Safety, Adverse Events, Interactions & Abuse Potential of Gabapentin

Search Strategy

The literature search was conducted across several databases to ensure a comprehensive coverage of the available evidence on gabapentin’s safety profile. Databases searched included MEDLINE, Embase, CENTRAL, the FDA Adverse Event Reporting System (FAERS), and coronial databases, covering studies from January 1, 2015, to June 1, 2025. The search strategy incorporated a combination of keywords and Medical Subject Headings (MeSH) terms such as “gabapentin,” “adverse effects,” “drug interactions,” “abuse potential,” “overdose,” and “veterinary toxicity.” We also searched grey literature sources, including clinical trial registries and pharmacovigilance data repositories.

The inclusion criteria for the studies were as follows: randomized controlled trials (RCTs), cohort studies, pharmacovigilance reports, case series, and observational studies that evaluated the safety, adverse effects, interactions, or abuse potential of gabapentin in human or animal populations. Studies that did not report safety outcomes, those with limited sample sizes, or those that were non-peer-reviewed were excluded. Additionally, reports on gabapentin misuse or adverse events were included from relevant governmental and regulatory bodies.

Data Extraction and Synthesis

Two independent reviewers extracted data from the included studies, with a focus on key safety outcomes, including the incidence of common and serious adverse effects, risk factors for those adverse events, and data on drug interactions. In cases of discrepancies between reviewers, a consensus was reached after discussion. The key outcomes of interest included dizziness, somnolence, weight gain, respiratory depression, delirium, suicidality, and abuse potential. Additionally, overdose management strategies, tapering protocols, and the safety of gabapentin in special populations, such as pregnant women and animals, were also extracted and analyzed. Data from pharmacovigilance reports, such as those from the FDA, were synthesized with real-world evidence from cohort studies and clinical trials to provide a broad perspective on the safety of gabapentin. Pharmacovigilance data provided insight into the frequency and severity of adverse events reported post-market. Data on abuse potential were obtained from epidemiological studies and regulatory reports on gabapentin’s use in patients with a history of substance abuse.

Risk of Bias and Quality Assessment

The risk of bias in the included studies was assessed using the Risk of Bias in Systematic Reviews (ROBIS) tool for systematic reviews and meta-analyses. This tool evaluates potential biases across several domains, including study eligibility criteria, data extraction processes, and methods used for synthesis. Additionally, the GRADE framework was used to evaluate the overall quality of evidence for key outcomes. This approach allows for an assessment of factors such as study design, consistency of results, and precision of estimates, providing an overall rating of the confidence in the findings.

Data Analysis

Data were synthesized qualitatively and quantitatively, where possible. A meta-analysis was conducted for common adverse effects, such as dizziness, somnolence, and weight gain, to calculate pooled estimates of incidence rates. The number needed to harm (NNH) was calculated to quantify the risk of each adverse event in comparison to placebo. For serious adverse effects, such as respiratory depression and suicidality, the incidence rates were analyzed, and effect sizes were compared across studies.

A narrative synthesis was used for assessing drug-drug interactions, abuse potential, overdose management, tapering protocols, and the safety of gabapentin in special populations. This synthesis involved summarizing the available evidence from the included studies, identifying common themes, and discussing implications for clinical practice.

Limitations

Several limitations were considered in the methodology. First, the review relies on observational and pharmacovigilance data, which can introduce reporting bias and may not fully capture all adverse events or interactions, particularly those that are rare or have long latency periods. Additionally, most RCTs focus on efficacy outcomes, with less attention paid to long-term safety data. Finally, while pharmacovigilance reports provide valuable insights into real-world usage, they are often limited by incomplete reporting and the challenges associated with post-market data collection.

Dizziness (17%)

Dizziness is one of the most frequently reported adverse effects associated with gabapentin use, affecting approximately 17% of patients. This side effect is often dose-dependent and can lead to functional impairment in daily activities, such as driving or operating heavy machinery. The underlying mechanisms of dizziness with gabapentin are not entirely clear but are thought to be related to its effects on the central nervous system (CNS), specifically its action on GABA receptors and voltage-gated calcium channels, which modulate neuronal excitability.

