Gabapentinoids-Induced Rhabdomyolysis/Myopathy: Clinical Characteristics, Management, Outcomes, and Critical Safety Alerts

Introduction

Rhabdomyolysis is a clinical syndrome characterized by rapid disintegration of skeletal muscle, resulting in the release of intracellular contents into the systemic circulation. It can be triggered by diverse etiologies including trauma, ischemia, medications, toxins, metabolic disorders, and infections, all of which compromise the integrity and stability of the sarcolemma. The ensuing massive release of muscle-derived components such as myoglobin, creatine kinase, and electrolytes can lead to tissue injury and multi-organ dysfunction. Systemic manifestations range from asymptomatic elevation of muscle enzymes to life-threatening complications, with acute kidney injury and severe electrolyte imbalances representing the most critical outcomes. Central to its pathogenesis are the nephrotoxic and cytotoxic effects of myoglobin and its metabolic derivatives.^1,2 Non-traumatic cases predominantly arise from drug toxicity (80% adult prevalence) through mitochondrial ATP disruption (statins via HMG-CoA inhibition);³ calcium dysregulation (anesthetic-induced hyperthermia); or direct sarcolemmal injury (alcohol metabolites).^4,5 Although statins/antipsychotics/immunosuppressants are still recognized as high-risk drugs, sporadic cases of rhabdomyolysis have also been reported with the emerging neuromodulator gabapentinoids.^4,6 Although the precise mechanisms of gabapentinoid-induced myotoxicity remain to be fully elucidated, proposed pathways include disruption of calcium homeostasis, synergistic interactions with other medications, such as statins, which may collectively precipitate muscle injury.^7,8

Despite the widespread use of gabapentinoids (gabapentin/pregabalin) as α2-δ voltage-gated calcium channel ligands for treating neuropathic pain, restless legs syndrome, and epilepsy via presynaptic inhibition of excitatory neurotransmitters (glutamate/substance P),⁹ their potential for muscular toxicity remains inadequately characterized. Current evidence remains limited to sporadic case reports with knowledge gaps in risk factor stratification and prognostic modeling. This systematic global analysis synthesizes gabapentin-induced myotoxicity profiles, therapeutic approaches, pharmacological interactions, and prognostic patterns, providing actionable insights for rhabdomyolysis recognition, management, and prevention.

Materials and Methods

Study Design and Literature Search Strategy

This systematic review aimed to investigate the clinical characteristics, management, and outcomes of gabapentinoid-induced rhabdomyolysis by analyzing published case reports. A systematic literature search was conducted across PubMed/Medline, Web of Science, Ovid, Embase, Cochrane Library, Elsevier, SpringerLink, and major Chinese databases (CNKI/Wanfang/VIP) using search terms: gabapentin, gabapentinoids, pregabalin, rhabdomyolysis, myopathy, myositis, spanning inception-December 2024 without language restrictions. Exclusion criteria were: non-clinical studies (mechanistic/animal/reviews), secondary literature (editorials/commentaries), duplicate publications, and unavailable full-text articles.

Data Analyse

A structured data collection instrument was developed and implemented to systematically capture patient demographics (sex, age), clinical characteristics (comorbidities, concomitant medications), therapeutic regimens, and clinical outcomes throughout the study protocol.

