgow presented: "Baclofen at a Tailored Dose Reduces Alcohol Use,
Craving and Consequences of Drinking in Alcoholics with Medical Disease due to
Alcohol Dependence" at the "Royal College of Pscychiatrists Faculty
of Addictions Psychiatry Annual Meeting". They used doses between 15 and
360 mg of baclofen per day and winning the conference prize for the best poster
raised the profile and increased interest in baclofen as anticraving drug.
In 2010, a small
study in Minnesota replicated findings from Italy indicating that off-label use
of the gamma-aminobutyric acid–derivative baclofen is effective in treating
symptoms of alcohol withdrawal syndrome (AWS).[20]
[edit]Description of compound
Baclofen is a
white (or off white) mostly odorless crystalline powder, with a molecular weight of 213.66 g/mol. It is slightly soluble in water, very slightly soluble in methanol, and insoluble in chloroform
Pharmacokinetics
The drug is rapidly absorbed after oral administration and is
widely distributed throughout the body. Biotransformation is low and the drug
is predominantly excreted in the unchanged form by the kidneys.
Routes of administration
Baclofen can be
administered either orally or intrathecally (directly into the cerebral spinal
fluid) using a pump implanted under the skin.
Oral doses are
typically 5–20 mg given 2-4 times/day. The maximum daily dosage is
80 mg. Titration generally occurs in 3 day increments e.g. 20 mg/day
for days 1-3, 40 mg/day for days 4-6, 60 mg/day for days 7-9, and
finally 80 mg/day for days 10-12. Careful titration of the medication
upwards from the minimum dose should provide a good enough indicator of how
much is needed for adequate spasticity relief. Baclofen can also be used on an
as needed basis, such as for pain relief of low back spasms; in these cases
dosing is the same (5–20 mg given 2-4 times/day, with the same
80 mg/day maximum) but taken only when symptoms arise.
Intrathecal
pumps offer much lower doses of
baclofen because they are designed to deliver the medication directly to the
spinal fluid rather than going through the digestive and blood system first.
They are often preferred in spasticity patients such as those with spastic diplegia, as very little of
the oral dose actually reaches the spinal fluid. Besides those with spasticity,
intrathecal administration is also used in patients with multiple sclerosis who have severe painful spasms which
are not controllable by oral baclofen. With pump administration, a test dose is
first injected into the spinal fluid to assess the effect, and if successful in
relieving spasticity, a chronic intrathecal catheter is inserted from the spine
through to the abdomen and attached to the pump which is implanted under the
abdomen's skin, usually by the ribcage. The pump is computer-controlled for
automatic dosage and the reservoir in the pump can be replenished by percutaneous injection.
In about 5% of
patients, the intrathecal route has absolutely no effect on the nervous system,
no matter how great a dose is administered.[citation needed] A similar lack of any effect have been
reported by those with spasticity who try the oral route,[citation
needed] but for
some, the oral route works while the intrathcal route does not. Again, there
are no known clinical theories as to why these discrepancies are present in the
baclofen-spastic CP pairing. Additionally, for some people with spasticity, a
lower dose of baclofen may be less effective, while for others that same dose
will be very effective. This is why clinicians always insist to a spastic
diplegic or similar person that s/he must start out with a low dose of baclofen
and increase the dosage slowly.
[edit]Dosage
Baclofen therapy
is usually started with an initial low dose of about 10 mg daily in
divided doses and gradually titrated up in a stepwise fashion until symptomatic
relief occurs. The usual maximum dose is 80 mg per day. However, it is
common to titrate the dosage until symptomatic control or relief is attained;
there is no inherent danger of baclofen in any dose in people with non-impaired
renal function as long as the dose is titrated properly, so as not to cause
undue side-effects such as oversedation. It is more common to use higher
dosages when attempting to treat drug cravings instead of spasticity.[5][21]
[edit]Withdrawal
syndrome
Discontinuation
of baclofen can be associated with a withdrawal syndrome which resembles benzodiazepine withdrawal and alcohol
withdrawal. Withdrawal symptoms are more likely if baclofen is used for
long periods of time (more than a couple of months) and can occur from low or
high doses. The severity of baclofen withdrawal depends on the rate at which
baclofen is discontinued. Thus to minimise baclofen withdrawal symptoms the
dose should be tapered down slowly when discontinuing baclofen therapy. Abrupt
withdrawal is most likely to result in severe withdrawal symptoms. Acute
withdrawal symptoms can be stopped by recommencing baclofen.[22]
Withdrawal
symptoms may include auditory
hallucinations, visual
hallucinations, tactile
hallucinations, delusions, confusion, agitation, delirium, disorientation, fluctuation of
consciousness, insomnia, dizziness,Nausea, Feeling Faint, inattention, memory
impairments, perceptual disturbances, pruritus/itching, anxiety, depersonalization, hypertonia, hyperthermia, formal thought disorder, psychosis, mania, mood disturbances, restlessness, and behavioral
disturbances, tachycardia, seizures, tremors, autonomic dysfunction, hyperpyrexia, extreme muscle rigidity resembling neuroleptic malignant syndrome and reboundspasticity.[22][23]