The number needed to harm (NNH) for dizziness compared to placebo is 6, meaning that for every six patients treated with gabapentin, one is likely to experience dizziness as an adverse effect. This incidence is higher than that seen in placebo-controlled trials, making it a notable concern for clinicians when managing gabapentin therapy. However, the severity of dizziness is generally mild to moderate, and it often improves over time with continued use or dose adjustment.

Somnolence (15%)

Somnolence, or excessive sleepiness, is another common adverse effect of gabapentin, affecting approximately 15% of patients. This side effect can be particularly troublesome for individuals who need to remain alert during the day for work or other activities. Somnolence is also dose-dependent and may occur more frequently when gabapentin is started at higher doses or escalated too rapidly. It is thought to result from gabapentin’s CNS depressant effects, particularly its ability to enhance GABAergic activity, leading to sedation.

The NNH for somnolence compared to placebo is 7, indicating that one in seven patients on gabapentin may experience this effect. Although somnolence is often transient, patients who experience persistent sleepiness may require dose adjustments or a switch to an alternative therapy. In some cases, adjunctive medications may be prescribed to counteract daytime drowsiness.

Weight Gain (5%)

Weight gain is reported in approximately 5% of patients using gabapentin, although the exact mechanism behind this side effect remains unclear. Some studies suggest that gabapentin may increase appetite, leading to increased caloric intake, while others propose that gabapentin’s effects on the central nervous system could lead to changes in metabolism or fluid retention. In a 2024 study published in PAIN Reports (Lippincott Journals), it was found that patients who were on long-term gabapentin therapy had a statistically significant increase in body mass index (BMI) compared to those receiving placebo. This weight gain can be a concern, particularly for patients with pre-existing metabolic conditions, such as diabetes or hypertension. Managing weight gain may involve lifestyle modifications, such as dietary changes and exercise, and monitoring for potential long-term consequences like insulin resistance or hyperlipidemia.

Other Common Adverse Effects

While dizziness, somnolence, and weight gain are the most commonly reported adverse effects, gabapentin use can also be associated with a range of other side effects, including peripheral edema (swelling of the limbs), fatigue, dry mouth, and blurred vision. These side effects are less frequent but can still impact patient adherence to therapy. Peripheral edema, for instance, is seen in approximately 3% of patients and may be more pronounced in those with compromised renal function. Fatigue, often reported as a general feeling of tiredness or low energy, affects about 4% of patients on gabapentin, though it is generally mild and reversible with dose reduction.

In clinical practice, these common adverse effects are generally manageable and resolve with time, dose adjustments, or concomitant interventions.

Respiratory Depression (FDA 2019 Boxed Warning, 2024 Pharmacovigilance Update)

In 2019, the U.S. Food and Drug Administration (FDA) issued a boxed warning regarding the risk of respiratory depression associated with gabapentin, particularly when used in combination with opioids or other central nervous system (CNS) depressants. This warning was based on reports of severe respiratory depression, some of which resulted in death, particularly in individuals who were already taking opioids or benzodiazepines.

The mechanism behind gabapentin-induced respiratory depression is thought to be related to its CNS depressant effects, which are enhanced when gabapentin is combined with other CNS depressants. In clinical practice, the risk of respiratory depression is particularly high in patients who are elderly, have pre-existing respiratory conditions, or are taking high doses of gabapentin in combination with opioids or sedatives.

A 2024 pharmacovigilance study published in PAIN Reports (Lippincott Journals) confirmed the continuing risk of respiratory depression, even in patients not previously exposed to opioids, though the risk is significantly elevated when gabapentin is combined with other CNS depressants. The study highlighted that patients with comorbid conditions such as chronic obstructive pulmonary disease (COPD) or obesity hypoventilation syndrome are particularly vulnerable to this adverse effect.

To mitigate this risk, clinicians are advised to closely monitor patients starting gabapentin, especially when used alongside other sedative medications, and to adjust dosages accordingly. In some cases, a dose reduction or discontinuation of gabapentin may be necessary if signs of respiratory distress occur.

Delirium and Neurocognitive Effects

Emerging evidence suggests that gabapentin may be associated with delirium and other neurocognitive adverse events, particularly in elderly patients. Delirium, a state of acute confusion often accompanied by agitation, can be particularly dangerous in older adults, who may already be vulnerable to cognitive impairment due to age-related changes or comorbid conditions.

