SEDATIVE HYPNOTICS

Paula J. Colescott MD

Board in Addiction Medicine

Board in Internal Medicine

OUTLINE

• Terminology

• Pharmacology

• Historical Perspectives

• Intoxication / Withdrawal Syndrome

• Efficacy / Adverse Effects

• Epidemiology

• Case Study

• Withdrawing Benzodiazepines

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

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 )

OPIUM Morphine

Quick Management of aggressive patients

Sedation of melancholic/delusional

In 1800—Most widely used sedative in asylums

1898

1804

1832

Massachusetts Asylum

MORPHINE

Opioids relieve emotional painand this is one of the behavioral mechanisms implicated in the

addiction cycle (Khantzian, 1985, 1990, 1997)

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 theepileptic patients’ sexuality”.

Sedative History

• 1870’s—Potassium Bromide

– Anticonvulsant--

– Widely used as sedative—Typical dose: a “few grams/day” certain hospitals used tons/yr.

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.

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

Dr. Miles’ NervineA Calmative1890-1960

Nervous ailments: nervous exhaustion, sleeplessness, hysteria, headache, neuralgia, backache, pain ,epilepsy, spasms, fits, and St.

Vitus’ dance

BROMISM

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

BARBITAL (VERONAL) BAYER PHARMA 1903

BARBITAL : hypnotic, sedative, anticonvulsant

Emil Fischer and Joseph von Mering

The Barbiturates

• Anticonvulsants

• Anxiolytics

• Soporifics

• Anesthetics

Alcohol Withdrawal

Benzodiazepine Taper

Anesthesia Induction

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

US production of barbiturates in Pounds (x1000)

Street Names

barbs,

bluebirds

Dolls

downers

goofballs

sleepers

'reds & blues

tooties

BARBITURATE SUICIDE/OVERDOSE

Barbiturate Overdoses

1954

Current uses of

Barbiturates

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

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.

New England Journal Of Medicine1954

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

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)..

Methaqualone– MANDRAXWhite Pipe

• 60% OF ALL DRUGS SEIZED ON THE STREET

• MIXED IN A PIPE WITH CANNABIS, BENADRYL, OR VALIUM.

• NOTABLE QUANTITIES OF TOLUIDINE---CARCINOGENIC.

MILTOWNThe Answer for the Syndrome of the

60’s

THE BATTERED PARENT

“Innocuous Panacea”

• 1958

BENZODIAZEPINE

Heterocyclic ringa fusion of the benzene and

diazepine ring systems.

1956

Dr. Leo Sternbach

LIBRIUMVALIUM

FLURAZEPAMCLONAZEPAM

Between 1969-1982 Valium was the most prescribed drug in America with over 2.3 billion

doses sold in 1978!

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,"

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

PHARMACOKINETICS

SEDATIVE HYPNOTICS

Mechanism of Action

GABA IS THE INHIBITORY NEUROTRANSMITTER

DOWN REGULATES BRAIN ACTIVITY

DEPRESSING CENTRAL NERVOUS SYSTEM FUNCTION

NERVE ACTION POTENTIALON YOUTUBE

• http://www.youtube.com/watch?v=oRYpt8_OJms&list=WLN3hoGZnOTd-h5WA

• http://www.youtube.com/watch?v=VQG90FxASWQ&list=WLN3hoGZnOTd-h5WAiVVCks03NdbEmKGCc

• http://www.youtube.com/watch?v=-6t_n6kTj1A

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

PHARMACOKINETICSBENZODIAZEPINES

• 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

LIPOPHILIC = LIPID LOVINGability 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

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

METABOLIC PATHWAY

POTENCY

TEMAZEPAMGEL CAPS

Temazepam, flunitrazepam and

diazepam are preferred BZDs in those using amphetamine and

heroin

Removed from the Market

TEMAZEPAM PROFILE

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

EMERGENCY ROOM VISITUnrecognized 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 zolpidemtablets 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.

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

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

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

Urine Toxicology • Immunoassay

• Detects (BZDs) metabolized to

desmethyldiazepamor 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

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

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

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.

“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.

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.

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.

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

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.

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.

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

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

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.

BZDs & SLEEPInt 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.

SLEEPING IN THE NURSING HOMESleep 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

FOR SLEEP

Findings do not support long-term

effectiveness of BZDs

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.

XANAX NOT ALCOHOL

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.

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

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.

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!

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, Polydrugusers, <18 yrs, >65, learning disabilities

“PROPOFOL apowerful 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

• 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.

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

AMERICAN CONTROLLED SUBSTANCE ACT 1970

Schedule IIa 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

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

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

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

DSM 5Sedative/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.

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)

• 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.

• 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

WHY

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

Physical Dependenceon 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

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

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)

OPIATE/BZD WITHDRAWALDrug 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.

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

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

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

NURSES IN PRIMARY CAREoverseeing 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

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

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

TOXICOLOGYtherapeutic levels of citalopram and phenytoin.

Zolpidem was not present.

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

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

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

BZD withdrawal and SleepEur 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).

EPIDEMIOLOGY

2012

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

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

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

ER VISITS FOR MISUSE/ABUSE OF PHARMACEUTICALS

RATE INCREASE

WHERE ARE WE GOING?

The Upward Trends

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

DAWNDrug Abuse Warning Network

• identified an 89% increase in ED visits associated withbenzodiazepines between 2004 and 2008.

• The estimated number of visits for alprazolam in 2008(104,800) was more than twice the number for the nextmost common benzodiazepine, clonazepam (48,400).

• The relative magnitudes of the rates shown generallyreflect 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 allthe city's overdose deaths in 2009.

MAINE

MAINE

OREGON

OREGON

OREGON

CALIFORNIA

CALIFORNIA

MARYLAND

MARYLAND

MASSACHEUSETTES

MASSACHEUSETTES

Oklahoma

Oklahoma

NEW MEXICO

NEW MEXICO

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.