Clonazepam is long-acting benzodiazepine agonist used in short-acting benzodiazepine withdrawal; however, recent observations suggest the existence of its abuse. We demonstrate a 40-year-old man with a 20-year history of psychiatric care with recently benzodiazepine dependence (daily intake of ∼60 mg of clonazepam and 10 mg of alprazolam). High serum levels of both drugs were analyzed 3 weeks before admission to hospitalization (clonazepam 543.9 ng/mL, alprazolam 110 ng/mL) and at the time of admission (clonazepam 286.2 ng/mL, alprazolam 140 ng/mL) without any signs of benzodiazepine intoxication. Gradual withdrawal of clonazepam with monitoring of its serum levels and increase of gabapentin dose were used to minimize physical signs and symptoms of clonazepam withdrawal. Alprazolam was discontinued promptly. Clinical consequences of the treatment were controllable tension, intermittent headache, and rarely insomia. It is the first case report showing utilization of therapeutic drug monitoring during withdrawal period in the patient with extreme toleration to severe benzodiazepine dependence.

From the Department of Clinical Pharmacology University Hospital Ostrava Czech Republic

Zobrazit více v PubMed

Dickinson B, Rush PA, Radcliffe AB. Alprazolam use and dependence. A retrospective analysis of 30 cases of withdrawal. West J Med 1990; 152:604–608. PubMed PMC

Quaglio G, Pattaro C, Gerra G, et al. High dose benzodiazepine dependence: description of 29 patients treated with flumazenil infusion and stabilised with clonazepam. Psychiatry Res 2012; 198:457–462.doi: 10.1016/j.psychres.2012.02.008. PubMed

Steentoft A, Linnet K. Blood concentrations of clonazepam and 7-aminoclonazepam in forensic cases in Denmark for the period 2002-2007. Forensic Sci Int 2009; 184:74–79.doi: 10.1016/j.forsciint.2008.12.004. PubMed

Storhaug LW, Enger A, Hjelmeland K, et al. Prolonged excretion of 7-aminoclonazepam in urine after repeated ingestion of clonazepam: a case report. Forensic Sci Int 2012; 222:33–35.doi: 10.1016/j.forsciint.2012.06.018. PubMed

Berlin A, Dahlström H. Pharmacokinetics of the anticonvulsant drug clonazepam evaluated from single oral and intravenous doses and by repeated oral administration. Eur J Clin Pharmacol 1975; 9:155–159. PubMed

Crevoisier C, Delisle MC, Joseph I, et al. Comparative single-dose pharmacokinetics of clonazepam following intravenous, intramuscular and oral administration to healthy volunteers. Eur Neurol 2003; 49:173–177. PubMed

Greenblatt DJ, Blaskovich PD, Nuwayser ES, et al. Clonazepam pharmacokinetics: comparison of subcutaneous microsphere injection with multiple-dose oral administration. J Clin Pharmacol 2005; 45:1288–1293. PubMed

Manchikanti KN, Manchikanti L, Damron KS, et al. Increasing deaths from opioid analgesics in the United States: an evaluation in an interventional pain management practice. J Opioid Manage 2008; 4:271–283. PubMed

Welch TR, Rumack BH, Hammond K. Clonazepam overdose resulting in cyclic coma. Clin Toxicol 1977; 10:433–436. PubMed

Baruzzi A, Bordo B, Bossi L, et al. Plasma levels of di-no-propylacetate and clonazepam in epileptic patients. Int J Clin Pharmacol Biopharm 1977; 15:403–408. PubMed

Regenthal R, Krueger M, Koeppel C, et al. Drug levels: therapeutic and toxic serum/plasma concentrations of common drugs. J Clin Monit Comput 1999; 15:529–544. PubMed

Burrows DL, Hagardorn AN, Harlan GC, et al. A fatal drug interaction between oxycodone and clonazepam. J Forensic Sci 2003; 48:683–686. PubMed

