Prescribing and Tapering Benzodiazepines

Introduction

• The use of benzodiazepines has grown over time and evidence has shown that long term use of these drugs has very little benefit with many risks involved.

• Many providers are receiving new patients on benzodiazepines and are uncomfortable with managing their treatment regimen

• This is an evidence based guideline for the use of benzodiazepines and related drugs in clinical office practice.

• A multidisciplinary work group was formed to develop this guideline for use

3

Rule #1

• Assess the symptoms

• Diagnosis Criteria

• SSRIs are first line in depression

• Adequate dosage• At least 6-8 weeks

• Don’t fire your antidepressant or first line agent too soon.

What Are the Symptoms of an Anxiety Disorder?

Feelings of panic, fear, and uneasinessProblems sleepingCold or sweaty hands and/or feetShortness of breathHeart palpitationsAn inability to be still and calmDry mouthNumbness or tingling in the hands or feetNauseaMuscle tensionDizziness

Medical causes

AnemiaInfectionHeart diseaseDiabetesThyroid problems, such as hypothyroidism or hyperthyroidismAsthmaDrug abuse or withdrawalIrritable bowel syndromeRare tumors that produce certain "fight-or-flight" hormonesPremenstrual syndrome

Medical causes

Breathing, difficulty Aortic Insufficiency Asthma Bronchitis Cardiac Arrhythmia Collagen Disease Emphysema Guillain-Barre Syndrome Hemothorax Left Ventricular Failure Lupus Mitral Stenosis Myasthenia Gravis Ovarian Cancer Pericardial Effusion Pleural Effusion Pneumoconiosis Pneumothorax Pulmonary Edema Chest Pain Angina Pectoris Coronary Artery Disease Heart attack Lupus Concentration, lack of Alzheimer's Disease Attention Deficit/Hyperactivity Disorder (ADHD) Brain Cancer Chronic Fatigue Syndrome Depression Insomnia Post Traumatic Stress Disorder Premenstrual Syndrome Dizziness Benign Positional Vertigo Cerebral Embolism Cerebral Hemorrhage Cerebral Thrombosis Dental Problems Ear Infections Fibromyalgia Food Allergy Food Poisoning Head Injury Heat Exhaustion Hypertension Insect Bites and Stings Labyrinthitis Meniere's Disease Menopause Miscarriage Motion Sickness Myocardial Infarction Nystagmus Postural Orthostatic Hypotension Stroke Temporomandibular Joint Dysfunction Transient Ischemic Attacks Dyspnea (Breathing discomfort or breathlessness) Anemia Asthma Bronchitis Chronic Obstructive Pulmonary Disease Collagen disease Colorectal Cancer Congestive Heart Failure Edema Emphysema Endocarditis Food Allergy HIV and AIDS Hyperkalemia Hypoxia Insect Bites and Stings Laryngitis Leukemia Lupus Myocardial Infarction Ovarian Cancer Pericarditis Pharyngitis Pulmonary Edema Pulmonary Fibrosis Pulmonary Hypertension Thyroiditis Fatigue Allergic Rhinitis Anemia Atherosclerosis Bone Cancer Bronchitis Chronic Fatigue Syndrome Cirrhosis Colorectal Cancer Congestive Heart Failure Crohn's Disease Cystic Fibrosis Depression Diabetes Mellitus Endocarditis Erythema Fibromyalgia Heat Exhaustion Hepatitis, Viral Herpes Zoster and Varicella Viruses Hyperkalemia Hypoglycemia Influenza Insomnia Intestinal Parasites Leukemia Lupus Lyme Disease Lymphoma Mononucleosis Motion Sickness Multiple Sclerosis Myeloproliferative Disorders Osteomyelitis Ovarian Cancer Pericarditis Premenstrual Syndrome Pulmonary Hypertension Radiation Damage Rheumatoid Arthritis Sarcoidosis Sleep Apnea Systemic Lupus Erythematosus Tension Headache Tuberculosis Heart symptoms Anemia arrhythmia Coronary artery disease Heart Attack Hyperthyroidism Infections Pericarditis Post-myocardial infarction Irritability Common Cold Depression Diabetes Mellitus Herpes Simplex Virus Hypoglycemia Hypothermia Insomnia Meningitis Menopause Migraine Headache Osteomyelitis Post Sleep Apnea Traumatic Stress Disorder Premenstrual Syndrome Seizure Disorders Tension Headache Food Allergy Sleep disorders Alcoholism Alzheimer's Disease Amyloidosis Chronic Fatigue Syndrome Depression Fibromyalgia Hyperthyroidism Menopause Premenstrual Syndrome Sleep Apnea Sweating Anaphylaxis Asthma Heat Exhaustion Hyperthyroidism Hypoglycemia Lung Cancer Motion Sickness Pancreatitis Radiation Damage Seizure Disorders Syncope Thyroiditis

