Because of popular demand, Dr. Morganson and I decided to make this important post available to PainDr.com blog followers. This article was written collaboratively with Daralyn A Morgenson BS, PharmD. whose biosketch appears below.
Neuropathic pain causes significant morbidity in the United States.
The incidence of peripheral neuropathy is estimated at about 2.4% of the population.1 Of the 14 million US individuals with diabetes, roughly 25% experience painful diabetic neuropathy.
Despite advances in vaccination for varicella zoster virus, around 25% of patients with a herpes zoster infection will develop persistent neuropathic pain.2 More than 85% of patients with neuropathic pain caused by peripheral neuropathy will require pharmacotherapy.
Unfortunately, there are few head-to-head trials comparing agents for neuropathic pain, so selecting the best option can be difficult.
Pregabalin and gabapentin are often considered first-line treatments for various neuropathic pain syndromes, generally irrespective of cause.1 Because the products are so variable, this article compares the pharmacokinetics (PK) and pharmacodynamics (PD) of pregabalin with various gabapentin formulations, and also covers conversion regimens.
Pharmacokinetics of pregabalin and gabapentin
Both pregabalin and gabapentin are antiepileptic medications that bare structural resemblance to gamma-aminobutyric acid (GABA), though neither agent has activity in GABA’s neuronal systems.
Although the exact mechanism of action is somewhat unclear, the drugs’ efficacy in neuropathic pain is linked to their ability to bind to voltage-gated calcium channels in the central nervous system (CNS), specifically to the alpha-2-delta protein. This binding decreases neurotransmitter release in the CNS as a result of reduced calcium influx through the gated channels.3
Gabapentin is indicated as adjunct therapy for partial seizures and postherpetic neuralgia.4 Pregabalin is indicated for the same uses as gabapentin, plus the management of fibromyalgia and neuropathic pain associated with diabetes, specifically diabetic neuropathy.5
Overall, the pharmacokinetic profiles of these 2 medications are somewhat similar, but they also have some significant differences.
For example, both drugs are structurally similar to the amino acid leucine. Because of this, they can both undergo facilitated transport across cellular membranes through system L-amino acid transporters.3 This is the major form of absorption for gabapentin and pregabalin, with the exception of an extended-release gabapentin prodrug to be discussed later.
However, pregabalin may either have an additional system of absorption or be better transported than gabapentin, as it is almost completely absorbed, while gabapentin is not. In addition, absorption of gabapentin is limited to the small intestine, while pregabalin is absorbed throughout the small intestine and extending to the ascending colon.
Gabapentin is more slowly and variably absorbed, with peak plasma concentrations around 3 hours post-dose. Pregabalin is quickly absorbed, with the maximum rate of absorption being 3 times that of gabapentin. It reaches peak blood concentrations within an hour after ingestion.
Absorption of gabapentin is saturable, leading to a non-linear pharmacokinetic profile. As gabapentin doses increase, the area under the curve (AUC) does not follow proportionally. Unlike gabapentin, absorption of pregabalin is not saturable, and the drug has a linear pharmacokinetic profile.
The bioavailability of generic gabapentin in tablet and capsule formulations equivalent to brand-name Neurontin is about 80% at lower doses such as 100 mg every 8 hours, but only 27% bioavailable at doses of 1600 mg every 8 hours.3,4 This differs greatly from pregabalin, which boasts a greater than 90% bioavailability across a dosage range from 75 mg to 900 mg daily in divided doses.3
Gabapentin’s bioavailability for its intended patient population is also more variable than pregabalin’s bioavailability. Variability among patients is believed to be 10% to 15% with pregabalin and 20% to 30% with gabapentin.3
Finally, food increases the AUC of gabapentin by about 10%, with no change in time to maximum concentration (tmax). In contrast, the AUC of pregabalin is unaffected by food, though absorption is slower.3
Distribution of gabapentin and pregabalin is very similar. Neither agent is bound by great extent to any plasma proteins, decreasing the likelihood of drug interactions due to protein binding. Both have high aqueous solubility, and the volume of distribution of each is similar (0.8 L/kg and 0.5 L/kg for gabapentin and pregabalin, respectively).3
Drug-drug interactions are unlikely for both pregabalin and gabapentin. Neither pregabalin nor gabapentin is affected by cytochrome (CYP) drug interactions, as neither drug is metabolized by CYP enzymes. Both undergo metabolism to a negligible extent (<1%).
Renal excretion is the major method of both drugs’ elimination from the body. Agents that decrease small bowel motility can theoretically cause an increase in the absorption of gabapentin, because it is not completely absorbed. However, as pregabalin is more than 90% absorbed, its absorption is not affected by changes in small bowel motility.3
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
Converting from gabapentin to pregabalin
For clinicians who wish to convert patients from gabapentin to pregabalin, there are a few studies that reviewed such a conversion.
One cohort study reviewed the utility of switching patients with neuropathic pain due to peripheral neuropathy from gabapentin to pregabalin.10 The study followed patients who were switched from gabapentin to pregabalin and then compared them to those who stayed on gabapentin. The authors also stratified the pregabalin group further into those who responded well or poorly to gabapentin, with gabapentin stopped after the nighttime dose and pregabalin started the following morning.
