Hyponatremia, which is a serum sodium level of less than 135 mmol/L, is a prevalent electrolyte abnormality with important clinical consequences, such as neurological symptoms, seizures, and in extreme instances, coma and death (Lu & Wang, 2017) [1]. A number of drugs, such as antiepileptic drugs (AEDs), have been found to cause hyponatremia. Among AEDs, carbamazepine and oxcarbazepine are established causes of drug-induced hyponatremia through their actions on arginine vasopressin secretion and renal sodium handling (Berghuis et al., 2017; Lin et al., 2010)[4, 8]. Gabapentin, a widely used AED and analgesic, has, however, garnered relatively less attention in this context.

Gabapentin is extensively used for the management of epilepsy, neuropathic pain, and other off-label uses. Unlike most traditional AEDs, gabapentin has not been shown to primarily act via sodium channels but instead modulates calcium channels through its action on the α2δ subunit, diminishing the release of excitatory neurotransmitters (Asconapé, 2002) [3]. Although it has an overall benign safety profile, new data indicate that gabapentin might add to electrolyte imbalances, such as hyponatremia. Although the precise mechanisms are not yet understood, possible mechanisms include renal loss of sodium and inappropriate antidiuretic hormone secretion (SIADH), consistent with the effects reported with other AEDs (Yamamoto et al., 2019) [7].

The clinical relevance of AED-related hyponatremia is considerable, as it is associated with hospitalizations and enhanced morbidity, especially in elderly individuals and patients with underlying renal impairment or polypharmacy (Falhammar et al., 2018) [2]. Recognition of the risk factors and prevalence of gabapentin-induced hyponatremia is important in maximizing patient care and avoiding complications. Since past large-scale research has been mostly centered on carbamazepine and oxcarbazepine, more research into gabapentin's involvement in sodium disturbance is necessary (Holtmann et al., 2002) [5, 6].

The objective of this article is to summarize current literature regarding gabapentin-induced hyponatremia, discuss possible pathophysiologic mechanisms, and consider clinical implications based on current epidemiological and pharmacological research. Understanding this association will allow physicians to make more informed choices in the use of gabapentin, especially in at-risk groups.

Study Design and Setting

The research was planned as a retrospective observational study at a tertiary care facility. The study aimed to analyze the incidence and risk factors of hyponatremia due to gabapentin in patients undergoing gabapentin therapy for various neurological and pain disorders. The study comprised both inpatient and outpatient cases, thereby analyzing different clinical scenarios. Medical records of the last five years were analyzed to collect cases of hyponatremia in gabapentin-treated patients.

Patient Selection and Eligibility Criteria

Participants of 18 years and above who had been treated with gabapentin for a minimum of four weeks were included in the study. Inclusion criteria included those diagnosed with epilepsy, neuropathic pain, or other off-label diseases that had been treated with gabapentin. Patients with prior hyponatremia, on concomitant sodium-wasting drugs like diuretics, and patients with severe renal, hepatic, or endocrine disease that affects sodium levels were excluded in order to avoid confounding. Those on other antiepileptic drugs, for example, carbamazepine or oxcarbazepine, known to cause hyponatremia were excluded so as to selectively evaluate the gabapentin effect.

Data Collection and Laboratory Assessments

Demographic information, such as age, gender, body mass index (BMI), and medical history, was obtained from electronic medical records. History of medications, dose, duration of gabapentin treatment, and concomitant drug use was recorded. Laboratory testing consisted of baseline and follow-up levels of serum sodium, renal function tests, and electrolyte panels. Hyponatremia was defined as serum sodium level of less than 135 mmol/L, and severity was categorized as mild (130–134 mmol/L), moderate (125–129 mmol/L), and severe (<125 mmol/L). Those patients developing hyponatremia were also assessed for symptoms such as dizziness, nausea, confusion, and seizures.

Statistical Analysis

Statistics software was utilized to analyze data, with continuous data presented as mean ± standard deviation and categorical data as percentages and frequencies. Patients with and without hyponatremia were compared using the chi-square test for categorical data and the t-test for continuous data. Multivariate logistic regression was used to determine independent risk factors for gabapentin-induced hyponatremia after adjustment for confounding variables including age, gender, renal function, and medication dosage. A p-value of less than 0.05 was regarded as statistically significant.

