Pregabalin …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 09.16.2021
Released 12.30.2005
Expires For CME 09.16.2024

Pregabalin

Author: K K Jain MD†

See Contributor Disclosures

Pregabalin

In This Article

Quick Link

Introduction

Historical note and terminology

Pregabalin is chemically related to the antiepileptic drug gabapentin and is a successor to it for management of neuropathic pain as well as an adjunct therapy for the management of partial onset seizures. Gabapentin, a GABA receptor agonist, is an approved as add-on therapy for intractable partial seizures in adults. Clinical trials of pregabalin started in 2000. It was approved by the FDA for treating diabetic neuropathy and postherpetic neuralgia in 2004 and for fibromyalgia in 2007.

In 2005 the Drug Enforcement Administration placed pregabalin into Schedule V of the Controlled Substances Act. Because of this rule, the regulatory controls and criminal sanctions of Schedule V will be applicable to the manufacture, distribution, dispensing, importation and exportation of pregabalin and products containing pregabalin. In 2012, the manufacturer paid a settlement for misleading promotion of the drug for off-label indications.

Pharmacology

The chemical name of pregabalin is: CI-1008 or (S)-3-isobutyl GABA, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid. It is an alpha2delta-ligand that has been found effective in a variety of animal models of neuropathic and nociceptive pain.

Pharmacodynamics. The mode of action of pregabalin is like that of gabapentin. Although pregabalin is a structural derivative of the inhibitory neurotransmitter gamma aminobutyric acid (GABA), it does not bind directly to GABA and has no effects on GABA uptake or degradation. Pregabalin selectively binds to the alpha2delta-subunit protein of voltage-gated calcium channels in various regions of brain and in the superficial dorsal horn of the spinal cord (20). It acts as a presynaptic inhibitor of the release of excitatory neurotransmitters in stimulated neurons. It reduces influx of calcium into isolated synaptic endings. Findings of a brain imaging study suggest that the mode of action of pregabalin is partly by reduction of insular glutamatergic activity, which reduces the increased functional connectivity between brain regions in chronic pain states (14).

Pharmacokinetics. Pregabalin oral bioavailability is approximately 90% and it is well absorbed after oral administration. Peak plasma concentrations are reached within 1.5 hours. Following repeated administration, steady state is achieved within 24 to 48 hours. Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0.5 L/kg. Pregabalin is a substrate for system L transporter, which is responsible for the transport of large amino acids across the blood brain barrier. Pregabalin has been shown to cross the blood brain barrier in experimental animals.

Pregabalin undergoes negligible metabolism in humans. Approximately 90% of the administered dose can be recovered in the urine as unchanged pregabalin. Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug with a mean elimination half-life of approximately 6 hours in subjects with normal renal function. Overall, pregabalin demonstrates highly predictable and linear pharmacokinetics, which makes it easy to use in clinical practice.

Formulations. The approved formulation of pregabalin is immediate release (IR) given twice or 3 times a day. A pharmacokinetic study in healthy adult volunteers has shown that total daily exposure with controlled-release (CR) multiple-dose pregabalin is equivalent to the corresponding pregabalin immediate release dose (07). Results of the only controlled trial of pregabalin CR for epilepsy were disappointing, but because it has some pharmacokinetic advantages, it should be further evaluated in specific populations of patients, especially fragile subjects with several comorbidities (26).

Pharmacogenetics. Studies in experimental animals indicate that effectiveness of gabapentin and pregabalin may correlate with genotype variation. No clinical studies have explored this idea.

Next generation pregabalin. Mirogabalin besylate (Tarlige®) has shown greater sustained analgesia than pregabalin due to a high affinity to, and slow dissociation from, the α2δ-1 subunits in the dorsal root ganglion and less central nervous system-specific adverse drug reactions (19). The equianalgesic daily dose for 30 mg of mirogabalin is 600 mg of pregabalin. The initial adult dose starts at 5 mg, given orally twice a day, and is gradually increased by 5 mg at an interval of at least a week, to 15 mg. In conclusion, mirogabalin is anticipated to be a novel and safe gabapentinoid anticonvulsant with a greater therapeutic effect for neuropathic pain.

Clinical trials

Clinical trials have been conducted in painful diabetic neuropathy, postherpetic neuralgia as well as epilepsy. A selection of those conducted during the past decade is shown in Table 1.

