Sedative Hypnotics

1. SEDATIVE HYPNOTICS
Paula J. Colescott MD
Board in Addiction Medicine
Board in Internal Medicine

2. OUTLINE
• Terminology
• Pharmacology
• Historical Perspectives
• Intoxication / Withdrawal Syndrome
• Efficacy / Adverse Effects
• Epidemiology
• Case Study
• Withdrawing Benzodiazepines

3. Terminology
• Sedative
– Induces sedation by reducing agitation/ decreases
CNS excitement in the awake patient
• Hypnotic
– Induces sleep (soporific)
• Anxiolytic
– Decreases anxiety
• Tranquilizer
– Older term
– Minor—anxiolytic
– Major—antipsychotic

4. Classification of
Sedative-Hypnotic-Anxiolytics
Brain Depressants
– Benzodiazepines: Azopam and Azolam
( Diazepam, Lorazepam, Midazolam, Alprazolam)
• Benzodiazepine-like drugs (zolpidem/zaleplon)
– Carbamates (Glutethiamide, Meprobamate)
– Barbiturates --(secobarbital)
• Barbiturate-Like (Methaqualone )

5. OPIUM Morphine
Quick Management of aggressive patients
Sedation of melancholic/delusional
In 1800—Most widely used sedative in asylums
1898
1804
1832

6. Massachusetts Asylum
MORPHINE

7. Opioids relieve emotional pain
and this is one of the behavioral
mechanisms implicated in the
addiction cycle
(Khantzian, 1985, 1990, 1997)

8. 1857—BROMIDES AS SEDATIVES
• Women catamenial or
hysteriform epileptic seizures
• Positive outcomes in 14
women out of a sample of 15.
• Bromides were widely
introduced in asylums and
similar institutions throughout
Europe, given their
• sedative and antiepileptic
properties
• It served “to reduce the
expression of the
epileptic patients’ sexuality”.

9. Sedative History
• 1870’s—Potassium Bromide
– Anticonvulsant--
– Widely used as sedative—Typical dose: a “few
grams/day” certain hospitals used tons/yr.

10. 1897--THE BROMIDE SLEEP
• 2.5 ounces of Sodium Bromide
• A morphine addicted woman, producing a
“bromide brom” of several days from which she
could not be roused.
• When the administration of sodium bromide
ceased, she gradually awakened and reported no
craving for morphine.
• Hypothesis: a 5-9 days Bromide Brom would
produce the same cessation of craving for alcoholics
and also would terminate an acute attack of mania.
• He replicated the treatment in 8 more patients and
achieved the desired results in all but one case. In
this one case, she died of pneumonia.

11. BROMO
SELTZER
the original formula: 3.2 mEq/teaspoon sodium bromide.
Their sedative effect probably accounted for Bromo-
Seltzer's popularity as a hangover remedy. Early formulas
also used acetanilide as the analgesic, a known
poisonous substance

12. Dr. Miles’ Nervine
A Calmative
1890-1960
Nervous ailments: nervous exhaustion,
sleeplessness, hysteria, headache, neuralgia,
backache, pain ,epilepsy, spasms, fits, and St.
Vitus’ dance

14. BROMISM

15. Barbituric Acid
• Von Baeyer 1864
• condensing urea (an animal waste
product) with diethyl malonate (an
ester derived from the acid of
apples).
• No direct effect on the central
nervous system

16. BARBITAL (VERONAL)
BAYER PHARMA 1903
BARBITAL : hypnotic,
sedative, anticonvulsant
Emil Fischer and Joseph von Mering

17. The Barbiturates
• Anticonvulsants
• Anxiolytics
• Soporifics
• Anesthetics

18. Alcohol Withdrawal
Benzodiazepine Taper
Anesthesia Induction

19. WW II Worried about US troops
being deployed to the
South Pacific, soldiers were
issued barbiturates. The
idea was to lower blood
pressures and respiratory
rates to help soldiers better
cope with the extreme heat
and humidity.
GOOFBALLS

