the mao handbook - neiglobal.comcdn.neiglobal.com/content/monographs/2011_mao_handbook.pdf · the...

ii

The MAO Handbook

Every effort has been made in preparing this book to provide accurate and up-to-date information that is in accord with accepted standards and practice at the time of pub-lication. Nevertheless, the author, editors, and publisher can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The author, edi-tors, and publisher therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

PUBLISHED BY NEI PRESS, an imprint of NEUROSCIENCE EDUCATION INSTITUTECarlsbad, California, United States of America

NEUROSCIENCE EDUCATION INSTITUTE1930 Palomar Point Way, Suite 101Carlsbad, California 92008

http://www.neiglobal.com

Copyright © 2011 Neuroscience Education Institute. All rights reserved.

This publication is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Neuroscience Education Institute.

Printed in the United States of AmericaFirst Edition, December 2011Electronic versions, January 2012

Typeset in Myriad Pro

Library of Congress Cataloging-in-Publication DataISBN 978-1-4225-0024-8 PrintISBN 978-1-4225-0029-3 Adobe® PDFISBN 978-1-4225-0025-5 EPUB

Adobe® PDF is either a registered trademark or trademark of Adobe SystemsIncorporated in the United States and/or other countries.

iii

CME Information ..........................................................................................................................v

Objectives ......................................................................................................................................ix

Chapter 1: Monoamine Oxidase Inhibitors (MAOIs): The Basics .................................1

Chapter 2: Myth #1: The Tyramine Reaction ......................................................................11

Chapter 3: Myths #2 and #3: The Cold Medication/Stimulant Interaction .............23

Chapter 4: Myth #4: The Anesthetic Interaction ...............................................................31

Chapter 5: Myth #5: The Tricyclic Interaction ....................................................................37

Chapter 6: Myth #6: The Painkiller Interaction ..................................................................43

Chapter 7: Myth #7: The Psychotropic Concomitant Medication Interaction .......49

Chapter 8: MAOIs: Tips and Pearls .........................................................................................61

Summary ........................................................................................................................................67

Suggested Reading ....................................................................................................................69

CME Posttest and Certificate ...................................................................................................71

Table of Contents

iv

The MAO Handbook

v

Overview Despite the fact that MAO inhibitors (MAOIs) can be highly effective therapeutic agents for depression and some anxiety disorders, they tend to be underutilized in clinical practice. Because these drugs are no longer emphasized in medical education, there is a great deal of misinformation and mythology about their dietary and drug interactions. This book is intended to serve as a guide for clinicians who are not particularly familiar with MAO inhibitors; its aim is to help these clinicians competently integrate these agents into clinical prac-tice when appropriate.

Target Audience This activity has been developed for psychiatrists specializing in psychopharmacology. There are no prereq-uisites. All other health care providers who are interested in psychopharmacology are welcome for advanced study, especially primary care physicians, nurse practitioners, psychologists, and pharmacists.

Statement of Need The following unmet needs and professional practice gaps regarding depression were revealed following a critical analysis of activity feedback, expert faculty assessment, and literature review, as well as through new medical knowledge:

• The timely detection, diagnosis, and treatment of major depression have been shown to increase the probability of positive clinical outcomes; however, only 60% of those with depression are actually being treated.• Even when correctly diagnosed and treated, as many as two-thirds of MDD patients will not respond to the first antidepressant prescribed, a substantial number may be treatment resistant.

To help fill these unmet needs, quality improvement efforts need to provide education regarding under-used evidence-based treatment strategies for patients with treatment-resistant depression.

Learning Objectives After completing this educational activity, participants should be better able to:

• Identify foods that can or cannot be consumed by patients on different types of MAO inhibitors• Identify medications that can or cannot be taken by patients on different types of MAO inhibitors• Implement safe management strategies when switching between MAO inhibitors and serotonin reuptake inhibitors• Integrate MAO inhibitors into clinical practice according to best practices standards

Accreditation and Credit Designation Statements The Neuroscience Education Institute is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The Neuroscience Education Institute designates this enduring material for a maximum of 3.0 AMA PRA Category 1 Credits TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses: for all of your CE requirements for recertification, the ANCC will accept category 1 credits from organizations accredited by the ACCME.

Physician Assistants: the NCCPA accepts AMA PRA Category 1 Credit ™ from organizations accredited by the AMA/ACCME.

A certificate of participation for completing this activity will also be available.

CME Information

vi

The MAO Handbook

Please note: the content of this electronic book activity also exists as a print monograph under the same title. If you received CME credit for the print monograph version, you will not be able to receive credit again for completing this electronic book version.

Activity Instructions This CME activity is available in the form of a printed monograph and an electronic book and incorporates instructional design to enhance your retention of the information and pharmacological concepts that are being presented. You are advised to read the book in sequence, and then complete the posttest and activity evaluation. The estimated time for completion of this activity is 3.0 hours.