Dosages were switched using the following algorithm:
- Gabapentin ≤900 mg/day → pregabalin 150mg/day
- Gabapentin 901 mg/day to 1500 mg/day → pregabalin 225 mg/day
- Gabapentin 1501 mg/day 2100 mg/day → pregabalin 300 mg/day
- Gabapentin 2101 mg/day 2700 mg/day → pregabalin 450 mg/day
- Gabapentin >2700 mg/day → pregabalin 600 mg/day
This rapid change was generally well tolerated by patients.
The authors found that those who responded well to gabapentin and those who did not showed additional benefit with decreased pain when they were switched to pregabalin. Patients taking pregabalin also had improved pain control compared with those who remained on gabapentin.
Switching to pregabalin resulted in improved pain relief and also fewer adverse events. This was particularly true for patients who previously responded to gabapentin.
Patients who experienced adverse events with gabapentin were more likely to also experience adverse events with pregabalin. These patients were also more likely to discontinue use of pregabalin than those who responded well to both gabapentin and pregabalin.10
Another small trial compared the degree of pain relief with gabapentin to pregabalin in patients with postherpetic neuralgia in order to more closely determine equivalent dosing between the 2 medications.11
Patients were switched from gabapentin to pregabalin using one-sixth the dose of gabapentin with unchanged dosage frequency. After switching medications, patients reported similar pain relief and side effects, with the exception of an increased incidence of peripheral edema in the pregabalin group.
The authors concluded that the analgesic effect of pregabalin was about 6 times that of gabapentin.11
Other studies have looked at methods for converting gabapentin to pregabalin. One such trial used population pharmacokinetic models to examine 2 possible scenarios for converting gabapentin to pregabalin, using a ratio of 6:1 gabapentin to pregabalin.9
The first scenario involved discontinuing gabapentin and immediately starting pregabalin at the next scheduled dosing period. The other option included a gradual transition from gabapentin to pregabalin.
In this second scenario, the gabapentin dose was decreased by 50%, and 50% of the desired pregabalin dose was given concurrently for 4 days. After this time, gabapentin was discontinued and pregabalin was increased to full desired dose.
The model looked at transitioning patients from gabapentin to pregabalin at various doses, including:
- Gabapentin 900 mg/day → pregabalin 150 mg/day
- Gabapentin 1800 mg/day → pregabalin 300 mg/day
- Gabapentin 3600 mg/day → pregabalin 600 mg/day
Both scenarios were quick and seamless, so the authors concluded that either technique could be an effective method to switch patients between the medications.9
Though pregabalin and gabapentin have somewhat similar pharmacokinetic and pharmacodynamic profiles, there are clearly significant differences. Overall, pregabalin has more predictable pharmacokinetics, and it also shows a stronger binding affinity to its target receptor, increased potency, and a steeper dose-response curve in neuropathic pain that does not plateau over recommended dosing levels.
A few studies have found that pregabalin has fewer side effects and may be more efficacious for neuropathic pain than gabapentin. Several studies reviewing conversion of gabapentin to pregabalin predict that a rough ratio for conversion is about 6:1 gabapentin to pregabalin. In addition, a direct switch from gabapentin to pregabalin seems to be well tolerated, making the conversion simple.
Clinicians should note that pregabalin has various pharmacokinetic and pharmacodynamic advantages over gabapentin, and a conversion between the 2 medications is often well tolerated.
As always, comments and experiences are welcome!
Dr. Morgenson received her BS in psychology from the University of Nebraska-Lincoln and her PharmD from the University of Nebraska Medical Center College of Pharmacy. She is currently completing a PGY1 pharmacy residency at the Stratton VA Medical Center, with a focus on ambulatory care.
- Toth C. Substitution of gabapentin therapy with pregabalin therapy in neuropathic pain due to peripheral neuropathy. Pain Med. 2010;11(3):456-65.
- Blommel ML, Blommel AL. Pregabalin: an antiepileptic agent useful for neuropathic pain. Am J Health Syst Pharm. 2007;64(14):1475-82.
- Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinetics. 2010;49(10):661-9.
- Neurontin [Package insert]. New York, NY: Park-Davis, Division of Pfizer; December 2013.
- Lyrica [Package insert]. New York, NY: Park-Davis, Division of Pfizer; December 2013.
- Horizant [Package insert]. Santa Clara, CA: Xenoport Inc; July 2015.
- Gralise [Package insert]. Newark, CA; May 2014.
- Moore RA, Wiffen PJ, Derry S, Toelle T, Rice AS. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2014;4:CD007938.
- Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010;49(10):661-9.
- Toth C. Substitution of gabapentin therapy with pregabalin therapy in neuropathic pain due to peripheral neuropathy. Pain Med. 2010;11(3):456-65.
- Ifuku M, Iseki M, Hidaka I, Morita Y, Komatus S, Inada E. Replacement of gabapentin with pregabalin in postherpetic neuralgia therapy. Pain Med. 2011;12(7):1112-6.
alpha-2-delta schematic above from Source: https://www.google.com/search?q=neuropathic+pain&biw=1018&bih=407&source=lnms&tbm=isch&sa=X&sqi=2&ved=0ahUKEwiW6crekqDLAhVD5yYKHRkWCHIQ_AUICCgD#tbm=isch&q=alpha+2+delta+receptors&imgrc=8ysMRJ0z1ta1iM%3A