Transcript Sedative Hypnotics: Avoiding Prescribing Pitfalls

Tom Fowlkes, MD
Director of Professional & Medical Relations
American Addiction Centers
Oxford Treatment Center
More Accurately We Will Talk About:
Non-alcohol Sedative Hypnotics
Objectives
 To review the history & pharmacology of
benzodiazepines and other sedative-hypnotics
 To educate prescribers about the indications for the
proper use of benzodiazepines
 To educate prescribers about the indications for
discontinuation of therapy and tapering strategies
 To review recent information about benzodiazepine
use and abuse
Disclosures
 I have nothing to disclose.
 Except perhaps that I make my living treating people
with substance abuse disorders and as a result I have
not become the biggest advocate for widespread
benzodiazepine use.
 Most of the information in this talk is taken from the
medical literature. Some of the information is my own
medical opinion. I have tried to point out when
information is my opinion.
What we are going to cover
 2 Case studies
 What are Sedative Hypnotics/How they work
 History – Older Sedative-Hypnotics>BZ>Newer Drugs
 Pharmacology
 Differences in benzodiazepines (=benzo’s, = BZ)
 Clinical Use
 Safe Prescribing
 Abuse & Dependence
Sedative-Hypnotics
 Suppress CNS activity
 Pharmacologically diverse
 Cause effects along a continuum of:
calming> sleep >unconsciousness > coma > death
 Uses:
 Anxiolytics
 Hypnotics
 Anti-convulsants
 Muscle relaxants
 Anesthesia induction
(Olkkola, 2008)
GABA System
 Most all of these sedative hypnotics act on this GABA
system.
 Gamma-aminobutyric acid is the primary inhibitory
neurotransmitter system in the CNS.
 There are GABA receptors with multiple sub-types in
different regions, etc.
 GABA binds to these receptor sites causing a chloride
ion channel to open and then all of these inhibitory
things take place.
(Roth et al., 2003)
Ƴ- aminobutyric acid = GABA
 GABA is the major inhibitory neurotransmitter system
in the CNS.
 Stimulation of the GABA receptors lead to all the
effects we are talking about: sedative, anti-convulsant,
hypnotic, amnestic
 Benzodiazepines bind at the alpha sub-unit to cause
positive modulation of the GABA receptors - meaning
that they augment the effect of GABA at the receptor.
(Roth et al., 2003)
Benzos vs. Barbiturates:
GABA A Receptor
(http://www.neurocypres.eu/science)
Case #1 to think about
56 yo female, new patient tells
you: “Can you please just give me
something for my nerves? My
husband has been diagnosed
with cancer. I just can’t sleep and
I feel so anxious inside. I just
need something to help me
through this.” (Case study)
Would it make a difference if you also knew?
 That she has no history of
 That she had in-patient
substance abuse.
 No history of depression or
mental illness.
 No family history of
substance abuse.
 Took clonazepam
(Klonopin©) for about a
month after the death of her
mother 12 years ago, it helped
and she discontinued it on
her own.
treatment of alcoholism
3 years ago.
 Has been treated for depression
and insomnia for past 20 years.
 PMP shows 8 benzo rx in past 4
months from 3 clinics.
 She says “I know Xanax
(alprazolam) will help. I
sometimes buy a few from my
neighbor and they help me
sleep.”
(Case study)
Case #2 to think about
My 91 y.o. aunt is almost deaf, has
lived alone since being widowed
in her 50’s, no h/o substance
abuse or mental health diagnosis
except insomnia. For the last 10
years (ever since she retired) she
has c/o insomnia to every doctor
she has seen. (Case study)
Case #2 – My Aunt
 Ambien
 Remeron
 Restoril
 Gabapentin
 Melatonin
 Flexeril
 Advil PM
History of Sedative-Hypnotics
 Alcohol is the oldest
 Very similar chemically
to what we are talking
about today
 There could be a whole
lecture devoted to
alcohol use, dependence
and withdrawal.
 We are not talking about
that further today.
(Miller, 2002)
History – Late 1800’s
 Chloral hydrate©
 ‘Mickey Finn’
 Paraldehyde
 Bromides
(Miller, 2002)
History- Early 1900’s-Barbiturates
 First prepared in 1864. Clinically
introduced in the early 1900’s for use
as sedative-hypnotics.
 Problems with safety: Dependence
and Overdose (death)
 Replaced in popularity in the 1950’s
and 1960’s by the benzodiazepines
because of safety concerns
(Miller, 2002)
Barbiturates
 Are actual agonists at the GABA
receptor (not just modulators).
 Causes prolonged opening of
the chloride ion channel of the
GABA receptor
 Paralysis of neurons
responsible for respiratory
drive
 Fatal overdose
(Page et al., 2002)
Barbiturates Today
 Phenobarbital Still in use as an anti-convulsant
 Relatively low abuse potential
 Dysphoria or at least not much euphoria
 Stopping suddenly can lead to withdrawal seizures
 Needs to be tapered
 Some ultra-short acting barbiturates used for
anesthesia induction
(Page et al., 2002)
Barbiturates Today
 Butalbital in Fiorinal©, Fioricet© & Esgic©
 Indication for tension headache
 Combined with aspirin or acetaminophen plus
caffeine
 Fioricet #3© adds codeine
 Occasionally we see a patient whose
primary drug of choice is butalbital
 Needs detox
 Can either taper or use a benzo
(Ries, 2009)
History- 1950’s- Minor Tranquilizers
 1955- Meprobamate
(Miltown©/Equanil©)
 Others: Methaqualone (Quaalude©)
 A pro-drug of meprobamate is still
available as: Carisprodol (Soma©)
 Marketed as a muscle relaxant.
 Different than other skeletal muscle
relaxants.
(Page et al., 2002)
History- 1960’s- Benzodiazepines
 1957: chlordiazepoxide
(Librium©) found to have
hypnotic, sedative, and muscle
relaxant effects
 Less toxic in overdose and
fewer drug interactions than
barbiturates
 Superior efficacy and safety
compared to meprobamate
 In the 1960’s & 1970’s
benzodiazepines became the
sedative-hypnotics of choice
(Miller, 2002)
History- 1970’s- Valium©
 1963- Valium©
(Diazepam)released.
 Became the most prescribed
benzodiazepine by 1973
(Miller, 2002)
Benzodiazepines- ‘The Pams’
 Many hundreds have been produced
 The differences are primarily in onset of action,
potency, efficacy and length of action (half-life).
 14 are on the market in the U.S.
(Olkkola, 2008)
Benzodiazepine in U.S.- 2016
 alprazolam = Xanax ®, Xanax XR, Niravam ®
 chlordiazepoxide = <Librium® >
 clobazam = Onfi®
 clonazepam = Klonopin ®
 clorazepate = Tranxene T-tab ®
 diazepam = Valium ®, Diastat®
 estazolam = Prosom
 flurazepam = <Dalmane®>
 lorazepam = Ativan®
 midazolam = <Versed® >
 oxazepam = Serax ®
 quazepam = Doral ®
 temazepam = Restoril ®
 triazolam = Halcion ®
< > = no longer sold as branded
(drugs.com 2016)
History- More Recent (1990’s)
Non-benzodiazepine Hypnotics – “The Z Drugs”
 Zolpidem = Ambien©
 Zaleplon = Sonata©
 Zopiclone –sold in U.S. only as the S-isomer –eszopiclone