20. US production of
barbiturates in Pounds (x1000)

21. Street Names
barbs,
bluebirds
Dolls
downers
goofballs
sleepers
'reds & blues
tooties

23. BARBITURATE SUICIDE/OVERDOSE

24. Barbiturate Overdoses

26. 1954

27. Current uses
of
Barbiturates

28. BARBITURATES:
DEATH
WITH
DIGNITY
• high doses of barbiturates effective for physician-
assisted suicide
• Opioids are less reliable for physician-assisted death due
to the unpredictable duration of the dying process even
after high doses. The same applies to benzodiazepines.
The most frequent undesired effect is an unexpectedly
long dying process due to impaired uptake of the drugs

29. ETHINAMATE
• Valmid-- is a short-acting carbamate-
derivative sedative-hypnotic
• Used to treat insomnia.
• Regular use leads to drug tolerance, and it is
usually not effective for more than 7 days.
• Prolonged use can lead to dependency.

30. New England Journal Of Medicine
1954

31. Methaqualone--Quaalude
• 1951- synthesized in India as an antimalarial
• 1965 --the most commonly prescribed sedative
in Britain
• 1972 -- the sixth-bestselling sedative in the USA
• JB Roerig & Company division of Pfizer,
discontinued the drug in 1985, mainly due to its
psychological addictiveness and recreational use

32. Effects can include euphoria, drowsiness, reduced heart rate,
reduced respiration, increased sexual arousal (aphrodisia), and
paresthesias (numbness of the fingers and toes). Larger doses
can bring about respiratory depression, slurred speech,
headache, and photophobia (a symptom of excessive
sensitivity to light).

33. Methaqualone– MANDRAX
White Pipe
• 60% OF ALL DRUGS SEIZED ON THE STREET
• MIXED IN A PIPE WITH CANNABIS, BENADRYL,
OR VALIUM.
• NOTABLE QUANTITIES OF TOLUIDINE---
CARCINOGENIC.

35. MILTOWN
The Answer for the Syndrome of the
60’s
THE BATTERED PARENT

43. “Innocuous Panacea”
• 1958

44. BENZODIAZEPINE
Heterocyclic ring
a fusion of the benzene and
diazepine ring systems.
1956
Dr. Leo Sternbach
LIBRIUM
VALIUM
FLURAZEPAM
CLONAZEPAM
Between 1969-1982 Valium was the most
prescribed drug in America with over 2.3 billion
doses sold in 1978!

45. BENZODIAZEPINES
“MOTHERS LITTLE HELPER”
Mick Jagger
I hear ev'ry mother say
They just don't appreciate that you get tired
They're so hard to satisfy, You can tranquilize your mind
So go running for the shelter of a mother's little helper
And four help you through the night, help to minimize
your plight
Doctor please, some more of these
Outside the door, she took four more
What a drag it is getting old
"Life's just much too hard today,"

46. ROLLING STONES
I hear ev'ry mother say
The pursuit of happiness just seems a bore
And if you take more of those, you will get an
overdose
No more running for the shelter of a mother's
little helper
They just helped you on your way, through your
busy dying day

47. PHARMACOKINETICS

48. SEDATIVE
HYPNOTICS
Mechanism of
Action
GABA IS THE INHIBITORY NEUROTRANSMITTER
DOWN REGULATES BRAIN ACTIVITY
DEPRESSING CENTRAL NERVOUS SYSTEM FUNCTION

49. NERVE ACTION POTENTIAL
ON YOUTUBE
• http://www.youtube.com/watch?v=oRYpt8_O
Jms&list=WLN3hoGZnOTd-h5WA
• http://www.youtube.com/watch?v=VQG90Fx
ASWQ&list=WLN3hoGZnOTd-
h5WAiVVCks03NdbEmKGCc
• http://www.youtube.com/watch?v=-
6t_n6kTj1A

50. Activation CL ions to flow through the pore
change in polarity inhibitory effect on
neurotransmission much less likely that a
successful action potential will occur

51. PHARMACOKINETICS
BENZODIAZEPINES
• Absorption
– Readily absorbed following oral administration
• Diazepam (Valium) is the most rapidly absorbed,
• BENZODIAZEPINES DIFFER IN :
– Potency—
– Onset of action
– Duration of Action elimination half life.
– BZD metabolites may be active and lengthen the
effect of the parent drug

