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3/16/06
[Slide 1] BENZODIAZEPINES AND SIMILAR DRUGS
Misuse, abuse and dependence
Introduction
Overview
Benzodiazepines (BZDs) = CNS depressants; useful for many disorders
Medical disorders. Examples include:
Muscular spasm in cerebral palsy, paraplegia
Involuntary movements e.g. myoclonus (twitching or spasm of muscle or group of muscles), restless leg syndrome
Convulsive disorders (epilepsy)
Sedation prior to endoscopy/minor surgery
Psychiatric disorders. Examples include:
Anxiety disorders and Sx
E.g. panic attacks ADDIN EN.CITE 19943rtpants.enlEndNote35<style face="normal" font="default" size="100%">Diagnostic and Statistical Manual of Mental Disorders, 4th ed </style>1 = discrete period of intense fear in absence of real dang e r + e" 4 / 1 3 s o m a t i c o r c o g n i t i v e s x . E x a m p l e s :
P a l p i t a t i o n s
S w e a t i n g
T r e m b l i n g
S h o r t n e s s o f b r e a t h
C h e s t p a i n
N a u s e a / a b d o m i n a l d i s t r e s s
A n x i e t y / s l e e p d i s t u r b a n c e d u e t o s t r e s s e s ; w o r k s h i f t c h a n g e ; j e t l a g
( N o t e t o s p e a k e r : m o u s e c l i c k t e x t b o x B U T . . .
[ S l i d e 2 ] K e y P o i n t s H o w e v e r , B Z D s c a n c a u s e p r o b l e m s
L o n g - t e r m B Z D u s e ( > 2 w e e k s ) r i s k y : a d v e r s e e f f e c t s , m i s u s e , a b u s e a n d d e p e n d e n c e .
C e r t a i n s i t u a t i o n s ! r i s k w e c a n r e d u c e r i s k : b e n e f i t
P r e s c r i b i n g p r a c t i c e / m e d c h a r a c t e r i s t i c s
S p e c i f i c B Z D p r e s c r i b e d ( p h a r m a c o l o g y i m p o r t a n t h e r e )
D o s e
D u r a t i o n
P a t i e n t c h a r a c t e r i s t i c s . F o r e x a m p l e
A g e
C o - m o r b i d i l l n e s s
L o n g - t e r m u s e ( > 2 w e e k s ) p h y s i o l o g i c a d a p t a t i o n t o B Z D s w i t h d r a w a l s y n d r o m e w i t h a b r u p t d i s c o n t i n u a t i o n o r d r a s t i c d o s e r e d u c t i o n . S o , t a p e r BZDs = slow (generally 4-20 weeks).
Patient Ken = 30 yo healthy male with ~1 year c/o persistent anxious feelings, difficulty concentrating, difficulty sleeping. Prior relief with diazepam from a friends supply. Requests daily diazepam. At first, we may want to help and provide the diazepam. Is this really in patients best interests?
[Slide 3] What are BZs (and related agents)?
Benzodiazepines (BZDs) = Central nervous system depressants acting via GABA receptor. Often used as sedative/hypnotic (sleep-inducing agent) or anxiolytic (anxiety-relieving agent). ADDIN EN.CITE Charney20011rtpants.enlEndNote15<style face='normal' font='default' size='100%'>Hypnotics and Sedatives</style>Juergens19982rtpants.enlEndNote25<style face='normal' font='default' size='100%'>The Pharmacology of Sedative-Hypnotics</style>Ballenger1998241mylibrary.enlEndNote2415<style face='normal' font='default' size='100%'>Benzodiazepines</style>2-4 Common examples:
Sedative/hypnotics
Flurazepam (Dalmane)
Temazepam (Restoril)
Triazolam (Halcion)
Anxiolytics
Alprazolam (Xanax)
Chlordiazepoxide (Librium)
Clonazepam (Klonopin)
Diazepam (Valium)
Non-BZD benzodiazepine receptor agon i s t s ( B Z R A s ) = A l s o = C N S d e p r e s s a n t s a c t i n g a t t h e G A B A r e c e p t o r . U s e d p r i m a r i l y f o r s e d a t i v e / h y p n o t i c e f f e c t s . S e l e c t i v i t y l e s s a n x i o l t i c
Z a l e p l o n ( S o n a t a )
Z o l p i d e m ( A m b i e n )
E s z o p i c l o n e ( L u n e s t a )
T h o u g h t h e s e m e d i c a t i o n s a r e u s e f u l i n c e r t a i n c l i n i c a l s e t t i n g s o v e r t h e s h o r t t e r m , t h e r e a r e r i s k s w i t h l o n g - t e r m p r e s c r i b i n g t o k e e p i n m i n d
[ S l i d e 4 ] A d v e r s e e f f e c t s
M o t o r i m p a i r m e n t
I m p a i r e d m o t o r s k i l l s ( e . g . s l o w e d r e s p o n s e t i m e , ! d r i v i n g s k i l l s ) A D D I N E N . C I T E < E n d N o t e > < C i t e > < A u t h o r > B a r k e r < / A u t h o r > 200418rtpants.enlEndNote1817<style face="normal" font="default" size="100%">Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis</style>Cumming200321rtpants.enlEndNote2117<style face="normal" font="default" size="100%">Benzodiazepines and risk of hip fractures in older people: a review of the evidence</style>Curran200319rtpants.enlEndNote1917<style face="normal" font="default" size="100%">Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life</style>Gray200320rtpants.enlEndNote2017<style face="normal" font="default" size="100%">Benzodiazepine use and physical performance in community-dwelling older women</style>Rickels19865rtpants.enlEndNote517<style face="normal" font="default" size="100%">One-year follow-up of anxious patients treated with diazepam</style>14-18
Recovers with gradual discontinuation ADDIN EN.CITE Barker200418rtpants.enlEndNote1817<style face="normal" font="default" size="100%">Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis</style>Curran200319rtpants.enlEndNote1917<style face="normal" font="default" size="100%">Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life</style>Gray200320rtpants.enlEndNote2017<style face="normal" font="default" size="100%">Benzodiazepine use and physical performance in community-dwelling older women</style>14, 16, 17
Studies
Barbone et al, Dundee UK. 19k + vehicle accidents over 3 years reviewed. Dose-relationship with BZD Rx and acciden t i n v o l v e m e n t .
R i c k e l s K e t a l . P e n n . 9 6 p a t i e n t s o n B Z D x m e a n 8 y r s w e r e t a p e r e d . ! r e a c t i o n t i m e o n t e s t b a t t e r y a t 5 w k s a n d 1 2 w e e k s a f t e r t a p e r .
