Two-related studies are presented here, detailing our early experience with benzodiazepine-dependent patients treated with a four-day flumazenil infusion using a novel delivery technique. Patients with long-term benzodiazepine dependence who attended the Australian Medical Procedures Research Foundation (AMPRF, Perth, Australia) for treatment were recruited for these studies. Self-reported psychological and physical symptoms, as well as objective vital signs data were collected at intervals before, during and 2 weeks postinfusion. Study A is a case series with cardiovascular measures; study B is an open trial that tracks the psychological profiles of 13 subjects. Withdrawal symptoms were tracked, however, the nature and severity of these symptoms differed between patients. No major complications or discomfort prompting study dropout was observed. Significant benzodiazepine abstinence occurred with this flumazenil infusion method despite high levels of initial dependence, comorbid substance use and comorbid psychiatric illness. Low-dose flumazenil infusion appears to be a safe and effective treatment resulting in withdrawal symptoms of lesser severity than any other cessation method currently available. Recommendations for future research are discussed.
Ali NJ Olsen RW (2001) Chronic benzodiazepine treatment of cells expressing recombinant GABA(A) receptors uncouples allosteric binding: studies on possible mechanisms. J Neurochem79: 1100–1108.
2.
Ashton H (1991) Protracted withdrawal syndromes from benzodiazepines. J Subst Abuse Treat8: 19–28.
3.
Ashton H (2005) The diagnosis and management of benzodiazepine dependence. Curr Opin Psychiatry18: 249–255.
4.
Assmann SF Pocock SJ Enos LE Kasten LE (2000) Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet355: 1064–1069.
5.
Bell C Forshall S Adrover M Nash J Hood S Argyropoulos S (2002) Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine. J Psychopharmacol16: 5–14.
6.
Bergman H Borg S Engelbrektson K Vikander B (1989) Dependence on sedative-hypnotics: neuropsychological impairment, field dependence and clinical course in a 5-year follow-up study. Br J Addict84: 547–553.
7.
Bond AJ Lader MH (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol47: 211–218.
8.
Bonetti EP Pieri L Cumin R Schaffner R Pieri M Gamzu ER (1982) Benzodiazepine antagonist Ro 15-1788: neurological and behavioral effects. Psychopharmacology (Berl)78: 8–18.
9.
Chouinard G (2004) Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J Clin Psychiatry65 (Suppl. 5): 7–12.
10.
Coupland NJ Bell C Potokar JP Dorkins E Nutt DJ (2000) Flumazenil challenge in social phobia. Depress Anxiety11: 27–30.
11.
Covi L Lipman RS Pattison JH Derogatis LR Uhlenhuth EH (1973) Length of treatment with anxiolytic sedatives and response to their sudden withdrawal. Acta Psychiatr Scand49: 51–64.
12.
de las CC, Sanz, EJ, de la Fuente, JA, Padilla, J, Berenguer, JC (2000) The Severity of Dependence Scale (SDS) as screening test for benzodiazepine dependence: SDS validation study. Addiction95: 245–250.
13.
Denis C Fatseas M Lavie E Auriacombe M (2006) Pharmacological interventions for benzodiazepine mono-dependence management in outpatient settings (CD005194). Cochrane Database of Systematic Reviews3: doi: 10.1002/14651858.CD005194.pub2.
14.
Dong Y Winslow M Chan YH Subramaniam M Whelan G (2007) Benzodiazepine dependence in Singapore. Subst Use Misuse42: 1345–1352.
15.
File SE Pellow S (1986) Intrinsic actions of the benzodiazepine receptor antagonist Ro 15-1788. Psychopharmacology (Berl)88: 1–11.
16.
Fresco DM Coles ME Heimberg RG Liebowitz MR Hami S Stein MB (2001) The Liebowitz Social Anxiety Scale: a comparison of the psychometric properties of self-report and clinician-administered formats. Psychol Med31: 1025–1035.
17.
Gerra G Zaimovic A Giusti F Moi G Brewer C (2002) Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebo-controlled study. Addict Biol7: 385–395.
18.
