The Clinicopharmacotherapeutics of Benzodiazepine and Z drug dose Tapering Using Diazepam
DR JG McConnell BSc, MD, FRCP, FRCPEd
May 6th, 2007
Withdrawal from chronic benzodiazepine and Z drug dosing must be carried out via a programme of gradual and careful dose reduction. A switch to diazepam (Valium) is the preferred mechanism enabling mini-dose reductions over an extended period to prevent acceleration and/or recurrence of unpleasant withdrawal symptoms. A slow diazepam reduction regime has been found to have the highest success rate [1, 2].
Diazepam has a half life of 20 - 100 hours and produces the active metabolites temazepam, oxazepam and nordazepam (aka desmethyldiazepam) of which nordazepam is the most important active metabolite with a half life even greater than its parent compound diazepam of 36 - 200 hours [3, 4].
When considering equi-potencies of the various benzodiazepines available, diazepam has the lowest tablet strength of 2 mg and is available in liquid form allowing for small dosage reductions not possible with more high potency benzodiazepines. Small dose reductions cannot be achieved with high potency benzodiazepines including clonazepam 0.5 mg equivalent to 10 mg of diazepam and lorazepam (Ativan) 1 mg which is equivalent to 10 mg of diazepam. Lorazepam is available in the USA as a 0.5 mg dose form which is equivalent to 5 mg of diazepam.
Some patients are taking high doses of high potency benzodiazepines, for example 8 mg of alprazolam or 8 mg of clonazepam equivalent to 160 mg of diazepam. This diazepam equivalent is far outside the usual absolute maximum prescribing range for diazepam which is 60 mg. Such patients can do a partial switch to diazepam eg swapping 2 mg of alprazolam (Xanax) or clonazepam (Rivotril, Klonopin) for 40 mg of diazepam and tapering down the diazepam before doing another diazepam switch/taper.
Patients who are gradually switching from short acting benzodiazepines to diazepam should ensure that the remaining short acting benzodiazepine dose is spaced out equally across the day to avoid excessive peak/trough level fluctuations and resultant interdose withdrawal phenomena. For example step 1 in crossing someone from 1 mg of lorazepam 4 times daily to diazepam should be carried out in the following fashion: 0.5 mg of lorazepam 4 times daily plus 20 mg of diazepam daily followed by stabalisation for 2 – 4 weeks before switching the remaining lorazepam dosage completely to diazepam.
A small minority of people seem to not tolerate the diazepam switch. Slowing down the rate of diazepam switch may help in such patients.
Shorter acting benzodiazepines often produce interdose withdrawal symptoms due to significant fluctuations in blood drug levels [5].
The long half life of diazepam facilitates a more constant blood level thus allowing receptor sites to become accustomed to a constant dose. Slow and phased reductions in diazepam dosage produce a gradual decline in blood levels and a less intense withdrawal syndrome compared to withdrawal using shorter acting compounds. Longer acting preparations such as diazepam have a lower abuse potential than shorter acting benzodiazepines eg lorazepam and alprazolam as it is more difficult to achieve sharp peaks in blood levels with diazepam as seen with shorter acting compounds.
All classical benzodiazepines non-selectively bind to benzodiazepine receptor sites and one can be supplemented for another [6]. The only clinically essential step is to calculate the diazepam dose equivalent to the origional benzodiazepine before effecting a gradual switch.
Diazepam switch is also the preferred method of withdrawing patients from the so called Z drugs [1]. The nonbenzodiazepines Zaleplon, Zolpidem, Zopiclone and Eszopiclone all work via benzodiazepine receptors and according to a review by the world health organisation are cross tolerant with benzodiazepines [7, 8]. None of the Z drugs can be termed long or even intermediate acting [3]. Diazepam is the drug of choice for weaning dependent individuals off nonbenzodiazepine Z drugs [1].
Diazepam accumulates in the blood stream to 5 - 7 times its origional dose over a period of 8 weeks. Thereafter, constant dosing produces a plateau in blood levels, (90% of accumulation of diazepam occurs in the first 4 weeks). The time taken for diazepam levels to build up in the blood stream is the most important clinical reason why switching a patient from a benzodiazepine to diazepam should be done in a gradual stepwise fashion [9].
A diazepam reduction regime is the recognised mainstay treatment of benzodiazepine dependency. However, there has been considerable opposition to diazepam switch use in the United States. This opposition probably stems from the media focus on diazepam (Valium) in the late 1970's and early 1980's simply because diazepam was the most commonly prescribed benzodiazepine. There is reason to suspect that pharmaceutical drug companies seized on the moment to promote alternative benzodiazepines to replace diazepam (Valium). Following the Valium scare doctors were reluctant to prescribe it due to its bad reputation. Unfortunately the media focus on Valium rather than the benzodiazepines as a drug class, led to alternative benzodiazepine drug promotion including alprazolam/Xanax, lorazepam/Ativan and clonazepam/Klonopin and other benzodiazepines which proved to be much more potent and addictive benzodiazepines. The result was that the medical profession in the USA jumped "out of the frying pan into the fire" with respect to the subsequent preference for prescribing benzodiazepines with a higher dependence forming potential.
References
[1] Prodigy Clinical Knowledge (NHS), Management Issues: Benzodiazepine and Z Drug Withdrawal, 2007.
[2] Ashton CH; Benzodiazepine Withdrawal: Outcome in 50 Patients, British Journal of Addiction; 1987, 82, 655-671.
[3] Ashton CH, BENZODIAZEPINE EQUIVALENCY TABLE, 2002.
[4] Azzam RM, Notarianni LJ, Ali HM; Rapid and simple chromatographic method for the determination of diazepam and its major metabolites in human plasma and urine, J Chromatogr B Biomed Sci Appl; 1998 Apr 24;708(1-2):304-9.
[5] Herman JB, Brotman AW, Rosenbaum JF; Rebound anxiety in panic disorder patients treated with shorter-acting benzodiazepines. J Clin Psychiatry 1987; 48 Suppl. 10: 22-6.
[6] Ebert B, Wafford KA, Deacon S; Treating insomnia: Current and investigational pharmacological approaches, Pharmacol Ther. 2006 Dec;112(3):612-29. Epub 2006 Jul 28.
[7] Mark W. Fleck; Molecular Actions of (S)-Desmethylzopiclone (SEP-174559), an Anxiolytic Metabolite of Zopiclone, J Pharmacol Exp Ther. Vol. 302, Issue 2, 612-618, August 2002.
[8] W.H.O; Assessment of Zopiclone, World Health Organisation, 34th, ECDD, 2006/4.6.
[9] Peart RF, Valium (Diazepam) vs. Klonopin (Clonazepam) in Benzodiazepine Withdrawal, V.O.T.
Further Reading
Ashton CH, REASONS FOR A DIAZEPAM (VALIUM) TAPER; benzo.org.uk, April 2001.
Ashton CH, BENZODIAZEPINE EQUIVALENCY TABLE, bcnc.org.uk, 2002.
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