Incidence of Gabapentin-Induced Hyponatremia

450 patients who underwent gabapentin therapy for several neurological and pain disorders were studied. Out of them, 58 patients (12.9%) developed hyponatremia during the course of the study. Hyponatremia was of mild severity in 34 patients (7.5%), moderate severity in 18 patients (4.0%), and severe severity in 6 patients (1.3%). The average serum sodium concentration in hyponatremic patients was 128.4 ± 4.2 mmol/L, whereas in non-hyponatremic patients it was 138.6 ± 2.3 mmol/L (p < 0.001). Hyponatremia was noticed between 8 to 12 weeks of gabapentin therapy in the majority of patients.

Demographic and Clinical Characteristics

Table 1 shows the baseline characteristics of hyponatremic and non-hyponatremic patients. Hyponatremic patients were older than non-hyponatremic patients, with a mean age of 62.1 ± 8.5 years compared to 55.6 ± 9.2 years in non-hyponatremic patients (p = 0.03). The incidence of hyponatremia was higher in female patients (14.6%) than in male patients (11.5%), although this was not statistically significant (p = 0.21). Most of the patients with hyponatremia had underlying comorbidities like CKD and diabetes mellitus, and these conditions were highly related to sodium imbalance (p < 0.05).

Table 1: Baseline Characteristics of Patients with and without Hyponatremia

Gabapentin Dosage and Hyponatremia Risk

The association between the dose of gabapentin and the risk of developing hyponatremia was evaluated, as presented in Table 2. Patients taking higher doses of gabapentin (≥1200 mg/day) had a significantly increased incidence of hyponatremia (18.5%) when compared to those taking lower doses (8.2%) (p = 0.007). The average duration of gabapentin treatment prior to the development of hyponatremia was 10.4 ± 3.2 weeks.

Table 2: Gabapentin Dosage and Incidence of Hyponatremia

Symptoms and Clinical Manifestations

Hyponatremic patients had a varied range of clinical symptoms, of which dizziness (46.5%), nausea (39.7%), weakness (32.7%), confusion (22.4%), and seizures (8.6%) were noted. Severe (serum sodium <125 mmol/L) hyponatremia were more prone to present with neurological symptoms and required hospitalization as well as correction of electrolytes. Figure 1 depicts the incidence of clinical symptoms among the patients with hyponatremia caused by gabapentin.

Statistical Analysis of Risk Factors

Multivariate logistic regression analysis revealed older age (OR: 1.45, 95% CI: 1.12–1.87, p = 0.02), CKD (OR: 2.31, 95% CI: 1.42–3.78, p = 0.008), diabetes mellitus (OR: 1.89, 95% CI: 1.10–3.24, p = 0.03), and high-dose gabapentin use (≥1200 mg/day) (OR: 2.74, 95% CI: 1.56–4.82, p = 0.004) as independent risk factors for the development of hyponatremia.

Figure 1: Frequency of clinical symptoms in patients with gabapentin-induced hyponatremia.

Figure 2: Mean serum sodium levels in patients with and without hyponatremia across different gabapentin doses.

Figure 3: Kaplan-Meier curve showing time to onset of hyponatremia in patients receiving gabapentin therapy.

These results emphasize the risk of hyponatremia linked with gabapentin treatment, especially for elderly patients and those with prior renal impairment. Monitoring serum sodium levels on a routine basis, especially in patients on higher doses of gabapentin, is indicated.

The results of this research point to the fact that gabapentin, an antiepileptic drug with primary application in the treatment of epilepsy and neuropathic pain, can potentially be a cause of hyponatremia, especially among elderly patients and those with existing renal impairment. While gabapentin has not been classically identified as a high-risk medication for sodium imbalance, our findings suggest that its administration, particularly at higher doses, results in a significant decrease in the level of serum sodium. The reported prevalence of hyponatremia (12.9%) concurs with past reports of antiepileptic drug (AED)-associated hyponatremia, although the specific mechanism of gabapentin's role in the process is yet to be explained.

Past literature has widely accounted for the role of sodium channel-blocking AEDs, like oxcarbazepine and carbamazepine, in inducing hyponatremia. For example, Steinhoff et al. (1992) [9] described a case of hyponatremic coma related to oxcarbazepine, highlighting the drug's powerful effect on sodium balance. Also, Nielsen et al. (1988) [13] in a cross-sectional study showed a high prevalence of oxcarbazepine-induced hyponatremia, especially among elderly patients. This is in agreement with other authors, such as Borusiak et al. (1998) [12], who observed that children treated with oxcarbazepine had a high risk of developing hyponatremia. In contrast with these sodium channel-blocking AEDs, however, gabapentin does not impact sodium channels directly, leaving us to conclude that other mechanisms could be contributing to its effect on sodium homeostasis.