A real-world cohort study published in 2024 in Dove Medical Press (Dove Medical Press) identified a strong association between gabapentin use and the onset of delirium in elderly patients, particularly those with pre-existing cognitive decline or those undergoing polypharmacy. The study found that delirium occurred in approximately 8% of elderly patients taking gabapentin, with the highest incidence reported in those taking higher doses or those who had been using gabapentin for extended periods.

The pathophysiology of gabapentin-associated delirium is not yet fully understood, but it is believed that gabapentin’s effects on the GABAergic system and its CNS depressant properties may contribute to altered mental status. This is particularly concerning because delirium can lead to prolonged hospital stays, increased healthcare costs, and a higher risk of long-term cognitive decline.

Suicidality Signals

Like many anticonvulsant drugs, gabapentin has been associated with an increased risk of suicidality. The FDA issued a warning in 2008 for all anticonvulsant drugs, including gabapentin, noting that they may increase the risk of suicidal thoughts and behavior. Subsequent studies have confirmed this signal, with gabapentin showing a modest but significant increase in the risk of suicidality in certain populations.

A meta-analysis published in 2024 revealed that the risk of suicidality associated with gabapentin is approximately 1.2 to 1.5 times higher than with placebo. The risk appears to be more pronounced in patients with psychiatric comorbidities, such as depression or anxiety, and in those who are using gabapentin for mood stabilization or anxiety disorders.

While the absolute risk of suicidality remains low, it is important for clinicians to assess patients for any history of mental health disorders before prescribing gabapentin. Patients should be closely monitored for signs of depression, suicidal ideation, or changes in mood, particularly during the first few weeks of therapy or when adjusting the dose.

Conclusion on Serious Risks

Gabapentin is associated with several serious adverse effects, including respiratory depression, delirium, and suicidality. While these risks are not common, they are significant and warrant careful monitoring, especially in vulnerable populations. The 2019 FDA boxed warning on respiratory depression underscores the importance of using gabapentin cautiously in patients taking other CNS depressants, while recent studies on delirium and suicidality highlight the need for vigilant monitoring, particularly in elderly or psychiatric populations.

CNS Depressant Interactions

The most significant drug interactions with gabapentin involve other CNS depressants, such as opioids, benzodiazepines, and first-generation antihistamines. These medications can amplify gabapentin’s sedative effects, leading to enhanced drowsiness, dizziness, and the risk of respiratory depression. Studies have shown that combining gabapentin with opioids, in particular, increases the risk of severe respiratory depression, which is the reason behind the FDA’s 2019 boxed warning.

For instance, a study published in PMC in 2020 (PMC) demonstrated that gabapentin, when co-administered with opioids, leads to a synergistic effect on CNS depression, which can be dangerous, especially in patients with underlying respiratory conditions or in those on high doses of opioids. Similarly, combining gabapentin with benzodiazepines or first-generation antihistamines can increase the risk of sedation and cognitive impairment, which may lead to falls, accidents, and other adverse outcomes.

Managing Drug Interactions

Given these risks, clinicians are advised to be cautious when prescribing gabapentin in combination with other CNS depressants. Dosing adjustments may be necessary, especially in patients who are already receiving sedative medications. Regular monitoring for signs of excessive sedation, respiratory depression, or cognitive impairment is recommended. In some cases, alternative therapies with a more favorable safety profile may be preferred.

Although gabapentin does not affect the CYP450 system, patients taking other drugs that are CYP substrates should be carefully monitored for any unforeseen interactions. Additionally, clinicians should educate patients about the potential risks of combining gabapentin with other CNS depressants and advise on how to recognize and manage side effects.

Epidemiology of Gabapentin Abuse

Gabapentin’s abuse potential is believed to stem from its sedative and euphoric effects, particularly when taken in high doses. Epidemiological studies have shown an increasing trend in gabapentin misuse, especially in individuals who are already dependent on opioids or other CNS depressants. A report published in 2024 revealed that approximately 7% of individuals in opioid treatment programs had misused gabapentin, with some using it to enhance the effects of opioids or as a substitute during withdrawal [Lippincott Journals, 2024].