Instructions for CME Credit To receive your certificate of CME credit or participation, please complete the posttest and activity evaluation, available only online, by clicking the link found at the end of this electronic book or at www.neiglobal.com/CME (under “Book”). If a passing score of 70% or more is attained (required to receive credit), you can immediately print your certificate. There is no fee for CME credits for this activity.

NEI Disclosure Policy It is the policy of the Neuroscience Education Institute to ensure balance, independence, objectivity, and scientific rigor in all its educational activities. Therefore, all individuals in a position to influence or control content development are required by NEI to disclose any financial relationships or apparent conflicts of interest that may have a direct bearing on the subject matter of the activity. Although potential conflicts of interest are identified and resolved prior to the activity being presented, it remains for the participant to determine whether outside interests reflect a possible bias in either the exposition or the conclusions presented.

These materials have been peer-reviewed to ensure the scientific accuracy and medical relevance of information presented and its independence from commercial bias. The Neuroscience Education Institute takes responsibility for the content, quality, and scientific integrity of this CME activity.

Individual Disclosure Statements Authors

Meghan GradyDirector, Content Development, Neuroscience Education Institute, Carlsbad, CANo other financial relationships to disclose.

Stephen M. Stahl, MD, PhDAdjunct Professor, Department of Psychiatry, University of California, San Diego School of Medicine Honorary Visiting Senior Fellow, University of Cambridge, UKGrant/Research: AstraZeneca, BioMarin, Dainippon Sumitomo, Dey, Forest, Genomind, Lilly, Merck, Pamlab, Pfizer, PGxHealth/Trovis, Schering-Plough, Sepracor/Sunovion, Servier, Shire, TorrentConsultant/Advisor: Advent, Alkermes, Arena, AstraZeneca, AVANIR, BioMarin, Biovail, Boehringer Ingelheim, Bristol-Myers Squibb, CeNeRx, Cypress, Dainippon Sumitomo, Dey, Forest, Genomind, Janssen, Jazz, Labopharm, Lilly, Lundbeck, Merck, Neuronetics, Novartis, Ono, Orexigen, Otsuka, Pamlab, Pfizer, PGxHealth/Trovis, Rexahn, Roche, Royalty, Schering-Plough, Servier, Shire, Solvay/Abbott, Sunovion/Sepracor, Valeant, VIVUS Speakers Bureau: Dainippon Sumitomo, Forest, Lilly, Merck, Pamlab, Pfizer, Sepracor/Sunovion, Servier, Wyeth

Peer ReviewerSteven S. Simring, MD, MPHClinical Associate Professor, Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York CityNo other financial relationships to disclose.

http://www.neiglobal.com/CME


vii

CME Information

Design StaffNancy MuntnerDirector, Medical Illustrations, Neuroscience Education Institute, Carlsbad, CA No other financial relationships to disclose.

Program DevelopmentThe following are employed by the Neuroscience Education Institute in Carlsbad, CA, and have no other financial relationships to disclose.Rory Daley, MPH, Associate Director, Program Development Steve Smith, President and COO

Disclosed financial relationships have been reviewed by the Neuroscience Education Institute CME Advisory Board to resolve any potential conflicts of interest. All faculty and planning committee members have attested that their financial relationships do not affect their ability to present well-balanced, evidence-based content for this activity.

Disclosure of Off-Label Use This educational activity may include discussion of products or devices that are not currently labeled for such use by the FDA. Please consult the product prescribing information for full disclosure of labeled uses.

Disclaimer The information presented in this educational activity is not meant to define a standard of care, nor is it intended to dictate an exclusive course of patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this educational activity should not be used by clinicians without full evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. Primary references and full prescribing information should be consulted.

Participants have an implied responsibility to use the newly acquired information from this activity to enhance patient outcomes and their own professional development. The participant should use his/her clinical judgment, knowledge, experience, and diagnostic decision-making before applying any information, whether provided here or by others, for any professional use

Sponsorship Information This activity is sponsored by the Neuroscience Education Institute.

Support This activity is supported by an educational grant from Dey Pharma, L.P.

Date of Release/Expiration Print Monograph Released: December 15, 2011Electronic Books Released: January, 2012CME Credit Expires: December 14, 2014

viii

The MAO Handbook

ix

• Identify foods that can or cannot be consumed by patients on different types of MAO inhibitors

• Identify medications that can or cannot be taken by patients on different types of MAO inhibitors

• Implement safe management strategies when switching between MAO inhibitors and serotonin reuptake inhibitors

• Integrate MAO inhibitors into clinical practice according to best practices standards

Objectives

x

The MAO Handbook

1

Chapter 1 Monoamine Oxidase Inhibitors (MAOIs):

The Basics

2

The MAO Handbook

FIGURE 1.1. The first clinically effective antidepressants discovered were inhibitors of the enzyme monoamine oxidase (MAO). Today, there are several agents with variations of this mechanism of action. Despite the fact that MAO inhibitors (MAOIs) can be highly effective therapeutic agents for depression and some anxiety disorders, they tend to be underutilized in clinical practice. There are many reasons for this, including the fact that there are many other treatment options, which prevent clinicians from becoming familiar with MAO inhibitors. Because these drugs are no longer emphasized in medical education, there is a great deal of misinformation and mythology about their dietary and drug interactions. This book is intended to serve as a guide for clinicians who are not particularly familiar with MAO inhibitors; its aim is to help these clinicians competently integrate these agents into clinical practice when appropriate.