52. LIPOPHILIC = LIPID LOVING
ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as
hexane or toluene
• BZ are all relatively lipophilic--
• Important in onset & duration of clinical effect
after single dose
• Diazepam & clorazepate highest lipid
Solubility & quickest onsets of action
• After a single dose, BZ will redistribute rapidly
out of CNS to other lipophilic tissues

53. ELIMINATION
• All BZDs are metabolized by the Liver
– Demethylation Oxidation (P450 3A4)-Valium
– Glucuronide conjugation---Lorazepam, Oxazepam, & Temazepam
– Nitroreduction—Clonazpeam
• With some BZ the metabolites are also active
• All BZ are excreted BY THE KIDNEY

54. METABOLIC PATHWAY

55. P
O
T
E
N
C
Y

56. TEMAZEPAM
GEL CAPS
Temazepam,
flunitrazepam and
diazepam are preferred
BZDs in those using
amphetamine and
heroin
Removed from the
Market

57. TEMAZEPAM PROFILE
The more rapidly absorbed, the quicker the
access to the brain, the more likely to be abused.

59. EMERGENCY ROOM VISIT
Unrecognized hand ischemia after intraarterial drug injection: successful management of a "near miss" event
Kyros Ipaktchi,corresponding author1 Ramin Ipaktchi,2 Andreas D Niederbichler,2 Peter M Vogt,2 and Karsten Knobloch2
• A 33 year old right handed
male i.v. drug abuser
• Presents three hours after
reportedly self injecting water
dissolved crushed zolpidem
tablets into the right forearm.
His chief complaint was
forearm tenderness extending
down to the hand.
• The patient described an
immediate onset of pain,
which radiated down the arm
into the hand.

60. 18 HOURS AFTER IV AMBIEN
• The right hand was found to be cold and held in a flexed position. There
was absent ulnar artery pulse and only a faint radial artery pulse palpable,
Allen's test was pathological. The hand showed blue discoloration and
there was tenderness over the thenar eminence and hypoesthesia over
the digits 1 through 5 as evidenced by a two point discrimination of
greater than 8 mm

61. Angiogram: Pre Urokinase
• Angiographic study of right hand showing absent contrast
flow in distal ulnar artery and deep palmar arch, incomplete
filling of superficial palmar arch, hypoperfusion of digits 1
and 2 and no detectable flow in digits 3 to 5

62. Three months after IV ambien
Within 3 hours after start of thrombolytic
therapy there was a return of normal skin color
to the right hand and restoration of a strong
Doppler detectable ulnar artery and palmar arch
pulse signal. Clinically, the Allen test turned
normal

63. Urine Toxicology
• Immunoassay
• Detects (BZDs)
metabolized to
desmethyldiazepam
or oxazepam
• Cutoff levels: 200 ng/ml
• ++ for 48‐72 hours post
single dose but as long
as a week post dose
• alprazolam , lorazepam ,
clonazepam , zolpidem,
will not be picked up on
routine screening

65. BZDs and PSYCH PATIENTS
• About 30% of psychiatric patients receive benzodiazepines
• Greatest use in patients with affective disorders, long
• duration of mental illness, and high users of psychiatric
• services
• Generally most patients tend to decrease anxiolytic doses
• over time.
• The use of antidepressants to treat anxiety has increased in
• recent years and the proportion of patients treated with
• anxiolytics has fallen slightly
• There are certain groups of high‐risk patients where longterm
• use, misuse, and abuse are greater than in patients
• with anxiety disorders

66. BZD USERS
• Most patients take benzodiazepines for periods of <1
• month.
• 12% of the U.S. population used a benzodiazepine for
• medical purposes at least once during a 1‐year period,
• 6 month use occurs in about 3% of the population
• 1% using the medication for a year or longer
• long‐term users are more likely to be older, female,
with more significant chronic health and/or
emotional problems

68. World Federation of Societies of Biological
Psychiatry (WFSBP) Guidelines for the
pharmacological treatment of anxiety,
Obsessive-compulsive and posttraumatic stress
disorders-1st revision. Biol Psychiatry 2008: 9:
248-312
• SSRI and SNRI are 1st choice for anxiety DO
• BZDs 2nd line option, but NOT recommended
for long term therapy due to limited amount
of data beyond the acute phase.

