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Pharmacoepidemiology of Benzodiazepine and Sedative–Hypnotic CPA media3

Pharmacoepidemiology of Benzodiazepine and Sedative–Hypnotic CPA media3

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Pharmacoepidemiology of Benzodiazepine and Sedative–Hypnotic
Pharmacoepidemiology of Benzodiazepine and Sedative–Hypnotic

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Original Research
Pharmacoepidemiology of Benzodiazepine andSedative–Hypnotic Use in a Canadian GeneralPopulation Cohort During 12 Years of Follow-up
Scott B Patten, MD, PhD
; Jeanne VA Williams MSc
; Dina H Lavorato MSc
;Aliya Kassam, PhD
; C David Sabapathy, MD
Key Words:
epidemiology, longitudinal studies, sedative–hypnotic medications, mood disorders, anxiety disorders, population studies
La Revue canadienne de psychiatrie, vol 55, no 12, décembre 2010792
Benzodiazepines (BDZs) and similar sedative–hypnotics (SSHs) can have bothbeneficial and adverse effects. Clinical practice guidelines indicate that the course of treatmentshould usually be brief (a few weeks), but patients often take these medications for longer periodsof time. We hypothesized that treatment with antidepressants (ADs) would be associated with ashorter duration of SSHs use as mood and anxiety disorders may underlie the symptoms usuallytargeted by BDZ treatment.
Our study used data from a Canadian longitudinal general health study, the NationalPopulation Health Survey, which has collected data since 1994. Data are currently available to2006. At each interview, all medications taken in the preceding 2 days are recorded. In our study,we used proportional hazard models to describe patterns of initiation and discontinuation of thesemedications in the general population.
At each interview, the frequency of BDZ–SSH use was 2% to 3%. About 1% of thepopulation initiated use in each 2-year follow-up period. Contrary to expectation, takingADspredicted initiation of BDZ–SSHs, but not discontinuation.
Unexpectedly, respondents taking ADs had a higher frequency of newBDZ–SSHuse. AD use may be a marker for depression severity or comorbidity, such that the observedresults may be an artifact of confounding by these factors. Irrespective of etiology, initiation of ADtreatment does not appear to negate the risk of long-term BDZ–SSH use.Can J Psychiatry. 2010;55(12):792–799.
Clinical Implications
Patients undergoing AD treatment have an elevated risk of long-term BDZ–SSH use.
The association between BDZ–SSH and AD use may be related to residual symptoms suchas sleep disturbances or anxiety symptoms or may occur because AD treatment is amarker for more severe or more highly comorbid episodes. Tolerance, abuse or dependence, as well as AD-induced insomnia or agitation may also contribute.
It may be valuable to incorporate BDZ–SSH discontinuation strategies proactively as acomponent of treatment when these are used in combination withADs.
The National Population Health Survey (NPHS) is an epidemiologic data source and cannotdiscern the details of therapeutic decisions. Survey data cannot determine theappropriateness of specific medication regimens.
The measure of medication use in the NPHS covers only the 2 days preceding an interviewsuch that episodic use may sometimes appear to represent new use or discontinued use.
The association of long-term BDZ use with AD treatment does not provide strong evidenceof a causal connection—AD treatment is better regarded as an indicator of long-term risk.
enzodiazepine and SSHs have sedative, hypnotic, anx-iolytic, muscle relaxant, and anticonvulsant properties.In addition to their therapeutic properties, BDZ–SSHs areassociated with adverse effects, including cognitive prob-lems,
anincreasedfrequencyof motor vehicle accidents,
and dependence and abuse.
For the most part, the pharmacoepidemiologic literature isrestricted to estimates of the prevalence and cross-sectionalcorrelates of BDZ–SSH use.
For example, the ESEMeDfoundthatanxietyanddepressivedisorders,femalesex,older age,helpseekingfor emotionalproblems,loweducation,and pain predicted BDZ use in 6 European countries.
Similarly,in Canada, cross-sectional correlates of BDZ use includefemale sex, (higher) age, low income, low education, and the presence of mood or anxiety disorders.
Few longitudinalstudies have examined BDZ use in Canada.Zopiclone (a cyclopyrrolone derivative) and zaleplon (a pyrazolopyrimidine) are non-BDZ–SSHs that share pharma-cological properties, adverse effects, and risks withBDZ.
However, these medications are used more spe-cifically for insomnia and less frequently for anxiety. Bothzopiclone and zaleplon are listed under Schedule IV by theInternational Narcotics Control Board.
However, neither zopiclone nor zaleplon are classified as controlled drugs inCanada, whereas BDZs are.TreatmentwithBDZ–SSHsisofteninitiatedduringtreatmentof depressive disorders, particularly when symptomsof anxi-ety are present.
