A double-blind comparison of the effects of gradual withdrawal of lorazepam, diazepam and bromazepam in benzodiazepine dependence SM Murphy and P Tyrer The British Journal of Psychiatry 1991 158: 511-516 Access the most recent version at doi:10.1192/bjp.158.4.511
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British Journalof Psychiatry (1991), 158,511—516
A Double-Blind Comparison of the Effects of Gradual Withdrawal of Lorazepam, Diazepam and Bromazepam in Benzodiazepine Dependence SIOBHAN M. MURPHY and PETER TYRER
Usinga double-blindprocedure,68 patientswith putativebenzodiazepinedependencewere randomlyallocatedto one of three groupsgiven lorazepam(n= 22), diazepam (n= 23) or bromazepam(n= 23) in dosesequivalentto those of the patients' originalbenzodiazepine. After four weeks the dosagewas reducedin 25% quantitiesuntilnofurtherbenzodiazepines were taken. A total of 23 patients dropped out during the study, ten on lorazepam (one of whom committed suicide), seven on diazepam and six on bromazepam.There were few differencesin withdrawal symptomsbetween the three groupsbut, despitethe higherdrop out rate, these symptomswere somewhat lessmarkedin the lorazepamgroup.Withdrawal symptomswere greaterin patientswho hadtaken a benzodiazepinefor >5 years and were most marked in those with personality disorders, predominantly dependent ones.
Despite much better awareness of the problems of dependence on benzodiazepines in recent years (Petursson & Lader, 1981; Higgitt et al, 1985; Tyrer & Murphy, 1987; Priest & Montgomery, 1988) it is still difficult to predict dependence in an individual case. Because of the absence of good predictors it is now recommended that in antianxiety treatment
the withdrawal effects of different benzodiazepines havebeencomparedsatisfactorily underdouble blind conditions. We therefore carried out a study in which patients who had taken prescribed benzo
benzodiazepines should not be prescribed for longer than one month (Priest & Montgomery, 1988). Nevertheless, a significant proportion of patients prescribed benzodiazepines, probably a majority (Tyrer, 1988), have no problems in stopping the
to one of three different benzodiazepines and then withdrawn using a double-blind procedure. Personality
diazepines regularly for six months or more and had
apparent withdrawal symptomson reduction (i.e. had putative dependence) were assigned at random status was determined beforewithdrawal, and in addition tootherassessments a new scale wasused todetect withdrawal symptoms.
medication after both short- and long-term treatment, so it would be of great help to the clinician to identify Method thekeyfactors thatpredispose todependence. There are several predisposing influences that are All patients presenting to P1's out-patient clinics between saidto adumbratepharmacological dependence. November 1985 and January 1988 were considered for the Theseincludedosageof benzodiazepine (higher study if they: (a) had taken a prescribed benzodiazepine in regular dosagecarrying greater risk) (Ayd,1979), longer dosage for six months or longer duration of treatment (Tyrer, 1978;Rickels etal, (b) were unable to reduce or stop their drug because 1983), personality status ofpatient (with dependent of apparent withdrawal symptoms personalities mostatrisk) (Cift, 1972;Tyreretal, (c) were taking no other psychotropic drugs 1983), and natureof benzodiazepine, withbenzo (d) weretaking their benzodiazepinein a daily dosage diazepines of shortelimination half-life and high of 2—16mg of diazepam (or equivalent dosage of potency(e.g.triazolam, lorazepam, alprazolam) another benzodiazepine) attracting mostconcern (Tyrer etal,1981;Griffiths (e) were taking their drugs for anxiety or insomnia or eta!,1985;Pecknoldetal,1988).
related neurotic
symptomatology
(0 wished to stop their benzodiazepines and were However,theevidence foreachofthese claims is willing to take part in the study as out-patients. relatively slight, partly because there havebeenfew studies thathavestudied sufficient patients toinvesti Patients included in the study changed to one of three gate these hypotheses adequately and also because differentbenzodiazepinesin roughlyequipotentdosageto of inherent difficulties in determining withdrawal that of their original benzodiazepine(equivalentdosages symptoms. There have also been no studies in which used for 5 mg of diazepam were lorazepam (1 mg), 511
512
MURPHY
nitrazepam
(3.5
mg),
chlordiazepoxide
(10 mg),
AND TYRER
Results
temazepain
(10 mg), triazolam (0.1 mg), flurazepam (10 mg) and clorazepate(5 mg)). Using double-blind procedurethechange
A total of 68 patientsenteredthe study. To ensureroughly
wasmade to the appropriate number of tablets, each con
equal
proportions of patients in each drug group, of patients was constrained so that there were
taming either diazepam(5 mg),bromazepam(3 mg)orloraze randomisation pam
(1 mg).
Each
patient
remained
on this
dosage
until
20 patients in each group after 60 had been allocated. Of the 68 patients, 22 were allocated to diazepam, 23 to lorazepamand 23to bromazepam.Thethreegroupsshowed
the
end of the fourth week,after whichthe dosagewasreduced in 25% aliquots at two-week intervals until complete with drawal by the end of the tenth week. Because we were inter ested in the time course of withdrawal symptoms from benzodiazepines of different half-lives it was felt important to follow the withdrawal program strictly. If patients were
no important differences
in demographic
characteristics
unable to reduce their drugs at the appropriate time they
(Table 1)andhadtakentheir benzodiazepines fora mean ofaroundeight years. A total of22(32%)weretaking 6mg orless ofdiazepam equivalents daily onentry and14(21%) weretaking15—16mg equivalents, withtheremaining 32
were regarded as drop-outs
patientstakingintermediatedosesbetween6 mgand 15mg.
for the purposes of the study.