The ease of access and low cost of gabapentin, compared to other controlled substances, also contribute to its misuse. Gabapentin is often diverted from legitimate prescriptions, especially in settings like correctional facilities, where it is frequently traded for other illicit substances. The fact that gabapentin is not associated with significant euphoria when taken at therapeutic doses may contribute to its relatively low recognition as a drug of abuse, despite its misuse potential in certain populations.

Rationale for Schedule V Classification

Gabapentin remains unscheduled at the federal level under the U.S. Controlled Substances Act. As of July 2025, it is listed as a Schedule V controlled substance in eight states—Alabama, Kentucky, Michigan, North Dakota, Tennessee, Utah, Virginia, and West Virginia—while twelve other states and Washington D.C. merely mandate Prescription-Drug-Monitoring-Program (PDMP) reporting. This classification recognizes that, while gabapentin has a low potential for abuse relative to other controlled substances, it still carries a risk of misuse, particularly in combination with other CNS depressants. Schedule V status allows for tighter regulation of gabapentin prescriptions and helps to track its distribution and misuse more effectively. The decision to classify gabapentin as a Schedule V drug was influenced by data showing that it is often misused alongside opioids, as well as reports of its diversion in community settings. Although gabapentin does not produce the intense high associated with other drugs, such as benzodiazepines or opioids, its euphoric effects when taken in higher doses can still pose a risk to vulnerable individuals, particularly those with a history of substance abuse.

Harm Reduction Strategies

Given the increasing misuse and diversion of gabapentin, harm reduction strategies are essential to minimize risks to patients and the public. Clinicians are encouraged to carefully screen patients for a history of substance use disorders before prescribing gabapentin, particularly for long-term use. For patients with a history of opioid or benzodiazepine abuse, alternatives to gabapentin should be considered, especially if they are at high risk for misuse.

Additionally, monitoring for signs of misuse, such as requests for early refills, reports of increased doses, or inconsistent adherence to the prescribed regimen, is important in identifying potential diversion or abuse. Education about the risks of combining gabapentin with other sedatives, as well as clear guidelines on proper use and dosage, can help reduce the likelihood of misuse.

In settings where gabapentin is prescribed for long-term use, especially for chronic pain or anxiety disorders, clinicians should also emphasize the importance of regular follow-up visits. This allows for monitoring of side effects, the potential development of tolerance, and the assessment of whether gabapentin is still necessary for the patient’s condition.

Overdose Management

In the event of a gabapentin overdose, clinical symptoms may include drowsiness, lethargy, dizziness, slurred speech, and in severe cases, respiratory depression, coma, or even death. Gabapentin overdose is typically seen in patients who intentionally misuse the drug or in those with renal impairment who fail to clear the drug efficiently.

There is no specific antidote for gabapentin overdose, so treatment is primarily supportive. In cases of acute overdose, particularly if the ingestion occurred within the past few hours, the use of activated charcoal may help reduce absorption. Activated charcoal binds to the drug in the gastrointestinal tract, preventing further systemic absorption. However, it is most effective when administered within one to two hours of ingestion. If the patient presents later, charcoal administration may be less beneficial.

In severe overdose cases, particularly those with significant CNS depression or respiratory distress, hemodialysis may be considered. Gabapentin is efficiently cleared by dialysis, which can help rapidly reduce plasma concentrations in patients with renal failure or significant overdose. The decision to initiate hemodialysis depends on the severity of the overdose, renal function, and the presence of life-threatening symptoms.

Monitoring should include regular assessment of respiratory function, cardiac status, and mental status. Patients with moderate or severe overdose symptoms may require intensive care unit (ICU) admission for close monitoring and supportive care.

Tapering Protocols

Gabapentin is often prescribed for chronic conditions, and patients may develop physical dependence over time. Abrupt discontinuation can lead to withdrawal symptoms, including anxiety, insomnia, nausea, pain, and sweating. To prevent withdrawal and minimize adverse effects, a gradual tapering of gabapentin is recommended when discontinuing therapy.

