, Volume 183, Issue 2, pp 133–143 | Cite as

A double-blind, placebo- and positive-internal-controlled (alprazolam) investigation of the cognitive and psychomotor profile of pregabalin in healthy volunteers

  • Ian HindmarchEmail author
  • Leanne Trick
  • Fran Ridout
Original Investigation



Pregabalin potently and selectively binds to the alpha2-delta subunit of voltage-dependent calcium channels, reducing calcium influx and modulating release of downstream excitatory neurotransmitters, such as glutamate. Pregabalin has demonstrated robust efficacy for several disease states, but its neuropharmacology is still being elucidated.


This study was conducted to evaluate the cognitive and psychomotor effects of oral pregabalin (150 mg t.i.d.) using alprazolam (1 mg t.i.d.) as a positive internal control and placebo.


Twenty-four healthy volunteers were randomised to a double-blind, three-way crossover study. Each period consisted of 3-day double-blind treatment followed by 1 day of single-blind placebo. Psychometrics included tests of Choice Reaction Time (CRT), CNS arousal (Critical Flicker Fusion, CFF), vigilance (Rapid Visual Information Processing, RVIP), serial memory scanning (Sternberg Short-Term Memory Scanning Test, STM), divided attention (Compensatory Tracking Task, CTT), Brake Reaction Time (BRT) in an on-the-road vehicle, and subjective Line Analogue Rating Scales (LARS) for sedation.


Pregabalin showed no significant effects on the objective psychometrics—CRT, BRT, RVIP, STM—compared with placebo. Pregabalin produced a limited, significant decrement on CFF and CTT and a significant effect on the LARS. Pregabalin was associated with improvement relative to placebo in BRT. The positive control, alprazolam, produced significant impairment on all objective measures and significant impairment on the LARS, thus establishing the sensitivity of the test battery used in the study.


Pregabalin did not differ on most assessments from placebo, producing only minor, transient impairment on some objective cognitive and psychomotor measures, suggesting a relatively benign CNS side-effect profile.


Pregabalin Benzodiazepine Alprazolam Psychometric test Brake reaction time 



This study was supported by an unrestricted research grant to the HPRU Medical Research Centre, University of Surrey, from Pfizer, Inc.

The authors would like to thank Drs. Neil Stanley, Richard Kavoussi, Gail Farfel, and Mark Versavel for their support and valuable comments.


