Abstract
Purpose
Pregabalin (PRG) is approved for the treatment of neuropathic pain, partial seizures and generalised anxiety disorder in many countries and currently under study for other indications. Supported by case reports and the results of a limited number of studies there is an ongoing debate on the potential of PRG to cause addictive behaviours. However, currently available evidence on this issue is sparse, and any definitive assessment of PRG’s potential for abuse and dependence is not yet in sight. The aim of our study was to identify the number of cases of PRG abuse or dependence reported to the database of a German medical regulatory body and to obtain insights into further usage-specific parameters.
Methods
We conducted a query of the entire database of the German Federal Institute for Drugs and Medical Devices (BfArM) regarding reports of PRG abuse or dependence and analysed these cases on the basis of several parameters.
Results
A total of 55 reports of PRG abuse or dependence were identified (mean age 36 years, 64 % of reports involved males). The first reports were submitted to BfArM in 2008, and the reporting frequency has increased up to the present. Mean daily PRG dosage was 1424 mg. Current or previous polytoxicomania was present in 40 and 42 % of cases, respectively. Psychiatric diagnoses other than substance-related disorders were reported in 13 (24 %) cases. In about one-third of the patients withdrawal syndromes subsequent to discontinuation of PRG were reported.
Conclusions
Cases of PRG abuse or dependence have been reported to the BfArM since 2008, with a marked increase of such reports in subsequent years. Male sex and a history of polytoxicomania may be possible risk factors for the development of addictive behaviours related to PRG.
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References
Dworkin R, Kirkpatrick P (2005) Pregabalin. Nat Rev Drug Discov 4:455–456
Federal Drug Administration (FDA) (2008) Living with fibromyalgia, drugs approved to manage pain. FDA, Washington D.C.
Wensel T, Powe K, Cates M (2012) Pregabalin for the treatment of generalized anxiety disorder. Ann Pharmacother 46:424–429
Richards B, Whittle S, van der Heijde D, Buchbinder R (2012) Efficacy and safety of neuromodulators in inflammatory arthritis: a Cochrane systematic review. J Rheumatol Suppl 90:28–33
Aboumarzouk O, Nelson R (2012) Pregabalin for chronic prostatitis. Cochrane Database Syst Rev 8:CD009063
Aurora R, Kristo D, Bista S, Rowley J, Zak R, Casey K, Lamm C, Tracy S, Rosenberg R (2012) The treatment of restless legs syndrome and periodic limb movement disorder in adults—an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine clinical practice guideline. Sleep 35:1039–1062
Balaban F, Yağar S, Özgök A, Koç M, Güllapoğlu H (2012) A randomized, placebo-controlled study of pregabalin for postoperative pain intensity after laparoscopic cholecystectomy. J Clin Anesth 24:175–178
Kapfhammer H (2012) Psychopharmacological treatment in patients with somatoform disorders and functional body syndromes. Nervenarzt 83:1128–1141
Strawn J, Dowling B, Geracioti TJ (2008) Pregabalin treatment of posttraumatic stress disorder. J Clin Psychopharmacol 28:596–597
Schönfeldt-Lecuona C, Wolf R, Osterfeld N, Vasic N, Connemann B, Schmid M, Freudenmann R (2008) Pregabalin in the treatment of schizophrenic anxiety. Pharmacopsychiatry 41:1–2
Oulis P, Konstantakopoulos G, Kouzoupis A, Masdrakis V, Karakatsanis N, Karapoulios E, Kontoangelos K, Papadimitriou G (2008) Pregabalin in the discontinuation of long-term benzodiazepines’ use. Hum Psychopharmacol 23:337–340
Biermann T, Bleich S, Kornhuber J, Hillemacher T (2007) Pregabalin in benzodiazepine withdrawal. Pharmacopsychiatry 40:292–293
Martinotti D, Di Nicola M, Tedeschi D, Mazza M, Janiri L, Bria P (2008) Efficacy and safety of pregabalin in alcohol dependence. Adv Ther 25:608–618
Oulis P, Konstantakopoulos G (2012) Efficacy and safety of pregabalin in the treatment of alcohol and benzodiazepine dependence. Expert Opin Investig Drugs 21:1019–1029
Toth C (2012) Drug safety evaluation of pregabalin. Expert Opin Drug Saf 11:487–502