Table 1. Clinical Trials of Pregabalin

Trial design	Results
A 14 week, randomized, double-blind, placebo-controlled trial of pregabalin for treating neuropathic pain of diabetic peripheral neuropathy in Japanese patients (32).	Pregabalin was well tolerated and effective in reducing pain as well as improving sleep disturbances due to pain.
Phase 1, randomized, placebo-controlled, parallel-group, dose-finding study in children with refractory partial seizures (21).	Pregabalin at doses up to 10 mg/kg/day in children aged 1 month to 16 years, and at doses up to 15 mg/kg/day in those over 6 years, was well tolerated. For children weighing < 30 kg, a dose increase of 40% (mg/kg dosing) is required to achieve comparable exposure with adults or children weighing ≥ 30 kg. These data will be used for dose selection in phase 3 trials.
A randomized, double-blind, placebo-controlled, multicenter, 2-period crossover study evaluated the efficacy and safety of pregabalin (150 to 300 mg/d) for treatment of patients with painful diabetic peripheral neuropathy who experienced pain while walking (15)	Results showed no significant treatment difference for pregabalin vs. placebo in the co-primary efficacy endpoints, mean diabetic neuropathic pain, and mean diabetic neuropathic pain on walking, which may be due to carryover effect from period 1 to period 2, lower pregabalin dose, or placebo response.
A randomized, double-blind, placebo-controlled trial of pregabalin in patients with sciatica, over the course of 8 weeks (25).	Treatment did not significantly reduce the intensity of leg pain or improve other outcomes as compared with placebo.

A systematic review of randomized controlled clinical trials showed that pregabalin, when used as an add-on drug for treatment-resistant partial epilepsy, is more effective than placebo at achieving a 50% or greater seizure reduction, with increasing efficacy of doses from 150 to 600 mg/day and increasing efficacy at 600 mg doses, but issues with tolerability were noted at higher doses (28).

A systematic review of randomized controlled trials showed efficacy of pregabalin in postherpetic neuralgia, painful diabetic neuralgia, and mixed or unclassified posttraumatic neuropathic pain (08). There is no efficacy in HIV neuropathy, and evidence of efficacy in central neuropathic pain is inadequate.

A prospective observational study has shown that pregabalin has a better safety profile and tolerability compared to duloxetine, but the latter is more effective in treating diabetic peripheral neuropathic pain (16).

Indications

Pregabalin is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, and as adjunctive therapy for adults with partial onset seizures.

Off-label uses

	(1) Generalized anxiety disorder (04).
	(2) Fibromyalgia syndrome (02).
	(3) Postoperative pain.
	(4) Vagoglossopharyngeal neuralgia.
	(5) According to a systematic review of clinical trials, effects of pregabalin for treating essential tremor are uncertain because of the low quality of evidence (05).
	(6) Restless legs syndrome associated with neuropathic pain.
	(7) Tremor associated with chronic inflammatory demyelinating peripheral neuropathy.
	(8) A randomized phase-2 trial showed that pregabalin is not more effective than placebo in treatment of painful HIV neuropathy (36).
	(9) A randomized, double-blind, multicenter, placebo-controlled, parallel group study of pregabalin for poststroke central pain showed that there was no reduction in pain, but there were improvements in sleep, anxiety, and clinicians global impression of change (18).
	(10) Chemotherapy-induced peripheral neuropathic pain (27).
	(11) Self-injurious behavior associated with Tourette syndrome (11).
	(12) An open pilot study has shown that pregabalin as an add-on therapy reduces seizures and anxiety in patients with brain tumors (23).
	(13) Refractory insomnia with symptoms resembling but not fulfilling the criteria for diagnosis of restless legs syndrome (Di lorio et al 2013).
	(14) A randomized study has shown that pregabalin is effective and well tolerated in patients with neuropathic pain due to spinal cord injury (06).
	(15) In a double-blind, placebo-controlled clinical trial, pregabalin reduced the severity of symptoms of combat-related posttraumatic stress disorder but it was not effective in improving the severity of depression, anxiety, and quality of life (03).
	(16) In a prospective, nonrandomized, observational study, both gabapentin and pregabalin effectively relieved neuropathic pain and prevented the conversion of acute pain to chronic pain at the 1-year follow-up after lumbar discectomy (10).
	(17) A randomized, double-blind trial on patients with restless legs syndrome who were treated with pregabalin as compared with placebo and pramipexole showed that pregabalin provided significantly improved treatment outcomes as compared with placebo, and aggravation rates were significantly lower with pregabalin than with 0.5 mg dose of pramipexole (01).
	(18) Results of a randomized, double-blind, placebo-controlled, crossover trial indicated that pregabalin is not effective in relieving neurogenic claudication associated with lumbar spinal stenosis (22).
	(19) An open study has shown that allodynia, ie, pain experienced from a nonpainful stimulation of the skin such as light touch, is present in approximately 65% of migraine patients, and can be relieved by use of pregabalin (37).
	(20) Results of a randomized pilot trial did not show effectiveness of pregabalin for preventing paclitaxel-induced acute pain syndrome or chemotherapy-induced peripheral neuropathy due to paclitaxel (35).
	(21) Off-label use of gabapentinoids, gabapentin as well as pregabalin, for pain types other than diabetic neuropathy, postherpetic neuralgia, and fibromyalgia as an alternative to opioids is a cause for concern because it may not relieve the pain adequately (13).
	(22) Pain in sickle cell disease (33).