= Lunesta©
Pharmacologically diverse but are not BZ
Very similar effects and mechanism of action to BZ (at the
GABA –α site)
Brought to market as potentially safer and less addiction
liability than BZ
Will talk more about later
(Huedo-Medina et al., 2012)
Suvorexant =
 Approved FDA August 2014
 First in kind mechanism of action
 Does not work via GABA, histamine or melatonin
 Is a DORA- dual orexin receptor antagonist
 DEA Response to comment opposing Schedule IV: The DEA does not agree. Suvorexant is
a novel, first in class, new chemical substance and information on actual abuse data is
not currently available. The legislative history of the CSA addresses the assessment of a
new drug's potential for abuse,\2\ and data from clinical studies investigating the abuse
potential for suvorexant suggests that its effect is similar to zolpidem (schedule IV).
Similarly, while the mechanism of action for suvorexant is distinct from any currently
marketed drug for insomnia, human abuse potential studies demonstrated that
suvorexant produced effects that were indistinguishable from zolpidem (schedule IV).
http://www.deadiversion.usdoj.gov/fed_regs/rules/2014/fr0828.htm
Benzodiazepine Pharmacology
 1, 4 benzodiazepine ring structure
 All have similar activity as modulators at
the GABA receptor.
 Differences are the additions at sites
around the ring
 The variations are in potency, efficacy and
onset of action.
 Has to do with lipophilicity, whether
metabolized to an active metabolite or
not, half-life
(Page et al., 2002)
(Ries, 2009)
Benzodiazepines- Potency
(Adapted from Ries, 2009)
Benzodiazepine Metabolism
 Hepatic metabolism involving oxidation by the