Result

Patient

Following systematic screening, nineteen case reports met inclusion criteria in Table 1.^7,8,10–24 No other types of studies, such as randomized clinical trials, cohort studies, or case series, related to our research question were identified through the systematic search. Among the 19 myopathy patients (10 males, 9 females) in this study (Table 2), the medication profiles revealed: Gabapentin use in 12 cases and Pregabalin in 7 cases. From a dosage perspective, 75% of gabapentin users and 85.7% of pregabalin users did not exceed the maximum recommended daily dose as stated in the prescribing information for each drug, a figure that includes one case each where the exact dosage was unknown. Analysis of dosing patterns revealed that six patients (31.6%) developed symptoms acutely, nine (47.4%) subacutely, and two (10.5%) chronically, whereas the pattern was not documented in the literature for the remaining two cases (10.5%). The cohort demonstrated a broad age range with a median age of 63 years. Indications for use primarily aligned with approved labeling: restless legs syndrome (3/19, 15.8%), pain management (13/19, 68.4%), and uremia-associated pruritus (1/19, 5.3%), though off-label high-dose use/misuse was also documented (2/19, 10.5%). Seventeen patients presented with comorbidities, including hypertension (9/17, 52.9%), nephrotic syndrome (6/17, 35.3%), psychiatric disorders (anxiety/depression/schizophrenia) (6/17, 35.3%), diabetes mellitus (6/17, 35.3%), and hyperlipidemia (5/17, 29.4%), necessitating concurrent pharmacotherapy. The median latency period for symptom onset was 3 days (range 1–52 days), with temporal distribution as follows: 5 cases (29.4%) occurred within 2 days, 4 cases (23.5%) between 3 and 7 days, 1 case (5.9%) during 8 and 14 days, and 7 cases (41.2%) manifesting after two weeks. Naranjo scale assessment categorized 16 cases (84.2%) as probable adverse drug reactions (with documented scores ranging from 5 to 8 where available) and 3 cases (15.8%) as possible (scores ranging from 1 to 4 where available).

Table 1 Gabapentinoids Related Rhabdomyolysis/Myopathy-Summary of Case Reports

Table 2 Characteristics of 19 Patients with Rhabdomyolysis Induced by Gabapentinoids

Clinical Characteristics and Treatments

Among the 19 included cases, all patients manifested clinical symptoms (Table 3). The most prevalent myopathic manifestations were weakness/numbness (13/19, 68.4%) and myalgia (9/19, 47.4%). Additional presentations included fatigue (2/19, 10.5%), muscle spasms (1/19, 5.3%), unconsciousness (1/19, 5.3%), and altered mental status (1/19, 5.3%). All 19 patients demonstrated elevated creatine CPK levels, with median values of 3,095 U/L (range 747–75,680). Serum myoglobin was quantified in 9 patients (median 2,855 ng/mL). Elevated lactate dehydrogenase (LDH) was observed in 7 cases, reaching a median concentration of 1,172 U/L (329–2,520). Literature-based analysis indicated renal impairment (either new-onset or exacerbation of pre-existing conditions) in 15 patients, with potential confounding factors in RLS-treated cases requiring consideration. Notably, myoglobinuria was documented in 4 patients.

Table 3 Clinical Characteristics of Rhabdomyolysis/Myopathy Caused by Gabapentinoids

Literature-documented therapeutic interventions demonstrated immediate discontinuation of suspected causative agents in all 19 myopathy cases, with 11 patients (11/19, 57.9%) receiving explicitly documented supportive care including hydration, urine alkalinization, and diuresis, while renal replacement modalities comprised intermittent hemodialysis in 6 patients (6/19, 31.6%), notably, including two preexisting dialysis-requiring cases developing complications post low-dose gabapentin therapy. Supplemented by continuous renal replacement therapy (CRRT) in two patients (2/19, 10.5%) and peritoneal dialysis in one patient (1/19, 5.3%).

Clinical outcomes demonstrated universal symptomatic improvement across the cohort, with creatine phosphokinase (CPK) normalization achieved in 15/19 patients (median 14 days; range 7–21+ days) whereas post-discharge CPK monitoring was unavailable for 4 resolved cases—specifically, biochemical recovery occurred within 7 days in 5 patients (33.3%), 8–14 days in 4 (26.7%), 15–21 days in 2 (13.3%), and exceeded three weeks in the remaining 4 (26.7%). Mortality was exclusively observed in an 83-year-old multimorbid patient who developed acute respiratory failure culminating in death on day 19 despite complete myopathy resolution, with autopsy findings dissociating the terminal event from muscular pathology. Our findings highlight a common challenge in outpatient settings: the documentation of laboratory parameters often begins after symptom appearance. Moving forward, a heightened clinical suspicion that triggers earlier and more frequent CPK testing could yield valuable insights into the early phases of this condition.

