Gabapentin works by changing the way that nerves send messages to your brain. If the messages are reduced, then the pain will be reduced.

Gabapentin was designed to mimic the neurotransmitter GABA. It does not, however, bind to GABA receptors. Its mechanism of action as an antiepileptic agent likely involves its inhibition of the alpha 2-delta subunit of voltage-gated calcium channels. It was first approved as an anticonvulsant in 1994 in the US and is now available worldwide. It was also approved in the US for postherpetic neuralgia in 2002 and is used commonly to treat neuropathic pain. Gabapentin is renally excreted and is not an enzyme-inducing anticonvulsant.

Gabapentin is a new chemical compound designed as a structural analog of GABA that is effective in the treatment of partial seizures. In contrast to GABA, gabapentin readily penetrates the blood–brain barrier. In man, gabapentin has been demonstrated to increase GABA concentrations [126]. Most probably the mechanism of action is related to events modulated through its interaction with a receptor thought to be associated with the L-system amino acid carrier protein. However, the primary mechanism of action remains to be defined.

 

The mechanism of gabapentin in neuropathic pain

Gabapentin is an anti-epileptic agent but now it is also recommended as first line agent in neuropathic pain, particularly in diabetic neuropathy and post herpetic neuralgia. α2δ-1, an auxillary subunit of voltage gated calcium channels, has been documented as its main target and its specific binding to this subunit is described to produce different actions responsible for pain attenuation.

The binding to α2δ-1 subunits inhibits nerve injury-induced trafficking of α1 pore forming units of calcium channels (particularly N-type) from cytoplasm to plasma membrane (membrane trafficking) of pre-synaptic terminals of dorsal root ganglion (DRG) neurons and dorsal horn neurons.

Furthermore, the axoplasmic transport of α2δ-1 subunits from DRG to dorsal horns neurons in the form of anterograde trafficking is also inhibited in response to gabapentin administration. Gabapentin has also been shown to induce modulate other targets including transient receptor potential channels, NMDA receptors, protein kinase C and inflammatory cytokines. It may also act on supra-spinal region to stimulate noradrenaline mediated descending inhibition, which contributes to its anti-hypersensitivity action in neuropathic pain.

Gabapentin has no direct GABAergic action and does not block GABA uptake or metabolism. Gabapentin blocks the tonic phase of nociception induced by formalin and carrageenan, and exerts a potent inhibitory effect in neuropathic pain models of mechanical hyperalgesia and mechanical/thermal allodynia.

Gabapentin binds preferentially to neurons in the outer layer of the rat cortex at sites that are distinct from other anticonvulsants [20]. It is likely that gabapentin acts at an intracellular site as the maximal anticonvulsant effect is achieved 2 h after an intravenous injection of gabapentin in rats. This occurs after the plasma and interstitial fluid concentrations have peaked and reflects the additional time required for intraneural transport .

Several theories have been proposed to explain the cellular mechanism of its anticonvulsant effect. The most favoured theory involves an interaction with an as yet undescribed receptor linked with the l‐system amino acid transporter protein.

Suman Chauhan et al.  demonstrated that l‐amino acids potently inhibited binding of an␣active enantiomer of gabapentin ([³H]gabapentin). This was further supported by Taylor et al.  who showed that the potent anticonvulsant, 3‐isobutyl GABA (an analogue of gabapentin) potently and stereoselectively bound to the same receptor. These findings renewed interest in the isolation of the receptor protein that may responsible for this anticonvulsant effect.

Other proposed biochemical events in the central nervous system (CNS) that may explain its anti‐epileptic effect include the increased extracellular GABA concentrations in some regions of the brain caused by an increase in activity of glutamic acid decarboxylase that produces GABA, and a decreased breakdown by GABA decarboxylase. Although a study , using magnetic resonance imaging (MRI) spectroscopy showed a global increase in GABA in the brain after the administration of gabapentin, there is no evidence that gabapentin increases intraneuronal GABA concentrations, binds GABA_A or GABA_B receptors, or exerts any GABA‐mimetic action .

Other effects of gabapentin have been described but are not considered to play a significant pharmacodynamic role. These include small decreases in the release of monoamine neurotransmitters (dopamine, noradrenaline and serotonin)  and the attenuation of sodium‐dependent action potentials (suggesting sodium channel blockade) after prolonged exposure to gabapentin .

The mode of action of gabapentin in the treatment of neuropathic pain has not been fully elucidated. Although early studies indicated that gabapentin had only a central anti‐allodynic effect, gabapentin has been shown to inhibit ectopic discharge activity from injured peripheral nerves .