GABAA Structure

4 or more subunits (alpha, beta, gamma, and delta) multiple subtypes of each subunit5 subunits come together to form the receptor complex

• approximately 100 variants of GABAA receptor possible• several exist in the mammalian CNS4 transmembrane

regions• both C and N terminus is extracellular• gamma unit must be present for BZDs to modulate

GABA

How do benzodiazepines work?

• GABA Receptor• CNS Depressant• Hypnotic/ Sedative• Most are fast acting and develop tolerance

and dependency quickly, thus requiring more to get the same effect.

• Works on the pleasure center of the brain• Just like alcohol to the brain!!!

Benzodiazepines (BZDs)

HypnoticAmnestic

Produce confusion

Short Term Use

• Short Term Use Definition: 2-6 weeks maximum• Benzodiazepines are not first line therapy agents• Benzodiazepine use beyond 4 to 6 weeks will result in:

• loss of effectiveness• the development of tolerance• dependence and potential for withdrawal syndromes• persistent adverse side effects• interference with the effectiveness of definitive medication and

counseling.

11

Indications for Short Term Use

• GAD• Phobias• PTSD• Panic Disorders• Severe anxiety associated with depression,

while waiting for the full effect of the antidepressant.

Indications for Short Term Use Continues

13

InsomniaThere is evidence for the effectiveness of benzodiazepines and other hypnotics in the relief of short-term (1 to 2 weeks), but not long-term insomnia.  Muscle relaxantBenzodiazepines are indicated for the short-term relief (1 to 2 weeks) of muscular discomfort associated with acute injuries or flare-ups of chronic musculoskeletal pain. Benzodiazepines may be combined with analgesics and nondrug therapies but not with other sedatives, hypnotics, or other muscle relaxants.  Other Indications:• Urgent treatment of acute psychosis with agitation• As part of a protocol for treating alcohol withdrawal• Seizures and a limited number of other neurological disorders• Sedation for office procedures

Indications for Long Term Use

Benzodiazepines may be used for longer than 6 weeks in the:• terminally ill• severely handicapped patient• certain neurological disorders• restless leg syndrome• no evidence to support long term use for a

mental health disorder

Contraindications to Benzodiazepine Use:

• Pregnancy and the patient at risk for pregnancy. Benzodiazepines are category D. If a hypnotic is necessary, Zolpidem (Ambien), which is category B, is preferred. Patients who conceive while on benzodiazepines should be tapered off completely or to the lowest possible dose.

• Active substance abuse, including alcohol.• Medical and mental health problems that may be aggravated

by benzodiazepines.• Fibromyalgia, chronic fatigue syndrome, other somatization

disorders, • depression (except for short-term use to treat associated anxiety),• bipolar disorder (except for urgent sedation in acute mania),• ADHD, kleptomania, and other impulse control disorders.)

Contraindications to Benzodiazepines Continued

• Benzodiazepines may worsen hypoxia and hypoventilation in asthma, sleep apnea, COPD, CHF, and other cardiopulmonary disorders.

• Patients being treated with opioids for chronic pain or replacement therapy for narcotic addiction.

• Grief reactions. Benzodiazepines are often used for short term treatment of insomnia in acute grief but should otherwise be avoided in treating grief reactions, as they may suppress and prolong the grieving process.