69. “Antidepressants for the treatment of Generalized
Anxiety Disorder: A placebo-controlled comparison of
imipramine, trazodone, and diazepam”. Arch Gen
Psychiatry 1993: 50: 884-5
• RCT x 8 weeks.
• Diazepam : most improvement in anxiety ratings
during 1st two weeks (somatic symptoms )
• trazodone = Diazepam & imipramine > Diazepam
in anxiolytic efficacy (psych symptoms) @ 3-8 wks.
Completed:
• Mod-Marked improvement :
• 73% imipramine
• 69% on trazodone
• 66% on Diazepam
• 47% on placebo.

70. A psychopharmacological treatment
algorithm for generalized anxiety disorder
(GAD). Psychopharmacol 2010; 24: 3-26
• “A” evidence Alprazolam (placebo/comparator
controlled studies)
• “A” Diazepam (placebo/comparator)
• Long-term Tx studies with BZDs in GAD are
lacking .
• BZDs should only be used when
other drugs or CBT have failed.

71. Practice Guidelines for the treatment of
patients with obsessive-compulsive disorder.
Am J Psychiatry 2007: 164; Suppl 7 5-53.
Koran LM
BZDs in OCD poorly supported
by available literature, if not
actually contraindicated.

72. World Federation of Societies of Biological Psychiatry (WFSBP)
Guidelines for the pharmacological treatment of anxiety,
Obsessive-compulsive and posttraumatic stress disorders-1st
revision. Biol Psychiatry 2008: 9: 248-312
• + BZDs : Clonazepam
• Work rapidly, well-
tolerated, useful for
episodic performance
related SA
• Trials without
comparators
• Potential withdrawal
• Limited data in preventing
relapse
Social Anxiety Disorder

73. Braum P. “Core Symptoms of PTSD unimproved
by alprazolam” J Clin Psychiatry 1990: 51:236-8
• OCD /PTSD lowest level of evidence supporting
the use of BZDs.
• Xanax: minimal improvement in overall anxiety
symptoms, with no improvement in the core
symptoms of PTSD
• Interfere with HPA-stress response in animals
with Increased vulnerability to repeat stress
• do not use as mono-therapy; questionable
benefit as an add on.

74. Chouinard G “Aprazolam in the tratment of generalized anxiety
and panic disorders: a double-blind placebo-controlled study. “
Psychopharmacology 1982; 77:229-33“
• Panic Disorder has the most robust evidence
of BZD efficacy in SHORT-TERM TREATMENT in
RCTs.
• Aprazolam: + FDA approval for PD
• Clonazepam, diazepam, lorazepam, all
beneficial.

75. American Psychiatric Association Practice Guideline for the
treatment of patients with major depressive disorder. 3rd Ed.
Washington DC: Arlington VA: 2010. 152p.
• BZDs: NOT recommended in depression, since they
have NO anti-depressant effects!
• 1960s: Augmentation strategy to enhance
anxiolytic/sedative/hypnotic effects in patients
taking TCA/MAOIs.
• Limit BDZs in patients with primary major
depression only to those with pronounced anxiety
or persistent insomnia not adequately relieve by an
SSNI/SNRI

76. I can’t sleep!
• Is insomnia due to medical/psychiatric
problem, or is it a primary disorder?
• Complete Review of Systems
– ? Comorbidity: psychiatric/medical
– Sleep Hygiene
– Drug or Alcohol Abuse
– Medication side effects

79. Passarella S.
Diagnosis and treatment of insomnia. Am J Health
Syst. Pharm 2008: 65:927-24
• 1. Hypnotics are FDA-approved and indicated only for
short-term use (less than 1 month)
• 2. BZDs /BZD-receptor agonists: the most effective
pharmacologic therapies for insomnia
• Z drugs: Zolpidem, Zalephlon, Eszopiclone
– Rapidly metabolized
– No active metabolites
– No muscle relaxant/anticonvulsant effects
– No rebound insomnia after discontinuation for short
periods
– No development of tolerance to any parameter of sleep
measurement observed over 6 months with eszopiclone.