Monoamine Oxidase (MAO)

3

Chapter 1: Monoamine Oxidase Inhibitors (MAOIs) - The Basics

TABLE 1.1. MAO is an enzyme that metabolizes monoamines as well as trace amines. It exists in two subtypes: A and B. The A form preferentially metabolizes the monoamines most closely linked to depression (i.e., serotonin and norepinephrine), whereas the B form preferentially metabolizes trace amines such as phenylethylamine. Both MAO-A and MAO-B metabolize dopamine and tyramine, and both are present in the brain. Noradrenergic and dopaminergic neurons are thought to contain both MAO-A and MAO-B, perhaps with MAO-A activity being predominant, whereas serotonergic neurons are thought to contain only MAO-B. With the exception of platelets and lymphocytes, which have MAO-B, MAO-A is the major form of this enzyme outside of the brain.

MAO Subtypes

TABLE 1.1.

MAO-A MAO-B

Substrates Serotonin (5HT)NorepinephrineDopamineTyramine

DopamineTyraminePhenylethylamine

Tissue distribution Brain, gut, liver, placenta, skin

Brain, platelets, lymphocytes

4

The MAO Handbook

MAO-A Inhibition:Antidepressant Action

5


FIGURE 1.2. An MAO inhibitor must inhibit MAO-A in the brain in order for antidepressant efficacy to occur. This is not surprising given that MAO-A preferentially metabolizes serotonin and norepinephrine, the two monoamines most strongly implicated in depression and the mechanisms of antidepressants (left, top two frames). MAO-A (along with MAO-B) also metabolizes dopamine (left, bottom frame).

This means that MAO-A inhibition increases serotonin, norepinephrine, and dopamine (right frames), but that the increase in dopamine is not as great as that of serotonin and norepinephrine, since MAO-B can still metabolize dopamine (right, bottom frame).

6

The MAO Handbook

MAO-B Inhibition:No Antidepressant Action

7


FIGURE 1.3. The inhibition of MAO-B is not effective as an antidepressant. This is because MAO-B metabolizes serotonin and norepinephrine only at high concentrations (left, top two frames). Since the role of MAO-B in destroying serotonin and norepinephrine is small, the inhibition of MAO-B is not likely to be relevant to the concentrations of these neurotransmitters (right, top two frames). The selective inhibition of MAO-B also has somewhat limited effects on dopamine concentrations because MAO-A continues to destroy dopamine. However, the inhibition of MAO-B does increase dopamine to some extent; this can be therapeutic in other disease states, such as enhancing the efficacy of levodopa in Parkinson’s disease.

8

The MAO Handbook

MAO-A and MAO-B Inhibition:Robust Antidepressant Action

9


FIGURE 1.4. The combined inhibition of MAO-A and MAO-B may have robust antidepressant actions owing to increases in not only serotonin and norepinephrine, but also dopamine. The inhibition of both MAO-A, which metabolizes all three monoamines, and MAO-B, which metabolizes primarily dopamine (left frames), leads to greater increases in each of these neurotransmitters than the inhibition of either enzyme alone (right frames).

10

The MAO Handbook

TABLE 1.2. Currently available MAO inhibitors include phenelzine, tranylcypromine, and isocarboxazid, which are irreversible inhibitors of both MAO-A and MAO-B; amphetamine, which is a weak inhibitor of MAO-A and MAO-B; transdermal selegiline, which inhibits both MAO-A and MAO-B in the brain but predominantly MAO-B in the gut; oral low-dose selegiline and rasagiline, which are selective for MAO-B; and moclobemide, which is a reversible inhibitor of MAO-A that is available outside of the United States.

Monoamine Oxidase Inhibitors

TABLE 1.2.

Name Inhibition of MAO-A

Inhibition of MAO-B

Amphetamine Properties

phenelzine + +

tranylcypromine + + +

isocarboxazid + +

amphetamines (high-dose) + + +

selegiline (transdermal)

brain + + +

gut +/- + +

selegiline(oral low-dose) - + +

rasagiline (Europe, Israel) - + -

moclobemide (not in U.S.) + - -

CX 157 + - -

11

Chapter 2 Myth #1:

The Tyramine Reaction

12

The MAO Handbook

The Myth

You can’t eat cheese, drink wine or beer, or eat lots of foods that contain tyramine, or else you

will develop hypertensive crisis...

…so if you go to pizza parties or wine and cheese receptions, eat in restaurants, or follow a

normal diet, you can’t take an MAOI.

13

Chapter 2: Myth #1 - The Tyramine Reaction

The Truth

There are a few things to avoid (which are easy to remember), but in practice, diet is not really a

problem…

…unless you plan to eat more than 25 pieces of pizza or drink more than 25 cans of beer or 25

glasses of wine.