Drug Enforcement Administration, Department of Justice (2005) Schedules of controlled substances: placement of pregabalin into Schedule V. Fed Regist 70(144):43633–43635
Chalabianloo F, Schjøtt J (2009) Pregabalin and its potential for abuse. Tidsskr Nor Laegeforen 129:186–187
Grosshans M, Mutschler J, Hermann D, Klein O, Dressing H, Kiefer F, Mann K (2010) Pregabalin abuse, dependence, and withdrawal: a case report. Am J Psychiatry 167:869
Skopp G, Zimmer G (2012) Pregabalin—a drug with abuse potential? Arch Kriminol 229:44–54
Filipetto F, Zipp C, Coren J (2010) Potential for pregabalin abuse or diversion after past drug-seeking behavior. J Am Osteopath Assoc 110:605–607
Schwan S, Sundström A, Stjernberg E, Hallberg E, Hallberg P (2010) A signal for an abuse liability for pregabalin–results from the Swedish spontaneous drug reaction reporting system. Eur J Clin Psychopharmacol 66:947–953
Caster O, Edwards I, Norén G, Lindquist M (2011) Earlier discovery of pregabalin’s dependence potential might have been possible. Eur J Clin Pharmacol 67:319–320
Schifano F, D’Offizi S, Piccione M, Corazza O, Deluca P, Davey Z, Di Melchiorre G, Di Furia L, Farré M, Flesland L, Mannonen M, Majava A, Pagani S, Peltoniemi T, Siemann H, Skutle A, Torrens M, Pezzolesi C, van der Kreeft P, Scherbaum N (2011) Is there a recreational misuse potential for pregabalin? Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data. Psychother Psychosom 80:118–122
Landmark C, Fossmark H, Larsson P, Rytter E, Johannessen S (2011) The prescription registry and abuse of pregabalin. Tidsskr Nor Laegeforen 131:223
[No authors listed]. Gabapentin and pregabalin: abuse and addiction (2012) Prescrire Int 21:152–154
Pfizer Inc. (2011). Lyrica (pregablin) capsules (prescribing information). Revised 06/2011. Pfizer, Inc, New York
Schwabe U, Paffrath D (2010) Arzneiverordnungs report 2010. Springer, Berlin Heidelberg New York
Martinotti G (2012) Pregabalin in clinical psychiatry and addiction: pros and cons. Expert Opin Investig Drugs 21:1243–1245
Terracciano A, Löckenhoff C, Crum R, Bienvenu O, Costa P (2008) Five-factor model personality profiles of drug users. BMC Psychiatry 8:22
Sills G (2006) The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol 6:108–113
Chesler E, Ritchie J, Kokayeff A, Lariviere W, Wilson S, Mogil J (2003) Genotype-dependence of gabapentin and pregabalin sensitivity: the pharmacogenetic mediation of analgesia is specific to the type of pain being inhibited. Pain 106:325–335
Martin D, McClelland D, Herd M, Sutton K, Hall M, Lee K, Pinnock R, Scott R (2002) Gabapentin-mediated inhibition of voltage-activated Ca2+ channel currents in cultured sensory neurons is dependent on culture conditions and channel subunit expression. Neuropsychopharmacology 42:353–366
Rose M, Kam P (2002) Gabapentin: pharmacology and its use in pain management. Anaesthesia 57:451–462
Lanneau C, Green A, Hirst W, Wise A, Brown J, Donnier E, Charles K, Wood M, Davies C, Pangalos M (2001) Gabapentin is not a GABAB receptor agonist. Neuropsychopharmacology 41:965–975
McClelland D, Evans R, Barkworth L, Martin D, Scott R (2004) A study comparing the actions of gabapentin and pregabalin on the electrophysiological properties of cultures DRG neurons from neonatal rats. BMC Pharmacol 4:14
Bian F, Li Z, Offord J, Davis M, McCormick J, Taylor C (2006) Calcium channel α(2)-δ type 1 subunit is the major binding protein for pregabalin in neocortex, hippocampus, amygdala, and spinal cord: an ex vivo autocardiographic study in α(2)-δ type 1 genetically modified mice. Brain Res 1:1–6
Arikkath J, Campbell K (2003) Auxiliary subunits: essential components of the voltage-gated calcium channel complex. Curr Opin Neurobiol 13:298–307
Gazulla J, Tintore M (2007) The P/Q-type voltage-dependent calcium channels as pharmacological target in spinocerebellar ataxia type 6: Gabapentin and pregabalin may be of therapeutic benefit. Med Hypotheses 68:131–136
Field M, Cox P, Stott E, Melrose H, Offord J, Su T, Bramwell S, Corradini L, England S, Winks J, Kinloch R, Hendrich J, Dolphin A, Webb T, Williams D (2006) Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proc Natl Acad Sci USA 103:17537–17542