The mechanisms of the anti‐allodynic effects of gabapentin proposed include: CNS effects (potentially at spinal cord or brain level) due to either enhanced inhibitory input of GABA‐mediated pathways (and thus reducing excitatory input levels); antagonism of NMDA receptors; and antagonism of calcium channels in the CNS and inhibition of peripheral nerves [29-46]. Of these, antagonism of the NMDA receptor and calcium channel blockade have the most supporting evidence. Field et al.

Discounted an antihyperalgesic action via opioid receptor binding after demonstrating that morphine tolerance does not alter the efficacy of gabapentin and naloxone does not reduce its antihyperalgesic effect.

Research into a peripheral site of action for gabapentin has produced contradictory results . Intrathecal administration of gabapentin blocks thermal and mechanical hyperalgesia without affecting sympathetic outflow or acute nociception, and this suggests a spinal site of action . Patel et al. demonstrated a presynaptic site of action for gabapentin in the rat spinal cord.

Although gabapentin does not bind to GABA_A or GABA_B receptors, increased synthesis and reduced breakdown of GABA have been described . Potentiation of inhibitory GABA‐ergic pathways seems unlikely to be responsible for its anti‐allodynic effect because GABA receptor antagonists do not reduce this effect .

The NMDA receptor complex is a ligand‐gated ion channel that mediates an influx of calcium ions when activated. The NMDA receptor complex has a number of binding sites for various ligands that regulate its activity, including the strychnine‐insensitive glycine binding site, phencyclidine binding site, polyamine binding site, redox modulatory site and a proton‐sensitive site. Partial depolarisation of the neuron after glutamine activation will release a magnesium plug and allow calcium influx into the neuron.

These receptors are known to be found in high concentrations in the hippocampus and have been attributed a key role in the process of central sensitisation of painful stimuli, commonly known as the ‘wind‐up’ phenomenon, leading to hyperalgesia.

Evidence linking gabapentin to the NMDA receptor follows research demonstrating the reversal of the antihyperalgesic effect of gabapentin by d‐serine, an agonist at the NMDA‐glycine binding site . However, receptor binding studies have failed to demonstrate a direct binding site for gabapentin at the NMDA receptor .

The α₂δ subunit of the voltage‐dependent calcium channel is a binding site for gabapentin and the S‐isomer of pregabolin (S‐(+)‐3‐isobutylgaba) . Because only gabapentin and the S‐isomer of pregabolin produce antihyperalgesic effects, it is postulated that the antihyperalgesic action for gabapentin is mediated by its binding to this site on the voltage‐dependent calcium channel. Fink et al.  showed that, in the rat neocortex, gabapentin inhibits neuronal calcium influx in a concentration‐dependent manner by inhibiting P/Q‐type calcium channels.

The decreased calcium influx reduces excitatory amino acid (e.g. glutamate) release leading to decreased AMPA receptor activation, and noradrenaline release in the brain.

These findings support the hypothesis that calcium channel inhibition mediates the analgesic effects of gabapentin in chronic neuropathic pain. A decrease in potassium ion‐evoked glutamate release from rat neocortical and hipppocampal slices by gabapentin has been demonstrated .

 

What Gabapentin is used for ?

Gabapentin is used to help control partial seizures (convulsions) in the treatment of epilepsy. This medicine cannot cure epilepsy and will only work to control seizures for as long as you continue to take it.

Gabapentin is also used in adults to manage a condition called postherpetic neuralgia, which is pain that occurs after shingles.

Gabapentin extended-release tablet is used to treat a condition called Restless Legs Syndrome (RLS). RLS is a neurologic disorder that makes the legs feel uncomfortable. This results in an irresistible feeling of wanting to move your legs to make them comfortable.

Gabapentin works in the brain to prevent seizures and relieve pain for certain conditions in the nervous system. It is not used for routine pain caused by minor injuries or arthritis. Gabapentin is an anticonvulsant.

Gabapentin is also used to treat certain types of long-lasting pain caused by damage to nerves. This type of pain, called neuropathic pain, can be caused by a number of different diseases, such as diabetes (where it is called diabetic neuropathy) andshingles (where it is called postherpetic neuralgia).

Although gabapentin is only licensed for use in epilepsy and neuropathic pain, it may also prescribed to help to prevent attacks of migraine. If you have been given it for this reason, then you should speak with your doctor if you have any questions about your treatment.

Gabapentin capsules, tablets, and oral solution are also used to relieve the pain of postherpetic neuralgia (PHN; the burning, stabbing pain or aches that may last for months or years after an attack of shingles).

Gabapentin extended-release tablets (Horizant) are used to treat restless legs syndrome (RLS; a condition that causes discomfort in the legs and a strong urge to move the legs, especially at night and when sitting or lying down).