14

The MAO Handbook

The Pharmacology

You should be cautious when combining an MAOI with anything that boosts

norepinephrine because this can raise blood pressure.

15


FIGURE 2.1. One of the biggest barriers to using MAO inhibitors has traditionally been the risk that a patient taking one of these drugs may develop a hypertensive reaction after ingesting tyramine in the diet.

How might the combination of tyramine in the diet plus MAO inhibition lead to a dangerous elevation in blood pressure? Tyramine works to elevate blood pressure because it is a potent releaser of norepinephrine. However, MAO-A normally acts to destroy norepinephrine to keep it in balance. Since accumulated norepinephrine can cause vasoconstriction and elevated blood pressure via increased binding at alpha-1 and other adrenergic receptors, its normal destruction by MAO-A helps prevent these negative effects.

The Pharmacology

16

The MAO Handbook

FIGURE 2.2. Tyramine is an amine that causes norepinephrine release (1). When foods high in tyramine content are ingested, MAO-A in the intestinal wall destroys tyramine before it is absorbed; MAO-A in the liver destroys any tyramine that gets absorbed; and if any tyramine reaches the noradrenergic sympathetic neuron, MAO-A readily destroys the excess norepinephrine released by tyramine (2), and no harm is done (i.e., no vasoconstriction or elevation in blood pressure).

The body thus has a huge capacity for processing tyramine, and the average person is able to handle around 400 mg of ingested tyramine before their blood pressure becomes elevated. A high-tyramine diet, by contrast, includes only around 40 mg of tyramine.

The Pharmacology (cont.)

17


The Pharmacology (cont.)

FIGURE 2.3. When MAO-A is inhibited, the body’s capacity to handle dietary tyramine is greatly reduced, and a high-tyramine meal is sufficient to raise blood pressure when a substantial amount of MAO-A is irreversibly inhibited. That is, tyramine increases the release of norepinephrine (1). However, MAO-A is also inhibited by an irreversible MAO-A inhibitor (2). This results in MAO-A stopping its destruction of norepinephrine (2). When MAO-A inhibition takes place in the presence of tyramine, the combination can lead to a very large accumulation of norepinephrine (3). Such an accumulation can lead to excessive stimulation of postsynaptic adrenergic receptors (3) and therefore dangerous vasoconstriction and elevation of blood pressure.

18

The MAO Handbook

TABLE 2.1. It may take as little as 10 mg of dietary tyramine to increase blood pressure when MAO-A is essentially knocked out by high doses of an MAO inhibitor. Some blood pressure elevations can be very large, sudden, and dramatic, causing a condition known as hypertensive crisis, which can rarely cause intracerebral hemorrhage or even death.

Hypertensive Crisis

TABLE 2.1.

Defined by diastolic blood pressure >120 mmHgPotentially fatal reaction characterized by:

Occipital headache that may radiate frontally

Palpitation

Neck stiffness or soreness

Nausea

Vomiting

Sweating (sometimes with fever)

Dilated pupils, photophobia

Tachycardia or bradycardia, which can be associated with constricting chest pain

19


TABLE 2.2. Because of the potential danger of a hypertensive crisis from a tyramine reaction in patients taking irreversible MAO inhibitors, a certain mythology has grown up around how much tyramine is in various foods and which dietary restrictions are necessary. Since the tyramine reaction is sometimes called a “cheese reaction,” there is a myth that all cheese must be restricted. That is true only for aged cheeses, but not for most processed cheese and for most cheese utilized in most commercial chain pizzas. Thus, it is not true that patients on MAO inhibitors must avoid the ingestion of any cheese. It is also not true that such patients must avoid all beer and wine. Canned and bottled beers are low in tyramine; generally, only tap and unpasteurized beers must be avoided. Many wines are actually quite low in tyramine. Of course, prescribers should counsel patients taking the classic MAO inhibitors about diet and keep current with the tyramine content of the foods their patients wish to eat.

*Not necessary for 6 mg transdermal or low-dose oral selegiline

The Owner’s Manual:Recommended Dietary Restrictions for MAOIs*

TABLE 2.2.

Foods to avoid Foods allowed

Dried, aged, smoked, fermented, spoiled, or improperly stored meat, poultry, and fish

Fresh or processed meat, poultry, and fish; properly stored pickled or smoked fish

Broad bean pods All other vegetables

Aged cheeses Processed cheese slices, cottage cheese, ricotta cheese, yogurt, cream cheese

Tap and unpasteurized beer Canned or bottled beer and alcohol

Marmite Brewer’s and baker’s yeast

Sauerkraut, kimchee

Soy products/tofu Peanuts

Banana peel Bananas, avocados, raspberries

Tyramine-containing nutritional supplement

20

The MAO Handbook

FIGURE 2.4. How can one inhibit MAO-A to achieve antidepressant actions but not inhibit MAO-A to avoid tyramine reactions? One method is through reversible inhibition of MAO-A. Irreversible inhibition of MAO-A, as with the older MAO inhibitors, prevents the enzyme from ever functioning again; enzyme activity returns only after a new enzyme is synthesized. Reversible inhibitors of MAO-A (RIMAs), on the other hand, can be removed from the enzyme by competitors. Thus, when tyramine increases norepinephrine release (1), it increases the competition for MAO-A. RIMAs can then be displaced (2), allowing for normal destruction of the extra norepinephrine (3) and reducing the risk of a tyramine reaction.

