Gabapentin and pregabalin exhibit unique pharmacokinetic properties that pose challenges in achieving therapeutic concentrations, especially in patients with renal impairment. Neither drug undergoes hepatic metabolism; instead, they are primarily excreted unchanged through the urine, minimizing the risk of hepatic cytochrome P450-related drug-drug and drug-food interactions. Gabapentin's clearance is linearly correlated with creatinine clearance (CrCl) and may involve active tubular secretion via organic cation transporter-1 (OCT-1), though this is not fully clinically significant due to its primary filtration excretion. Pregabalin undergoes some tubular reabsorption, with a clearance rate lower than that of gabapentin. Both drugs require dose adjustments based on the degree of renal impairment. For instance, pregabalin maximum recommended dosages are altered based on CrCl values: 100 mg TID or 150 mg BID for CrCl 30-59 mL/min, 50 mg TID or 75 mg BID for CrCl 15-29 mL/min, 75 mg once daily for CrCl <15 mL/min, and 75-150 mg post-dialysis; gabapentin follows a similar adjustment strategy. Hemodialysis effectively removes about 35% of gabapentin and 50-60% of pregabalin, necessitating supplementary dosing post-treatment. Despite these dosing guidelines, most relevant pharmacokinetic studies have been conducted in healthy individuals, with limited data on clinical efficacy in patients with renal dysfunction. Therefore, while therapeutic dosing targets have been established for neuropathic pain, careful consideration of individual patient factors, such as side effect profiles and tolerability, alongside pharmacokinetic calculations, is critical for effective management in patients with chronic kidney disease. [1]
A 2018 clinical epidemiology study examined the association between the use of gabapentin and pregabalin and the risk of adverse outcomes in a substantial cohort of hemodialysis patients. The researchers utilized the US Renal Data System to identify 140,899 Medicare-covered adults undergoing hemodialysis with Part D coverage in 2011. Gabapentin and pregabalin were modeled as separate time-varying exposures to evaluate their association with time to first emergency room visit or hospitalization due to altered mental status, fall, and fracture. The risk was assessed according to daily dose categories: for pregabalin (0-100 and >100 mg). Notably, 68% of the users were diagnosed with neuropathic pain, pruritus, or restless legs syndrome. Results found that increased doses of pregabalin were associated with greater rates of altered mental status, falls, and fractures. Specifically, when comparing no pregabalin use to low-dose (0–100 mg) and high-dose (>100 mg) use, the incidence of altered mental status was 15, 26, and 25 per 100 person-years, respectively. For falls, the incidence was seven, ten, and 14 per 100 person-years, respectively, and for fractures, it was four, five, and five per 100 person-years, respectively. Both low-dose (HR 1.51; 95% CI, 1.32 to 1.74) and high-dose pregabalin (HR 1.46; 95% CI, 1.24 to 1.71) were associated with a higher hazard of altered mental status. Only high-dose pregabalin was linked to an increased hazard of falls (HR 1.68; 95% CI, 1.36 to 2.08), while neither dose significantly increased fracture risk. Additionally, a shorter duration of pregabalin exposure (<30 days) was linked to a significantly higher hazard of altered mental status (HR 1.29; 95% CI, 1.07 to 1.54) and falls (HR 1.32; 95% CI, 1.02 to 1.72) compared to longer durations. The findings were consistent even in sensitivity analyses restricted to low-income subsidy recipients. These results underscore the caution needed when prescribing pregabalin, particularly at higher doses, due to the associated increased risks of these adverse outcomes. [2]