References

01: Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med 2014;370(7):621-31. PMID 24521108
02: Arnold LM, Emir B, Murphy TK, et al. Safety profile and tolerability of up to 1 year of pregabalin treatment in 3 open-label extension studies in patients with fibromyalgia. Clin Ther 2012;34(5):1092-102. PMID 22503162
03: Baniasadi M, Hosseini G, Fayyazi Bordbar MR, Rezaei Ardani A, Mostafavi Toroghi H. Effect of pregabalin augmentation in treatment of patients with combat-related chronic posttraumatic stress disorder: a randomized controlled trial. J Psychiatr Pract 2014;20(6):419-27. PMID 25406046
04: Both C, Kojda G, Lange-Asschenfeldt C. Pharmacotherapy of generalized anxiety disorder: focus and update on pregabalin. Expert Rev Neurother 2014;14(1):29-38. PMID 24308277
05: Bruno E, Nicoletti A, Quattrocchi G, Filippini G, Colosimo C, Zappia M. Pregabalin for essential tremor. Cochrane Database Syst Rev 2016;10:CD009682. PMID 27763691
06: Cardenas DD, Nieshoff EC, Suda K, et al. A randomized trial of pregabalin in patients with neuropathic pain due to spinal cord injury. Neurology 2013;80(6):533-9. PMID 23345639
07: Chew ML, Alvey CW, Plotka A, et al. Pregabalin controlled-release pharmacokinetics in healthy volunteers: analysis of four multiple-dose randomized clinical pharmacology studies. Clin Drug Investig 2014;34(9):627-37. PMID 25078977
08: Derry S, Bell RF, Straube S, Wiffen PJ, Aldington D, Moore RA. Pregabalin for neuropathic pain in adults. Cochrane Database Syst Rev 2019;1:CD007076.** PMID 30673120
09: Di Iorio G, Matarazzo I, Di Tizio L, Martinotti G. Treatment-resistant insomnia treated with pregabalin. Eur Rev Med Pharmacol Sci 2013;17(11):1552-4. PMID 23771546
10: Dolgun H, Turkoglu E, Kertmen H, et al. Gabapentin versus pregabalin in relieving early post-surgical neuropathic pain in patients after lumbar disc herniation surgery: a prospective clinical trial. Neurol Res 2014;36(12):1080-5. PMID 24938318
11: Fornaro M, Maremmani AG, Colicchio MG, et al. A case of severe oral self-injurious Tourette's syndrome alleviated by pregabalin. Gen Hosp Psychiatry 2012;34(3):321.e1-4. PMID 22133981
12: Gallego H, Aleshaki JS. Raynaud phenomenon of the nipple successfully treated with nifedipine and gabapentin. Cutis 2020;105(6):E22-3. PMID 32717000
13: Goodman CW, Brett AS. Gabapentin and pregabalin for pain - Is increased prescribing a cause for concern? N Engl J Med 2017;377(5):411-14. PMID 28767350
14: Harris RE, Napadow V, Huggins JP, et al. Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients. Anesthesiology 2013;119(6):1453-64. PMID 24343290
15: Huffman C, Stacey BR, Tuchman M, et al. Efficacy and safety of pregabalin in the treatment of patients with painful diabetic peripheral neuropathy and pain on walking. Clin J Pain 2015;31(11):946-58. PMID 25565583
16: Jha S, Sahani OP, Siddiqui S, Verma MK, Mazumder A, Waghdhare S. Effectiveness of pregabalin compared to duloxetine in diabetic peripheral neuropathic pain: an observational study. J Assoc Physicians India 2019;67(11):32-6. PMID 31793266
17: Johnson P, Becker L, Halpern R, Sweeney M. Real-world treatment of post-herpetic neuralgia with gabapentin or pregabalin. Clin Drug Investig 2013;33(1):35-44. PMID 23179473
18: Kim JS, Bashford G, Murphy TK, Martin A, Dror V, Cheung R. Safety and efficacy of pregabalin in patients with central post-stroke pain. Pain 2011;152(5):1018-23. PMID 21316855
19: Kim JY, Abdi S, Huh B, Kim KH. Mirogabalin: could it be the next generation gabapentin or pregabalin? Korean J Pain 2021;34(1):4-18.** PMID 33380563
20: Li Z, Taylor CP, Weber M, et al. Pregabalin is a potent and selective ligand for α(2)δ-1 and α(2)δ-2 calcium channel subunits. Eur J Pharmacol 2011;667(1-3):80-90. PMID 21651903
21: Mann D, Liu J, Chew ML, et al. Safety, tolerability, and pharmacokinetics of pregabalin in children with refractory partial seizures: a phase 1, randomized controlled study. Epilepsia 2014;55(12):1934-43. PMID 25377429