Reversible Monoamine Oxidase AInhibitors (RIMAs)

21


FIGURE 2.5. Another method of reducing the risk of tyramine reactions while continuing to exert antidepressant effects is the use of a transdermal delivery system for selegiline. Selegiline is a selective MAO-B inhibitor at low doses, and it must be administered in high doses in order to inhibit MAO-A. Delivering selegiline through a transdermal patch enables the inhibition of both enzymes in the brain while bypassing the inhibition of MAO-A in the gut. That is, transdermal delivery is like an intravenous infusion without a needle, delivering a drug directly into systemic circulation, hitting the brain in high doses, and avoiding a first pass through the liver. By the time the drug recirculates to the intestine and the liver, it has much decreased levels, and it significantly inhibits only MAO-B in these tissues.

Transdermal Delivery of SelectiveMAO-B Inhibitors

22

The MAO Handbook

FIGURE 2.6. A meal that contains 40 mg of tyramine is considered high in this substance; however, in normal individuals (i.e., those not taking an MAO-A inhibitor), it takes as much as 400 mg of tyramine to elevate blood pressure (far right column). Patients taking low-dose oral selegiline, which inhibits only MAO-B, may ingest as much tyramine as those not taking an MAO inhibitor; however, they will not experience any antidepressant effect (fourth column). In contrast, patients taking a nonselective irreversible MAO inhibitor, such as tranylcypromine or phenelzine, may be able to ingest as little as 10 mg of tyramine before experiencing a tyramine reaction (first column). These patients experience antidepressant effects but are at high risk for a tyramine reaction. Transdermal selegiline, on the other hand, inhibits MAO-A and MAO-B in the brain but mosty MAO-B in the gut; this means that it achieves antidepressant efficacy but is less likely to cause a tyramine reaction. Patients taking transdermal selegiline may be able to ingest a high-tyramine meal of 40 mg or more with safety. This has been proven for the 6 mg dose but there is insufficient data to confirm this for the 9 and 12 mg doses.

How Much Tyramine Is DangerousWith MAO Inhibitors?

23

Chapter 3 Myths #2 and #3:

The Cold Medication/Stimulant Interaction

24

The MAO Handbook

The Myths

You can’t take cold medications, such as decongestants, antihistamines, or cough

medicines, with MAOIs, so patients who get colds cannot take MAOIs.

You can’t take stimulants with MAOIs, so patients who need stimulants cannot take

MAOIs.

25

Chapter 3: Myths #2 and #3 - The Cold Medication/Stimulant Interaction

The Truth

Sympathomimetic decongestants and stimulants should be used with caution while

monitoring blood pressure in patients for which the benefits are greater than the risks and

should be avoided only in high-risk/low-benefit populations.

26

The MAO Handbook

The Pharmacology


norepinephrine because this can raise blood pressure.

You should completely avoid combining an MAOI with anything that blocks serotonin

reuptake because this can cause a dangerous or fatal serotonin syndrome/toxicity.

27


FIGURE 3.1. Decongestants that stimulate postsynaptic alpha-1 receptors, such as phenylephrine, may interact with MAO inhibitors to increase the risk of hypertension. Decongestants work by constricting nasal blood vessels, but they do not typically elevate blood pressure at therapeutic doses. However, the direct alpha-1 stimulation of a decongestant combined with the noradrenergic action of an MAO inhibitor may be sufficient to cause hypertension or even hypertensive crisis.

The Pharmacology

28

The MAO Handbook

TABLE 3.1. For patients with colds who are on MAO inhibitors, it is probably best to use antihistamines, which are safe with the exception of those that are also serotonin reuptake inhibitors (e.g., brompheniramine and chlorpheniramine). Cough medicines with expectorants or codeine are safe, but avoid dextromethorphan, a weak serotonin reuptake inhibitor.

Stimulants are useful as bridging medications when starting or stopping MAOIs and as augmenting medications to boost partial response to MAOIs. They should not be used in patients who are known cocaine/methamphetamine/stimulant abusers. Although formally contraindicated, stimulants can be given by experts with caution and appropriate monitoring, either as augmenting agents or bridging medications.

The Owner’s Manual:Drugs That Boost Norepinephrine and Thus

Should Be Used With Caution With MAO Inhibitors

TABLE 3.1.