Gabapentin is in a class of medications called anticonvulsants. Gabapentin treats seizures by decreasing abnormal excitement in the brain. Gabapentin relieves the pain of PHN by changing the way the body senses pain. It is not known exactly how gabapentin works to treat restless legs syndrome.

Medical uses

Gabapentin is approved in the United States to treat seizures and neuropathic pain. It is primarily administered by mouth, with a study showing that “rectal administration is not satisfactory”. It is also commonly prescribed for many off-label uses, such as treatment of anxiety disorders, insomnia, and bipolar disorder. About 90% of usage is for off-label conditions. There are, however, concerns regarding the quality of the trials conducted and evidence for some such uses, especially in the case of its use as a mood stabilizer in bipolar disorder.

Seizures

Gabapentin is approved for treatment of focal seizures and mixed seizures. There is insufficient evidence for its use in generalized epilepsy.

Neuropathic pain

A 2018 review found that gabapentin was of no benefit in sciatica or low back pain.^[28] It may be effective in reducing pain and spasticity in multiple sclerosis.

A 2010 European clinical guideline recommended gabapentin as a first-line treatment for diabetic neuropathy, postherpetic neuralgia, or central pain. It found good evidence that a combination of gabapentin with morphine, oxycodone, or nortriptyline worked better than either drug alone; the combination of gabapentin and venlafaxine may be better than gabapentin alone.

A 2017 Cochrane review found evidence of moderate quality showing a reduction in pain by 50% in about 15% of people with postherpetic neuralgia and diabetic neuropathy. Evidence finds little benefit and significant risk in those with chronic low back pain. It is not known if gabapentin can be used to treat other pain conditions, and no difference among various formulations or doses of gabapentin was found.

A 2010 review found that it may be helpful in neuropathic pain due to cancer. It is not effective in HIV-associated sensory neuropathy and does not appear to provide benefit for complex regional pain syndrome.

A 2009 review found gabapentin may reduce opioid use following surgery, but does not help with post-surgery chronic pain.^] A 2016 review found it does not help with pain following a knee replacement.

It appears to be as effective as pregabalin for neuropathic pain and initially costs less. Both uses are off-patent and their costs are comparable as of 2020. Doses between 900 and 3,600 mg per day appear to result in similar pain relief.

Migraine

The American Headache Society (AHS) and American Academy of Neurology (AAN) guidelines classify gabapentin as a drug with “insufficient data to support or refute use for migraine prophylaxis”. A 2013 Cochrane review concluded that gabapentin was not useful for the prevention of episodic migraine in adults.

Anxiety

Gabapentin has been used off-label for the treatment of anxiety disorders. However, there is dispute over whether evidence is sufficient to support it being routinely prescribed for this purpose.  While pregabalin may have efficacy in the treatment of refractory anxiety in people with chronic pain, it is unclear if gabapentin is equally effective. Gabapentin may be useful in the treatment of comorbid anxiety in people with bipolar; however, it is not effective as a mood-stabilizing treatment for manic or depressive episodes themselves.

Drug dependence

Gabapentin may reduce symptoms of alcohol withdrawal (but it does not prevent the associated seizures), alcohol dependence and craving. There is some evidence for its role in the treatment of alcohol use disorder; the 2015 VA/DoD guideline on substance use disorders lists gabapentin as a “weak for” and is recommended as a second-line agent.^[47] Use for smoking cessation has had mixed results. There is insufficient evidence for its use in cannabis dependence.

Diabetic neuropathy

A double‐blind, placebo‐controlled, parallel group multicentre study of 165 diabetic patients with a 1–5‐year history of painful peripheral diabetic neuropathy reported a beneficial effect with gabapentin . Eighty‐four patients were allocated to the␣gabapentin group and 81 to the placebo group. Gabapentin was titrated to a maximum of 3600 mg daily. Gabapentin was generally well tolerated and 67% of the gabapentin group reached 3600 mg.day⁻¹. A statistically significant (p < 0.0001) reduction in mean daily pain score (using an 11‐point Likert scale) in the gabapentin group (baseline 6.4, endpoint 3.9), compared with placebo (baseline 6.5, endpoint 5.1), was achieved.

The number‐needed‐to‐treat (NNT, defined as the number of patients needed to be treated for one patient to receive at least 50% pain relief) for the analgesic effects in neuropathic pain with gabapentin in this study was 3.8 . This compares with a NNT of 2.3 for carbemazepine and 2.1 for phenytoin in other randomised controlled trials . Another double‐blind, placebo‐controlled trial of gabapentin in 32 diabetic patients with neuropathic pain showed a statistically significant analgesic effect during the first month of treatment.

