How Gabapentin works

Gabapentin is a medicine that may be used for the treatment of certain seizure disorders or nerve pain.

Gabapentin is a structural analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) that was first approved for use in the United States in 1993.

It was originally developed as a novel anti-epileptic for the treatment of certain types of seizures – today it is also widely used to treat neuropathic pain.

Gabapentin has some stark advantages as compared with other anti-epileptics, such as a relatively benign adverse effect profile, wide therapeutic index, and lack of appreciable metabolism making it unlikely to participate in pharmacokinetic drug interactions.

It is structurally and functionally related to another GABA derivative, pregabalin.

 

Experts aren’t sure exactly how gabapentin works, but research has shown that gabapentin binds strongly to a specific site (called the alpha2-delta site) on voltage-gated calcium channels. This action is thought to be the mechanism for its nerve-pain relieving and anti-seizure properties.

Gabapentin enacarbil (brand name Horizant) is a prodrug of gabapentin which has been designed to overcome the limitations of gabapentin, such as poor absorption and a short duration of action. Gabapentin enacarbil is effective for restless legs syndrome (RLS) and postherpetic neuralgia (nerve pain that occurs following Shingles).

Gabapentin belongs to the group of medicines known as anticonvulsants.

The precise mechanism through which gabapentin exerts its therapeutic effects is unclear.

The primary mode of action appears to be at the auxillary α2δ-1 subunit of voltage-gated calcium channels (though a low affinity for the α2δ-2 subunit has also been reported).

The major function of these subunits is to facilitate the movement of pore-forming α1 subunits of calcium channels from the endoplasmic reticulum to the cell membrane of pre-synaptic neurons.

There is evidence that chronic pain states can cause an increase in the expression of α2δ subunits and that these changes correlate with hyperalgesia.

Gabapentin appears to inhibit the action of α2δ-1 subunits, thus decreasing the density of pre-synaptic voltage-gated calcium channels and subsequent release of excitatory neurotransmitters.

It is likely that this inhibition is also responsible for the anti-epileptic action of gabapentin.

There is some evidence that gabapentin also acts on adenosine receptors and voltage-gated potassium channels, though the clinical relevance of its action at these sites is unclear.

 

Gabapentin may help control your pain but will not cure it

Gabapentin is the generic name of a prescription drug used to treat epilepsy. Gabapentin works by decreasing abnormal excitement in the brain.

It also may change the way the body senses pain. Gabapentin is in a class of medications called anticonvulsants.

The U.S. Food and Drug Administration (FDA) approved gabapentin in 1993 under the brand name Neurontin for the drug manufacturer Pfizer. The medication comes in capsule form, as a regular or extended-release tablet, and as a liquid.gabapentin100mg

Gabapentin interacts with voltage-sensitive calcium channels in cortical neurons. Gabapentin increases the synaptic concentration of GABA, enhances GABA responses at non-synaptic sites in neuronal tissues, and reduces the release of mono-amine neurotransmitters.

gabapentin
gabapentin

One of the mechanisms implicated in this effect of gabapentin is the reduction of the axon excitability measured as an amplitude change of the presynaptic fibre volley (FV) in the CA1 area of the hippocampus.

This is mediated through its binding to presynaptic NMDA receptors.

Other studies have shown that the antihyperalgesic and antiallodynic effects of gabapentin are mediated by the descending noradrenergic system, resulting in the activation of spinal alpha-2 adrenergic receptors.  Gabapentin has also been shown to bind and activate the adenosine A1 receptor.

Gabapentin may help to control your condition but will not cure it. Continue to take gabapentin even if you feel well. Do not stop taking gabapentin without talking to your doctor, even if you experience side effects such as unusual changes in behavior or mood.

gabapentin600mgIf you suddenly stop taking gabapentin tablets, capsules, or oral solution, you may experience withdrawal symptoms such as anxiety, difficulty falling asleep or staying asleep, nausea, pain, and sweating. If you are taking gabapentin to treat seizures and you suddenly stop taking the medication, you may experience seizures more often.

Your doctor may decrease your dose gradually over at least a week.

There is moderate-quality evidence that oral gabapentin at doses of 1200 mg daily or more has an important effect on pain in some people with moderate or severe neuropathic pain after shingles or due to diabetes.

Background

Neuropathic pain comes from damaged nerves. It is different from pain messages that are carried along healthy nerves from damaged tissue (for example, from a fall or cut, or arthritic knee). Neuropathic pain is often treated by different medicines (drugs) to those used for pain from damaged tissue, which we often think of as painkillers. Medicines that are sometimes used to treat depression or epilepsy can be effective in some people with neuropathic pain. One of these is gabapentin. Our definition of a good result was someone with a high level of pain relief and able to keep taking the medicine without side effects making them stop.

Study characteristics

In January 2017 we searched for clinical trials in which gabapentin was used to treat neuropathic pain in adults. We found 37 studies that satisfied the inclusion criteria, randomising 5914 participants to treatment with gabapentin, placebo, or other drugs. Studies lasted 4 to 12 weeks. Most studies reported beneficial outcomes that people with neuropathic pain think are important. Results were mainly in pain after shingles and pain resulting from nerve damage in diabetes.

Key results

In pain after shingles, 3 in 10 people had pain reduced by half or more with gabapentin and 2 in 10 with placebo. Pain was reduced by a third or more for 5 in 10 with gabapentin and 3 in 10 with placebo. In pain caused by diabetes, 4 in 10 people had pain reduced by half or more with gabapentin and 2 in 10 with placebo. Pain was reduced by a third or more for 5 in 10 with gabapentin and 4 in 10 with placebo. There was no reliable evidence for any other type of neuropathic pain.