• PTSD – longer term use of these agents compromise the needed exposure and cognitive processing of the trauma which is known to result in symptom amelioration.

There is no evidence supporting the long-term use of benzodiazepines for any mental health indication

Do not prescribe - No Effectiveness:

Clinical trials have shown no effectiveness with the use of benzodiazepines in the following conditions:• Tinnitus• Chronic tension headache• Essential Tremor• Meniere’s• Post-traumatic stress disorder (Provided a “D” rating as being

of “No Benefit/Harm ” classification by the VA/DOD official PTSD CPG)

• Concussion• Evidence of substance abuse

Dose Equivalency

Approximate Equivalent Oral

Doses, mgTime to Peak Level,

hours Half-life, hoursAlprazolam (Xanax) 0.5 1-2 12Chlordiazepoxide (Librium) 25 1-4 100Clonazepam (Klonopin) 0.25 1-4 34Diazepam (Valium) 5 1-2 100Lorazepam (Ativan) 1 1-4 15Oxazepam (Serax) 15 1-4 8Temazepam (Restoril) 10 2-3 11Triazolam (Halcion) 0.25 1-2 2

New Prescriptions

• Only use for the short-term treatment of severe anxiety or insomnia

• anxiety maximum of 4-8 weeks• insomnia maximum of 10 nights• Duration should be as short as possible. The risk of

dependence increases with dose and duration.• Urine Drug Screen should be completed prior to prescribing

controlled substances• History and ROI for previous provider if needed• Alternatives have been tried or are combination

New Prescriptions

• Provide information on behavioral strategies for anxiety reduction. Supplement with sleep guides, diaries and leaflets e.g.: relaxation techniques, biofeedback, etc.

• Educate patient on short term use and non drug therapies Non-drug strategies can be effective in the management of anxiety and insomnia and may address the underlying cause, rather than just relieving symptoms.

• Write one script for a specific amount of days and no refills.

Tapering Benzodiazepines

Basic principles: • Expect anxiety, insomnia, and resistance. Patient education

and support very important.• Try decrease dose and frequency with long term users at first. • The slower the taper, the better the change is tolerated.• Only one provider should prescribe the benzodiazepine and

should be agreed upon by the treatment team when patient is treat across specialties.

• Calculate exactly how many pills they will need and give only one prescription with no refills.

• Abrupt withdrawal is not recommended. Risk of seizures and/or delirium increases with abrupt withdrawal.

Slow Taper (3-6 months)

1. Calculate the total daily dose. Switch from short acting agent (alprazolam, lorazepam) to longer acting agent (diazepam, clonazepam). Upon initiation of taper reduce the calculated dose by 25% to adjust for possible metabolic variance.

2. First Follow up is 1 week after initiating the taper to determine need to adjust initial calculated dose.

3. Reduce the total daily dose by 5-10% per week in divided doses.

4. Once ½ of the original dose has been reach, the taper can be slowed further by decreasing the dose each month thereafter.

Slow Taper (3-6 months)

5. Consider an adjunctive agent to help with symptoms or to replace the benzodiazepine such as: buspirone, vistaril (advised not to use with the elderly), clonidine, SSRIs (Celexa 40mg maximum with elderly – get ekg), and/or sleeping aids.

6. Educate patient on nondrug therapies available to assist with symptoms such as: relaxation techniques, deep breathing, exercise, psychotherapy, etc.

Dose Equivalency

Approximate Equivalent Oral

Doses, mgTime to Peak Level,

hours Half-life, hoursAlprazolam (Xanax) 0.5 1-2 12Chlordiazepoxide (Librium) 25 1-4 100Clonazepam (Klonopin) 0.25 1-4 34Diazepam (Valium) 5 1-2 100Lorazepam (Ativan) 1 1-4 15Oxazepam (Serax) 15 1-4 8Temazepam (Restoril) 10 2-3 11Triazolam (Halcion) 0.25 1-2 2

Fast Taper (2-6 Weeks)

1. Use an equivalent dose - replace with diazepam or clonazepam two times daily for 1-2 weeks.

2. Add an anticonvulsant (carbamazepine, valproate, gabapentin) at a maintenance dose. These work on the same GABA receptors and help to facilitate a faster taper.