Comparing our findings to large-scale data analyses of AED-induced hyponatremia, Arif et al. (2010) [10] presented a comparative assessment of 10 AEDs in older persons and noted that hyponatremia was of particular concern with some of these AEDs, though not with gabapentin per se. Intravooth et al. (2018) [11] had studied 560 in-hospital patients and discovered that hyponatremia caused by AED was most frequently associated with carbamazepine and oxcarbazepine, yet gabapentin was not well studied in this research. The results of the present study indicate that gabapentin might not have such a high prevalence of hyponatremia compared to these drugs, yet their impact cannot be ignored, especially in susceptible individuals with risk factors for electrolyte imbalance.

Life-threatening AED-induced hyponatremia has also been reported in elderly subjects. Valentini et al. (2009) [14] described an episode of severe oxcarbazepine-induced hyponatremia in an elderly patient, highlighting the susceptibility of the elderly to imbalances in sodium levels. This was consistent with the findings in our study, wherein older age was a highly predictive risk factor for hyponatremia due to gabapentin. In addition, Nasrallah and Silver (2005) [15] reported hyponatremia following repeated dosing of levetiracetam, establishing that non-sodium channel-blocking AEDs are also involved in electrolyte disturbances. The current study provides additional evidence by showing that even gabapentin, with its unique pharmacologic profile, has the potential to cause clinically important hyponatremia.

The pathogenesis of gabapentin-induced hyponatremia is also speculative. In contrast to carbamazepine and oxcarbazepine, which are reported to increase antidiuretic hormone (ADH) release and reduce renal sodium excretion, gabapentin does not have a direct effect on sodium channels or ADH mechanisms. Nevertheless, gabapentin has been proposed to modify renal sodium handling by its action on calcium channels, which are involved in tubular sodium reabsorption. In addition, patients treated with gabapentin also frequently have comorbid conditions including chronic kidney disease and diabetes mellitus, which are known to predispose the patient to hyponatremia. This is borne out in our study, as CKD and diabetes were recognized as independent predictors.

Our data also demonstrate a dose-dependent correlation between gabapentin therapy and hyponatremia. Patients on ≥1200 mg/day had a much higher prevalence of hyponatremia compared to lower doses. This dose-response relationship holds true with observations on other AEDs like oxcarbazepine in which increased doses have been linked with an elevated risk of sodium imbalance (Intravooth et al., 2018) [11]. The median time to develop hyponatremia in our study was around 10 weeks, similar to earlier findings that electrolyte abnormalities caused by AEDs tend to manifest within weeks to months of initiating therapy.

From a clinical standpoint, the identification of gabapentin-induced hyponatremia is significant, especially in susceptible populations. Monitoring serum sodium levels regularly in patients receiving long-term gabapentin treatment, particularly those on high doses, is advised. Since symptoms like dizziness, nausea, and confusion were prevalent in our study, early detection and correction of hyponatremia may avoid more serious complications, including seizures and altered mental status.

Overall, although earlier studies emphasized sodium channel-blocking AEDs as the primary cause of hyponatremia, our results indicate that gabapentin may also be considered a potential cause. Larger sample-size prospective studies and mechanistic analyses are needed to define the precise mechanisms by which gabapentin influences sodium balance. Clinicians should remain cautious until then about prescribing gabapentin, especially to patients with risk factors for hyponatremia.

This research proves that gabapentin, although not classically linked with sodium disturbances, may be a causative agent in the production of hyponatremia, especially in elderly patients and those with chronic kidney disease or diabetes mellitus. The risk was found to be dose-dependent, with increased doses (≥1200 mg/day) having a significant risk of sodium loss. Although the mechanism is uncertain, the results imply that gabapentin could change renal sodium handling, causing clinically important electrolyte imbalances. Comparisons with earlier research on sodium channel-blocking antiepileptic drugs like oxcarbazepine and carbamazepine show that although less commonly reported, gabapentin-induced hyponatremia is still a significant clinical issue. Due to the risk of severe complications, such as neurological manifestations and hospitalizations, routine monitoring of serum sodium levels in patients on gabapentin therapy is advisable. More studies are required to elucidate the underlying mechanisms and develop complete guidelines for the safe administration of gabapentin in vulnerable populations.

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