Side effects were more common with gabapentin (6 in 10) than with placebo (5 in 10). Dizziness, sleepiness, water retention, and problems with walking each occurred in about 1 in 10 people who took gabapentin. Serious side effects were uncommon, and not different between gabapentin and placebo. Slightly more people taking gabapentin stopped taking it because of side effects.

Gabapentin is helpful for some people with chronic neuropathic pain. It is not possible to know beforehand who will benefit and who will not. Current knowledge suggests that a short trial is the best way of telling.

Quality of the evidence

The evidence was mostly of moderate quality. This means that the research provides a good indication of the likely effect. The likelihood that the effect will be substantially different is moderate.

 

 

 

 

Gabapentin is used to treat Restless Legs Syndrome

Restless legs syndrome (RLS) is a disorder of the part of thenervous system that causes an urge to move the legs. Because it usually interferes with sleep, it also is considered a sleep disorder.

Causes of Restless Legs Syndrome

In most cases, doctors do not know the cause of restless legs syndrome; however, they suspect that genes play a role. Nearly half of people with RLS also have a family member with the condition.

Other factors associated with the development or worsening of restless legs syndrome include:

  • Chronic diseases. Certain chronic diseases and medical conditions, including iron deficiency, Parkinson’s disease, kidney failure,diabetes, and peripheral neuropathy often include symptoms of RLS. Treating these conditions often gives some relief from RLS symptoms.
  • Medications. Some types of medications, including antinausea drugs, antipsychotic drugs, some antidepressants, and cold and allergymedications containing sedating antihistamines, may worsen symptoms.
  • Pregnancy. Some women experience RLS during pregnancy, especially in the last trimester. Symptoms usually go away within a month after delivery.

Other factors, including alcohol use and sleep deprivation, may trigger symptoms or make them worse. Improving sleep or eliminating alcohol use in these cases may relieve symptoms.

Treatment for Restless Legs Syndrome

Treatment for RLS is targeted at easing symptoms. In people with mild to moderate restless legs syndrome, lifestyle changes, such as beginning a regular exercise program, establishing regular sleep patterns, and eliminating or decreasing the use of caffeine, alcohol, and tobacco, may be helpful. Treatment of an RLS-associated condition also may provide relief of symptoms.

Other non-drug RLS treatments may include:

Leg massages
Hot baths or heating pads or ice packs applied to the legs
Good sleep habits
A vibrating pad called Relaxis
Medications may be helpful as RLS treatments, but the same drugs are not helpful for everyone. In fact, a drug that relieves symptoms in one person may worsen them in another. In other cases, a drug that works for a while may lose its effectiveness over time.

Drugs used to treat RLS include:

  • Dopaminergic drugs, which act on the neurotransmitter dopamine in the brain.
  • Mirapex, Neupro, and Requip are FDA-approved for treatment of moderate to severe RLS. Others, such as levodopa, may also be prescribed.
  • Benzodiazepines, a class of sedative medications, may be used to help with sleep, but they can cause daytime drowsiness.
  • Narcotic pain relievers may be used for severe pain.
  • Anticonvulsants, or antiseizure drugs, such as Tegretol, Lyrica, Gabapentin ( Neurontin ), and Horizant.

Although there is no cure for restless legs syndrome, current treatments can help control the condition, decrease symptoms, and improve sleep.

Usual Adult Dose for Restless Legs Syndrome

Gabapentin enacarbil available under the trade name Horizant (R):
600 mg orally once daily with food at about 5 PM

Take Gabapentin as an Anticonvulsant

Anticonvulsants (also commonly known as antiepileptic drugs or as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder and borderline personality disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain.

Anticonvulsants suppress the rapid and excessive firing of neurons during seizures. Anticonvulsants also prevent the spread of the seizure within the brain. Some investigators have observed that anticonvulsants themselves may cause reduced IQ in children.   However these adverse effects must be balanced against the significant risk epileptic seizures pose to children and the distinct possibility of death and devastating neurological sequelaesecondary to seizures.

gabapentin800mg-anticonvulsant

Anticonvulsants are more accurately called antiepileptic drugs (abbreviated “AEDs”), and are often referred to as antiseizure drugs because they provide symptomatic treatment only and have not been demonstrated to alter the course of epilepsy.

Gabapentin (Neurontin) has been approved as adjunctive therapy in adults with partial seizures with or without secondary generalization . Begin with 300 mg daily; increase to 900 to 1,800 mg daily given every 6 to 8 hours.  Side Effects maybe: Somnolence, fatigue, ataxia, dizziness, gastrointestinal upset, dyspnea.

A gamma-aminobutyric acid (GABA) analog, gabapentin does not interact with GABA receptors. Its mechanism of action is unknown.

Gabapentin is well absorbed orally, circulates mostly unbound in the plasma and is excreted unchanged in the kidneys without appreciable metabolism in the body. Oral bioavailability is approximately 60 percent and is not affected by food. The half-life is five to seven hours and is related to the creatinine clearance. Therefore, excretion is decreased in patients with renal impairment and decreased cardiac function, and in elderly patients. Gabapentin can be removed from the system through hemodialysis.

In clinical studies,  gabapentin was found to be effective in adults with refractory partial seizures and was also effective in preventing the progression of partial seizures to generalized tonic-clonic seizures.

Because gabapentin has no known pharmacokinetic interactions with any other antiepileptic drugs, it is useful in patients taking other antiepileptic medication.