Morello et al.  conducted a randomised, double‐blind cross‐over study comparing the efficacy of gabapentin with that of amitriptyline in diabetic peripheral neuropathy and found both drugs provided equal pain relief.

In an open‐label pilot study over 12 weeks involving 25 randomised patients (13 received gabapentin, 12 received amitriptyline), gabapentin significantly reduced pain scores (p = 0.026) and paraesthesia (p = 0.004) compared with amitriptyline . Adverse effects were also less frequent in the gabapentin group (p = 0.003). Further trials are required to confirm these preliminary results indicating that gabapentin is more efficacious than amitriptyline in diabetic peripheral neuropathy.

Other

Gabapentin may be effective in acquired pendular nystagmus and infantile nystagmus (but not periodic alternating nystagmus).

It is effective for treating hot flashes.

It is an established treatment of restless legs syndrome. Gabapentin may help sleeping problems in people with restless legs syndrome and partial seizures due to its increase in slow-wave sleep and augmentation of sleep efficiency.

Other psychiatric conditions, such as borderline personality disorder, have also been treated off-label with gabapentin.^[21] There is insufficient evidence to support its use in obsessive–compulsive disorder and treatment-resistant depression.

Gabapentin is effective in alleviating itching in kidney failure (uremic pruritus) and itching of other causes. Gabapentin may be an option in essential or orthostatic tremor. Evidence does not support the use of gabapentin in tinnitus.

 

What is the side Effects of Gabapentin ?

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

1. Clumsiness or unsteadiness
2. continuous, uncontrolled, back-and-forth, or rolling eye movements

More common in children

1. Aggressive behavior or other behavior problems
2. anxiety
3. concentration problems and change in school performance
4. crying
5. depression
6. false sense of well-being
7. hyperactivity or increase in body movements
8. rapidly changing moods
9. reacting too quickly, too emotional, or overreacting
10. restlessness
11. suspiciousness or distrust

Less common

1. Black, tarry stools
2. chest pain
3. chills
4. cough
5. depression, irritability, or other mood or mental changes
6. fever
7. loss of memory
8. pain or swelling in the arms or legs
9. painful or difficult urination
10. sore throat
11. sores, ulcers, or white spots on the lips or in the mouth
12. swollen glands
13. unusual bleeding or bruising
14. unusual tiredness or weakness

Incidence not known

1. Abdominal or stomach pain
2. blistering, peeling, or loosening of the skin
3. clay-colored stools
4. coma
5. confusion
6. convulsions
7. dark urine
8. decreased urine output
9. diarrhea
10. difficult or troubled breathing
11. dizziness
12. fast or irregular heartbeat
13. headache
14. increased thirst
15. irregular, fast or slow, or shallow breathing
16. itching or skin rash
17. joint pain
18. large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
19. loss of appetite
20. muscle ache or pain
21. nausea
22. pale or blue lips, fingernails, or skin
23. red skin lesions, often with a purple center
24. red, irritated eyes
25. unpleasant breath odor
26. vomiting of blood
27. yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

1. Blurred vision
2. cold or flu-like symptoms
3. delusions
4. dementia
5. hoarseness
6. lack or loss of strength
7. lower back or side pain
8. swelling of the hands, feet, or lower legs
9. trembling or shaking

Less common or rare

1. Accidental injury
2. appetite increased
3. back pain
4. bloated or full feeling
5. body aches or pain
6. burning, dry, or itching eyes
7. change in vision
8. change in walking and balance
9. clumsiness or unsteadiness
10. congestion
11. constipation
12. cough producing mucus
13. decrease in sexual desire or ability
14. dryness of the mouth or throat
15. earache
16. excess air or gas in the stomach or intestines
17. excessive tearing
18. eye discharge
19. feeling faint, dizzy, or lightheadedness
20. feeling of warmth or heat
21. flushed, dry skin
22. flushing or redness of the skin, especially on the face and neck
23. frequent urination
24. fruit-like breath odor
25. impaired vision
26. incoordination
27. increased hunger
28. increased sensitivity to pain
29. increased sensitivity to touch
30. increased thirst
31. indigestion
32. noise in the ears
33. pain, redness, rash, swelling, or bleeding where the skin is rubbed off
34. passing gas
35. redness or swelling in the ear
36. redness, pain, swelling of the eye, eyelid, or inner lining of the eyelid
37. runny nose
38. sneezing
39. sweating
40. tender, swollen glands in the neck
41. tightness in the chest
42. tingling in the hands and feet
43. trouble sleeping
44. trouble swallowing
45. trouble thinking
46. twitching
47. unexplained weight loss
48. voice changes
49. vomiting
50. weakness or loss of strength
51. weight gain

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.