cytochrome P-450 system
Some are converted to an active metabolite which is
then slowly cleared.
Final phase involves conjugation with a glucuronide.
Safest for use with impaired hepatic function, or liver
failure: Lorazepam (Ativan©), oxazepam (Serax©), and
temazepam (Restoril©).
Do not require hepatic oxidation, but only hepatic
glucuronide conjugation, with rapid excretion.
(Page et al., 2002)
Special Note- Non-U.S. Benzo
 Flunitrazepam = Rohypnol©
 Not sold in U.S.
 Sold in Mexico and Central
America as an hypnotic
 Prominent antero-grade
amnesia
 Known as “Roofies” or the
“Date Rape Drug”
(Miller, 2002)
Short term indications: < 6-8 weeks
 Initial management of panic, GAD, severe anxiety
associated with depression while waiting on full effect
of the first line meds
 Insomnia -1-2 weeks
 Alcohol and other drug withdrawal
 Muscle relaxation/spasm
 Seizure prophylaxis
 Single use for phobias (e.g. flying)
(Ries, 2009)
Anxiety Disorders: Prevalence
Lifetime Prevalence of
Anxiety Disorders: 28.8%
17%
10%
(Kessler et al., 2005)
8%
5%
3.5%
2.5%
(Sadock,BJ, et al., 2009)
Anxiety disorders: Treatment
Pharmacologic:
1) Selective serotonin reuptake inhibitors (SSRIs)
2) Tricyclic antidepressants(TCAs)
3) Benzodiazepines
4) Monoamine oxidase inhibitors (MAOIs)
5) Other drugs- beta blockers, buspirone (buspar©)
Psychological:
1) Supportive and insight-oriented psychotherapy
2) Cognitive behavior therapy
3) Group therapy
(Ries, 2009)
Antianxiety Drug
Starting dosage (mg per day)*
Usual dosage (mg per day)
Selective serotonin reuptake inhibitors(SSRIs)
Paroxetine(Paxil)
5-1o
20-60
Fluoxetine(Prozac)
5-10
20-60
Sertraline(Zoloft)
Citalopram(Celexa)
12.5-25
10
50-200
20-40
Escitalopram(Lexapro)
5
10-30
Triclylic antidepressants(TCAs)
Clomipramine(Anafranil)
5-12.5
50-125
Imipramine(Tofranil)
10-25
150-500
Desipramine(Norpramin)
10-25
150-200
Benzodiazepines
Alprazolam(Xanax)
0.25-0.5 TID
0.5-2 TID
Clonazepam(Klonopin)
0.25-0.5 BID
0.5-2 BID
Diazepam(Valium)
2-5 BID
5-30 BID
Lorazepam(Ativan)
0.25-0.5 BID
0.5-2mg BID
Chlordiazepoxide(Librium)
5-10 BID
25-50 BID
Monoamine Oxidase Inhibitors(MAOIs)
Phenelzine(Nardil)
15 BID
15-45 BID
Tranylcypromine(Parnate)
10 BID
10-30 BID
Serotonin-norepinephrine reuptake inhibitors(SNRIs)
Venlafaxine(Effexor)
6.25-25
50-150
Other drugs
Valproic Acid(Depakote)
125 BID
500-750 BID
Gabapentin(Neurontin)
100-200
600-3400
Buspirone(Buspar)
5-15 BID or TID
15-30 BID
Hydroxyzine(Vistaril, Atarax)
12.5-50 BID
50-100 QD
Propranolol(Atenolol)
10-20 TID
10-40 TID
SSRIs: Start low, go slow and aim high!
(Sadock et al., 2009)
Anxiety and CBT
 The majority of anxiety disorders are optimally
treated with cognitive behavioral therapies (CBT)
 CBT and other psychological therapies are evidence
based, effective interventions with a sustained
impact on anxiety disorders.
 There is a considerable overlap in the symptoms of
the major anxiety disorders
 Effective treatments for one often address the other
 Developing simple referral pathways with
psychologists, primary care providers can begin to
offer alternatives to benzodiazepines.
(Ries, 2009)
Adverse Effects: Acute
 Excessive sedation, fatigue/ psychomotor impairment
 Memory and other cognitive impairment
 Altered sleep physiology
 Ataxia with falls, especially in elderly
 Dysarthria
 Hypotonia
 Confusion
 Paradoxical excitement/ release of anxiety/ hostility
(Ries, 2009)
Long term use of Benzodiazepines
 Long term use is ≥ 8-12 months
 90% experience withdrawal symptoms, whether
withdrawn slowly or rapidly
 Gradual taper off alprazolam after long-term
treatment of panic disorder results in rebound panic
and anxiety, exceeding pretreatment levels in 50-90%
of patients.
(Saddock et al., 2009)
Adverse Effects: Chronic
Increased rates of:
1)
2)
3)
4)
5)
6)
7)
Accidents, falls (hip fractures etc.)
Motor vehicle accidents
General decline in functional status
Cognitive decline/memory impairment
Self poisoning
Withdrawal
Dependence
(Saddock et al., 2009)
Benzodiazepine Use & Risk of Alzheimer’s Disease
 Case control study in Quebec published in the British
Medical Journal
 1796 people who were diagnosed with Alzheimer’s and
were followed for at least 6 years prior matched with
7184 controls
 Benzodiazepine use associated with increased risk of
Alzheimer’s
 The strength of the association increased with long
term exposures
(Billioti de Gage et al., 2014)
Relative Contraindications
 Age/Elderly- increased risk of falls/fractures
 History of Substance Abuse
 Presently abusing alcohol or other substances
 On chronic opiates
 Pregnancy – Class D (??cleft lip)- used in detox
(Ries, 2009)
Benzo use and APA Guidelines
 “Benzodiazepines and other sedative-hypnotics carry
the potential for abuse or dependence and should
rarely be prescribed to patients with co-occurring
substance use disorders, except as part of a brief
detoxification regimen.”
(APA Practice Guidelines, October 2010)
Benzodiazepines:
Two Patterns of Abuse
 Two patterns of abuse:
Recreational abuse: nonmedical use for purpose of getting
high
a.
Intermittent pattern of high doses
b.
Polysubstance users
c.
Often illicitly obtained
d.
Similar to rates of abuse of other illicit substances
2) Chronic quasi-therapeutic use: long term use for a duration
inconsistent with accepted medical practice
a.
Older
b.
May or may not have history of alcohol or substance abuse
c.
Chronic pain problems
(Ries, 2009)
1)
Recreational Abusers
 Usually in conjunction with abuse of other
substances
 To either augment the effects of or ameliorate the
side effects of or withdrawal from
 Alcohol
 Opiates- ‘boost’ the opiate
 Cocaine/amphetamines- to counter the
stimulant/help sleep or ‘come down’
(Ries, 2009)
Benzo Addiction
 Primary/Sole BZ addiction is relatively uncommon





