Gabapentin is an anticonvulsive medication which first discovered in the 1970s in Japan. Its original use was as a muscle relaxer and anti-spasmodic medication, but later, it was discovered the potential of the medication as anticonvulsive medication and as an adjunct to stronger anticonvulsants. Gabapentin is an anticonvulsant medication that got FDA approval for partial seizure therapy in 1993. Currently, gabapentin has FDA approval for:
- Postherpetic neuralgia
- Adjunctive therapy in the treatment of partial seizures with or without secondary generalization in patients over the age of 12 years old with epilepsy, and in the pediatric population, 3 to 12 year-olds with a partial seizure
- Moderate to severe restless leg syndrome (RLS) moderate to severe
It also has off-label use for neuropathic pain, fibromyalgia, bipolar disorder, postmenopausal hot flashes, essential tremors, anxiety, resistant depressant and mood disorders, irritable bowel syndrome (IBS), alcohol withdrawal, postoperative analgesia, nausea and vomiting, migraine prophylaxis, headache, interstitial cystitis, painful diabetic neuropathy, social phobia, generalized tonic-clonic seizures, pruritus (itching), insomnia, post-traumatic stress disorder (PTSD), and refractory chronic cough.
In one placebo-controlled, retrospective study that investigated the effects of gabapentin on about 700 patients with refractory partial seizure disorder, there was an improvement in overall well-being in patients. The effect prompted a controlled investigation of the drug in primary psychiatric conditions.
An important benefit of gabapentin is that there is no interaction with valproate, lithium, and carbamazepine. Also, gabapentin has minor side effects.
Gabapentin in Alcohol Withdrawal
For the first time, the DSM-V includes the diagnostic guidelines for alcohol dependency. There are a variety of severe diseases that result from or are influenced by alcohol dependence include stomach ulcers, liver issues, increased risk of heart disease, and neuropathy. Researchers assess that 3.8% of worldwide deaths result from direct or indirect effects of alcohol abuse.
While gabapentin's mechanism of action is generally understood, it appears to be a logical pharmacologic option for treating issues involving the GABA receptor system. Gabapentin is a safe, readily available, and effective drug for alcohol-use disorder treatment, specifically for the abstinence maintenance phase. A 2014 trial bolstered the evidence base for gabapentin use in the treatment of alcohol use disorder. Results for insomnia and cravings, two symptoms of alcohol use disorder abstinence maintenance, demonstrated significant improvement with gabapentin pharmacotherapy. Gabapentin has also shown a statistical benefit when used as adjunctive therapy to naltrexone (the FDA-approved alcohol use disorder medication). It is also clear that higher doses of gabapentin, 1800 mg per day, seem to have a stronger effect on alcohol-use disorder abstinence maintenance. However, the trials investigating gabapentin as monotherapy have shown mixed results.
For gabapentin, unlike disulfiram and naltrexone, there is no need for hepatic dose adjustments. Gabapentin can also be used in patients whose renal function is below 20 mg/dl (although a dosing adjustment is needed).
In 2007, Melcolm and his team compared gabapentin to lorazepam, and they concluded that there were significant reductions in self-reported sleep disturbance and daytime sleepiness in patients undergoing outpatient treatment for alcohol withdrawal.
A double-blind study investigated the use of 1200 mg/ per day gabapentin in alcohol use disorder. Specifically, the researchers found gabapentin to be superior to the benzodiazepine lorazepam in the treatment of outpatients with moderate alcohol withdrawal. This outcome was measured by a lower chance of drinking, and by a superior, but clinically, similar alcohol withdrawal symptom reduction.
Gabapentin in the Treatment of Anxiety and Depression
Gabapentin is rarely prescribed for patients with only anxiety disorder but is commonly prescribed for patients with bipolar disorder to reduce anxiety levels. Clinicians can also use it for patients who have anxiety and depression. Since anxiety is the coping skill, there is no drug to treat anxiety, but the medications used for this purpose make it possible to live at the moment, and this gives patients a chance to undergo anxiety treatment with non-pharmaceuticals. Even though the studies show that gabapentin is ineffective in the treatment of bipolar disorder, a case-control study with 60 patients in an acute phase of mania, had a significant reduction in symptoms of anxiety with lithium and 900 mg of gabapentin. In another study with 21, mixed-state patients refractory to mood stabilizers received gabapentin (up to 2000 mg per day) for eight weeks, and patients with depressive symptoms had significant improvement in their CGI-BP (Clinical Global Impression-Bipolar) scores.
A meta-analysis of 7 trials pointed to gabapentin's greater efficacy versus placebo in generalized anxiety disorder (GAD), although the effect size was approximately 0.35 for mental anxiety symptoms. A study of 153 patients who responded to the initial treatment of 450 mg per day for maintenance treatment of social anxiety disorder.
There are no clinical studies on the effectiveness of gabapentin as monotherapy or adjunctive therapy in major depressive disorders. However, there are case reviews that show some patients with depression who are refractory to standard antidepressants but showed therapeutic improvement when using gabapentin as adjunctive therapy.
In a randomized, double-blind study, with 130 patients that had under eye surgery, a one-time dose of 600 mg gabapentin significantly reduced the perioperative anxiety in comparison to a placebo. However, there was no significant difference compared to melatonin.