  1. Arroyo S, Anhut H, Kugler AR, Lee CM, Knapp LE, Garofalo EA, Messmer S (2004) Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose–response study in adults with partial seizures. Epilepsia 45:20–27CrossRefPubMedGoogle Scholar
  2. Beydoun A, Uthman BM, Kugler AR, Greiner MJ, Knapp LE, Garofalo EA, Pregabalin 1008-009 Study Group (2005) Safety and efficacy of two pregabalin regimens for add-on treatment of partial epilepsy. Neurology 64:475–480PubMedGoogle Scholar
  3. Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P, Perucca E (2002) Progress report on new antiepileptic drugs: a summary of the Sixth Eilat Conference (EILAT VI). Epilepsy Res 51:31–71CrossRefPubMedGoogle Scholar
  4. Coldwell SE, Milgrom P, Getz T, Ramsay DS (1997) Amnestic and anxiolytic effects of alprazolam in oral surgery patients. J Oral Maxillofac Surg 55:1061–1070CrossRefPubMedGoogle Scholar
  5. Coull JT, Frith CD, Frackowiak RS, Grasby PM (1996) A fronto-parietal network for rapid visual information processing: a PET study of sustained attention and working memory. Neuropsychologia 34:1085–1095CrossRefPubMedGoogle Scholar
  6. Crofford LJ, Rowbotham MC, Mease PJ, Russell IJ, Dworkin RH, Corbin AE, Young JP Jr, LaMoreaux LK, Martin SA, Sharma U, and the Pregabalin 1008-105 Study Group (2005) Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 52:1264–1273CrossRefPubMedGoogle Scholar
  7. Curran HV (1999) Effects of anxiolytics on memory. Hum Psychopharmacol Clin Exp 14:S72–S79CrossRefGoogle Scholar
  8. Curran S, Wattis JP (2000) Critical flicker fusion threshold: a potentially useful measure for the early detection of Alzheimer's disease. Hum Psychopharmacol Clin Exp 15(2):103–112CrossRefGoogle Scholar
  9. Dworkin RH, Corbin AE, Young JP Jr, Sharma U, LaMoreaux L, Bockbrader H, Garofalo EA, Poole RM (2003) Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 60:1274–1283PubMedGoogle Scholar
  10. Fairweather DB, Kerr JS, Hilton S, Hindmarch I (1993a) A placebo controlled double-blind evaluation of the pharmacodynamics of fengabine vs. amitriptyline following single and multiple doses in elderly volunteers. Br J Clin Pharmacol 35:278–283PubMedGoogle Scholar
  11. Fairweather DB, Kerr JS, Harrison DA, Moon CAL, Hindmarch I (1993b) A double-blind comparison of the effects of fluoxetine and amitriptyline on cognitive function in elderly depressed patients. Hum Psychopharmacol Clin Exp 8:41–47CrossRefGoogle Scholar
  12. Fairweather DB, Stanley N, Yoon J-S, Hindmarch I (1999) The effects of fluoxetine and dothiepin on cognitive function in depressed patients in general practice. Hum Psychopharmacol Clin Exp 14:325–332CrossRefGoogle Scholar
  13. Feltner DE, Crockatt JG, Dubovsky SJ, Cohn CK, Shrivastava RK, Targum SD, Liu-Dumaw M, Carter CM, Pande AC (2003) A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder. J Clin Psychopharmacol 23(3):240–249CrossRefPubMedGoogle Scholar
  14. French JA, Kugler AR, Robbins JL, Knapp LE, Garofalo EA (2003) Dose–response trial of pregabalin adjunctive therapy in patients with partial seizures. Neurology 60:1631–1637PubMedGoogle Scholar
  15. Freynhagen R, Strojek K, Griesing T, Whalen E, Balkenohl M (2005) Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Pain 115:254–263PubMedGoogle Scholar
  16. Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, Woodruff GN (1996) The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2-delta subunit of calcium channel. J Biol Chem 271:5768–5776CrossRefPubMedGoogle Scholar
  17. Gilburt SJA, Fairweather DB, Kerr JS, Hindmarch I (1992) The effects of acute and repeated doses of suriclone on subjective sleep, psychomotor performance and cognitive function in young and elderly volunteers. Fundam Clin Pharmacol 6:251–258PubMedGoogle Scholar
  18. Golombok S, Moodley P, Lader M (1988) Cognitive impairment in long-term benzodiazepine users. Psychol Med 18:365–374PubMedCrossRefGoogle Scholar
  19. Hindmarch I (1975) A 1,4 benzodiazepine, temazepam (K 3917), its effect on some psychological parameters of sleep and behaviour. Arzneimittelforschung 25:1836–1839PubMedGoogle Scholar
