8
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Rational dosing of gabapentin and pregabalin in chronic kidney disease

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Introduction Renal dose adjustments for gabapentin and pregabalin are ubiquitously evident in the medical literature. All manufacturers for these branded and generic dosage forms list dosing recommendations relative to creatinine clearance (CrCl) for both medications (Table 1).1,2 However, the basis of these recommendations has not been well articulated. Pharmacology Gabapentin and pregabalin are commonly used first-line agents for diabetic peripheral neuropathy and other common neuropathies. Pharmacologically, both agents inhibit alpha-2-delta (α2δ) subunit of N-type voltage-gated calcium channels, a key receptor involved in regulating the excitability of neurons.3 Peripheral nerve injury results in the upregulation of α2δ-1 receptors in the dorsal root ganglion neurons and subsequent increase in the trafficking of α2δ-1 to nerve terminals within the spinal cord.3–5 Inhibition of α2δ-1 receptors decreases calcium-mediated release of excitatory neurotransmitters into the dorsal horn and subsequently reduces pain signaling.4–6 Despite sharing the same mechanism of action, there are key pharmacologic differences between both agents. Pregabalin has six times higher binding affinity for the α2δ-1 receptor compared to gabapentin.7 Gabapentin follows zero-order saturable absorption, where its bioavailability decreases as the dose increases.1,7 Following oral administration, gabapentin’s bioavailability is 60%, 47%, 34%, and 33%, with 900, 1200, 2400, and 3600 mg/day in three divided doses, respectively.1 Notwithstanding, the two extended-release branded products, Horizant (gabapentin enacarbil) and Gralise (a prodrug), are pharmaceutically designed to enhance absorption.8,9 Pregabalin exhibits linear absorption with bioavailability equal to or greater than 90% irrespective of the dose, which gives it a more predictable pharmacokinetic profile.2,7 Pharmacokinetics and renal handling Challenges to achieving therapeutic concentrations necessary to achieve efficacy require consideration of the pharmacokinetic properties of both gabapentin and pregabalin. Both medications do not undergo hepatic metabolism and are primarily excreted unchanged in the urine.7 A pharmacokinetic advantage is the absence of hepatic cytochrome P450-related drug–drug and drug–food interactions. In pharmacokinetic studies, clearance of both medications was linearly correlated with CrCl. Gabapentin’s apparent total clearance is 100 mL/min in adults with normal renal function, which is essentially equivalent to CrCl and does not suggest the involvement of tubular reabsorption.1 Some evidence suggest that active tubular secretion mediated by organic cation transporter-1 (OCT-1) may play a role in gabapentin’s renal clearance. Individuals with genetic variation in OCT-1 may have altered renal clearance; however, the clinical significance has yet to be elucidated and may be negligible as gabapentin is primarily excreted unchanged via filtration.10 Pregabalin’s apparent total clearance is 67–81 mL/min in young healthy subjects and is therefore thought to undergo tubular reabsorption to some extent.2 Hemodialysis (HD) removes approximately 35% of gabapentin and 50%–60% of pregabalin, where supplemental doses are generally recommended post-HD.1,2 Therapeutic dosing targets Therapeutic dosing targets of both medications have been established in clinical trials for neuropathic pain (gabapentin 1800–3600 mg/day; pregabalin 150–600 mg/day). However, patients with renal impairment were often excluded from these studies.11–17 The aforementioned renal dose adjustments were mainly based on pharmacokinetic studies, some of which were conducted in healthy individuals. To date, no study has evaluated the impact of recommended dosing strategies on clinical efficacy in the management of neuropathic pain for patients with renal dysfunction. Dosing considerations in chronic kidney disease (CKD) CKD alters renal drug elimination by affecting glomerular blood flow, filtration rate, tubular secretion and reabsorption, and renal bioactivation and metabolism.18 Additionally, pharmacokinetic handling of medications (absorption, distribution, metabolism, and elimination) may be affected.19 Reducing the dose is recommended for medications with narrow therapeutic index.20 Extending the interval is recommended for medications with prolonged half-life in renal impairment; however, this may be subtherapeutic and may cause end-of-dose failure. Understanding the pharmacokinetic and pharmacodynamic profiles of medications is important when making these adjustments. Nevertheless, while dosing gabapentinoids, we must also consider reports by the patient that include side effect profile and tolerability as measured against efficacy, irrespective of the theoretical calculations. A theoretical approach: the Rowland and Tozer equation A widely accepted approach to individualize drug dosing in CKD patients based on CrCl is the Rowland–Tozer method.21 Figure 1 correlates with the manufacturer’s recommendation for pregabalin to follow a 50% dose reduction in patients with CrCl below 60 mL/min and greater than 30 mL/min. For medications with concentration-dependent efficacy, extending the interval while maintaining the same dose is appropriate. For medications with area under the curve (AUC)-dependent efficacy, extending the interval or reducing the dose is appropriate while maintaining the same AUC. The efficacy of pregabalin and gabapentin for neuropathic pain with respect to blood concentration or AUC remains unclear. Notwithstanding, most reports of toxicities were associated with concentrations higher than 15 mg/L for gabapentin and concentrations higher than 13 mg/L for pregabalin, whereas individuals with normal renal function on maximum recommended dosing yielded concentrations of ~5–8 mg/L for gabapentin and 2.8–8.2 mg/L for pregabalin.22–25 The elimination half-lives of gabapentin and pregabalin are prolonged with renal impairment leading up to accumulation with repeated dosing. The half-life of gabapentin immediate-release formulation is 5–7 hours in patients with normal renal function and is prolonged up to 52 hours in patients with CrCl<30 mL/min.26 The half-life of pregabalin is 16.7 hours in patients with CrCl 30–59 mL/min, 25 hours in patients with CrCl 15–29 mL/min, and 48.7 hours in patients with CrCl<15 mL/min.27 Therefore, finding the right pharmacokinetic balance is key to promote safety and efficacy, yet this balance remains unknown. Conclusion Gabapentin and pregabalin are commonly used for neuropathic pain in CKD patients but are not fully understood as this population remains excluded from efficacy and safety trials. Renal adjustments for the gabapentinoids are prodigiously recommended in the literature. However, current guidance is based on pharmacokinetic and toxicity studies, but studies confirming efficacy of these dosing strategies are lacking. Considering their widespread use for numerous neuropathic pain conditions, studies evaluating their efficacy at recommended doses in renal impairment should be a priority for future research.