80. BZDs & SLEEP
Int J Geriatr Psychiatry. 2011; 26(9):908-15 (ISSN: 1099-1166
• Seniors' Health Survey (ESA) , community-dwelling,
older population in Quebec
• Collège des Médecins du Québec suggests a maximum
length of use of 3 months but the mean length of
benzodiazepine use is longer
• Long-term benzodiazepine users:
– were more likely to report poor sleep quality.
– Sleep quality of initial probable problematic sleepers
tended to increase over 1 year but sleep quality in
benzodiazepines users increased less rapidly than in non-
users.
– Also, women were more likely to report using
benzodiazepines and having poorer sleep quality.

81. SLEEPING IN THE NURSING HOME
Sleep Med. 2013; 14(7):614-21 (ISSN: 1878-5506)
• 300 residents, 178 (59%) were long-term BZD
users and 122 were nonusers
• Mean age, 85.5 y; range, 57-100; 75% women
• BZD use remained strongly associated with
poor sleep (r=0.173; P=.003)
– difficulties with falling asleep
– more midnight awakenings
– felt less rested in the morning
– poorer self-perceived sleep quality

82. FOR SLEEP
Findings do not
support long-term
effectiveness of
BZDs

83. GROUPS AT RISK FOR BZDs
• Alcohol Use Disorders
– Combined Sedation
• Drivers
– Increased RR of MVA 1.5-6.5, depending on dose,
# of BZDs, time of last use, half life.
– Daytime anxiolytics impaired driving performance
irrespective of half-life. Short & Long acting BZDs
taken as hypnotics impaired driving during the 1st
2-4 wks of ingestion.
– Young drivers particularly at risk.

85. XANAX NOT ALCOHOL

86. THE ELDERLY
• More sensitive to BZDs effects
• Over sedation, decreased alertness,
confusion: “pseudo-dementia”
• 50% risk of hip fractures: no difference
between short or long-acting medications.
• Multiple Meds with interactions.

87. 73year old found
unconscious by family in
his bedroom
• Objective: lethargic/intermittently following
commands. 138/90 65 RR: 12 O2SAT: 94%
• PMH: + Hypertension +CAD
• MEDS: Started a new sleeping aid
• In ER: episodic bradypnea, with drop in O2
Saturations to 90%
• FAMILY BRINGS IN THE SLEEP AID

88. Zolpidem (ambien)
• His sedation was reversed with
flumazenil (1mg IV) upon which
he awoke!!
• He admitted to “having a few
drinks” and had taken his new
medication to help him sleep.
• His blood alcohol level was
180mg/dl
• He was discharged 24 hrs. later.

89. THE PREGNANT
• Rarely cause cleft palate
• Floppy baby syndrome
• Neonatal withdrawal reactions
– Lowest effective dose
– Shortest possible duration
– Avoid in the 1st trimester
– Avoid poly-drug use
– BZDs pass into the breast milk!

90. Paradoxical Reactions to BZDs
• BZDs have a disinhibitory effect: acute
excitement, increased anxiety, hyperactivity,
aggressive impulses, hostility, rage, assault,
rape.
• Incidence: < 1% to 20%
• High-risk patients: Borderline PDO, Impulse
control Disorder, Chronic alcoholism, Polydrug
users, <18 yrs, >65, learning disabilities

92. “PROPOFOL a
powerful anesthetic, and the
sedative Lorazepam were the
primary drugs responsible for
Jackson's death. Other
drugs detected in his
system were Midazolam,
Diazepam, Lidocaine and
Ephedrine”.
CORONER’S REPORT

93. • On the morning Jackson died, Murray tried to induce sleep
without using propofol, according to the affidavit. He said he
gave Jackson valium at 1:30 a.m. When that didn't work, he
said, he injected lorazepam intravenously at 2 a.m. At 3 a.m.,
when Jackson was still awake, Murray administered midazolam.
• Over the next few hours, Murray said he gave Jackson various
drugs. Then at 10:40 a.m., Murray administered 25 milligrams
of propofol after Jackson repeatedly demanded the drug,
according to the court records...
• ... Other drugs that were confiscated in the search included
valium, tamsulosin, lorazepam, temazepam, clonazepam,
trazodone and tizanidine. They also found propofol in Murray's
medical bag. Murray told detectives that he was not the first
doctor to administer the powerful anesthetic to Jackson.