  20. Hindmarch I (1980) Psychomotor function and psychoactive drugs. Br J Clin Pharmacol 10(3):189–209PubMedGoogle Scholar
  21. Hindmarch I (1982) Critical flicker fusion frequency (CFFF): the effects of psychotropic compounds. Pharmacopsychiatria 15:44–48Google Scholar
  22. Hindmarch I (1983) Measuring the side-effects of psychoactive drugs: a pharmacodynamic profile of alprazolam. Alcohol Alcohol 18:361–367Google Scholar
  23. Hindmarch I (1994) Relevant psychomotor tests for antidepressants and anxiolytics. Int Clin Psychopharmacol 9(Suppl 1):27–33PubMedCrossRefGoogle Scholar
  24. Hindmarch I, Gudgeon AC (1980) The effects of clobazam and lorazepam on aspects of psychomotor performance and car handling ability. Br J Clin Pharmacol 10(2):145–150PubMedGoogle Scholar
  25. Hindmarch I, Tiplady B (1994) A comparison of the psychometric effects of remoxipride with those of haloperidol, thioridazine, and lorazepam in healthy volunteers. Hum Psychopharmacol Clin Exp 9:43–49CrossRefGoogle Scholar
  26. Hindmarch I, Subhan Z, Stoker MJ (1983) The effects of zimeldine and amitriptyline on car driving and psychomotor performance. Acta Psychiatr Scand 308(68):141–146Google Scholar
  27. Hindmarch I, Haller J, Sherwood N, Kerr JS (1990) Comparison of five anxiolytic benzodiazepines on measures of psychomotor performance and sleep. Neuropsychobiology 24:84–89PubMedCrossRefGoogle Scholar
  28. Hindmarch I, Rigney U, Stanley N, Quinlan P, Rycroft J, Lane J (2000) A naturalistic investigation of the effects of day-long consumption of tea, coffee and water on alertness, sleep onset and sleep quality. Psychopharmacology (Berl) 149:203–216CrossRefGoogle Scholar
  29. Hindmarch I, Patat A, Stanley N, Paty I, Rigney U (2001) Residual effects of zaleplon and zolpidem following middle of the night administration five hours to one hour before awakening. Hum Psychopharmacol Clin Exp 16:159–167CrossRefGoogle Scholar
  30. Hindmarch I, Shamsi Z, Kimber S (2002) An evaluation of the effects of a high-dose of fexofenadine on the central nervous system: a double-blind, placebo-controlled study in healthy volunteers. Clin Exp Allergy 32:133–139CrossRefPubMedGoogle Scholar
  31. Hindmarch I, Dawson J, Stanley N (2005) A double-blind study in healthy volunteers to assess the effects on sleep of pregabalin compared with alprazolam and placebo. Sleep 28:187–193PubMedGoogle Scholar
  32. Kerr JS, Fairweather DB, Hindmarch I (1992) The effects of acute and repeated doses of moclobemide on psychomotor performance and cognitive function in healthy elderly volunteers. Hum Psychopharmacol Clin Exp 7(4):273–279CrossRefGoogle Scholar
  33. Kerr JS, Fairweather DB, Hindmarch I (1993) The effects of brofaromine alone and in conjunction with alcohol on cognitive function, psychomotor performance, mood and sleep in healthy volunteers. Hum Psychopharmacol Clin Exp 8:107–116CrossRefGoogle Scholar
  34. Kerr JS, Dunmore C, Hindmarch I (1994) The psychomotor and cognitive effects of a new antihistamine, mizolastine, compared to terfenadine, triprolidine and placebo in healthy volunteers. Eur J Clin Pharmacol 47(4):331–335PubMedCrossRefGoogle Scholar
  35. Lesser H, Sharma U, LaMoreaux L, Poole RM (2004) Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized clinical trial. Neurology 63:2104–2110PubMedGoogle Scholar
  36. Moss E, Hindmarch I, Pain AJ, Edmondson RS (1987) Comparison of recovery after halothane or alfentanil anaesthesia for minor surgery. Br J Anaesth 59:970–977PubMedCrossRefGoogle Scholar
  37. Pande AC, Crockatt JG, Feltner DE, Janney CA, Smith WT, Weisler R, Londborg PD, Bielski RJ, Zimbroff DL, Davidson JR, Liu-Dumaw M (2003) Pregabalin in generalized anxiety disorder: a placebo-controlled trial. Am J Psychiatry 160:533–540PubMedCrossRefGoogle Scholar
  38. Pande AC, Feltner DE, Jefferson JW, Davidson JR, Pollack M, Stein MB, Lydiard RB, Futterer R, Robinson P, Slomkowski M, DuBoff E, Phelps M, Janney CA, Werth JL (2004) Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo-controlled, multicenter study. J Clin Psychopharmacol 24:141–149CrossRefPubMedGoogle Scholar