On entryto thestudypatients had theirpsychiatric All but five of the patients had received previous psychiatric symptoms assessed using the Comprehensive Psychopatho logical Rating Scale (CPRS; Asberg et al, 1978), together with the Brief Scale for Anxiety (BAS) which scores the
treatment,
17 as in-patients. Previous benzodiazepines
taken
included diazepam (n= 25), lorazepam (n=19),nitrazepam (n =10), temazepam (n = 7), chlordiazepoxide (n = 3),
items of the CRPS commonly associated with anxiety diagnoses(Tyrer et al, 1984).Pre-morbid personalitywas
flurazepam
(n = 2), and
triazolam
and
clorazepate
(one
Alexander, 1979; Tyrer et al, 1988). Withdrawal symptoms were assessed using the Benzodiazepine Withdrawal
each). Forty-five patients completed thestudyandexamination ofserumbenzodiazepine levels showedallhad probably complied withthewithdrawal regime apart fromonepatient allocated to bromazepamwho was foundto be taking
SymptomQuestionnaire(BWSQ),a 20-itemself-ratingscale
diazepam
recording the severity of common (Tyrer et al, 1990).
nordiazepam 760nmol/l; nobromazepam detected). Asthere
also assessed, preferably at an interview with an informant, using the Personality
Assessment
Schedule
(PAS;
withdrawal
Tyrer &
symptoms
at week 12 (serum diazepam
570 nmol/1; serum
were no differencesbetweenthe results of analyseswhen
The CPRS, BASand BWSQwereadministeredat two
these datawerenotincluded, this violation ofthestudy
week intervals between entry to the study and week 14, by
protocol had no important influence on the fmdings. Of the
whichtime patients who had withdrawnfrom their benzo diazepinescompletelywould havetaken no drugs for four
23drop-outs 10had beenallocatedto lorazepam, sevento bromazepam and six to diazepam (x2= 1.5; d.f. 2, NS). weeks. Blood pressure,restingpulseand weight were Onlysix(26%)of the 23drop-outsweretakingtheirbenzo recorded atweek4 (immediately before reduction ofthe diazepinedrug as a hypnoticcomparedwith 19(42%)of the
allocated benzodiazepine) and at week 12, two weeks after 45completers (@ = 1.08), NS).The drop-outs tookplace thebenzodiazepine was stopped. Venousbloodsamples atirregular intervals throughout thestudy, withnoconsistent weretaken for serumbenzodiazepineestimationsat weeks pattern beingshown (Fig.1).Most ofthepatients who ofincreased symptoms(Fig. 1) 4 and12also, using a high-pressure liquid chromatographydroppedoutdidsobecause further reduction attheplannedtime. (HPLC) technique. Thecodewasbrokenbya pharmacist whichprecluded independent of themain studyinorderto indicate the Thesesymptomsincludedrepeated sensationsof ‘¿internal appropriate benzodiazepine forestimation, although ifthere raining' (a form of tactile hallucination), hot ‘¿patches' in weresignificantquantitiesof other benzodiazepinespresent theskin, andnumbnessandweakness inbotharms(which thesecouldalsobe detected. disappeared whenthebenzodiazepine wasresumed). One allocated todiazepam wasadmitted inthe13thweek Thedatawereanalysed mainlyusing repeated measures patient analysis of variance, although t@statistics were used for ofthestudy, andanother, allocated tolorazepam, committed suicide by drowningafter12weeks'treatment. categorical data. Table 1 Basic demographic
differenceMean
data of patients
drug Diazepam In = 22)Trial Lorazepam
of
(n=23)Bromazepam (n=23)Significance age (s.d.): years49.5 P=0.07Mean NStreatment duration of90
(12.6)42.1 (6-300)103
(9.1)43.4
(7-300)83
(12.0)F=2.7, d.f. 2, (6-204)F=0.31,
d.f. 2,
(70)f=l.9,
d.f. 2.
monthsNo. (range): of female patients (%)19 NSNo. status:single with marital (%)2 (22)married (%) divorced (%)11(50) widowed (%)2
(86)17 (9)6 7 (32)13 (9)01
(74)16 (26)5 (57) 4 (17)12
(52)
5 (22)—5 (4)
1 d f 6 NS
513
DOUBLE-BLINDWITHDRAWALFROM BENZODIAZEPINES
a, 0 C) C') U)
a C) C
a a)
0
2
4
6
8
10
14 Weeks
12
It'
change to trial benzoreductionof trial benzo- f Benzediazepinestopped diazepine inequivalent diazepine in25% aliquots dosage Fig. 1 Mean CPRS scores against time for patients who dropped out during the study.
18 16 °@14
24 22 @2O
@10 2
8,
0 0
2
4
6 8 Weeks
10 12
14
0
2
4
6 8 Weeks
10
12
14
Fig. 2 Mean scores for withdrawal symptoms (BWSQ) and total psychopathology (CPRS) in 45 patients randomly allocated to lorazepam; (—-;
n =
13),
diazepam
(—0—;
n =
16)
and
bromazepam
(—.-;
a =
16)
who
completed
the
full
withdrawal
programme.
There were significant changes in CPRS (F= 3.3; d.f. 7,36; P