Discussion

Our analysis of 19 globally reported cases provides critical insights into the clinical profile of gabapentinoid-induced rhabdomyolysis. The key findings include a rapid median onset of symptoms (3 days), a high prevalence of polypharmacy (89.5%) and comorbidities, and a strong association with concomitant statin use (noted in 7 cases). Despite these risks, prompt drug discontinuation and supportive care led to biochemical resolution in most patients.

These findings both align with and refine the existing understanding of drug-induced rhabdomyolysis. The rapid symptom onset observed in our cohort (≤7 days in 52.9% of cases) suggests a direct toxic effect on muscle cells rather than a slow metabolic accumulation. The exceedingly high rate of polypharmacy underscores that gabapentinoid-induced myotoxicity is rarely an isolated event but frequently occurs in a complex pharmacological context, where drug interactions and additive toxicities play a significant role. This is strongly supported by the Naranjo scale assessment, which confirmed a probable causal relationship in 84.2% of cases. The association with statins, a well-known risk factor for myopathy, highlights a potentially synergistic mechanism of muscle injury that clinicians must be vigilant about.

Our analysis robustly identifies three critical risk dimensions that converge to heighten vulnerability to gabapentinoid-induced rhabdomyolysis: pre-existing comorbidities, polypharmacy-driven drug interactions, and advanced age. First, the near-universal presence of comorbidities (89.5%) in our cohort is by no means coincidental. Conditions such as hypertension, diabetes, and chronic kidney disease inherently contribute to microangiopathy, chronic inflammatory states, and elevated baseline oxidative stress, thereby compromising skeletal muscle homeostatic reserve and tolerance. This renders patients’ muscle tissue more vulnerable to potentially myotoxic agents, significantly lowering the threshold for toxicity.^25–27 Our findings suggest that gabapentinoids likely act as the “last straw,” triggering muscle injury on a substrate already weakened by underlying comorbidities. Notably, the widespread use of polypharmacy further exacerbates the risk of drug-drug interactions. The observation that as many as seven patients were concurrently using statins is of particular clinical concern. Statins are well-established myotoxic agents due to their inhibition of HMG-CoA reductase and impact on mitochondrial function.²⁸ When co-administered with gabapentinoids, these drugs may exhibit marked synergistic toxicity—potentially through concerted mitochondrial inhibition or additive disruption of myocyte calcium homeostasis—thereby substantially accelerating the onset of rhabdomyolysis. This interaction reflects a broader clinical challenge. Beyond statins, other medications commonly used in this population, such as psychotropic agents (which may affect muscle tone via neurotransmitter systems) and diuretics (which can precipitate dehydration and electrolyte disturbances), may increase the risk of muscle toxicity through distinct mechanisms.^5,29–31 Therefore, a comprehensive medication review is essential before prescribing gabapentinoids. For patients already taking other potentially myotoxic drugs, it is advisable to initiate gabapentinoids at a lower dose, apply a more gradual titration scheme, educate patients on monitoring muscular symptoms, and consider baseline and periodic creatine kinase monitoring. Age is another critical risk factor, with a median age of 63 years in this cohort. Advanced age is closely associated with physiological decline in renal function, reduction in muscle mass (sarcopenia), multimorbidity, and polypharmacy.^32,33 Elderly patients exhibit altered pharmacokinetics and reduced physiological reserve, rendering them not only more susceptible to drug toxicity but also more likely to present with atypical clinical manifestations that are easily overlooked. Of particular importance, gabapentin is primarily excreted unchanged by the kidneys,³⁴ in the setting of impaired renal function, gabapentinoids are prone to accumulation. Hence, dose adjustment and enhanced therapeutic drug monitoring are recommended for elderly patients and those with chronic kidney disease.