  39. Parkin C, Kerr JS, Hindmarch I (1997) The effects of practice on choice reaction time and critical flicker fusion threshold. Hum Psychopharmacol 12:65–70CrossRefGoogle Scholar
  40. Parkin C, Fairweather DB, Shamsi Z, Stanley N, Hindmarch I (1998) The effects of cigarette smoking on overnight performance. Psychopharmacology (Berl) 136:172–178CrossRefGoogle Scholar
  41. Pohl RB, Feltner DE, Fieve RR, Pande AC (2005) Efficacy of pregabalin in the treatment of generalized anxiety disorder: double-blind, placebo-controlled comparison of BID versus TID dosing. J Clin Psychopharmacol 25:151–158CrossRefPubMedGoogle Scholar
  42. Richter RW, Portenoy R, Sharma U, LaMoreaux L, Bockbrader H, Knapp LE (2005) Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. J Pain 6:253–260CrossRefPubMedGoogle Scholar
  43. Rickels K, Pollack MH, Feltner DE, Lydiard RB, Zimbroff DL, Bielski RJ, Tobias K, Brock JD, Zornberg GL, Pande AC (2005) Pregabalin for treatment of generalized anxiety disorder: a 4-week multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam. Arch Gen Psychiatry (in press)Google Scholar
  44. Ridout F, Hindmarch I (2001) Effects of tianeptine and mianserin on car driving skills. Psychopharmacology (Berl) 154:356–361CrossRefGoogle Scholar
  45. Ridout F, Hindmarch I (2003) The effects of acute doses of fexofenadine, promethazine and placebo on cognitive and psychomotor function in healthy Japanese volunteers. Ann Allergy Asthma & Immun 90:404–410CrossRefGoogle Scholar
  46. Ridout F, Gould S, Nunes C, Hindmarch I (2003a) The effects of carbon dioxide in champagne on psychometric performance and blood–alcohol concentration. Alcohol Alcohol 38(4):381–385PubMedGoogle Scholar
  47. Ridout F, Meadows R, Johnsen S, Hindmarch I (2003b) A placebo-controlled investigation into the effects of paroxetine and mirtazapine on measures related to car driving performance. Hum Psychopharmacol Clin Exp 18(4):261–269CrossRefGoogle Scholar
  48. Rigney U, Kimber S, Hindmarch I (1999) The effects of acute doses of standardized Ginkgo biloba extract on memory and psychomotor performance in volunteers. Phytother Res 13:408–415CrossRefPubMedGoogle Scholar
  49. Rosenstock J, Tuchman M, LaMoreaux L, Sharma U (2004) Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain 110:628–638CrossRefPubMedGoogle Scholar
  50. Sabatowski R, Gálvez R, Cherry DA, Jacquot F, Vincent E, Maisonobe P, Versavel M, 1008-045 Study Group (2004) Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain 109:26–35CrossRefPubMedGoogle Scholar
  51. Shamsi Z, Hindmarch, I (2000) Sedation and antihistamines: a review of inter-drug differences using proportional impairment ratios. Hum Psychopharmacol Clin Exp 15(1):S3–S30CrossRefGoogle Scholar
  52. Sherwood N, Kerr JS (1993) The reliability, validity, and pharmacosensitivity of four psychomotor tests. In: Stonier PD, Hindmarch I (eds) Human psychopharmacology: measures and methods. Wiley, Chichester, UK, pp 1–14Google Scholar
  53. Sternberg S (1966) High speed scanning in human memory. Science 153:652–654PubMedCrossRefGoogle Scholar
  54. Subhan Z, Hindmarch I (1984) Effects of zopiclone and benzodiazepine hypnotics on search in short-term memory. Neuropsychobiology 12(4):244–248PubMedCrossRefGoogle Scholar
  55. Subhan Z, Harrison C, Hindmarch I (1986) Alprazolam and lorazepam single and multiple-dose effects on psychomotor skills and sleep. Eur J Clin Pharmacol 29:709–712PubMedCrossRefGoogle Scholar
  56. Wesnes K, Warburton DM (1983) Effects of smoking on rapid information processing performance. Neuropsychobiology 9:223–229PubMedCrossRefGoogle Scholar
  57. Woodworth RS, Schlosberg H (1958) Experimental psychology. Methuen, LondonGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  1. 1.HPRU Medical Research Centre, School of Biomedical and Molecular SciencesUniversity of SurreySurreyUK

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