Decongestants Stimulants Antidepressants With NRIs

Other

Phenylephrine Amphetamine Most TCAs Phentermine

Pseudoephedrine Methylphenidate NRIs Local anesthetics containing vasoconstrictors

Modafinil SNRIs Tramadol, tapentadol

Armodafinil NDRIs Cocaine, methamphetamine

29


TABLE 3.2. Small, open-label studies have been conducted to investigate potential drug-drug interactions between pseudoephedrine and transdermal selegiline (Azzaro et al., 2007). Change in heart rate and blood pressure was evaluated in a sample of 25 healthy controls during administration of pseudoephedrine (or phenylpropanolamine) alone, transdermal selegline alone, or the combination. No significant differences were found. Nonetheless, the combination of transdermal selegiline with sympathomimetics is still formally contraindicated.

Drug Interaction Data:Transdermal Selegiline and Sympathomimetics

Table 3.2. Mean systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR) before and during multiple-dose treatment with a sympathomimetic [pseudoephedrine (PSE) or phenylpropanolamine (PPA)] and/or transdermal selegiline (TS) 6 mg/24 hr

Baseline End of PSE Treatment

Parameter Untreated Control

TS PSE TS + PSE

SBP (mm Hg) 118.4 109.1 122.9 122.2

DBP (mm Hg) 71.0 63.2 68.9 67.9

HR (bpm) 62.7 59.4 73.5 75.5

Baseline End of PPA Treatment

Parameter Untreated Control

TS PPA TS + PPA

SBP (mm Hg) 120.2 123.5 121.2 125.1

DBP (mm Hg) 72.3 71.2 71.9 74.0

HR (bpm) 64.7 64.3 62.2 64.1

30

The MAO Handbook

31

Chapter 4 Myth #4:

The Anesthetic Interaction

32

The MAO Handbook

The Myth

You can’t have a local or a general anesthetic when on an MAOI, so patients who need dental work, stitches, or surgery cannot take an MAOI.

33

Chapter 4: Myth #4 - The Anesthetic Interaction

The Truth

Be careful using local anesthetics that contain epinephrine and also be careful using general anesthesia, as both can cause blood pressure

changes.

34

The MAO Handbook

The Pharmacology

Pressor agents inadvertently injected intravenously can raise blood pressure;

inhalation anesthetics can causeblood pressure changes.

35

Chapter 4: Myth #4 - The Anesthetic Interaction

TABLE 4.1. For a patient taking an MAO inhibitor who needs to have a local anesthetic, choose an agent that does not contain vasoconstrictors. For elective surgery, one should wash out the MAO inhibitor 10 days prior to the surgery. For urgent surgery or elective surgery when the patient is still taking an MAO inhibitor, one can cautiously use a benzodiazepine, mivacurium, rapacuronium, morphine, or codeine.

The Owner’s Manual:Use of Anesthetics

Table 4.1.

Local anesthetic Elective surgery Urgent or elective surgery when patient is still taking an MAO inhibitor

Choose an agent that does not contain vasoconstrictors

Wash out the MAO inhibitor 10 days prior to surgery

Cautiously use a benzodiazepine, mivacurium, rapacuronium, morphine, or codeine

36

The MAO Handbook

37

Chapter 5 Myth #5:

The Tricyclic Interaction

38

The MAO Handbook

The Myth

Tricyclic antidepressants are so dangerous that patients on MAO inhibitors cannot take them or anything that resembles them, including

carbamazepine and cyclobenzaprine.

39

Chapter 5: Myth #5 - The Tricyclic Interaction

The Truth

Other than clomipramine, tricyclic antidepressants and related agents can be used with caution in patients taking MAO inhibitors.

40

The MAO Handbook

The Pharmacology


norepinephrine because this canraise blood pressure.



41

Chapter 5: Myth #5 - The Tricyclic Interaction

TABLE 5.1. The only tricyclic antidepressant to be strictly avoided in combination with an MAO inhibitor is clomipramine. Other tricyclic antidepressants can be used with caution for severely treatment-resistant patients. If this option is selected, one should start the MAO inhibitor at the same time as the tricyclic antidepressant (both at low doses) after an appropriate drug washout; then, one should alternately increase the doses of these agents every few days to a week as tolerated. The MAOI should not be started first.

Cyclobenzaprine, carbamazepine, and oxcarbazepine can be used with caution because they do not block serotonin or norepinephrine reuptake.

The Owner’s Manual:Using Tricyclic Antidepressants With

MAO Inhibitors

Table 5.1.

Contraindicated Use with caution

clomipramine other tricyclic antidepressantscyclobenzaprinecarbamazepineoxcarbazepine

42

The MAO Handbook

43

Chapter 6 Myth #6:

The Painkiller Interaction

44

The MAO Handbook

The Myth

You can’t take painkillers with MAOIs because they will kill you, so patients who have sprained

ankles, sore muscles, dental extractions, or surgeries cannot take MAOIs, as they must avoid all opiate and non-opiate painkillers.

45

Chapter 6: Myth #6 - The Painkiller Interaction

The Truth

There are a few things to avoid (which are easy to remember), and in practice, this is not really

a problem.

46

The MAO Handbook

The Pharmacology

There is no interaction of MAOIs with opiate mechanisms; however, meperidine is a potent

serotonin reuptake inhibitor and should be avoided.