Such use is often intended to be brief, withdiscontinuation of the BDZ–SSH being intended when acoprescribedADbeginstowork.SomecoursesofBDZ–SSHtreatment may become prolonged if there are residual symp-toms of depression or comorbidities that lead to longer-termtreatment. Some ADs, may cause insomnia or agitation as anadverse effect and this may also lead to an increased or more prolonged coprescribingofBDZ–SSHs.Toleranceandabusemay also lead to prolonged BDZ–SSH exposure. Theobjectives of our study included estimation of the incidenceand pattern of new use and the frequency and pattern of dis-continuation of BDZ–SSH medications in relation to MDEsand the use of ADs.
TheNPHSisalongitudinalstudybasedonanationallyrepre-sentative sample of 17 276 respondents selected from theCanadianhouseholdpopulationbyStatisticsCanadain1994.The NPHS longitudinal cohort has been interviewed every2 years since thattime.The NPHS methodology is describedin previous publications.
The estimated response rate to2006 is 77.0%.
This response rate does not include NPHSrespondents who left the sampling frame (died or were insti-tutionalized) during follow-up as they were considered tohave been successfully followed. The 1994 baseline inter-viewswereconductedinperson(75%),but99%offollow-upinterviews were conducted over the phone.TheNPHSinterviewincludesitemscovering demographics,health status, health care use, and health determinants.Respondents were also asked to retrieve containers (boxes, bottles,tubes,orpackages)ofmedicationstakeninthe2days preceding an interview. Specific medications were recordedusingATCcodes.TheseATCcodeswereusedinthecurrentanalysis to identify respondents who were taking aBDZ–SSH and to identify the use of ADs. We examined theincidence of new use of BDZ–SSH as the frequency of reporteduseatsubsequentcyclesafternotreportinguseataninitial cycle. A particular concern is the pattern of persistentBDZ–SSH use, as this may be more problematic thanshort-term use. An analysis was therefore performed requir-ing2consecutivecyclesofnewuse.Asthepatternsofinitia-tion and discontinuation maydiffer depending on the typeof medication, additional analyses were performed in whichzopiclone and zaleplon were analyzed separatelyfrom BDZ.As the 2-day record of use covers a brief period of time, wealso examined (for comparative purposes) the incidence of use of sleeping pills in the preceding month, as documented by responses to a different item: “In the past month, did youtake sleeping pills?”ToexaminetrendsinthefrequencyofBDZ–SSHuse,weini-tially tabulated unadjusted frequencies by year of interview.We also tabulated the types of medications used and the fre-quency of use of more than one BDZ–SSH at the same time.To examine the impact of ADs and MDEs on initiation anddiscontinuation of BDZ–SSHs, we used discrete (grouped)time proportional hazard models to estimate HRs. Thesemodelsincludedbothageandsextogenerateestimatesoftheeffect of ADs and MDE on subsequent BDZ–SSHs adjustedfor these nonmodifiable determinants of use. We also devel-oped modelsincorporating additional potentialdeterminantstoassesspossibleconfoundingeffects.Aswewereinterestedin the effects of AD use on subsequent BDZ–SSH use, ADuse was incorporated into these models as a time-varying
Pharmacoepidemiology of Benzodiazepine and Sedative–Hypnotic Use in a Canadian General Population Cohort During 12 Years of Follow-upThe Canadian Journal of Psychiatry, Vol 55, No 12, December 2010
Abbreviations used in this article
 AD antidepressant ATC Anatomic Therapeutic ClassificationBDZ benzodiazepineCIDI-SFMD Composite International DiagnosticInterview—Short Form for Major DepressionDSM Diagnostic and Statistical Manual of MentalDisordersESEMeD European Study of the Epidemiology of MentalDisordersHR hazard ratioMDE major depressive episodeNPHS National Population on Health StudySSH similar sedativehypnotic
covariate. Where applicable, other covariates were alsoallowed to vary over time. These included self-reported pro-fessionallydiagnosed painful conditions (migraine,injury, or  back pain), employment status, education level, alcohol con-sumption, smoking, and income. Employment status wasdichotomized into working, compared with not working, sta-tus. Education was categorized according to whether arespondent had more or less than secondary level education.Excessive alcohol consumption was classified usingself-reportitemsinwhichconsumptionof5ormoredrinksona single occasion was recorded. Smoking was categorized bydistinguishing between current smokers and nonsmokers,with the latter category including both former andnever-smokers. In the analysis concerned with initiation of use,wealsoincludedavariablethatwasintendedtorepresentageneral propensity toaccesshealthservices assuch propen-sity could plausibly be a determinant of exposure toBDZ–SSH.Forthispurpose, weusedcountsofpast-yearvis-its to general practitioners or family physicians, categorizingthese counts as 1, 2, or 3 or more visits. Terms representinginteractions between the predictive variables and time-periodindicatorvariableswereusedtoevaluatetheproportionalhaz-ards assumption. Statistical significance was evaluated usinglikelihood ratio tests for the set of relevant interaction terms.Other 
values reported in the paper derive from Wald tests.The NPHS interview included the CIDI-SFMD,
whichassesses past-year MDE. The CIDI-SFMD is scored with a predictive probability algorithm based on the number of symptom-basedcriteriafulfilledduringa2-weekperiodintheyear preceding the interview. The instrument was scored atthe 90% predictive probability level, indicating endorsementof 5 symptoms.TheapproachtoscoringoftheCIDI-SFMDisbroadlyconsis-tent with the DSM-IV A criterion requirement for MDE.