Gabapentin in Non-Epilepsy Neuropathic Pain like Postherpetic Neuralgia
The FDA approved gabapentin for the management of postherpetic neuralgia in adults. Recently, gabapentin underwent systemic evaluation in the management of diabetic neuropathy. In 1998, Rowbotham and his research team concluded that in 229 postherpetic neuralgia patients, gabapentin had more significant pain reduction as early as two weeks after initiating the treatment. Furthermore, other measurements of mood, depression, anger-hostility, fatigue, physical functioning, were more effectively managed with gabapentin compared to placebo.
During the same time, Backonja reviewed the effect of gabapentin in 165 diabetic neuropathy patients and showed the result that pain reduction in the gabapentin group is greater (as measured with an 11-point Likert scale) in comparison to the placebo group. And the results were significant from 2 weeks of initiation of therapy and stayed significant during the eight weeks of study. Patients in the treatment group also reported improvement in their quality of life. This medication was well tolerated in 67% of patients who received a maximum daily dosage of 3600 mg.
Gabapentin in Movement Disorders
Gabapentin is effective for many movement disorders, for example, amyotrophic lateral sclerosis (ALS), parkinsonism, and essential tremor. The study populations were not as large as neuropathic pain groups.
In 1996, Miller et al. treated 152 ALS patients randomly assigned to received 2400 mg gabapentin per day compared to a placebo group. Results showed a slower decline in muscle strength in the treatment group.
In 1998, Pahwa et al. reviewed the efficacy of gabapentin in the treatment of essential tremor in comparison to a placebo. The first 14 days of the study showed no difference between patients receiving 1800 mg gabapentin per day in comparison to placebo. But in 2000, Ondo did six weeks of research on a group of patients receiving up to 3600 mg gabapentin per day in contrast to the placebo, and patients demonstrated significant improvements in self-report scores for tremor, observed tremor scores, and daily activity improvement scores.
In 1997, Olson and his team performed a one month double-blind, placebo-controlled evaluation of the efficacy of gabapentin in 19 patients with advanced parkinsonism who were suffering from rigidity and bradykinesia. The treatment group received a total daily dosage of 1200 mg gabapentin per day. The results in this group were superior to the placebo group in reducing rigidity and bradykinesia as measured by the United Parkinson Disease Rating Scale. In the treatment group, there was a significant reduction in tremor, which was independent.
Mechanism of Action
The exact mechanism of action with the GABA receptors is unknown; however, researchers know that gabapentin freely passes the blood-brain barrier and acts on neurotransmitters. Gabapentin has a cyclohexyl group to the structure of neurotransmitter GABA as a chemical structure. Even though it has a similar structure to GABA, it does not bind to GABA receptors and does not influence synthesis or uptake of GABA. Gabapentin works by showing a high affinity for binding sites throughout the brain correspondent to the presence of the voltage-gated calcium channels, especially alpha-2-delta-1, which seems to inhibit the release of excitatory neurotransmitters in the presynaptic area which participate in epileptogenesis. Even though there is no evidence for direct action at the serotonin, dopamine, benzodiazepine, or histamine receptors, research has shown gabapentin to increase total-blood levels of serotonin in healthy control subjects.
The elimination half-life of gabapentin is 5 to 7 hours, and it takes two days for the body to eliminate gabapentin from its system.
One benefit of gabapentin use is its mild side-effect profile. The most common side effects are fatigue, dizziness, and headache.
Gabapentin is highly lipophilic but not bound to plasma proteins, which show linear pharmacokinetics and do not show a link with any significant protein binding or liver metabolization. It has an oral bioavailability of greater than 90%, which is independent of dose. Generally, patients achieve steady-state plasma levels within 24 to 48 hours. There is no clinically significant effect in administration with food nor on the extent of absorption or elimination. The elimination half-life of the drug is approximately 6.5 hours. Gabapentin readily crosses the blood-brain barrier. It is primarily excreted through the renal path, with no active metabolites. Dosage adjustment is necessary for patients with renal impairment. Pregabalin does not induce or inhibit CYP enzymes. Also, none of the CYP enzyme inhibitors alter its pharmacokinetics as a consequence.
- Initial treatment with gabapentin is usually started with one dose of 300 mg per day and later increase the frequency to 3 times a day and dosage up to 4800 mg per day. The recommendation is to start the first dose in the evening and taken three times a day.
- Usually, the effects are apparent in the first week of treatment but sometimes takes about a month for significant improvement.
- Taper the dose over more than seven days to discontinue the medication.
For Partial seizure
- 300 to 1200 mg 3 times per day by mouth
- Max: 3600 mg per day
For Post-Herpetic Neuralgia
- 300 to 600 mg 3 times per day by mouth
- Max: 1800 mg per day
For Neuropathic Pain
- 300 to 1200 mg 3 times per day by mouth
- Max: 3600 mg per day
- 400 to 800 mg 3 times per day by mouth
- Max: 2400 mg per day
Adjust the dose amount and frequency.
- Creatinine clearance of 30 to 60: 200 to 700 mg twice per day
- Creatinine clearance of 16 to 29: 200 to 700 mg once daily
- Creatinine clearance of 15: 100 to 300 mg once daily
- Creatinine clearance of less than 15: 125 to 350 mg as a supplement