Methadone and tramadol are weak serotonin reuptake inhibitors and should be avoided.

Tapentadol is a norepinephrine reuptake inhibitor and should be avoided.

47

Chapter 6: Myth #6 - The Painkiller Interaction

TABLE 6.1. There is no interaction between MAOIs and opioid mechanisms; instead, the reason why some opioids must be avoided is that certain agents—meperidine, methadone, and tramadol—have serotonin reuptake inhibition, while tapentadol has norepinephrine reuptake inhibition.

The Owner’s Manual:Using Painkillers With MAO Inhibitors

Table 6.1.

Use With MAOIs Should Be Cautious

Use With MAOIs Not Recommended But May Sometimes Be Done By Experts

Use With MAOIs Strictly Prohibited

acetaminophenaspirinbuprenorphinebutophanolcodeinehydrocodonenalbuphineNSAIDspentazocine

hydromorphonemorphineoxycodoneoxymorphone

fentanylmeperidinemethadonetapentadoltramadol

48

The MAO Handbook

49

Chapter 7 Myth #7:

The Psychotropic Concomitant Medication Interaction

50

The MAO Handbook

The Myth

Since you can’t take any medications that block serotonin reuptake while taking an MAOI, you can’t take any psychotropic medications. Since

all patients who are candidates for an MAOI need concomitant medications, no one can

take an MAOI.

Besides, you cannot get there from here because in order to start an MAOI, you have to disrupt everything, stopping all other meds for 2 weeks after taper. And if you have to stop an MAOI to go back to a psychotropic medication, you have to go without all meds for another 2

weeks. This is an unacceptable risk and a hassle.

51

Chapter 7: Myth #7 - The Psychotropic Concomitant Medication Interaction

The Truth

You must completely avoid only agents that block serotonin reuptake. There are

many options for not only bridging between serotonin reuptake inhibitors and MAOIs, but

also augmenting MAOIs.

52

The MAO Handbook

The Pharmacology


norepinephrine because this canraise blood pressure.



53


FIGURE 7.1. This figure illustrates the mechanism by which serotonin reuptake inhibition combined with MAO inhibition can lead to serotonin toxicity. The inhibition of the serotonin transporter (SERT) leads to the increased synaptic availability of serotonin (1). Similarly, the inhibition of MAO leads to increased serotonin levels (2). In combination, these two mechanisms can cause excessive stimulation of postsynaptic serotonin receptors, the most important of which is perhaps the 5HT2A receptor in the hypothalamus.

The Pharmacology

54

The MAO Handbook

TABLE 7.1. Any agent with serotonin reuptake blockade has the potential to cause a fatal “serotonin syndrome” or “serotonin toxicity.” The general clinical features of serotonin toxicity can range from migraines, myoclonus, agitation, and confusion on the mild end of the spectrum, to hyperthermia, seizures, coma, cardiovascular collapse, permanent hyperthermic brain damage, and even death at the severe end of the spectrum. For this reason, it is important to closely monitor all concomitant medications in patients on MAO inhibitors, even in patients taking RIMAs or transdermal selegiline, for which these drug interactions also apply.

Serotonin Toxicity:Potential Clinical Features

Table 7.1.

Neuromuscular hyperactivity

Autonomic hyperactivity

Altered mental status

Akathisia Diaphoresis Agitation

Tremor Fever Excitement

Clonus Tachycardia Confusion

Myoclonus Tachypnea

Hyperreflexia

Rigidity

Nystagmus

55


TABLE 7.2. Early diagnostic criteria for serotonin toxicity (syndrome) were developed by Sternbach based on examination of published case reports and are listed above. However, these criteria can lack both sensitivity and specificity.

Serotonin Toxicity:Sternbach Criteria

Table 7.2.

Recent addition or increase in a known serotonergic agent

Absence of other possible etiologies (infection, substance abuse, withdrawal, etc.)

No recent addition or increase of a neuroleptic agent

At least three of the following:

Agitation

Myoclonus

Hyperreflexia

Diaphoresis

Shivering

Tremor

Diarrhea

Ataxia/incoordination

Fever

56

The MAO Handbook

TABLE 7.3. The apparent limitations of the Sternbach criteria for serotonin toxicity prompted another group to develop a set of diagnostic criteria. These criteria—called the Hunter Serotonin Toxicity Criteria—are based on retrospective analysis of more than 2200 patients who experienced overdose from a serotonergic drug. It was determined that only five of the clinical features associated with serotonin toxicity were needed to make an accurate diagnosis: clonus, agitation, diaphoresis, tremor, and hyperreflexia. In addition, hypertonicity and hyperpyrexia were present in all life-threatening cases of serotonin toxicity. They also developed decision rules for diagnosis, based on the presence or absence of the seven clinical features.

Serotonin Toxicity:Hunter Criteria

Table 7.3.