However, the CIDI-SFMD was originally validated againstDSM-IIIR criteria.
The scoring algorithm stipulates that atleast one of these symptoms must be depressed mood or lossofinterestorpleasure,alsobroadlyconsistentwithDSM-IV.The NPHS used a stratified multistage sampling procedure.Replicate sampling weights provided by Statistics Canadaandanassociatedbootstrapprocedureforvarianceestimationwere used to account for design effects. All analyses wereconductedusingStata
atthePrairieRegionalDataCentreonthe University of Calgary Campus. Our study was approved bytheUniversityofCalgaryConjointHealthResearchEthicsBoard.
Amongthe17276respondents intheNPHSlongitudinalfile,15254wereconsideredeligibleforthisanalysisbecausetheywere aged 13 years and older at the baseline interview. Con-sistent with prior reports,
the frequency of prevalentBDZ–SSH use was between 2% and 3% at each NPHS cycle,with no clear trend suggesting an increasing or decreasingfrequencyofuse(Figure1).Adetaileddescriptionofthedis- positionofthesampleisprovidedinFigure2.Whenthesam- ple was restricted to 7780 respondents with completedinterviews at each of the 7 NPHS cycles from 1994 to 2006(thisincludessomerespondentswithpartialresponses),90%reported no BDZ–SSH use at any cycle. A small proportion(less than 0.5%) reported use at each of the 7 NPHS cycles(Table 1). At each cycle, more than 90% of the respondentswho reported taking a BDZ–SSH were taking only one suchmedication. The most commonly used medications werelorazepam and zopiclone. In 2006, 50.6% (95% CI 44.3% to56.8%) of respondents taking a BDZ–SSH were takinglorazepamand 18.9% (95% CI14.2% to23.5%) were takingzopiclone.Among 15 254 potentiallyeligiblerespondents, 14 825 werenot taking BDZ–SSHs at the baseline interview and wereconsidered eligible for analyses concerned with BDZ–SSHinitiation. At the first follow-up visit 2 years later, 1.3%(95% CI 1.1% to 1.5%) reported using BDZ–SSHs, 0.9%(95% CI 0.6% to 1.2%) of men and 1.7% (95% CI 1.3% to2.1%) of women. This frequency of use increased with age:from0.6%(95%CI0.4%to0.9%)inthegroupaged12to45yearsto2.1%(95%CI1.5%to2.7%)inthegroup aged46to65 years and 3.4% (95% CI 2.2% to 4.5%) in the group aged66 years and older category. The onset of new long-term useas characterized by new use at 2 consecutive cycles waslower, varying between 0.3% and 0.5% at each cycle. Thefrequency of new past-month sleeping pill use ranged between 2.1% and 3.6% across the cycles. The pattern of effectofage(older>younger)andsex(female>male)onthefrequencyofnewusewascomparableinanalysesthatexam-ined consecutive cycle new use and new self-reported sleep-ing pill use. Also, inclusion or exclusion of zopiclone or zaleplonintheoutcomecategorydidnotchangethispattern. No violations of the proportional hazard assumption werefound. In unadjusted analyses, AD use was strongly predic-tive of initiation of BDZ–SSHs (unadjusted HR 3.8, 95% CI2.9 to 4.9). In a proportional hazard model including MDE,age,sex,andinteractionterms,asexbyMDEinteractionwasidentified(HRfortheinteractionterm0.3,95%CI0.1to0.7,
= 0.006). In men, the age-adjusted HR for ADs was 4.6(95% CI 1.8 to 11.6) and for MDE was 8.4 (95% CI 3.6 to19.7), whereas in women these HRs were 6.8 (95% CI 4.4 to10.5) and 2.2 (95% CI1.3 to3.9), respectively.Table2 pres-ents a model incorporating a broader set of covariates. Asexpected, age and sex were associated with initiation of BDZ–SSH, as were pain complaints, smoking, and having 3or more primary care visits in the past year. These adjust-ments attenuated the associations of MDE and AD use withBDZ–SSHs, but the associations remained evident and werestatistically significant. There were no significant interac-tions involving sex, but there was an interaction betweenMDE and age, with the effect of MDE being smaller in peo- ple aged 66 years and older. The model presented in Table 2
La Revue canadienne de psychiatrie, vol 55, no 12, décembre 2010794Original Research

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