How Gabapentin Differs From Pregabalin

SEPTEMBER 21, 2015
Gabapentin formulations
Gabapentin is also available in 2 extended-release formulations: a tablet (Gralise) and a gastro-retentive prodrug, gabapentin enacarbil (Horizant).
Both have different pharmacokinetics and are not interchangeable with standard formulations, the original of which is Neurontin. Side effects of these newer formulations are similar to standard formulations.6,7
Gralise is indicated for postherpetic neuralgia and taken as an 1800 mg maintenance dose once a day. The AUC of 1800 mg of Gralise is slightly less than 1800 mg of the standard formulation. In addition, the average maximum concentration (Cmax) of Gralise is slightly higher than 1800 mg of the standard form, and minimum concentration (Cmin) is slightly lower. Finally, Tmax is increased in the extended-release form.
Although food does not palpably affect the AUC of standard forms of gabapentin, Gralise should be taken with food because the bioavailability is greatly increased (33% to 118%, depending on the meal’s fat content).6
Horizant is a prodrug of gabapentin indicated for postherpetic neuralgia and restless leg syndrome. The recommended maintenance dose is 600 mg twice a day. Doses greater than 1200 mg daily are not recommended, as side effects increase without a corresponding increase in efficacy.7
Bioavailability of gabapentin enacarbil is about 75%, which is somewhat improved over the standard formulation. It is absorbed through the small intestine through a proton-linked monocarboxylate transporter (MCT-1).
Unlike the original formulation, absorption of gabapentin enacarbil is not saturated at high doses, as MCT-1 is expressed in high levels in the intestinal tract. The drug undergoes near-complete first pass hydrolysis to gabapentin by non-specific carboxylesterases mainly in enterocytes, as well as in the liver to a lessor degree.
Consumption of alcohol increases the release of gabapentin enacarbil from the extended-release tablet. Therefore, alcohol should be avoided when taking Horizant due to increased risk of side effects.7
Like standard formulations of gabapentin, Gralise and Horizant are not metabolized to an appreciable extent by phase I metabolism, and they are neither a substrate nor an inhibitor of p-glycoprotein. All forms of gabapentin must be adjusted in renal dysfunction, similar to standard formulations.6,7
One review found that these extended-release formulations have similar efficacy to standard ones, and they might also have fewer adverse events.8
Both pregabalin and gabapentin are well tolerated. Dizziness and somnolence are the most common side effects in both drugs (>20% seen in gabapentin).3-5 Confusion and peripheral edema have also been reported with gabapentin.4
With both drugs, side effects are dose dependent and reversible if the medication is discontinued.3 The abrupt discontinuation of any form of gabapentin is not recommended because withdrawal symptoms such as anxiety, insomnia, nausea, pain, and sweating may present. When discontinuing gabapentin it is recommended to taper the dose over a week at least. 
As with all antiepileptic drugs, increased risk of suicidal ideation is possible.4,5
Pharmacodynamics of pregabalin and gabapentin
Gabapentin and pregabalin vary in terms of binding affinity and potency. Pregabalin has an increased binding affinity for the alpha-2-delta protein and is a more potent analgesic in neuropathic pain compared with gabapentin.3
One study developed a population pharmacokinetic model comparing pregabalin with gabapentin.9 The authors calculated values for the concentration of the drug that will give one-half the maximum pharmacologic response (EC50) and used these values to assess potency of the 2 medications.
Based on studies of gabapentin and pregabalin in epilepsy, the EC50 values of pregabalin and gabapentin were estimated to be about 9.77 mg/mL and 23.9 mg/mL, respectively.9 From these data, pregabalin was estimated to be about 2.4 times more potent. For neuropathic pain, pregabalin’s potency ratio may be even greater.
Using studies in postherpetic neuralgia, the EC50 values of pregabalin and gabapentin were estimated to be about 4.21 mg/mL and 11.7 mg/mL, respectively. Based on these values, pregabalin was estimated to be about 2.8 times more potent than gabapentin.9
Pregabalin and gabapentin differ somewhat in terms of their dose-response curves.
One study analyzed data from phase 2 trials of gabapentin and pregabalin and created a pharmacodynamic model.3 The authors found that in patients with postherpetic neuralgia, mean pain scores decreased as the dose of both gabapentin and pregabalin increased.
However, the study also uncovered a plateau of gabapentin’s effect on reducing pain at around 3600 mg/day. In contrast, the pain-relieving effect of pregabalin continued to increase up to the maximum dose of 450 mg/day.3
Pregabalin also exhibited a steeper dose-response curve than gabapentin. Based on the dose-response curves predicted in this model, a dose of 450 mg/day of pregabalin equates to about 3600 mg/day of gabapentin.3

Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP
Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP
Dr. Jeff Fudin graduated from Albany College of Pharmacy & Health Sciences with a BS and PharmD. He is a Diplomate to the Academy of Integrative Pain Management, a Fellow to ACCP and ASHP, and a member of several other professional organizations. He is President and Director, Scientific and Clinical Affairs for Remitigate, LLC (, a software platform for interpreting urine drug screens (Urintel) and risk for opioid-induced respiratory depression (Naloxotel). Dr. Fudin is a section editor for Pain Medicine and serves on the editorial board for Practical Pain Management. He practices as a clinical pharmacy specialist (WOC) and director of PGY-2 pharmacy pain residency programs at the Stratton Veterans Administration Medical Center in Albany, New York and has academic affiliations with Western New England University and Albany Colleges of Pharmacy.
Pharmacy Times Strategic Alliance

Pharmacist Education
Clinical features with downloadable PDFs

Personalize the information you receive by selecting targeted content and special offers.