Gabapentin in Brief
- Generic name : Gabapentin
- Brand names:
Gralise® (gabapentin extended release)
Horizant® (gabapentin enacarbil)
- Therapeutic class: Anti-epileptic, Anticonvulsant
- Pharmacologic class: 1-amino-methyl cyclohexoneacetic acid,
Gamma-aminobutyric acid (GABA) analogue
- FDA Approved: December 30, 1993
- Chemical Formula: C9H17NO2
- Pregnancy Category: C
- Habit forming? No
Gabapentin was originally discovered over 40 years ago by the Japanese,
who initially were looking for an antispasmodic or muscle relaxant.
It was later sold to Parke-Davis (Warner-Lambert, which merged with
Pfizer in 2000), who discovered effectiveness of gabapentin for treating
epileptics. During Parke-Davis' initial clinical studies, Gabapentin
was given in low doses and therefore efficacy was established as an
add-on. In other words, the patient was first given another anti-convulsant,
and then Gabapentin was added. Another study, being done
at this time, but as yet incomplete, will establish Neurontin as a mono
therapy. Currently, gabapentin is used by some doctors in doses up to 6,000 mg per day.
FDA approved indications
- Postherpetic neuralgia
Adjunctive therapy in the treatment of partial seizures with and without
secondary generalization in patients over 12 years of age with epilepsy.
Adjunctive therapy in the treatment of partial seizures in pediatric patients age 3–12 years.
- Moderate-to-severe restless legs syndrome (RLS) (Horizant® only)
Off-label & Investigational uses
- fibromyalgia 5
- bipolar disorder 8, 30
- postoperative analgesic 9
- migraine prophylaxis 10
- headache 31
- postmenopausal hot flashes 12
- interstitial cystitis (IC) 13
- painful diabetic neuropathy 14, 15
- social phobia 16
- depression 18
- panic disorder 19
- essential tremor 20
- generalized tonic-clonic seizures
- restless legs syndrome (RLS) 21, 22
- insomnia 23
- posttraumatic stress disorder (PTSD) 17
- irritable bowel syndrome (IBS) 24
- trigeminal neuralgia 25
- alcohol dependence 36
- refractory chronic cough 11
Gabapentin for Fibromyalgia
Gabapentin (1200-2400 mg per day) is safe and effective for the treatment
of pain and other symptoms associated with fibromyalgia. In a 12-week,
randomized, double-blind study a significantly greater proportion of
gabapentin-treated patients achieved response than placebo-treated patients
(51% versus 31%). Gabapentin compared with placebo also significantly
improved the BPI average pain interference score, the Fibromyalgia Impact
Questionnaire total score, the Clinical Global Impression of Severity,
the Patient Global Impression of Improvement, the Medical Outcomes Study
Sleep Problems Index , but not the mean tender point pain threshold
or the Montgomery Asberg Depression Rating Scale 5.
Gabapentin for Bipolar disorder
Evidence suggests that it may have mood-stabilizing and possibly antidepressant
properties in bipolar depression. However, gabapentin off-label use for bipolar
disorder is increasingly controversial.
Gabapentin may have a role as adjunctive agent in the treatment of
patients with bipolar disorders when complicated by co-morbid anxiety
disorder or substance abuse 29.
Small, randomized clinical trial comparing the prophylactic efficacy
of adjunctive gabapentin to placebo suggests that, despite lack of acute
efficacy, treatment with gabapentin might provide some benefit on the
long-term outcome of bipolar disorder 3.
In small, uncontrolled, heterogeneous study gabapentin, either alone
or as an adjunct, appeared moderately effective for depressive and manic
The findings of placebo-controlled study did not demonstrate that gabapentin
is an effective adjunctive treatment when administered to outpatients
with bipolar disorder 4.
Gabapentin for restless leg syndrome (RLS)
Restless legs syndrome is a disorder characterized by sensory and motor
symptoms in the legs that is best treated with dopaminergic drugs and
opiates. RLS is often difficult to treat. Gabapentin
provides a well-tolerated and effective treatment of RLS. It
improves sensory and motor symptoms in RLS and also improves sleep.
In clinical study gabapentin was associated with reduced symptoms
on RLS Rating Scale, Clinical Global Impression, pain analogue scale,
and Pittsburgh Sleep Quality Index. Also, studies showed significantly
reduced periodic leg movements during sleep and improved sleep architecture
(increased total sleep time, sleep efficiency, and slow wave sleep,
and decreased stage 1 sleep). Patients whose symptoms included pain
benefited most from gabapentin 22.
Gabapentin "pros" and "cons"
- Lack of cardiovascular or respiratory side effects
- Very good tolerability
- Benign side-effect profile
- Lack of hepatic metabolism
- Lack of liver and enzyme-inducing or -inhibiting effects
- Absence of drug interactions with other AEDs
- Available in liquid formulation
- Gabapentin may be effective in treatment-resistant depression 18
and refractory bipolar disorder 30
- Can be rapidly titrated 32
- Broad therapeutic index -- gabapentin can be prescribed in a wide range of doses, based on individual patient needs, without increased risk of dose-dependent side effects.