22: Markman JD, Frazer ME, Rast SA, et al. Double-blind, randomized, controlled, crossover trial of pregabalin for neurogenic claudication. Neurology 2015;84(3):265-72. PMID 25503625
23: Maschio M, Dinapoli L, Sperati F, et al. Effect of pregabalin add-on treatment on seizure control, quality of life, and anxiety in patients with brain tumour-related epilepsy: a pilot study. Epileptic Disord 2012;14(4):388-97. PMID 23248037
24: Mathieson S, Lin CC, Underwood M, Eldabe S. Pregabalin and gabapentin for pain. BMJ 2020;369:m1315. PMID 32345589
25: Mathieson S, Maher CG, McLachlan AJ, et al. Trial of pregabalin for acute and chronic sciatica. N Engl J Med 2017;376(12):1111-20. PMID 28328324
26: Morano A, Palleria C, Citraro R, et al. Immediate and controlled-release pregabalin for the treatment of epilepsy. Expert Rev Neurother 2019;19(12):1167-77. PMID 31623493
27: Nakashima T, Kiba T, Ogawa Y, et al. A case of neurotoxicity reduced with pregabalin in R-CHOP chemotherapy for diffuse large B-cell lymphoma. [Japanese] Gan To Kagaku Ryoho 2012;39(5):809-12. PMID 22584337
28: Panebianco M, Bresnahan R, Hemming K, Marson AG. Pregabalin add-on for drug-resistant focal epilepsy. Cochrane Database Syst Rev 2019;7:CD005612. PMID 31287157
29: Patorno E, Bateman BT, Huybrechts KF, et al. Pregabalin use early in pregnancy and the risk of major congenital malformations. Neurology 2017;88(21):2020-5. PMID 28446648
30: Perez Lloret S, Amaya M, Merello M. Pregabalin-induced parkinsonism: a case report. Clin Neuropharmacol 2009;32(6):353-4. PMID 19952879
31: Ryvlin P. Defining success in clinical trials--profiling pregabalin, the newest AED. Eur J Neurol 2005;12 Suppl 4:12-21. PMID 16144536
32: Satoh J, Yagihashi S, Baba M, et al. Efficacy and safety of pregabalin for treating neuropathic pain associated with diabetic peripheral neuropathy: a 14 week, randomized, double-blind, placebo-controlled trial. Diabet Med 2011;28(1):109-16. PMID 21166852
33: Schlaeger JM, Molokie RE, Yao Y, et al. Management of sickle cell pain using pregabalin: a pilot study. Pain Manag Nurs 2017;18(6):391-400. PMID 28843636
34: Sendra JM, Junyent TT, Pellicer MJ. Pregabalin-induced hepatotoxicity. Ann Pharmacother 2011;45(6):e32. PMID 21652790
35: Shinde SS, Seisler D, Soori G, et al. Can pregabalin prevent paclitaxel-associated neuropathy?--An ACCRU pilot trial. Support Care Cancer 2016;24(2):547-53. PMID 26155765
36: Simpson DM, Schifitto G, Clifford DB, et al. Pregabalin for painful HIV neuropathy: a randomized, double-blind, placebo-controlled trial. Neurology 2010;74(5):413-20. PMID 20124207
37: Zhang N, Chen CF, Yu FY. Effects of pregabalin on central sensitization in patients with migraine. Int J Clin Pharmacol Ther 2015;53(4):277-83. PMID 25669613

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Pregabalin

Other Pertinent Drugs

Gabapentin
mirogabalin

Also Relevant

Anticonvulsants
Central neuropathic pain
Diabetic neuropathies
Epilepsy
Medical complications of stroke
- Neuropathic pain: treatment
- Neuropharmacology
- Pharmacological treatment of epilepsy in adolescents and adults
- Restless legs syndrome
- Varicella-zoster virus infections of the nervous system

Pregabalin …

Pregabalin

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Pregabalin

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

NF2-related schwannomatosis

Familial dysautonomia

Photosensitive occipital lobe epilepsy

Primary headache associated with sexual activity

Peripheral nerve complications of HIV-1 infection

Neuropathies associated with cytomegalovirus infection

Intermittent explosive disorder

Coma due to drug intoxication

Pregabalin

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Pregabalin

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

NF2-related schwannomatosis

Familial dysautonomia

Photosensitive occipital lobe epilepsy

Primary headache associated with sexual activity

Peripheral nerve complications of HIV-1 infection

Neuropathies associated with cytomegalovirus infection

Intermittent explosive disorder

Coma due to drug intoxication

This is an article preview.
Start a Free Account
to access the full version.