R i c k e l s K e t a l . 3 y e a r s a f t e r t a p e r , ! a n x i e t y S x
C u r r a n e t a l , L o n d o n . 1 3 9 s u b j e c t s > 6 5 y o o n l o n g - t e r m B Z D s . 1 0 4 w i t h d r a w n , 3 5 c o n t i n u e d . W i t h d r a w e r s ! c o g n i t i v e a n d p s y c h o m o t o r f u n c t i o n a t 2 4 a n d 5 2 w e e k s .
G r a y e t a l , S e a t t l e . 8 8 5 w o m e n > 6 5 f o l l o w e d f o r 4 y e a r s . M e a s u r e s : s t a n d i n g b a l a n c e , w a l k i n g s p e e d , a n d c h a i r r a i s e s . T h o s e o n B Z D s e x p e r i e n c e d g r e a t e r d e g r e e s o f f u n c t i o n a l d e c l i n e . D o s e a n d R x d u r a t i o n - r e l a t e d , w h e n b a s e l i n e p e r f o r m a n c e a n d i l l n e s s i n d i c a t o r s c o n t r o l l e d .
I n c r e a s e d r i s k
O l d e r ( > 6 5 )
! f a l l s a n d h i p / f e m u r f r a c t u r e s A D D I N E N . C I T E < E n d N o t e > < C i t e > < A u t h o r > B a r k e r < / A u t h o r > < Y e a r > 2 0 0 4 < / Y e ar>18rtpants.enlEndNote1817<style face="normal" font="default" size="100%">Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis</style>Cumming200321rtpants.enlEndNote2117<style face="normal" font="default" size="100%">Benzodiazepines and risk of hip fractures in older people: a review of the evidence</style>Curran200319rtpants.enlEndNote1917<style face="normal" font="default" size="100%">Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life</style>Herings199535rtpants.enlEndNote3517<style face="normal" font="default" size="100%">Benzodiazepines and the risk of falling leading to femur fractures. Dosage more important than elimination half-life</style>Cumming200321rtpants.enlEndNote2117<style face="normal" font="default" size="100%">Benzodiazepines and risk of hip fractures in older people: a review of the evidence</style>Wagner200455rtpants.enlEndNote5517<style face="normal" font="default" size="100%">Benzodiazepine use and hip fractures in the elderly: who is at greatest risk?</style>Bloem200163rtpants.enlEndNote6317<style face="normal" font="default" size="100%">Prospective assessment of falls in Parkinson's disease</style>Wang200165rtpants.enlEndNote6517<style face="normal" font="default" size="100%">Hazardous benzodiazepine regimens in the elderly: effects of half-life, dosage, and duration on risk of hip fracture</style>14-16, 19-22.
! r i s k i f h i g h e r f u n c t i o n a l s t a t u s . A D D I N E N . C I T E < E n d N o t e > < C i t e > < A u t h o r > G r a y < / A u t h o r > < Y e a r > 2 0 0 3 < / Y e a r > < R e c N u m > 2 0 < / R e c N u m > < r e c o r d > < d a t a b a s e n a m e = " r t p a n t s . e n l " p a t h = " C : \ D o c u m e n t s a n d S e t t i n g s \ r t b r o w n \ M y D o c u m e n t s \ e n d n o t e l i b s \ r t p a n t s . e n l " > r t p a n t s . e n l < / d a t abase>EndNote2017<style face="normal" font="default" size="100%">Benzodiazepine use and physical performance in community-dwelling older women</style>Ensrud200361rtpants.enlEndNote6117<style face="normal" font="default" size="100%">Central nervous system active medications and risk for fractures in older women</style>17, 23
2 + BZDs ADDIN EN.CITE Pierfitte200166rtpants.enlEndNote6617<style face="normal" font="default" size="100%">Benzodiazepines and hip fractures in elderly people: case-control study.[see comment]</style>24 or concomitant alcohol use ADDIN EN.CITE Barbone199880rtpants.enlEndNote8017<style face="normal" font="default" size="100%">Association of road-traffic accidents with benzodiazepine use.[see comment]</style>Hindmarch198381rtpants.enlEndNote8117<style face="normal" font="default" size="100%">The effects of midazolam in conjunction with alcohol on sleep, psychomotor performance and car driving ability</style>25, 26
Motor impairment w/ BZRAs < BZDs ADDIN EN.CITE Allain1995400rtpants.enlEndNote40017<style face="normal" font="default" size="100%">Comparative study of the effects of zopiclone, zolpidem, flunitrazepam, and placebo on nocturnal cognitive performance in healthy subjects in relation to pharmacokinetics</style>O'Hanlon1995401rtpants.enlEndNote40117<style face="normal" font="default" size="100%">Zopiclone's residual effects on psychomotor and information processing skills involved in complex tasks such as car driving</style>27, 28
Cognitive impairment
Anterograde amnesia = impaired recall of new information ADDIN EN.CITE Allen199127rtpants.enlEndNote2717<style face="normal" font="default" size="100%">The effects of repeated doses of clomipramine and alprazolam on physiological, psychomotor and cognitive functions in normal subjects</style>Eves198828rtpants.enlEndNote2817<style face="normal" font="default" size="100%">The effects on memory of pipequaline, alone or in combination with diazepam</style>Curran198729rtpants.enlEndNote2917<style face="normal" font="default" size="100%">Differential amnesic properties of benzodiazepines: a dose-response comparison of two drugs with similar elimination half-lives</style>Birzele199239rtpants.enlEndNote3917<style face="normal" font="default" size="100%">Benzodiazepine induced amnesia after long-term medication and during withdrawal</style>Tonne199575rtpants.enlEndNote7517<style face="normal" font="default" size="100%">Neuropsychological changes during steady-state drug use, withdrawal and abstinence in primary benzodiazepine-dependent patients</style>29-33
Useful for medical procedures (no recall for discomfort)
Same as alcoholic blackout
Sedation/drowsiness ADDIN EN.CITE Birzele199239rtpants.enlEndNote3917<style face='normal' font='default' size='100%'>Benzodiazepine induced amnesia after long-term medication and during withdrawal</style>Rickels199934rtpants.enlEndNote3417<style face='normal' font='default' size='100%'>Psychomotor performance of long-term benzodiazepine users before, during, and after benzodiazepine discontinuation</style>Atack200360rtpants.enlEndNote6017<style face='normal' font='default' size='100%'>Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site</style>Rickels198393rtpants.enlEndNote9317<style face='normal' font='default' size='100%'>A controlled clinical trial of alprazolam for the treatment of anxiety</style>Lapierre198294rtpants.enlEndNote9417<style face='normal' font='default' size='100%'>A therapeutic and discontinuation study of clobazam and diazepam in anxiety neurosis</style>Kleber198096rtpants.enlEndNote9617<style face='normal' font='default' size='100%'>Ketazolam compared to diazepam and placebo in the treatment of anxiety</style>Botter198097rtpants.enlEndNote9717<style face='normal' font='default' size='100%'>Single daily dose treatment of anxiety with clobazam: a double-blind study versus normal multiple-dose treatment with diazepam</style>Kim198098rtpants.enlEndNote9817<style face='normal' font='default' size='100%'>Anxiolytic efficacy and safety of ketazolam compared with diazepam and placebo</style>Roehrs2003223mylibrary.enlEndNote22317<style face='normal' font='default' size='100%'>Hypnotics: an update</style>13, 32, 34-40
Impairs work
Increases accidents
Respiratory depression rare unless combined with other drugs ADDIN EN.CITE Man200467rtpants.enlEndNote6717<style face="normal" font="default" size="100%">Relationship between prescribing and risk of opiate overdose among drug users in and out of maintenance treatment</style>41
Studies: Rickels et al, 2000, Penn. Randomized 310 Ss to diazepam, placebo, or other med. Significant drowsiness and fatigue reported for diazepam even at 6 week f/u.