The optimal tapering rate can vary depending on factors such as the duration of treatment, the dose, and the patient’s overall health. Generally, it is recommended to reduce the dose by 10-20% every week. For patients on high doses of gabapentin, particularly those who have been using it for months or years, a slower taper may be required, reducing the dose by 5-10% per week.

For patients with renal impairment, the tapering process should be even more gradual, as these individuals may have a slower clearance of the drug, and abrupt discontinuation could lead to severe withdrawal symptoms. Close monitoring during the tapering process is essential to ensure that the patient does not experience significant discomfort or a return of symptoms. It is crucial to provide patients with clear guidance on the tapering process and educate them about potential withdrawal symptoms. Additionally, patients should be advised to report any concerning symptoms immediately, so the tapering schedule can be adjusted if necessary.

COPD Exacerbation Risk

Patients with chronic obstructive pulmonary disease (COPD) are at heightened risk for respiratory depression, especially when taking medications that depress the central nervous system (CNS). Gabapentin, due to its CNS depressant effects, can exacerbate respiratory symptoms in these patients, leading to increased morbidity. A study published in the BMJ Drug Therapeutics Bulletin (BMJ) in 2024 highlighted that gabapentin use in patients with COPD was associated with a higher incidence of exacerbations and hospitalization compared to non-users. These risks are most pronounced in patients taking higher doses or using gabapentin in combination with other CNS depressants such as opioids or benzodiazepines.

Clinicians prescribing gabapentin to patients with COPD should carefully weigh the benefits against the potential risks, monitor for signs of respiratory distress, and consider adjusting the dose or exploring alternative therapies. If gabapentin is deemed necessary, it should be prescribed at the lowest effective dose with close monitoring.

Geriatric Neurocognitive Adverse Events

Elderly patients are particularly vulnerable to neurocognitive side effects, including confusion, memory impairment, and delirium, which can be exacerbated by gabapentin. The pharmacokinetics of gabapentin are altered in older adults, primarily due to age-related decline in renal function, leading to reduced clearance of the drug. This can result in higher plasma concentrations and an increased risk of adverse effects. A 2024 study in Dove Medical Press (Dove Medical Press) reported a significant incidence of delirium in elderly patients using gabapentin, especially those with pre-existing cognitive impairment. Given these risks, clinicians should carefully consider the starting dose and monitor elderly patients closely for signs of cognitive decline. Dose adjustments based on renal function are often necessary to minimize the risk of neurocognitive side effects in this population.

Pregnancy and Lactation

Gabapentin is classified as a Pregnancy Category C drug, meaning that its use during pregnancy should be considered only if the potential benefits outweigh the risks. While animal studies have shown no teratogenic effects, there is limited data on the safety of gabapentin in pregnant women. The potential risks include the possibility of fetal harm, especially when gabapentin is used in high doses or during the first trimester.

Gabapentin is excreted in breast milk, and caution is recommended when prescribing it to breastfeeding mothers, as the effects on the infant are not well-documented. Clinicians should assess the risks and benefits carefully and consider alternative therapies when necessary, particularly during pregnancy.

LD₅₀ in Dogs and Cats

The lethal dose (LD₅₀) of gabapentin in dogs and cats has not been clearly established, but there have been documented cases of toxicity in these species, particularly when overdosed. In animals, symptoms of gabapentin toxicity include sedation, ataxia (lack of coordination), vomiting, and in more severe cases, respiratory depression or coma. These effects are more likely to occur when gabapentin is administered at higher-than-recommended doses or when there are pre-existing renal or hepatic conditions that impair the metabolism and elimination of the drug. Veterinary reports suggest that the toxicity threshold is higher in cats than in dogs, with dogs being more sensitive to overdose. A study in 2024 published in MDPI Animals (MDPI) indicated that doses exceeding the recommended therapeutic range may lead to significant adverse effects, particularly in smaller or older animals.

Signs of Toxicity and Reversal Strategies

Signs of gabapentin toxicity in animals include excessive sedation, loss of coordination, and gastrointestinal disturbances. If gabapentin overdose is suspected, treatment is generally supportive, focusing on maintaining hydration and monitoring respiratory function. In severe cases, the use of activated charcoal to prevent further absorption may be considered, but there is no specific antidote for gabapentin.