          Related collections

          Most cited references 25

          • Record: found
          • Abstract: found
          • Article: not found

          Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial.

          Pain is the most disturbing symptom of diabetic peripheral neuropathy. As many as 45% of patients with diabetes mellitus develop peripheral neuropathies. To evaluate the effect of gabapentin monotherapy on pain associated with diabetic peripheral neuropathy. Randomized, double-blind, placebo-controlled, 8-week trial conducted between July 1996 and March 1997. Outpatient clinics at 20 sites. The 165 patients enrolled had a 1- to 5-year history of pain attributed to diabetic neuropathy and a minimum 40-mm pain score on the Short-Form McGill Pain Questionnaire visual analogue scale. Gabapentin (titrated from 900 to 3600 mg/d or maximum tolerated dosage) or placebo. The primary efficacy measure was daily pain severity as measured on an 11-point Likert scale (0, no pain; 10, worst possible pain). Secondary measures included sleep interference scores, the Short-Form McGill Pain Questionnaire scores, Patient Global Impression of Change and Clinical Global Impression of Change, the Short Form-36 Quality of Life Questionnaire scores, and the Profile of Mood States results. Eighty-four patients received gabapentin and 70 (83%) completed the study; 81 received placebo and 65 (80%) completed the study. By intent-to-treat analysis, gabapentin-treated patients' mean daily pain score at the study end point (baseline, 6.4; end point, 3.9; n = 82) was significantly lower (P<.001) compared with the placebo-treated patients' end-point score (baseline, 6.5; end point, 5.1; n = 80). All secondary outcome measures of pain were significantly better in the gabapentin group than in the placebo group. Additional statistically significant differences favoring gabapentin treatment were observed in measures of quality of life (Short Form-36 Quality of Life Questionnaire and Profile of Mood States). Adverse events experienced significantly more frequently in the gabapentin group were dizziness (20 [24%] in the gabapentin group vs 4 [4.9%] in the control group; P<.001) and somnolence (19 [23%] in the gabapentin group vs 5 [6%] in the control group; P = .003). Confusion was also more frequent in the gabapentin group (7 [8%] vs 1 [1.2%]; P = .06). Gabapentin monotherapy appears to be efficacious for the treatment of pain and sleep interference associated with diabetic peripheral neuropathy and exhibits positive effects on mood and quality of life.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens.