Impaired visual-spatial ability ADDIN EN.CITE Golombok198825rtpants.enlEndNote2517<style face="normal" font="default" size="100%">Cognitive impairment in long-term benzodiazepine users</style>Sakol198838rtpants.enlEndNote3817<style face="normal" font="default" size="100%">The effects of long-term benzodiazepine treatment and graded withdrawal on psychometric performance</style>42, 43
Cognitive impairment w/BZRAs
Zolpidem = similar to BZDs ADDIN EN.CITE Berlin1993225mylibrary.enlEndNote22517<style face='normal' font='default' size='100%'>Comparison of the effects of zolpidem and triazolam on memory functions, psychomotor performances, and postural sway in healthy subjects</style>Wesensten1995226mylibrary.enlEndNote22617<style face='normal' font='default' size='100%'>Effects of daytime administration of zolpidem versus triazolam on memory</style>Roehrs1994224mylibrary.enlEndNote22417<style face='normal' font='default' size='100%'>Sedative, memory, and performance effects of hypnotics</style>44-46
Zopiclone < BZDs ADDIN EN.CITE Allain1995232mylibrary.enlEndNote23217<style face='normal' font='default' size='100%'>Comparative study of the effects of zopiclone, zolpidem, flunitrazepam, and placebo on nocturnal cognitive performance in healthy subjects in relation to pharmacokinetics</style>O'Hanlon1995233mylibrary.enlEndNote23317<style face='normal' font='default' size='100%'>Zopiclone's residual effects on psychomotor and information processing skills involved in complex tasks such as car driving</style>27, 28
Increased risk (cognitive impairment)
Patient characteristics
> age 65 generally at increased risk ADDIN EN.CITE Wagner200455rtpants.enlEndNote5517<style face="normal" font="default" size="100%">Benzodiazepine use and hip fractures in the elderly: who is at greatest risk?</style>Clark200453rtpants.enlEndNote5317<style face="normal" font="default" size="100%">Benzodiazepine prescription practices and substance abuse in persons with severe mental illness</style>20, 47, but higher function/ better physical health decrease risk ADDIN EN.CITE Ensrud200361rtpants.enlEndNote6117<style face="normal" font="default" size="100%">Central nervous system active medications and risk for fractures in older women</style>23
Alcohol use ADDIN EN.CITE Hindmarch198381rtpants.enlEndNote8117<style face="normal" font="default" size="100%">The effects of midazolam in conjunction with alcohol on sleep, psychomotor performance and car driving ability</style> < / a c c e s s i o n - n u m > < u r l s > < / u r l s > < / r e c o r d > < / C i t e > < / E n d N o t e > 2 6
P r e s c r i b i n g p a t t e r n s : F a s t e r - a c t i n g , m o r e h i g h l y l i p i d s o l u b l e a g e n t s g r e a t e r r i s k o f s e d a t i o n A D D I N E N . C I T E < E n d N o t e > < C i t e > < A u t h o r > R i c k e l s < / A u t h o r > < Y e a r > 1 9 8 3 < / Y e a r > < R e c N u m > 9 3 < / R e c N u m > < r e c o r d > rtpants.enlEndNote9317<style face="normal" font="default" size="100%">A controlled clinical trial of alprazolam for the treatment of anxiety</style>Lapierre198294rtpants.enlEndNote9417<style face="normal" font="default" size="100%">A therapeutic and discontinuation study of clobazam and diazepam in anxiety neurosis</style>Kleber198096rtpants.enlEndNote9617<style face="normal" font="default" size="100%">Ketazolam compared to diazepam and placebo in the treatment of anxiety</style>Botter198097rtpants.enlEndNote9717<style face="normal" font="default" size="100%">Single daily dose treatment of anxiety with clobazam: a double-blind study versus normal multiple-dose treatment with diazepam</style>Kim198098rtpants.enlEndNote9817<style face="normal" font="default" size="100%">Anxiolytic efficacy and safety of ketazolam compared with diazepam and placebo</style>35-39
Treatment = discontinue BZDs/BZRAs slowly (more later)
Transition: Another set of problems to keep in mind are use disorders, since BZDs and BZRAs are potentially habit-f o r m i n g .
[ S l i d e 5 ] M i s u s e , a b u s e , a n d d e p e n d e n c e
M i s u s e
M i s u s e `" f o r m a l d i a g n o s t i c c a t e g o r y ; u s e d t o d e s c r i b e u s e o u t s i d e r e c o m m e n d e d p r a c t i c e ( n o t a b u s e / d e p e n d e n c e )
L o n g - t e r m u s e = 2 + w e e k s
S o m e s a y i s n o t p r o b l e m a t i c A D D I N E N . C I T E < E n d N o t e > < C i t e > < Author>Laux1987115rtpants.enlEndNote11517<style face='normal' font='default' size='100%'>Long-term use of benzodiazepines in psychiatric inpatients</style>DuPont1990285rtpants.enlEndNote28517<style face='normal' font='default' size='100%'>A practical approach to benzodiazepine discontinuation</style>48, 49
Most patients take less than prescribed ADDIN EN.CITE Caplan1985120rtpants.enlEndNote12017<style face="normal" font="default" size="100%">Social effects of diazepam use: a longitudinal field study</style>Apsler1984121rtpants.enlEndNote12117<style face="normal" font="default" size="100%">Correlates of compliance with psychoactive prescriptions</style>50, 51
Romach et al. Toronto. Conducted 3 surveys 1 year apart of 312 regular alprazolam users. No reported dose escalation. 75% reported ongoing symptom relief. BUT most had attempted to DC on their own & experienced withdrawal Sx. Most physicians had not discussed discontinuation.