(Ries, 2009)
These are the patients who look ‘stoned’ –ataxia, slurred
speech, falling asleep. (Different than opiate addicts)
Often involved in MVA/DUI
The most difficult patients I have in treatment.
Anxiety, insomnia, walk around in a fog, seizures
30 day treatment is not enough. They are just then starting
to clear mentally.
(My opinion)
Bachhuber, 2016
Benzodiazepine use: Mississippi
Data from 2015 MS PMP-Most Prescribed Drugs







#1=Hydrocodone – 1.9 million rx’s = 116 million pills
#2=Alprazolam(Xanax) – 580,000 rx’s = 34 million pills
#3=Tramadol
#4=Oxycodone
#5= Amphetamine
#6= Zolpidem (Ambien)- 444,000 rx’s = 14 million pills
#7 = Clonazepam (Klonopin)- 363,000 rx’s = 20 million pills
MS population 2015: approx. 3.0 million
% of Population in the U.S. With
Any Benzodiazepine Use in 2008 By Age & Sex
(Olfson, 2015)
(Olfson, 2015)
Recent Trends-Positive
 Decrease in chronic opiate prescribing
 Recognition of the dangers of combining opiates and
benzos
 Decrease in Soma use (& less “Holy Trinity” combo)
 Don’t see a huge illicit supply- unlike opiates and
amphetamines
 Realization that chronic opiate use and chronic benzo
use just don’t work well to treat the conditions for
which they are being used
 Lack of big pharma influence
(My Opinion)
Recent Trends-Negative
 Continuing escalation of #’s of prescriptions
 Continuing increase in overdose deaths
 Increasing use among the elderly
 Patients more likely now to have illicit source of
opiates. More potent heroin & more difficult to know
they are on it.
(My Opinion)
Ways I Could Impact My Practice
 Follow a clinical practice guideline:
JPS Health Network, Prescribing & Tapering
Benzodiazepines, E-Resource, October 2014
https://www.jpshealthnet.org/sites/default/files/prescri
bing_and_tapering_benzodiapines.pdf
Clinical Practice Guideline
 Inquire about substance abuse history and do not
prescribe benzos to those patients, even short term
 Don’t automatically continue hospital/ER
prescriptions
 When starting benzo, make clear that it will be for
short term (maximum 4-8 weeks for anxiety, 10-14 days
for insomnia) and stick to that
(JPS Health, 2014)
Clinical Practice Guideline
(JPS Health, 2014)
Clinical Practice Guideline
(JPS Health, 2014)
That only leaves you with:
Patients on long-term benzo that
you already have or inherit
 Develop a plan to get as many off chronic
benzodiazepines as you or able or at least examine
each patient’s situation to reduce the quantity, etc.
(JPS Health, 2014)
(Bostwick, 2012)
Non-Benzodiazepine Hypnotics
 Zolpidem(Ambien©), Zaleplon(Sonata©),





