Gabapentin

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Continuing Education Activity

Gabapentin is an anticonvulsive medication that originally saw use as a muscle relaxer and anti-spasmodic medication, but later it was discovered it had the potential of the medication as anticonvulsive medication and as an adjunct to more potent anticonvulsants. It is also useful in certain types of neural pain control. This activity outlines the indications, mechanism of action, dosing, significant adverse effects, contraindications, monitoring, and toxicity of gabapentin and increases practitioners' knowledge about how to approach this medication and all health professionals in how to monitor it to drive better patient outcomes.

Objectives:

  • Summarize the different indications for gabapentin.
  • Review the mechanism of action of gabapentin.
  • Describe the potential toxicity of gabapentin.
  • Explain the importance of the interprofessional team to enhance the delivery of care for patients taking gabapentin.

Indications

Gabapentin is an anticonvulsive medication which first discovered in the 1970s.[1] It received FDA approval in 1993 and has been available generically in the USA since 2004. Its original use was as a muscle relaxer and anti-spasmodic medication, but later its potential as anticonvulsive medication and as an adjunct to more potent anticonvulsants came to light.[2][3][4] 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 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 an 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 conditions that result from or are influenced by alcohol dependence, including 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 misuse.[5]

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 study published in 2015 showed evidence base for gabapentin use in treating alcohol withdrawal and dependence.[6] Gabapentin has also demonstrated 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).

A 2018 clinical review examined gabapentin as well as other drugs as anti-craving therapy in alcohol use disorder. The author felt there was a need for clinicians to expand their therapeutic choices to other drugs beyond those with FDA approval for this condition, including gabapentin.[7]

A double-blind study investigated the use of up to 1200 mg per day of gabapentin compared to placebo in alcohol use disorder. The research suggested that gabapentin might be most effective following the initiation of abstinence as a means to sustain abstinence and that it might be most effective in patients with a history of more severe alcohol withdrawal symptoms.[8] Another study examined using up to 1200 mg of gabapentin vs. the benzodiazepine lorazepam; the researchers found gabapentin to be superior to lorazepam in treating outpatients with moderate alcohol withdrawal. This outcome was measured by a lower chance of drinking and a superior but clinically similar alcohol withdrawal symptom reduction.[9]

Gabapentin in the Treatment of Anxiety and Depression

Gabapentin is sometimes prescribed off-label for patients with bipolar disorder to reduce anxiety levels or for anxiety disorders. Clinicians have also used it for patients who have anxiety and depression. A 2015 systematic review examined the available study data gabapentin use for psychological disorders and concluded that further research is necessary to determine whether gabapentin has a place in treating such conditions. The authors felt that there was some evidence that gabapentin may have a benefit in some anxiety disorders but noted that there are no studies for generalized anxiety disorder. They also determined that evidence showed that gabapentin is less likely to benefit as an adjunct in treating bipolar disorder. Their research determined that gabapentin has clearer efficacy for alcohol craving and withdrawal symptoms and may play an adjunct role in treating opioid dependence. They found no clear evidence for gabapentin therapy in depression, PTSD prevention, OCD, or other types of substance abuse.[10]

In 2019 researchers conducted another systematic review examining gabapentin's role in treating substance abuse and psychiatric disorders. Their findings were that gabapentin appears to have some efficacy in certain forms of anxiety disorder, such as pre-operative anxiety and anxiety in breast cancer survivors, as well as social phobia. They also saw evidence that gabapentin showed effectiveness in treating alcohol dependence, although this was more an adjunctive measure than monotherapy. They concluded that additional clinical trials were needed with larger patient populations to support using gabapentin in psychiatric disorders, especially inasmuch as a number of the trials in their analysis were open-label trials, with inherently less rigorous analysis.[11]

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, and 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.[12]

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, and the research may be considered dated.

In 1996, Miller et al. treated 152 ALS patients randomly assigned to receive 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 treating essential tremor compared to a placebo. The first 14 days of the study showed no difference between patients receiving 1800 mg gabapentin per day compared 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. The treatment group showed a significant reduction in tremors.

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 the 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.[13]

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.[13]

One benefit of gabapentin use is its mild side-effect profile. The most common side effects are fatigue, dizziness, and headache.

Administration

Gabapentin is highly lipophilic but not bound to plasma proteins, showing linear pharmacokinetics and not demonstrating any significant protein binding or liver metabolization. It has an oral bioavailability of greater than 90%, 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 renally, 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 increases 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 then take the drug three times a day.
  • Usually, the effects are apparent in the first week of treatment but sometimes take 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

For Fibromyalgia

  • 400 to 800 mg 3 times per day by mouth
  • Max: 2400 mg per day

Renal Dosing

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

Adverse Effects

Serious Reactions[14]

  • Suicidality
  • Depression
  • Steven-Johnson syndrome
  • Anaphylaxis
  • Angioedema
  • Erythema multiforme
  • Rhabdomyolysis
  • Withdrawal seizure or withdrawal symptoms if discontinued abruptly

More Common Reactions

  • Ataxia
  • Dizziness
  • Fatigue
  • Somnolence
  • Fever
  • Nystagmus
  • Peripheral edema
  • Hostility and hyperkinesia (pediatric)
  • Nausea and vomiting
  • Tremor
  • Asthenia
  • Diplopia
  • Diarrhea
  • Xerostomia
  • Infection
  • Amblyopia
  • Headache
  • Constipation
  • Weight gain
  • Abnormal thinking
  • Amnesia
  • Back pain
  • Impotence
  • Depression

Monitoring

Check baseline creatinine levels before and during the treatment. Inform patients and screen for depression, behavioral changes, and suicidality.[14][15]

Toxicity

At the federal level, gabapentin is not listed as a controlled drug, is considered a non-addictive medication, and is considered by the Centers for Disease Control and Prevention as a substitute for opiates for chronic pain. However, there are growing concerns about its potential for misuse.[16] Several US states have moved gabapentin to the Schedule V controlled substance category. Gabapentin does not have a high risk of an overdose but can increase the euphoria caused by opioids and reduce drug withdrawals. An Australian study examined fatal gabapentinoid-related poisoning and discovered that concomitant other drug use to be almost universal in such cases.[17] Furthermore, gabapentin can bypass the blocking effects of addiction treatment medications, and unfortunately, does not show up in urine drug tests.[18]

Enhancing Healthcare Team Outcomes

Gabapentin is a widely prescribed drug by primary care providers, mid-level practitioners, neurologists, internists, and orthopedic surgeons for a range of medical disorders. The drug has several uses besides its antiseizure properties. While gabapentin has a relatively safe profile, the pharmacist should assist the team and monitor the patient's medication list to ensure no potential drug interactions exist. Nursing can answer patient questions, review dosing, and serve as a point of contact for the clinician. All interprofessional team members should be aware of the possibility of misuse of gabapentin. This type of interprofessional team coordination will serve to optimize gabapentin therapy while minimizing potential adverse effects. [Level 5]


Article Details

Article Author

Rama Yasaei

Article Author

Shravan Katta

Article Editor:

Abdolreza Saadabadi

Updated:

5/2/2022 3:46:06 AM

PubMed Link:

Gabapentin

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