Most patients decrease (not increase) their dose over time ADDIN EN.CITE Romach1992122rtpants.enlEndNote12217<style face="normal" font="default" size="100%">Characteristics of long-term alprazolam users in the community</style>52
Controversial due to
Risks of side effects (e.g. cognitive/motor impairment)
Tolerance is likely
Loss of effects (sedative/hypnotic) +/- dose escalation
Prevalence/incidence (long-term use) = 2% of individuals who have ever used (APA Task Force) ADDIN EN.CITE Salzman1991106rtpants.enlEndNote10617<style face="normal" font="default" size="100%">The APA Task Force report on benzodiazepine dependence, toxicity, and abuse</style>APA1990107rtpants.enlEndNote10727<style face="normal" font="default" size="100%">Benzodiazepine dependence, toxicity, and abuse: A task force report of the American Psychiatric Association</style>Kan1997108rtpants.enlEndNote10817<style face="normal" font="default" size="100%">High prevalence of benzodiazepine dependence in out-patient users, based on the DSM-III-R and ICD-10 criteria</style>Lader1993109rtpants.enlEndNote10917<style face="normal" font="default" size="100%">Guidelines for the prevention and treatment of benzodiazepine dependence: summary of a report from the Mental Health Foundation</style>53-56
Non-medical use (to get high)
Prevalence/incidence
> age 12: 2-12% ever, 0.3% in last year, 0.1-0.2% used in last month (National Survey on Drug Use and Health, Monitoring the Future) ADDIN EN.CITE Lader1993109rtpants.enlEndNote10917<style face='normal' font='default' size='100%'>Guidelines for the prevention and treatment of benzodiazepine dependence: summary of a report from the Mental Health Foundation</style>SAMHSA2004130rtpants.enlEndNote13027<style face='normal' font='default' size='100%'>Results from the 2003 National Survey on Drug Use and Health: National findings</style>Anthony1994114rtpants.enlEndNote11417<style face='normal' font='default' size='100%'>Comparative epidemiology of dependence on tobacco, alcohol, controlled substances and inhalants: Basic findings from the National Comorbidity Survey</style>Goodwin2002224rtpants.enlEndNote22417<style face='normal' font='default' size='100%'>Sedative use and misuse in the United States</style>SAMHSA200473mylibrary.enlEndNote7327<style face='normal' font='default' size='100%'>Results from the 2003 National Survey on Drug Use and Health: National findings</style>Wallace2003209mylibrary.enlEndNote20917<style face='normal' font='default' size='100%'>Gender and ethnic differences in smoking, drinking and illicit drug use among American 8th, 10th and 12th grade students, 1976-2000</style>SAMHSA2004210mylibrary.enlEndNote21045<style face='normal' font='default' size='100%'>Monitoring the Future Study: Data tables</style>56-61
Highest among age 25-44 ADDIN EN.CITE SAMHSA200473mylibrary.enlEndNote7327<style face='normal' font='default' size='100%'>Results from the 2003 National Survey on Drug Use and Health: National findings</style>Goodwin2002240mylibrary.enlEndNote24017<style face='normal' font='default' size='100%'>Sedative use and misuse in the United States</style>57, 62
25-50% of alcoholics have used BZDs non-medically ADDIN EN.CITE Schmidt1989110rtpants.enlEndNote11017<style face="normal" font="default" size="100%">Prevalence of benzodiazepine abuse and dependence in psychiatric in-patients with different nosology. An assessment of hospital-based drug surveillance data</style>Busto1983111rtpants.enlEndNote11117<style face="normal" font="default" size="100%">Objective determination of benzodiazepine use and abuse in alcoholics</style>Allgulander1987112rtpants.enlEndNote11217<style face="normal" font="default" size="100%">Long-term prognosis in addiction on sedative and hypnotic drugs analyzed with the Cox regression model</style>63-65
Includes individuals not prescribed BZDs, but borrowed from friends/family ADDIN EN.CITE Schuckit2002113rtpants.enlEndNote11317<style face="normal" font="default" size="100%">The prevalence and clinical course of sedative-hypnotic abuse and dependence in a large cohort</style>66
Abuse ADDIN EN.CITE 19943rtpants.enlEndNote35<style face="normal" font="default" size="100%">Diagnostic and Statistical Manual of Mental Disorders, 4th ed </style>1
Diagnostic criteria: >= one of the following in 12 month period
Failure to fulfill major obligations (work, school, home)
Recurrent use in hazardous situations
Recurrent legal consequences
Continued use despite recurrent/persistent interpersonal problems
Not dependence
Prevalence/incidence
Unknown, mixed with dependence in most large surveys ADDIN EN.CITE Anthony1994114rtpants.enlEndNote11417<style face='normal' font='default' size='100%'>Comparative epidemiology of dependence on tobacco, alcohol, controlled substances and inhalants: Basic findings from the National Comorbidity Survey</style>SAMHSA2004130rtpants.enlEndNote13027<style face='normal' font='default' size='100%'>Results from the 2003 National Survey on Drug Use and Health: National findings</style>Robins1991243mylibrary.enlEndNote2436<style face='normal' font='default' size='100%'>Psychiatric Disorders in America: The Epidemiologic Catchment Area Study</style>57, 58, 67
Estimated lifetime prevalence of 0.4% ADDIN EN.CITE Schuckit200278mylibrary.enlEndNote7817<style face="normal" font="default" size="100%">The prevalence and clinical course of sedative-hypnotic abuse and dependence in a large cohort</style>66: Schuckit et al. San Diego. 2002. Part of Collaborative Study on the Genetics of Alcoholism. 9330 subjects in overall sample. 34 had sed-hyp abuse (mainly BZDs). ! r i s k w i t h y o u n g e r a g e , u n e m p l o y e d , s e p a r a t e d / d i v o r c e d , c a n n a b i s , c o c a i n e , a l c o h o l u s e d i s o r d e r .