            Pregabalin binds with high affinity to the alpha2-delta subunit protein of voltage-gated calcium channels and, thereby, reduces release of excitatory neurotransmitters. This 12-week randomised, double-blind, multicentre, placebo-controlled, parallel-group study evaluated the efficacy and safety of pregabalin in patients with chronic postherpetic neuralgia (PHN) or painful diabetic peripheral neuropathy (DPN). Patients were randomised to placebo (n=65) or to one of two pregabalin regimens: a flexible schedule of 150, 300, 450, and 600 mg/day with weekly dose escalation based on patients' individual responses and tolerability (n=141) or a fixed schedule of 300 mg/day for 1 week followed by 600 mg/day for 11 weeks (n=132). Both flexible- and fixed-dose pregabalin significantly reduced endpoint mean pain score (primary outcome) versus placebo (P=0.002, P<0.001) and were significantly superior to placebo in improving pain-related sleep interference (P<0.001). The most common adverse events (AEs) for pregabalin-treated patients were dizziness, peripheral oedema, weight gain (not affecting diabetes control), and somnolence. These results are consistent with previous studies' demonstrating pregabalin's efficacy, tolerability, and safety for treatment of chronic neuropathic pain associated with DPN or PHN. Pregabalin dosing aimed at optimal balance of efficacy and tolerability provides significant pain relief and may reduce risks for AEs and therapy discontinuation.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin.

              Pregabalin and gabapentin share a similar mechanism of action, inhibiting calcium influx and subsequent release of excitatory neurotransmitters; however, the compounds differ in their pharmacokinetic and pharmacodynamic characteristics. Gabapentin is absorbed slowly after oral administration, with maximum plasma concentrations attained within 3-4 hours. Orally administered gabapentin exhibits saturable absorption--a nonlinear (zero-order) process--making its pharmacokinetics less predictable. Plasma concentrations of gabapentin do not increase proportionally with increasing dose. In contrast, orally administered pregabalin is absorbed more rapidly, with maximum plasma concentrations attained within 1 hour. Absorption is linear (first order), with plasma concentrations increasing proportionately with increasing dose. The absolute bioavailability of gabapentin drops from 60% to 33% as the dosage increases from 900 to 3600 mg/day, while the absolute bioavailability of pregabalin remains at > or = 90% irrespective of the dosage. Both drugs can be given without regard to meals. Neither drug binds to plasma proteins. Neither drug is metabolized by nor inhibits hepatic enzymes that are responsible for the metabolism of other drugs. Both drugs are excreted renally, with elimination half-lives of approximately 6 hours. Pregabalin and gabapentin both show dose-response relationships in the treatment of postherpetic neuralgia and partial seizures. For neuropathic pain, a pregabalin dosage of 450 mg/day appears to reduce pain comparably to the predicted maximum effect of gabapentin. As an antiepileptic, pregabalin may be more effective than gabapentin, on the basis of the magnitude of the reduction in the seizure frequency. In conclusion, pregabalin appears to have some distinct pharmacokinetic advantages over gabapentin that may translate into an improved pharmacodynamic effect.
                Bookmark

                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2017
                27 January 2017
                : 10
                : 275-278
                Affiliations
                [1 ]VA Tennessee Valley Healthcare System, Murfreesboro, Nashville, TN
                [2 ]Stratton VA Medical Center
                [3 ]Albany College of Pharmacy and Health Sciences, Albany, NY
                [4 ]Western New England University College of Pharmacy, Springfield, MA
                [5 ]Scientific and Clinical Affairs, Remitigate LLC, Delmar, NY, USA
                Author notes
                Correspondence: Timothy J Atkinson, VA Tennessee Valley Healthcare System, 3400 Lebanon Pike, Murfreesboro, TN 37129, USA, Email timothy.atkinson@ 123456va.gov
                Article
                jpr-10-275
                10.2147/JPR.S130942
                5291335
                © 2017 Raouf et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Editorial

                Anesthesiology & Pain management

                Comments

                Comment on this article