Harrison-Read PE Tyrer P Lawson C Lack S Fernandes C File SE (1996) Flumazenil-precipitated panic and dysphoria in patients dependent on benzodiazepines: a possible aid to abstinence. J Psychopharmacol10: 89–97.
19.
Heberlein A Bleich S Kornhuber J Hillemacher T (2008) Neuroendocrine pathways in benzodiazepine dependence: new targets for research and therapy. Hum Psychopharmacol23: 171–181.
20.
Hollister LE Motzenbecker F Degan R (1961) Withdrawal reactions from chlordiazepoxide (“Librium”). Psychopharmacologia2: 63–68.
21.
Hulse G White J Cape G (2002) The Management of Alcohol and Other Drug Problems. Oxford University Press, Melbourne.
22.
Jazvinscak JM Svob SD Vlainic J Pericic D (2008) The role of transcriptional and translational mechanisms in flumazenil-induced up-regulation of recombinant GABA(A) receptors. Neurosci Res61: 234–241.
23.
Jurand A Martin LV (1994) Cleft palate and open eyelids inducing activity of lorazepam and the effect of flumazenil, the benzodiazepine antagonist. Pharmacol Toxicol74: 228–235.
24.
Lader M (1983) Dependence on benzodiazepines. J Clin Psychiatry44: 121–127.
25.
McNair DM Lorr M Droppleman LF (1988) Manual for the Profile of Mood States. San Diego: Educational and Industrial Testing Service.
26.
Nutt DJ Costello MJ (1988) Rapid induction of lorazepam dependence and reversal with flumazenil. Life Sci43: 1045–1053.
27.
Petursson H Lader MH (1981a) Withdrawal from long-term benzodiazepine treatment. Br Med J (Clin Res Ed)283: 643–645.
28.
Petursson H Lader MH (1981b) Withdrawal from long-term benzodiazepine treatment. Br Med J (Clin Res Ed)283: 643–645.
29.
Potokar J Coupland N Glue P Groves S Malizia A Bailey J (1997) Flumazenil in alcohol withdrawal: a double-blind placebo-controlled study. Alcohol Alcohol32: 605–611.
30.
Quaglio G Lugoboni F Fornasiero A Lechi A Gerra G Mezzelani P (2005) Dependence on zolpidem: two case reports of detoxification with flumazenil infusion. Int Clin Psychopharmacol20: 285–287.
31.
Sacristan JA Soto J Galende I Hylan TR (1998) Randomized database studies: a new method to assess drugs' effectiveness. J Clin Epidemiol51: 713–715.
32.
Saxon L Hjemdahl P Hiltunen AJ Borg S (1997) Effects of flumazenil in the treatment of benzodiazepine withdrawal–a double-blind pilot study. Psychopharmacology (Berl)131: 153–160.
33.
Schlappi B Bonetti EP Burgin H Strobel R (1988) Toxicological investigations with the benzodiazepine antagonist flumazenil. Arzneimittelforschung38: 247–250.
34.
Sheehan DV Lecrubier Y Sheehan KH Amorim P Janavs J Weiller E (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry59 (Suppl. 20): 22–33.
35.
Smith BJ Bickel WK (1999) Flumazenil discrimination by humans under a two-response and a novel-response procedure. J Pharmacol Exp Ther291: 1257–1268.
36.
Spielberger CD Gorsuch RL Lushene R Vagg PR Jacobs GA (1983) Manual for the Stait Trait Anxiety Inventory. Consulting Psychologists' Press, Palo Alto, CA.
37.
Thomson JS Donald C Lewin K (2006) Use of Flumazenil in benzodiazepine overdose. Emerg Med J23: 162.
38.
Weinbroum A Rudick V Sorkine P Nevo Y Halpern P Geller E (1996) Use of flumazenil in the treatment of drug overdose: a double-blind and open clinical study in 110 patients. Crit Care Med24: 199–206.
39.
Wilkins JN Majewska MD Van GW Li SH Hinken C Plotkin D (2005) DHEAS and POMS measures identify cocaine dependence treatment outcome. Psychoneuroendocrinology30: 18–28.