94. AMERICAN CONTROLLED SUBSTANCE
ACT 1970
Schedule I
Schedule I drugs, substances, or chemicals are defined as
drugs with no currently accepted medical use and a high
potential for abuse. Schedule I drugs are the most
dangerous drugs of all the drug schedules with potentially
severe psychological or physical dependence. Some
examples of Schedule I drugs are:
heroin, lysergic acid diethylamide (LSD), marijuana
(cannabis), 3,4-methylenedioxymethamphetamine
(ecstasy), methaqualone, and peyote

95. AMERICAN CONTROLLED SUBSTANCE
ACT 1970
Schedule II
a high potential for abuse, less abuse potential
than Schedule I
potentially leading to severe psychological or
physical dependence.
cocaine, methamphetamine, methadone, hydromorphone
(Dilaudid), meperidine (Demerol), oxycodone (OxyContin),
fentanyl, Dexedrine, Adderall, and Ritalin , Pentobarbital,
secobarbital and amobarbital

96. AMERICAN CONTROLLED SUBSTANCE
ACT 1970
Schedule III
a moderate to low potential for physical and
psychological dependence.
Combination products with less than 15 milligrams of
hydrocodone per dosage unit (Vicodin), Products containing less
than 90 milligrams of codeine per dosage unit (Tylenol with
codeine), ketamine, anabolic steroids, testosterone,
butabarbital

97. AMERICAN CONTROLLED SUBSTANCE
ACT 1970
Schedule IV
• low potential for abuse and low risk of
dependence.
• Xanax, Soma, Darvon, Darvocet, Valium,
Ativan, Talwin, Ambien
barbital and phenobarbital

98. AMERICAN CONTROLLED SUBSTANCE
ACT 1970
• Schedule V
• lower potential for abuse than Schedule IV and consist of
preparations containing limited quantities of certain
narcotics.
• Schedule V drugs are generally used for antidiarrheal,
antitussive, and analgesic purposes. Some examples of
Schedule V drugs are:
• cough preparations with less than 200 milligrams of
codeine or per 100 milliliters (Robitussin AC), Lomotil,
Motofen, Lyrica, Parepectolin

99. DSM 5
Sedative/Hypnotic/Anxiolytic Use
disorder
A problematic pattern of use leading to
clinically significant impairment or distress
as manifested by at least 2 of the following
occurring within a 12-month period.

100. Sedative
Hypnotic/Anxiolytic
Use Disorder
• Taken in larger amounts or over a longer period
than was intended.
• Persistent desire /unsuccessful efforts to cut
down or control use
• A great deal of time spent in activities necessary
to obtain the drug
• Use results in failure to fulfill major role
obligations @ work/school/home (repeated absences,
poor work performance, suspensions, expulsions from school, neglect of
children or household)

101. • Continued use despite persistent/recurrent social or
interpersonal problems caused by or exacerbated by the
effects of the drug.
• Important social occupational or recreational activities
are given up or reduced because of
sedative/hypnotic/anxiolytic use.
• Recurrent use in situations in which it is physically
hazardous (driving, operating a machine)
• Continued use despite knowledge of having a persistent
or recurrent physical/psychological problem that is likely
to have been caused or exacerbated by these drugs.