R i s k f a c t o r s s i m i l a r t o t h o s e f o r m i s u s e ( n o n - m e d i c a l u s e ) o r d e p e n d e n c e A D D I N E N . C I T E < E n d N o t e > < C i t e > < A u t h o r > S c h u c k i t < / A u t h o r > < Y e a r > 2 0 0 2 < / Y e a r > < R e c N u m > 1 1 3 rtpants.enlEndNote11317<style face='normal' font='default' size='100%'>The prevalence and clinical course of sedative-hypnotic abuse and dependence in a large cohort</style>Posternak200115rtpants.enlEndNote1517<style face='normal' font='default' size='100%'>Assessing the risks and benefits of benzodiazepines for anxiety disorders in patients with a history of substance abuse or dependence</style>Schuckit200278mylibrary.enlEndNote7817<style face='normal' font='default' size='100%'>The prevalence and clinical course of sedative-hypnotic abuse and dependence in a large cohort</style>66, 68
Dependence
Diagnostic criteria: ADDIN EN.CITE 19943rtpants.enlEndNote35<style face="normal" font="default" size="100%">Diagnostic and Statistical Manual of Mental Disorders, 4th ed </style>1 3+ in 12 month period, repetetively:
Tolerance
Larger amounts to achieve desired fx
Lesser fx with same amount
Withdrawal
Characteristic withdrawal syndrome (stay tuned)
Use to relieve or prevent withdrawal
Consumed larger amounts/longer periods than intended
Persistent desire/multiple failed attempts to quit or cut back
Much time obtaining, using, or recovering from effects
Other important activities sacrificed
Use continues despite knowledge of adverse effects
(Note to speaker: Mouse click h i g h l i g h t i n g o f t o l e r a n c e a n d w i t h d r a w a l , e m p h a s i z i n g t h a t p h y s i c a l d e p e n d e n c e i s o n l y p a r t o f s u b s t a n c e d e p e n d e n c e . ) D i s t i n c t i o n f r o m p h y s i c a l d e p e n d e n c e : P h y s i c a l d e p e n d e n c e o n l y p a r t o f s u b s t a n c e d e p e n d e n c e A D D I N E N . C I T E < E n d N o t e > < C i t e > < A u t h o r > K aran200322rtpants.enlEndNote225<style face="normal" font="default" size="100%">Pharmacokinetic and pharmacodynamic principles</style>5
Definition physical dependence
physiologic adaptation to substance;
emergence of withdrawal during abstinence
withdrawal relieved by readministration of the substance
Expected effect of chronic administration of a psychoactive medication
Prevalence/incidence of BZD dependence (National Survey on Drug Use and Health, ADDIN EN.CITE SAMHSA2004130rtpants.enlEndNote13027<style face="normal" font="default" size="100%">Results from the 2003 National Survey on Drug Use and Health: National findings</style>57 National Comorbidity Survey, ADDIN EN.CITE Anthony1994114rtpants.enlEndNote11417<style face='normal' font='default' size='100%'>Comparative epidemiology of dependence on tobacco, alcohol, controlled substances and inhalants: Basic findings from the National Comorbidity Survey</style>Goodwin2002224rtpants.enlEndNote22417<style face='normal' font='default' size='100%'>Sedative use and misuse in the United States</style>58, 59, Epidemiologic Catchment Area Study, ADDIN EN.CITE Robins1991225rtpants.enlEndNote2256<style face="normal" font="default" size="100%">Psychiatric Disorders in America: The Epidemiologic Catchment Area Study</style>67 Drug Abuse Warning Network)
0.3-5% lifetime risk general population (sedative/hypnotic dependence, mainly BZDs) ADDIN EN.CITE Anthony1994114rtpants.enlEndNote11417<style face='normal' font='default' size='100%'>Comparative epidemiology of dependence on tobacco, alcohol, controlled substances and inhalants: Basic findings from the National Comorbidity Survey</style>Schuckit2002113rtpants.enlEndNote11317<style face='normal' font='default' size='100%'>The prevalence and clinical course of sedative-hypnotic abuse and dependence in a large cohort</style>SAMHSA2004130rtpants.enlEndNote13027<style face='normal' font='default' size='100%'>Results from the 2003 National Survey on Drug Use and Health: National findings</style>Goodwin2002224rtpants.enlEndNote22417<style face='normal' font='default' size='100%'>Sedative use and misuse in the United States</style>Robins1991225rtpants.enlEndNote2256<style face='normal' font='default' size='100%'>Psychiatric Disorders in America: The Epidemiologic Catchment Area Study</style>Schuckit200278mylibrary.enlEndNote7817<style face='normal' font='default' size='100%'>The prevalence and clinical course of sedative-hypnotic abuse and dependence in a large cohort</style>57-59, 66, 67
10-15% of past-year users ADDIN EN.CITE SAMHSA2004130rtpants.enlEndNote13027<style face="normal" font="default" size="100%">Results from the 2003 National Survey on Drug Use and Health: National findings</style>57
What can we as care providers do to minimize the risk of these agents for our patients?
[Slide 6] Medication characteristics/prescribing practices
Lipid solubility affects CNS penetration & onset of subjective effects.
Categories:
Low. Examples: clonazepam (Klonopin), oxazepam
Intermediate. Examples: lorazepam (Ativan), alprazolam (Xanax)
High. Examples: diazepam (Valium), clorazepate
(Note to speaker: mouse click f o l l o w i n g t e x t : ) ! l i p i d s o l u b i l i t y ! a b u s e / d e p e n d e n c e
[ S l i d e 1 2 ] M e t a b o l i s m a f f e c t s d u r a t i o n o f a c t i o n ( h a l f - l i f e ) A D D I N E N . C I T E < E n d N o t e > < C i t e > < A u t h o r > A t a c k < / A u t h o r > < Y e a r > 2 0 0 3 < / Y e a r > < R e c N u m > 6 0 < / R e c N u m > < r e c o r d > < d a t a b a s e n a m e = ' r t p a n t s . e n l ' p a t h = ' C : \ D o cuments and Settings\rtbrown\My Documents\endnote libs\rtpants.enl'>rtpants.enlEndNote6017<style face='normal' font='default' size='100%'>Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site</style>Charney20011rtpants.enlEndNote15<style face='normal' font='default' size='100%'>Hypnotics and Sedatives</style>Juergens19982rtpants.enlEndNote25<style face='normal' font='default' size='100%'>The Pharmacology of Sedative-Hypnotics</style>Karan200322rtpants.enlEndNote225<style face='normal' font='default' size='100%'>Pharmacokinetic and pharmacodynamic principles</style>2, 3, 5, 13
BZD/BZRA half-lives
Anxiolytics
Oxazepam = 6-20 hrs
Alprazolam = 6-20 hrs
Diazepam = 30-100 h r s
S e d a t i v e - h y p n o t i c s
T r i a z o l a m = < 6 h r s
T e m a z e p a m = 6 - 2 0 h r s
( N o t e t o s p e a k e r : t e x t b o x a p p e a r s w i t h m o u s e c l i c k h e r e ) ! h a l f - l i f e ! a b u s e p o t e n t i a l
A c t i v e m e t a b o l i t e s a f f e c t d u r a t i o n o f a c t i o n
E x a m p l e ( N o t e t o s p e a k e r : a r r o w a p p e a r s o n s l i d e t o r e p r e s e n t d i a z e p a m o x a z e p a m ) = D i a z e p a m d e s m e t h y l d i a z e p a m o x a z e p a m
N o a c t i v e m e t a b o l i t e s : l o r a z e p a m , o x a z e p a m , t e m a z e p a m
t 1 / 2 v a r i e s w i d e l y b e t w e e n i n d i v i d u a l s . D u r a t i o n a n d e l i m i n a t i o n h a l f - l i f e v a r i e s w i t h