The mechanistic pathway underlying these clinical observations, while not fully elucidated, appears to center on intracellular calcium disruption.^4,35 As observed in our cases with rapid symptom progression, calcium homeostasis disruption from channel inhibition causes overload, triggering protease activation (eg, calpains) and phospholipases that degrade contractile proteins and membrane components, ultimately leading to sarcolemmal rupture.^36–38 This process may be compounded by mitochondrial dysfunction through respiratory chain interference or oxidative phosphorylation disruption, while calcium imbalance exacerbates mitochondrial damage.³⁹ Additionally, renal-excreted gabapentinoids may accumulate in impaired renal function, potentiating toxicity risks.^40,41 The oxidative muscle damage via free radical overproduction or compromised antioxidant defenses represents another plausible pathway that may contribute to the observed clinical manifestations.⁴² Though mechanistic certainty awaits clarification,^16,43 the evidence points to multifactorial pathways.

From a clinical management perspective, our cases demonstrate that rhabdomyolysis can occur regardless of whether renal function is normal or not, requiring rigorous dose titration with serial creatinine kinase and renal function monitoring. The renal-dependent pharmacokinetics of these drugs, characterized by prolonged half-life (132 hours) in renal impairment,¹⁵ elevate intoxication risks. However, their low molecular weight (171 Da and 159 Da) and limited protein binding permit effective dialysis,⁴⁴ which was required in 31.6% of our cases. Management should focus on trigger removal and metabolic correction, utilizing diuretics to enhance toxin clearance. In severe cases, continuous renal replacement therapy (CRRT) or plasma exchange demonstrate efficacy against gabapentinoids-related neurotoxicity.⁴⁵

Several limitations inherent to this study should be considered when interpreting its findings. Firstly, as a case series constructed from retrospectively reported data, the availability of specific clinical parameters was heterogeneous. Most notably, the exact length of hospital stay and detailed data regarding intensive care unit (ICU) admission were not consistently documented across all cases. This reflects a common challenge in aggregating real-world clinical data where documentation priorities may differ. Nevertheless, the universal outcome of “hospitalization leading to improvement and discharge” was confirmed for all surviving patients, providing clear qualitative evidence of the clinical course.

In conclusion, our analysis establishes that gabapentinoids represent emerging myotoxic agents capable of inducing rhabdomyolysis, particularly in patients with renal impairment, polypharmacy, or genetic susceptibility. While mechanistic certainty awaits clarification,^16,43 clinicians should maintain vigilance for gabapentinoids-associated myopathy, particularly in high-risk populations. Future pharmacogenomic studies are imperative to identify genetic susceptibility factors, which could pave the way for personalized prescribing and risk stratification. Future prospective studies should also aim to standardize the collection of healthcare utilization metrics, such as hospital stay duration, to better quantify the burden of this adverse event. Ultimately, as gabapentinoid prescriptions continue to rise, a balanced approach weighing therapeutic benefits against these underappreciated myotoxic risks is crucial for ensuring patient safety.

Conclusion

This systematic analysis establishes gabapentinoids as emerging myotoxic agents capable of inducing rhabdomyolysis, particularly in patients with renal impairment, polypharmacy, or genetic susceptibility. Our synthesis of 19 global cases reveals consistently rapid symptom onset, universal CPK elevation, and frequent renal involvement, with most cases demonstrating probable causality according to the Naranjo assessment. Although immediate drug discontinuation and supportive care often led to biochemical resolution within a few weeks, the high prevalence of comorbidities and complex drug interactions underscores the necessity for rigorous risk stratification. Looking forward, our findings necessitate a paradigm shift in clinical practice. The proposed evidence based monitoring framework emphasizes renal function guided dosing, vigilant CPK surveillance, and heightened awareness of drug interactions, especially with statins. This framework should be integrated into routine care for patients prescribed these medications. However, critical knowledge gaps persist. The precise mechanistic pathways, whether through calcium dysregulation, mitochondrial toxicity, or inflammatory modulation, remain elusive and warrant dedicated in vitro and translational research. Future pharmacogenomic studies are imperative to identify genetic susceptibility factors, which could pave the way for personalized prescribing and risk stratification. Ultimately, as gabapentinoid prescriptions continue to rise, a balanced approach is crucial. Clinicians must weigh their therapeutic benefits against these underappreciated myotoxic risks. Vigilance, prompt intervention upon unexplained biochemical abnormalities, and further mechanistic investigations are essential to mitigate the burden of this serious adverse event and ensure patient safety.