102. • Tolerance
• Withdrawal
305.40 (F13.10) Mild: 2-3 symptoms
304.10 (F13.20) Moderate: 4-5 symptoms
304.10 F13.20) Severe: > 6 symptoms

103. W
H
Y

104. 1. Euphoria is rare unless BZDs are used to boost an opiate effect
(combined with methadone)
2. Tolerance to the desired sedative effect leads to escalation in
dose, with withdrawal occurring with dose reduction.
3. BZDs with the highest abuse potential produce a rapid onset of
pleasant mood, well-being, relief of dysphoria, a sense of increased
popularity, the belief that thoughts flow more easily, and a general
state of contentment. (Aprazolam and Valium )
Mechanism of
Addiction

105. Physical Dependence
on Benzodiazepines
• Becomes apparent when withdrawal occurs
upon discontinuation of the drug
• Can occur after continued use over 2 to 4
months
• Reported in 50% of patients on treatment for
> 4‐6 months

106. BZD WITHDRAWAL SEIZURES
J Okla State Med Assoc. 2011; 104(2):62-5 (ISSN: 0030-1876)
• 1961
• Occur with : short, medium, and long half-life BZD
• Long time/ high doses
• 15 days of use and at therapeutic dosage
• Grand Mal
• severity of seizures range from a single episode to
coma and death

107. Benzodiazepine co-dependence exacerbates the opiate
withdrawal syndrome
Drug Alcohol Depend. 2004; 76(1):31-5 (ISSN: 0376-8716)
• Patients dependent only on opiates (n = 39),
and patients dependent on both opiates and
benzodiazepines (n = 22), were recruited from
consecutive admissions to an in-patient drug
treatment unit.
• Quantity and duration of prior opiate use was
similar for both groups
• daily self-ratings of opiate withdrawal (SOWS)

108. OPIATE/BZD WITHDRAWAL
Drug Alcohol Depend. 2004; 76(1):31-5 (ISSN: 0376-8716
Co-dependent patients reported a
more severe withdrawal symptoms
than patients withdrawing from
opiates alone. Co-dependent patients
had significantly more severe opiate
withdrawal symptoms.

109. Gabapentin treatment in a female patient with panic disorder
and adverse effects under carbamazepine during
benzodiazepine withdrawal
Psychiatr Prax. 2007; 34(2):93-4 (ISSN: 0303-4259
• Alprazolam dependence, who initially was
treated with carbamazepine because of severe
withdrawal symptoms
• Gabapentin: the patient showed a dramatic
relief of withdrawal symptoms and of the
panic attacks recurring during withdrawal

110. Benzodiazepine withdrawal in subjects on
opiate substitution treatment
Presse Med. 2006; 35(4 Pt 1):599-606 (ISSN: 0755-4982
The best evidence supports a procedure
where the patient is switched to a long-
lasting benzodiazepine and the dose then
tapered by 25% of the initial dose each
week. Diazepam is the drug most often
used in the framework

111. BZD WITHDRAWAL IN SPAIN
BMC Res Notes. 2012; 5:684 (ISSN: 1756-0500)
• 1150 patients, 79 were identified.
They were over 44 years old and
had been daily users of BZD for a
period exceeding six months. Out of
the target group 51 patients agreed
to participate. BZD dosage was
reduced every 2-4 weeks by 25% of
the initial dose with the optional
support of Hydroxyzine or Valerian

112. NURSES IN PRIMARY CARE
overseeing BZD withdrawal
• By the end of the 6 month intervention, 80.4%
of the patients had discontinued BZD and
64% maintained abstinence at one year
• Improvement in Depression and anxiety
scales
• Increase in quality of life scale
• No reduction in the sleep quality

114. A fatal case of benzodiazepine withdrawal.
Am J Forensic Med Pathol. 2009; 30(2):177-9 (ISSN: 1533-404X)
• Female presented to the hospital
with hypertension, elevated
temperature, worsening bizarre
behavior, and movement
irregularities.
• While in the hospital, the decedent
developed seizure-like activity and
died approximately 15 hours after
admission

115. Family’s History:
• She had been taking diazepam for several years
but had recently been switched to alprazolam.
• The decedent had abruptly stopped taking the
alprazolam approximately 4 days before
admission when she ran out of the medication,
after taking approximately 200 mg in a 6-day
period