3. Consider an adjunctive agent to help with symptoms or to replace the benzodiazepine such as: buspirone, vistaril (advised not to use with the elderly), clonidine, SSRIs (Celexa 40mg maximum with elderly – get ekg), and/or sleeping aids. After 1-2 weeks decrease the dose of diazepam to once daily.

4. Then cut the diazepam or clonazepam to ¼ of the initial dose once daily for 1-2 weeks

Fast Taper (2-6 Weeks)

5. Discontinue the Diazepam.6. Continue the anticonvulsant for 2-3 months after

discontinuing the benzodiazepine.7. Educate patient on nondrug therapies available to assist with

symptoms such as: relaxation techniques, deep breathing, exercise, psychotherapy, etc.

Dose Equivalency

Approximate Equivalent Oral

Doses, mgTime to Peak Level,

hours Half-life, hoursAlprazolam (Xanax) 0.5 1-2 12Chlordiazepoxide (Librium) 25 1-4 100Clonazepam (Klonopin) 0.25 1-4 34Diazepam (Valium) 5 1-2 100Lorazepam (Ativan) 1 1-4 15Oxazepam (Serax) 15 1-4 8Temazepam (Restoril) 10 2-3 11Triazolam (Halcion) 0.25 1-2 2

BZD Tolerance

The higher the dose, andThe more frequently the dose is taken, andThe longer the dose is taken, thenThe greater the tolerance

BZD Dependence

The higher the dose, andThe more frequently the dose is taken, andThe longer the dose is taken, thenThe greater the physical dependencePhysical Dependence = an abstinence syndrome when:

• drug administration stops (spontaneous)• an antagonist is given (precipitated)

BZD Dependence

Shorter half-life drugs give nastier signs and symptoms of withdrawalLonger half-life drugs give less severe signs and symptoms of withdrawal, but they are more protracted.If withdrawal is threatening to become intolerable or if seizures are likely, consider administering a longer acting BZD

Drug Interactions with BZDs

Cimetidine (Tagamet) inhibits liver mixed-function oxidase. Prolongs the action of most BZDs.• Use alprazolam, lorazepam or oxazepam for patients taking cimetidine

Alternative Medications

• Vistaril/Atarax 25-50mg TID • Propranolol 10-20mg TID caution low blood pressure• Clonidine 0.1 mg BID caution low blood pressure• Buspirone 5-20mg TID• Lyrica 50-150mg TID off label indication• Neurontin/Gabapentin 100-300mg TID off label indication

BZD Dependence

Nasty problem1. Initial anxiety returns during withdrawal2. Additional anxiety occurs because of withdrawalNet effect is intolerable anxietySymptoms of withdrawal occur before signs of withdrawal, and anxiety is the first withdrawal symptom

Withdrawal symptoms – feeling tapped behind (Xanax) bars

• Severe sleep disturbance• Irritability• Increased tension and anxiety• Hand tremor• Sweating• Difficulty with concentration• Confusion and cognitive difficulty• Headache• Muscular pain and stiffness• Seizures• Psychosis• Tachycardia• Hypertension• Loss of appetite• Delirium Tremens

Managing Resistance

• Understand the etiology of withdrawal• Educate early• Need network wide consistency• Provide support and alternatives• Don’t argue but remain firm • For those that have been using long term the goal is to

decrease dosage and frequency

Questions?

Thank you

Elimination half-lives

What Is Autonomic Dysfunction?

The autonomic nervous system (ANS) controls many basic bodily functions including: heart rate, body temperature, breathing rate, and digestionThe ANS provides the connection between your brain and your internal organs - connects to the heart, liver, sweat glands, and interior muscles of your eye.The ANS:

sympathetic autonomic nervous system (SANS) fight or flight

parasympathetic autonomic nervous system (PANS)