- Delay in response due to need for dosage titration
- Dosage adjustment is required in patients with renal impairment
- Frequent dosing regimen due to the short half-life
- Low antiepileptic potency, not effective for all
types of seizures 34, 35
- High rate of somnolence and dizziness 33
- Gabapentin may cause weight gain 7
- Possible withdrawal syndrome after discontinuation 8
- Decreased bioavailability at the high doses.
- Non-predictable dose-response relationship due to nonlinear pharmacokinetics requires careful titration.
Mechanism of action
The chemical structure of gabapentin is derived by addition
of a cyclohexyl group to the backbone of neurotransmitter GABA (gamma-aminobutyric acid).
Gabapentin is structurally related to GABA. However, it does not bind
to GABAA or GABAB receptors, and it does not appear to influence synthesis
or uptake of GABA. High affinity gabapentin binding sites have been
located throughout the brain; these sites correspond to the presence
of voltage-gated calcium channels specifically possessing the alpha-2-delta-1
subunit. This channel appears to be located presynaptically, and may
modulate the release of excitatory neurotransmitters which participate in epileptogenesis and nociception.
Gabapentin works by changing the way in which nerves send messages to the brain.
The mechanism by which Gabapentin exerts its analgesic action is unknown,
but in animal models of analgesia, Gabapentin prevents allodynia (pain-related
behavior in response to a normally innocuous stimulus) and hyperalgesia
(exaggerated response to painful stimuli). In particular, Gabapentin
prevents pain-related responses in several models of neuropathic pain
in rats or mice (e.g. spinal nerve ligation models, streptozocin-induced
diabetes model, spinal cord injury model, acute herpes zoster model).
It also decreases pain-related responses after peripheral
inflammation (carrageenan footpad test, late phase of formalin test).
Gabapentin did not alter immediate pain-related behaviors (rat tail
flick test, formalin footpad acute phase, acetic acid abdominal constriction
test, footpad heat irradiation test). The relevance of these models to human pain is not known.
The mechanism by which Gabapentin exerts its anticonvulsant action is
unknown, but in animal test systems designed to detect anticonvulsant
activity, Gabapentin prevents seizures as do other marketed anticonvulsants.
Gabapentin exhibits antiseizure activity in mice and rats in both the
maximal electroshock and pentylenetetrazole seizure models and other
preclinical models (e.g., strains with genetic epilepsy, etc.). The
relevance of these models to human epilepsy is not known.
Gabapentin has no activity at GABAA or GABAB receptors of GABA uptake
carriers of brain. It interacts with a high-affinity binding
site in brain membranes. Gabapentin crosses several lipid membrane barriers
via system L amino acid transporters. In vitro, gabapentin modulates
the action of the GABA synthetic enzyme, glutamic acid decarboxylase
(GAD) and the glutamate synthesizing enzyme, branched-chain amino acid
transaminase. Results with human and rat brain NMR spectroscopy indicate
that gabapentin increases GABA synthesis. It increases non-synaptic
GABA responses from neuronal tissues in vitro. In vitro, gabapentin
reduces the release of several mono-amine neurotransmitters. Gabapentin
prevents pain responses in several animal models of hyperalgesia and
prevents neuronal death in vitro and in vivo with models of the neurodegenerative
disease amyotrophic lateral sclerosis (ALS). Gabapentin is also active
in models that detect anxiolytic activity. Although gabapentin may have
several different pharmacological actions, it appears that modulation
of GABA synthesis and glutamate synthesis may be important 6.
Half-life & Time to clear out of the system
The elimination half-life is 5-7 hours and is unaltered by dose or
following multiple dosing. It usually takes 2 days for gabapentin to leave the system.
How long does it take for Gabapentin to work?
While some people notice the antimanic and antidepressant effects
within a week or two of starting treatment, others have to take a therapeutic
amount of gabapentin for up to a month before feeling a significant improvement.
You should notice that your pain starts to alleviate over 1-2 weeks after starting gabapentin, but it may take a little
longer in some people. On the other hand, some people feel the benefit straight away.
Gabapentin and Alcohol interaction
There are no known interactions between gabapentin and alcohol. Gabapentin does not alter the effects of alcohol2.
Gabapentin should be tapered off gradually. Abrupt discontinuation of gabapentin is associated with development of a syndrome resembling alcohol or benzodiazepine withdrawal, perhaps due to a similar mechanism of action at GABA levels8.
Withdrawal symptoms can present after 1-2 days upon abrupt discontinuation of gabapentin.
Though gabapentin is not a controlled substance, it does produce psychoactive
effects. It is regarded as having little or no abuse potential.
Currently, case reports indicate that gabapentin misuse is possible in certain populations26.
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Published: October 6, 2008
Last updated: July 30, 2015
- Gabapentin has advantages over other anticonvulsants because of its safety profile and lack of drug interactions.
- By some estimates, off-label prescriptions account for roughly
90% of Neurontin sales.27