116. TOXICOLOGY
therapeutic levels of citalopram and phenytoin.
Zolpidem was not present.

117. Sedative, Hypnotic, Anxiolytic
Intoxication 292.89
a. Recent use of a sedative, hypnotic, anxiolytic
b. Maladaptive behavioral/psychological changes (inappriate sexual/aggressive
behavior, mood lability, impaired judgment)
c. One or more of the following shortly after sedative/hypnotic/anxiolytic use:
a. Slurred speech
b. Incoordination
c. Unsteady gait
d. Nystagmus
e. Impairment in cognition (attention, memory)
–antegrade amnesia
f. Stupor or coma

118. Sedative/Hypnotic/Anxiolytic
Withdrawal
• Cessation/ or reduction in sedative/hypnotic/anxiolytic that has been
prolonged.
• 2 or more of the following develop within several hours to a few days after
cessation/reduction of
sedative/hypnotic/anxiolytic
Autonomic hyperactivity (sweating or pulse > 100BPM
Hand tremor
Insomnia
Nausea/vomiting
Transient visual,tactile, or auditory hallucinations or illusions
Psychomotor agitation
Anxiety
Grand Mal Seizures

119. WITHDRAWING BZDs
• Prolonged taper with currently prescribed
benzodiazepine
• Fairly rapid to 50% of initial dose then 10% reduction
per week.
• Conversion to a long acting benzodiazepine
– Clonazepam or Chlordiazepoxide
• Conversion to non‐benzodiazepine
– phenobarbital or carbamazepine.
• Prolonged Withdrawal
• Alternative medication strategies—Gabapentine
• CBT

120. BZD withdrawal and Sleep
Eur Addict Res. 2011; 17(5):262-70 (ISSN: 1421-9891)
• 12-week prospective, open noncontrolled study
in 282 patients who met DSM-IV-TR criteria for
BZD dependence
• Mean (±SD) pregabalin dose was 315 ± 166
mg/day at the end of the trial.
• significant and clinically relevant improvement
in sleep outcomes at the endpoint, measured by
MOS, with a total score reduction from 55.8 ±
18.9 to 25.1 ± 18.0 at week 12 (i.e. a 55%
reduction).

121. EPIDEMIOLOGY

123. 2012

124. Figure 5.3 Mean Age at First Use for Specific Illicit
Drugs among Past Year Initiates Aged 12 to 49: 2012

125. Figure 7.2 Specific Illicit Drug Dependence or Abuse in the Past
Year among Persons Aged 12 or Older: 2012

126. Figure 5.2 Past Year Initiates of Specific Illicit Drugs among
Persons Aged 12 or Older: 2012

127. ER VISITS FOR MISUSE/ABUSE OF
PHARMACEUTICALS

128. RATE INCREASE

129. WHERE ARE WE GOING?

130. The Upward Trends

131. Highlights of the 2010 Drug Abuse Warning Network (DAWN)
Findings on Drug-Related Emergency Department Visits

132. DAWN
Drug Abuse Warning Network
• identified an 89% increase in ED visits associated with
benzodiazepines between 2004 and 2008.
• The estimated number of visits for alprazolam in 2008
(104,800) was more than twice the number for the next
most common benzodiazepine, clonazepam (48,400).
• The relative magnitudes of the rates shown generally
reflect prescription volumes.
• 44 million alprazolam prescriptions in 2008.
• New York City Department of Health also showed
benzodiazepines were tied to more than 30 percent of all
the city's overdose deaths in 2009.

133. MAINE

134. MAINE

135. OREGON

136. OREGON

137. OREGON

138. CALIFORNIA

139. CALIFORNIA

140. MARYLAND

141. MARYLAND

142. MASSACHEUSETTES

143. MASSACHEUSETTES

144. Oklahoma

145. Oklahoma

146. NEW MEXICO

147. NEW MEXICO

148. In Summary
• In certain anxiety states, alcohol withdrawal, panic
disorder, sleep, the agitated schizophrenic
antipsychotic-induced acute akathisia, BZDs have short
term benefit
• Poor evidence of efficacy in the long-term
• No evidence of relapse prevention
• Well established cognitive side effects
• Addictive Potential
• Significant Withdrawal even with therapeutic dosing
• BZDs can be lethal when combined with alcohol,
opiates, or other sedative/hypnotics.