Frauger E, Pauly V, Pradel V, et al. Evidence of clonazepam abuse liability: results of the tools developed by the French Centers for Evaluation and Information on Pharmacodependence (CEIP) network. Fundam Clin Pharmacol 2011; 25:633–641.doi: 10.1111/j.1472-8206.2010.00882.x. PubMed

Mowla A, Firoozabadi A, Borhani Haghighi A, et al. Megadose clonazepam dependence: a case report. J Clin Psychopharmacol 2007; 27:542–543. PubMed

Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs-best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia 2008; 49:1239–1276.doi: 10.1111/j.1528-1167.2008.01561.x. PubMed

Hiemke C, Baumann P, Bergemann N, et al. AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011. Pharmacopsychiatry 2011; 44:195–235.doi: 10.1055/s-0031-1286287. PubMed

Forrester MB. Alprazolam abuse in Texas, 1998–2004. J Toxicol Environ Health A 2006; 69:237–243. PubMed

Greenblatt DJ, Wright CE. Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clin Pharmacokinet 1993; 24:453–471. PubMed

Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Alprazolam pharmacokinetics, metabolism, and plasma levels: clinical implications. J Clin Psychiatry 1993; 54: discussion 12-4. PubMed

Wincor MZ, Munjack DJ, Palmer R. Alprazolam levels and response in panic disorder: preliminary results. J Clin Psychopharmacol 1991; 11:48–51. PubMed

Greenblatt DJ, Harmatz JS, Shader RI. Plasma alprazolam concentrations. Relation to efficacy and side effects in the treatment of panic disorder. Arch Gen Psychiatry 1993; 50:715–722. PubMed

Maremmani AG, Rovai L, Rugani F, et al. Clonazepam as agonist substitution treatment for benzodiazepine dependence: a case report. Case Rep Psychiatry 2013; 2013:367594.doi: 10.1155/2013/367594. PubMed PMC

Liebrenz M, Boesch L, Stohler R, et al. Agonist substitution—a treatment alternative for highdose benzodiazepine-dependent patients? Addiction 2010; 105:1870–1874.doi: 10.1111/j.1360-0443.2010.02933.x. PubMed

Grundmann M, Kacirova I. Significance of TDM, phenotyping and genotyping for the correct drug dosage (in Czech). Cas Lek Ces 2010; 149:482–487. PubMed

Grundmann M, Kacirova I, Urinovska R. Therapeutic monitoring of psychoactive drugs—antidepressants: a review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2015; 159:35–43.doi: 10.5507/bp.2013.020. PubMed

Grundmann M, Kacirova I, Urinovska R. Therapeutic drug monitoring of atypical antipsychotic drugs. Acta Pharm 2014; 64:387–401.doi: 10.2478/acph-2014-0036. PubMed

Boukhabza A, Lugnier AA, Kintz P, et al. Simple and sensitive method for monitoring clonazepam in human plasma and urine by high performance liquid chromatography. J Chromatogr Biomed Sci Appl 1990; 529:210–216. PubMed

Mucha M, Kurka P, Kalina J. HPLC method for analysis of benzodiazepines (in Czech). Chem Listy 2012; 106:77–81.

Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs 2009; 23:19–34.doi: 10.2165/0023210-200923010-00002. PubMed

Klein RL, Whiting PJ, Harris RA. Benzodiazepine treatment causes uncoupling of recombinant GABAA receptors expressed in stably transfected cells. J Neurochem 1994; 63:2349–2352. PubMed

Ali NJ, Olsen RW. Chronic benzodiazepine treatment of cells expressing recombinant GABAA receptors uncouples allosteric binding: studies on possible mechanisms. J Neurochem 2001; 79:1100–1108. PubMed

Gerada C, Ashworth M. ABC of mental health. Addiction and dependence—I: illicit drugs. BMJ 1997; 315:297–300. PubMed PMC