O l d e r t h a n ~ 6 5 s l o w e d m e t a b o l i s m
P r e s e n c e o f l i v e r d i s e a s e s l o w e d
M e d i c a t i o n i n t e r a c t i o n s
G e n e t i c s
B Z R A s
Z o l p i d e m ( A m b i e n ) = 0 . 5 - 3 h r s
Z a l e p l o n ( S o n a t a ) = 1 h r
E s z o p i c l o n e ( L u n e s t a ) = 3 . 5 - 6 h r s
[ S l i d e 7 ] P a t i e n t f a c t o r s a l s o a f f e c t r i s k
S u b s t a n c e d e p e n d e n c e h i s t o r y
S e d a t i v e / h y p n o t i c s A D D I N E N.CITE Brunette200359rtpants.enlEndNote5917<style face="normal" font="default" size="100%">Benzodiazepine use and abuse among patients with severe mental illness and co-occurring substance use disorders</style>Clark200453rtpants.enlEndNote5317<style face="normal" font="default" size="100%">Benzodiazepine prescription practices and substance abuse in persons with severe mental illness</style>Voyer200454rtpants.enlEndNote5417<style face="normal" font="default" size="100%">Unconventional indicators of drug dependence among elderly long-term users of benzodiazepines</style>47, 69, 70
Alcoholism ADDIN EN.CITE Allgulander1987112rtpants.enlEndNote11217<style face="normal" font="default" size="100%">Long-term prognosis in addiction on sedative and hypnotic drugs analyzed with the Cox regression model</style>Busto1983111rtpants.enlEndNote11117<style face="normal" font="default" size="100%">Objective determination of benzodiazepine use and abuse in alcoholics</style>Johansson200368rtpants.enlEndNote6817<style face="normal" font="default" size="100%">Dependence on legal psychotropic drugs among alcoholics</style>Ciraulo200164rtpants.enlEndNote6417<style face="normal" font="default" size="100%">A benzodiazepine mood effect scale: reliability and validity determined for alcohol-dependent subjects and adults with a parental history of alcoholism</style>Clark200453rtpants.enlEndNote5317<style face="normal" font="default" size="100%">Benzodiazepine prescription practices and substance abuse in persons with severe mental illness</style>Johansson200368rtpants.enlEndNote6817<style face="normal" font="default" size="100%">Dependence on legal psychotropic drugs among alcoholics</style>Schuckit2002113rtpants.enlEndNote11317<style face="normal" font="default" size="100%">The prevalence and clinical course of sedative-hypnotic abuse and dependence in a large cohort</style>Busto1996128rtpants.enlEndNote12817<style face="normal" font="default" size="100%">Multiple drug use and psychiatric comorbidity in patients admitted to the hospital with severe benzodiazepine dependence</style>47, 64-66, 71-73
Opioids ADDIN EN.CITE Ross200016rtpants.enlEndNote1617<style face='normal' font='default' size='100%'>The nature of benzodiazepine dependence among heroin users in Sydney, Australia</style>Schuckit2002113rtpants.enlEndNote11317<style face='normal' font='default' size='100%'>The prevalence and clinical course of sedative-hypnotic abuse and dependence in a large cohort</style>Busto1996128rtpants.enlEndNote12817<style face='normal' font='default' size='100%'>Multiple drug use and psychiatric comorbidity in patients admitted to the hospital with severe benzodiazepine dependence</style>Malcolm1993129rtpants.enlEndNote12917<style face='normal' font='default' size='100%'>Types of benzodiazepines abused by chemically dependent inpatients</style>Iguchi1993287rtpants.enlEndNote28717<style face='normal' font='default' size='100%'>Benzodiazepine and sedative use/abuse by methadone maintenance clients</style>66, 73-76
Stimulants ADDIN EN.CITE Schuckit2002113rtpants.enlEndNote11317<style face="normal" font="default" size="100%">The prevalence and clinical course of sedative-hypnotic abuse and dependence in a large cohort</style>Malcolm1993129rtpants.enlEndNote12917<style face="normal" font="default" size="100%">Types of benzodiazepines abused by chemically dependent inpatients</style>66, 75
Specific psychiatric diagnoses
Anxiety disorders
Panic ADDIN EN.CITE Schuckit2002113rtpants.enlEndNote11317<style face="normal" font="default" size="100%">The prevalence and clinical course of sedative-hypnotic abuse and dependence in a large cohort</style>Busto1996128rtpants.enlEndNote12817<style face="normal" font="default" size="100%">Multiple drug use and psychiatric comorbidity in patients admitted to the hospital with severe benzodiazepine dependence</style>Busto1996128rtpants.enlEndNote12817<style face="normal" font="default" size="100%">Multiple drug use and psychiatric comorbidity in patients admitted to the hospital with severe benzodiazepine dependence</style>66, 73
Any anxiety disorder = 17-27% lifetime BZD abuse or dependence (vs. 0.3-5% in general population) ADDIN EN.CITE Kessler1997103rtpants.enlEndNote10317<style face="normal" font="default" size="100%">Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey</style>Bowen1984104rtpants.enlEndNote10417<style face="normal" font="default" size="100%">Alcoholism, anxiety disorders, and agoraphobia</style>Kushner1990105rtpants.enlEndNote10517<style face="normal" font="default" size="100%">The relation between alcohol problems and the anxiety disorders.[see comment]</style>77-79
Major depression ADDIN EN.CITE Schuckit2002113rtpants.enlEndNote11317<style face='normal' font='default' size='100%'>The prevalence and clinical course of sedative-hypnotic abuse and dependence in a large cohort</style>Busto1996128rtpants.enlEndNote12817<style face='normal' font='default' size='100%'>Multiple drug use and psychiatric comorbidity in patients admitted to the hospital with severe benzodiazepine dependence</style>Garvey1986127rtpants.enlEndNote12717<style face='normal' font='default' size='100%'>Prevalence of misuse of prescribed benzodiazepines in patients with primary anxiety disorder or major depression</style>Goodwin2002240mylibrary.enlEndNote24017<style face='normal' font='default' size='100%'>Sedative use and misuse in the United States</style>62, 66, 73, 80
Antisocial personality disorder ADDIN EN.CITE 19943rtpants.enlEndNote35<style face='normal' font='default' size='100%'>Diagnostic and Statistical Manual of Mental Disorders, 4th ed </style>Schuckit2002113rtpants.enlEndNote11317<style face='normal' font='default' size='100%'>The prevalence and clinical course of sedative-hypnotic abuse and dependence in a large cohort</style>1, 66 = pervasive pattern of disregard for/violation of rights of others beginning in childhood or early adolescence
Borderline personality disorder ADDIN EN.CITE 19943rtpants.enlEndNote35<style face='normal' font='default' size='100%'>Diagnostic and Statistical Manual of Mental Disorders, 4th ed </style>Petrovic200270rtpants.enlEndNote7017<style face='normal' font='default' size='100%'>Personality traits and socio-epidemiological status of hospitalised elderly benzodiazepine users</style>1, 81 = pervasive pattern of instability of relationships, self-image, and affect. Marked impulsivity. Frantic efforts to avoid real or imagined abandonment.
