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. treatment of alcoholism No history of depression or 3 years ago. mental illness. Has been treated for depression No family history of and insomnia for past 20 years. substance abuse. PMP shows 8 benzo rx in past 4 Took clonazepam months from 3 clinics. (Klonopin©) for about a She says “I know Xanax month after the death of her (alprazolam) will help. I mother 12 years ago, it helped sometimes buy a few from my and she discontinued it on neighbor and they help me her own. 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 =
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
17% Lifetime Prevalence of Anxiety Disorders: 28.8% 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) 12.5-25 50-200 Citalopram(Celexa) 10 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 0.5-2TID 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 (Sadock et al., 2009) Propranolol(Atenolol) 10-20 TID 10-40 TID SSRIs: Start low, go slow and aim high! 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) Accidents, falls (hip fractures etc.) 2) Motor vehicle accidents 3) General decline in functional status 4) Cognitive decline/memory impairment 5) Self poisoning 6) Withdrawal 7) 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: 1) 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) 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( 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 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.