Eszopiclone(Lunesta©)- The Z-drugs
Rapid onset(<one hour)
Short half-lives
Decrease sleep latency(time to onset of sleep)
Little effect on other sleep stages(unlike benzos)
Benzodiazepine effects on sleep: Prolong stage 1 and 2;
shorten stages 3 and 4(deep sleep); Shorten duration of
REM sleep
(Huedo-Medina et al., 2012; Ries, 2009)
Zolpidem
©
(Ambien )
 Zolpidem is the second most commonly prescribed
hypnotic in the USA(alprazolam is number 1);
approved by FDA in 1999.
 Limit use to ≤7 days, to avoid rebound insomnia
 Zolpidem can produce dependence and withdrawal
delirium
 Do not use in patients with history of addiction
(Miller, 2002; Ries, 2009)
Zolpidem
©
(Ambien )
 Clearly is abused and can become dependent on it.
 Can cause amnesia and ‘complex sleep behaviors’.
 Very similar to benzodiazepines and we see very similar
addiction syndrome/treat similarly. (Olkkola, 2008)
Zolpidem
©
(Ambien )
Other Treatments for Insomnia
 Treat Underlying Conditions
 Anxiety/Depression
 Obstructive Sleep Apnea
 GERD
 CHF/COPD
 Sleep Hygiene
 Meds
 Mirtazapine(Remeron©)
 Trazodone
 TCAs: Amitriptyline (Elavil©)
 Hydroxyzine(Vistaril©/diphenyhydramine(Benadryl©)
 Melatonin
 Ramelteon (Rozerem©)
(Ries, 2009)
References
 American Psychiatric Association. (2000). Diagnostic and




statistical manual of mental disorders (4th ed., text rev.).
Washington, DC: Author.
American Psychiatric Association. (2013). Diagnostic and
statistical manual of mental disorders (5th ed.). Washington, DC:
Author.
Huedo-Medina, TB; Kirsch, I; Middlemass, J, et al. (2012).
Effectiveness of non-benzodiazepine hypnotics in treatment of
adult insomnia: meta-analysis of data submitted to the Food and
Drug Administration. BMJ (Clinical research ed.) 345: e8343.
Kemp, A et al.(2013) Prescription Drug Abuse. J MSMA
2013,54(5):139.
Kessler RC, Berglund P, Demler O, et al. Lifetime Prevalence and
Age-of-Onset Distributions of DSM-IV Disorders in the National
Comorbidity Survey. Arch Gen Psychiatry. 2005;62(6):593-602.
References
 Miller RL (2002). Drugs of abuse: a reference guide to their history

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


and use. Westport, Conn.: Greenwood Press. p. 168.
Page C, Michael C, Sutter M, Walker M, Hoffman BB (2002).
Integrated Pharmacology (2nd ed.). Philadelphia: Mosby/Elsevier
Science.
Olkkola KT, Ahonen J (2008). Handb Exp Pharmacol. Handbook of
Experimental Pharmacology 182 (182): 335–60.
Ries, RK. (2009) Principles of Addiction Medicine (5th ed.). Chevy
Chase, MD: American Society of Addiction Medicine.
Roth RJ, Cooper JR, Bloom FE (2003). The Biochemical basis of
neuropharmacology. Oxford [Oxfordshire]: Oxford University
Press. p. 106.
Sadock,BJ, et al.(2009) Kaplan & Sadock’s comprehensive textbook
of psychiatry. (9th ed.) Philadelphia: Wolters Kluwer
Health/Lippincott Williams & Wilkins.
References
 Billioti de Gage, S et al. Benzodiazepine use and risk of
Alzheimer’s disease: case-control study. BMJ. 2014;349:g5205
 Bachhuber, M et al. (2016) Increasing Benzodiazepine
Prescriptions & Overdose Mortality in the United States,
1996-2013. Am Journal of Public Health. 2016; 106(4):686-688
 Olfson, M et al. (2015) Benzodiazepine Use in the United
States. JAMA Psychiatry. 2015; 72(2):136-142
 Bostwick JR, Casher MI, Yasugi S. Benzodiazepines: a
versatile clinical tool. Current Psychiatry 2012;11(4):55-64.