Social/demographic factors
Unemployment ADDIN EN.CITE de las Cuevas200312rtpants.enlEndNote1217<style face='normal' font='default' size='100%'>Benzodiazepines: more "behavioural" addiction than dependence</style>Kan2001275rtpants.enlEndNote27517<style face='normal' font='default' size='100%'>Cross-validation of the benzodiazepine dependence self-report questionnaire in outpatient benzodiazepine users</style>82, 83
Poor social support: separated, divorced or widowed marital status ADDIN EN.CITE O'Connor200456rtpants.enlEndNote5617<style face='normal' font='default' size='100%'>Psychological distress and adaptational problems associated with benzodiazepine withdrawal and outcome: a replication</style>Schuckit2002113rtpants.enlEndNote11317<style face='normal' font='default' size='100%'>The prevalence and clinical course of sedative-hypnotic abuse and dependence in a large cohort</style>Goodwin2002240mylibrary.enlEndNote24017<style face='normal' font='default' size='100%'>Sedative use and misuse in the United States</style>62, 66, 84
Low socioeconomic status ADDIN EN.CITE de las Cuevas200312rtpants.enlEndNote1217<style face='normal' font='default' size='100%'>Benzodiazepines: more "behavioural" addiction than dependence</style>Schuckit2002113rtpants.enlEndNote11317<style face='normal' font='default' size='100%'>The prevalence and clinical course of sedative-hypnotic abuse and dependence in a large cohort</style>Goodwin2002240mylibrary.enlEndNote24017<style face='normal' font='default' size='100%'>Sedative use and misuse in the United States</style>62, 66, 82
Female ADDIN EN.CITE Schuckit2002113rtpants.enlEndNote11317<style face='normal' font='default' size='100%'>The prevalence and clinical course of sedative-hypnotic abuse and dependence in a large cohort</style>de las Cuevas200312rtpants.enlEndNote1217<style face='normal' font='default' size='100%'>Benzodiazepines: more "behavioural" addiction than dependence</style>Anthony1994114rtpants.enlEndNote11417<style face='normal' font='default' size='100%'>Comparative epidemiology of dependence on tobacco, alcohol, controlled substances and inhalants: Basic findings from the National Comorbidity Survey</style>Goodwin2002240mylibrary.enlEndNote24017<style face='normal' font='default' size='100%'>Sedative use and misuse in the United States</style>Kan2001275rtpants.enlEndNote27517<style face='normal' font='default' size='100%'>Cross-validation of the benzodiazepine dependence self-report questionnaire in outpatient benzodiazepine users</style>58, 62, 66, 82, 83
Detection of misuse, abuse, dependence ADDIN EN.CITE Heit2003112mylibrary.enlEndNote11217<style face='normal' font='default' size='100%'>Addiction, physical dependence, and tolerance: precise definitions to help clinicians evaluate and treat chronic pain patients</style>Marcus1345113mylibrary.enlEndNote11317<style face='normal' font='default' size='100%'>Treatment of nonmalignant chronic pain.[see comment]</style>Heit2003112mylibrary.enlEndNote11217<style face='normal' font='default' size='100%'>Addiction, physical dependence, and tolerance: precise definitions to help clinicians evaluate and treat chronic pain patients</style>Weaver1999114mylibrary.enlEndNote11417<style face='normal' font='default' size='100%'>Role of the primary care physician in problems of substance abuse</style>DuPont1990285rtpants.enlEndNote28517<style face='normal' font='default' size='100%'>A practical approach to benzodiazepine discontinuation</style><style face='normal' font='default' size='100%'>GABA systems, benzodiazepines, and substance dependence</style>Nutt1990284rtpants.enlEndNote28417<style face='normal' font='default' size='100%'>Pharmacological mechanisms of benzodiazepine withdrawal</style>95, 96
Downregulation of GABAergic inhibitory function
! g l u t a m a t e / N M D A r e c e p t o r f u n c t i o n
A b r u p t d i s c o n t i n u a t i o n u n o p p o s e d e x c i t a t o r y C N S a c t i v i t y
C l a s s i c s i g n s a n d s y m p t o m s o f s e d a t i v e w i t h d r a w a l
L e s s s e v e r e / m o r e c o m m o n : a n x i e t y , a g i t a t i o n , d i a p h o r e s i s , t a c h y c a r d i a , h y p e r t e n s i o n
S e v e r e / u n c o m m o n : h a l l u c i n o s i s , s e i z u r e s
B Z R A s a l s o m a y p h y s i c a l d e p e n d e n c e / w i t h d r a w a l
M u c h m o r e r a r e t h a n f o r B Z D s A D D I N E N . C I T E < E n d N o t e > < C i t e > < A u t h o r > G r i f f i t h s < / A u t h o r > < Y e a r > 1 9 9 2 < / Y e a r > < R e c N u m > 2 2 7 < / R e c N u m > < r e c o r d > < d a t a b a s e n a m e = ' m y l i b r a r y . e n l ' p a t h = ' C : \ D o c u m e n t s a n d S e t t i n g s \ doughboy\My Documents\mylibrary.enl'>mylibrary.enlEndNote22717<style face='normal' font='default' size='100%'>Zolpidem behavioral pharmacology in baboons: self-injection, discrimination, tolerance and withdrawal</style>Bruun1993228mylibrary.enlEndNote22817<style face='normal' font='default' size='100%'>[Abuse potential during use and withdrawal psychosis after treatment with the hypnotic zolpidem (Stilnoct)].[see comment]</style>Evans1990229mylibrary.enlEndNote22917<style face='normal' font='default' size='100%'>Zolpidem and triazolam in humans: behavioral and subjective effects and abuse liability</style>< / p u b - d a t e s > < / d a t e s > < a c c e s s i o n - n u m > < s t y l e f a c e = ' n o r m a l ' f o n t = ' d e f a u l t ' s i z e = ' 1 0 0 % ' > 2 2 6 2 9 0 4 < / s t y l e > < / a c c e s s i o n - n u m > < u r l s > < / u r l s > < / r e c o r d > < / C i t e > < / E n d N o t e > 9 7 - 9 9