Gee N, Brown J, Dissanayake V, Offord J, Thurlow R, Woodruff G (1996) The novel anticonvulsant drug, gabapentin (Neurontin), binds to the α2-δ subunit of a calcium channel. J Biol Chem 271:5768–5776
Taylor C (2004) The biology and pharmacology of calcium channel α2-δ proteins. CNS Drug Rev 10:183–188
Jones D, Sorkin L (1998) Systematic gabapentin and S(+)-3-isobutyl-y-aminobutyric acid block secondary hyperalgesia. Brain Res 810:93–99
Luo Z, Chaplan S, Higuera E, Sorkin L, Staudermann K, Williams M, Yaksh T (2001) Upregulation of the dorsal root ganglion α2-δ calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J Neurosci 21:1868–1875
Fink K, Dooley D, Meder D, Suman-Chauhan N, Duffy S, Clusmann H, Göthert M (2002) Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex. Neuropharmacology 42:229–236
Dooley D, Donovan C, Pugsley T (2000) Stimulus-dependent modulation of [(3)H]norepinephrine release from rat neocortical slices by gabapentin and pregabalin. J Pharmacol Exp Ther 295:1086–1093
Maneuf Y, Hughes J, McKnight A (2001) Gabapentin inhibits the substance P-facilitated K(+)-evoked release of [(3)H]glutamate from rat caudal trigeminal nucleus slices. Pain 93:191–196
Cunningham M, Woodhall G, Thompson S, Dooley D, Jones R (2004) Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro. Eur J Neurosci 20:1566–1576
Fehrenbacher J, Taylor C, Vasko M (2003) Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain 105:133–141
Li C, Zhang X, Matthews E, Li K, Kurwa A, Boroujerdi A, Gross J, Gold M, Dickenson A, Feng G, Luo Z (2006) Calcium channel alpha2delta1 subunit mediates spinal hyperexcitability in pain modulation. Pain 206:20–34
Chizh B, Gohring M, Troster A, Quartey G, Schmelz M, Koppert W (2007) Effects of oral pregabalin and aprepitant on pain and central sensitization in the electrical hyperalgesia model in human volunteers. Br J Anaesth 98:246–254
Chen S, Xu Z, Pan H (2001) Stereospecific effect of pregabalin on ectopic afferent discharges and neuropathic pain induced by sciatic nerve ligation in rats. Anesthesiology 95:1473–1479
Ashton C (2005) Benzodiazepine dependence. In: Haddad P, Dursun D, Deakin B (eds) Adverse syndromes and psychiatric drugs: a clinical guide. Oxford University Press, Oxford, pp 239–260
Lader M (2011) Benzodiazepines revisited—will we ever learn? Addiction 106:2086–2109
Stewart B, Kugler A, Thompson P, Bockbrader H (1993) A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharm Res 10:276–281
Ben-Menachem E (2004) Pregabalin pharmacology and its relevance to clinical practice. Epilepsia 45[Suppl 6]:13–18
Bockbrader H, Radulovic L, Posvar E, Strand J, Alvey C, Busch J, Randinitis E, Corrigan B, Haig G, Boyd R, Wesche D (2010) Clinical pharmacokinetics of pregabalin in healthy volunteers. J Clin Pharmacol 50:941–950
Tassone D, Boyce E, Guyer J, Nuzum D (2007) Pregabalin: a novel gamma-aminobutyric acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders. Clin Ther 29:26–48
Bockbrader H, Burger P, Knapp L (2011) Pregabalin effect on steady-state pharmacokinetics of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproate, and tiagabine. Epilepsia 52:405–409
Brodie M, Wilson E, Wesche D, Alvey C, Randinitis E, Posvar E, Hounslow N, Bron N, Gibson G, Bockbrader H (2005) Pregabalin drug interaction studies: lack of effect on the pharmacokinetics of carbamazepine, phenytoin, lamotrigine, and valproate in patients with partial epilepsy. Epilepsia 46:1407–1413
Bockbrader H, Wesche D, Miller R, Chapel S, Janiczek N, Burger P (2010) A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet 49:661–669
McAuley D (2005) How does pregabalin compare to gabapentin in the treatment of neuropathic pain? Available at: http://www.globalrph.com/pregabalin.htm. Accessed 30 Aug 2012
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Gahr, M., Freudenmann, R.W., Hiemke, C. et al. Pregabalin abuse and dependence in Germany: results from a database query. Eur J Clin Pharmacol 69, 1335–1342 (2013). https://doi.org/10.1007/s00228-012-1464-6
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DOI: https://doi.org/10.1007/s00228-012-1464-6