L e s s d e p e n d e n c e / w i t h d r a w a l t h a n B Z D s d u e t o ! s i d e e f f e c t s ( n a u s e a , a n x i e t y ) w i t h ! d o s e f o r B Z RAs ADDIN EN.CITE Evans1990229mylibrary.enlEndNote22917<style face="normal" font="default" size="100%">Zolpidem and triazolam in humans: behavioral and subjective effects and abuse liability</style>99
Risk even lower for zopiclone. ADDIN EN.CITE Yanagita1983234mylibrary.enlEndNote23417<style face='normal' font='default' size='100%'>Dependence potential of zopiclone studied in monkeys</style>Yanagita1983235mylibrary.enlEndNote23517<style face='normal' font='default' size='100%'>Dependence studies on zopiclone</style>Dorian1983236mylibrary.enlEndNote23617<style face='normal' font='default' size='100%'>Evaluation of zopiclone physical dependence liability in normal volunteers</style>Aranko1991237mylibrary.enlEndNote23717<style face='normal' font='default' size='100%'>Misuse of zopiclone and convulsions during withdrawal</style>100-103
BZRA withdrawal severity can = BZD (rare seizures) ADDIN EN.CITE Gilbert1997277rtpants.enlEndNote27717<style face="normal" font="default" size="100%">Seizure after withdrawal from supratherapeutic doses of zolpidem tartrate, a selective omega I benzodiazepine receptor agonist</style>104
Tapering BZDs is way to avoid withdrawal ADDIN EN.CITE Schweizer199086rtpants.enlEndNote8617<style face='normal' font='default' size='100%'>Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper</style>DuPont1990285rtpants.enlEndNote28517<style face='normal' font='default' size='100%'>A practical approach to benzodiazepine discontinuation</style>Smith1990286rtpants.enlEndNote28617<style face='normal' font='default' size='100%'>Benzodiazepine dependency discontinuation: focus on the chemical dependency detoxification setting and benzodiazepine-polydrug abuse</style>49, 105, 106
Dont abruptly stop BZDs/BZRAs if taken daily for 2+ weeks
Slow taper
Divide daily dose into BID-QID
Taper 25% every 3-7 days initially
Last half of taper often more difficult
!! r e b o u n d a n x i e t y a n d w i t h d r a w a l s y m p t o m s ( e s p e c i a l l y w i t h s h o r t - a c t i n g a g e n t s A D D I N E N . C I T E < E n d N o t e > < C i t e > < A u t h o r > B l i d i n g < / A u t h o r > < Y e a r > 1 9 7 8 < / Y e a r > < R e c N u m > 7 7 < / R e c N u m > < r e c o r d > < d a t a b a s e n a m e = " r t p a n t s . e n l " p a t h = " C : \ D o c u m e n t s a n d S e t t i n g s \ r t b r o w n \ M y D o c u m e nts\endnote libs\rtpants.enl">rtpants.enlEndNote7717<style face="normal" font="default" size="100%">The abuse potential of benzodiazepines with special reference to oxazepam</style>Clark200453rtpants.enlEndNote5317<style face="normal" font="default" size="100%">Benzodiazepine prescription practices and substance abuse in persons with severe mental illness</style>de las Cuevas200312rtpants.enlEndNote1217<style face="normal" font="default" size="100%">Benzodiazepines: more "behavioural" addiction than dependence</style>< / d a t e s > < a c c e s s i o n - n u m > < s t y l e f a c e = " n o r m a l " f o n t = " d e f a u l t " s i z e = " 1 0 0 % " > 1 2 6 6 9 1 7 4 < / s t y l e > < / a c c e s s i o n - n u m > < u r l s > < / u r l s > < / r e c o r d > < / C i t e > < / E n d N o t e > 4 7 , 8 2 , 8 7 )
! r a t e o f t a p e r d u r i n g l a s t h a l f o f t a p e r . ( e . g . I n i t i a l d a i l y d o s e = 1 0 0 m g , ! r a t e o f t a p e r w h e n r each 50mg daily.) ADDIN EN.CITE Schweizer199086rtpants.enlEndNote8617<style face="normal" font="default" size="100%">Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper</style>105
Appropriate support may improve outcome ADDIN EN.CITE Juergens1993282rtpants.enlEndNote28217<style face='normal' font='default' size='100%'>Benzodiazepines and addiction</style>DuPont1990285rtpants.enlEndNote28517<style face='normal' font='default' size='100%'>A practical approach to benzodiazepine discontinuation</style>49, 107
Cognitive behavioral therapy ADDIN EN.CITE Baillargeon2003100rtpants.enlEndNote10017<style face="normal" font="default" size="100%">Discontinuation of benzodiazepines among older insomniac adults treated with cognitive-behavioural therapy combined with gradual tapering: a randomized trial.[see comment]</style>108
Higher self-rating of social support ADDIN EN.CITE O'Connor200456rtpants.enlEndNote5617<style face="normal" font="default" size="100%">Psychological distress and adaptational problems associated with benzodiazepine withdrawal and outcome: a replication</style>84
Weekly p h y s i c i a n f o l l o w - u p
[ S l i d e 9 ] S u m m a r y
L o n g - t e r m u s e o f B Z D s a n d s i m i l a r d r u g s ! r i s k f o r :
S i d e e f f e c t s
M i s u s e , a b u s e , d e p e n d e n c e
W i t h d r a w a l
P r e s c r i b i n g p r a c t i c e s a n d p a t i e n t c h a r a c t e r i s t i c s i n c r e a s e r i s k
P r e s c r i b i n g
> 2 w e e k d u r a t i o n
D o s e o u t s i d e a c c e p t e d r a n g e
H i g h l y l i p i d s o l u b l e & s h o r t h a l f - l i f e a g e n t s
P a t i e n t s
> 6 5 y o
S u b s t a n c e u s e ( e s p e c i a l l y B Z D s & E t O H ) & p s y c h i a t r i c h i s t o r y
S o c i a l s t r e s s o r s ( u n e m p l o y m e n t , m a r i t a l s t a t u s )
I f t a k e n d a i l y f o r > 2 w e e k s , t a p e r s l o w l y & ! r a t e d u r i n g l a s t o f t a p e r
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