ClinicalFeatures

Decision Rules:In the presence of a serotonergic agent

Clonus IF (spontaneous clonus=yes) THEN serotonin toxicity=YES

Agitation ELSE IF (inducible clonus=yes) AND [(agitation=yes) OR (diaphoresis=yes) THEN serotonin toxicity=YES

Diaphoresis ELSE IF (ocular clonus=yes) AND [(agitation=yes) OR (diaphoresis=yes) THEN serotonin toxicity=YES

Tremor ELSE IF (tremor=yes) AND (hyperreflexia=yes) THEN serotonin toxicity=YES

Hyperreflexia ELSE IF (hypertonic=yes) AND (temperature>38°C) AND [(ocular clonus=yes) OR (inducible clonus=yes)] THEN serotonin toxicity=YES

Hypertonicity ELSE serotonin toxicity=NO

Hyperpyrexia

57


TABLE 7.4. One can essentially never combine agents that have potent serotonin reuptake inhibition with agents given in doses that cause substantial MAO inhibition. This includes any selective serotonin reuptake inhibitor (SSRI); any serotonin-norepinephrine reuptake inhibitor (SNRI), including the appetite suppressant sibutramine; and the tricyclic antidepressant clomipramine. Opioids that block serotonin reuptake, especially meperidine but also tramadol, methadone, and dextromethorphan, must also be avoided when an MAO inhibitor is given. Several drugs of abuse (listed above) also block serotonin reuptake; thus, diligent questioning about drug use is necessary when considering prescribing an MAO inhibitor.

Although it is commonly believed that serotonin 1A partial agonism could contribute to serotonin syndrome, this mechanism is not actually a contraindication for combination with MAO inhibition.

The Owner’s Manual:Drugs to Avoid Due to Risk of Serotonin

Syndrome/Toxicity

TABLE 7.4.

Antidepressants Drugs of Abuse Opioids Other

SSRIs MDMA (ecstasy) meperidine non-subcutaneous triptans

SNRIs cocaine tramadol chlorpheniramine

clomipramine meth-amphetamine

methadone brompheniramine

St. John’s wort High-dose or injected amphetamine

dextro-methorphan

58

The MAO Handbook

FIGURE 7.2. Because of the risk of serotonin toxicity, complete washout of a serotonergic drug is necessary before starting an MAO inhibitor. One must wait at least 5 half-lives after discontinuing the serotonergic drug before starting the MAO inhibitor. For most drugs, this means waiting 5–7 days; a notable exception is fluoxetine, for which one must wait 5 weeks due to its long half-life.

The Owner’s Manual:Switching From a Serotonergic Drug to an MAOI

59


FIGURE 7.3. If one is switching from an MAO inhibitor to a serotonin reuptake inhibitor, one must wait at least 14 days following the discontinuation of the MAO inhibitor before starting the serotonergic drug.

The Owner’s Manual:Switching From an MAOI to a Serotonergic Drug

60

The MAO Handbook

TABLE 7.4. Because there is a required gap in antidepressant treatment when switching to or from an MAO inhibitor, clinicians may be concerned about managing symptoms during that time period. There are many medication options, depending on the individual patient’s situation. These include benzodiazepines, Z drug sedative hypnotics, trazodone, lamotrigine, valproate, several other anticonvulsants, stimulants, and atypical antipsychotics. Specifically, although trazodone does have serotonin reuptake inhibition at antidepressant doses (i.e., 150 mg or higher), this property is not clinically relevant at the low doses used for insomnia while bridging an MAO inhibitor. The atypical antipsychotic ziprasidone also has serotonin reuptake inhibition, but this is not likely to be potent enough at therapeutic doses to be a problem.

The Owner’s Manual:How to Bridge

Table 7.4.

Use these drugs while waiting to start an MAOI or when discontinuing an MAOI

benzodiazepines

Z drug hypnotics

trazodone

lamotrigine

valproate

gabapentin, pregabalin, topiramate, carbamazepine, oxcarbazepine

stimulants

atypical antipsychotics

61

Chapter 8 MAOIs: Tips and Pearls

62

The MAO Handbook

FIGURE 8.1. Dosing and safety information for phenelzine.

Phenelzine:Tips and Pearls

Therapeutics

Mechanism:Irreversible, nonselective MAO inhibitor

Approved for:Depressed patients characterized as “atypical,” “nonendogenous,” or “neurotic”

Special PopulationsNot recommended for use under age 16

Pregnancy risk category C (some animal studies show adverse effects; no controlled studies in humans)

Contraindicated in patients with congestive heart failure or hypertension; any other cardiac impairment may require lower than usual adult dose; patients with angina pectoris or coronary artery disease should limit their exertion

May require lower dose in patients with renal impairment; use with caution, as drug may accumulate in plasma

Contraindicated

Dosing Tips

Formulations:Tablets: 15 mg

Dosage Range:45–75 mg/day

Tips:Once dosing is stabilized, some patients may tolerate once- or twice-daily dosing rather than 3-times-a-day dosing; orthostatic hypotension, especially at high doses, may require splitting into 4 daily doses; patients receiving high doses may need to be evaluated periodically for effects on the liver; little evidence to support efficacy below 45 mg/day

Side Effects and Safety

Hypertensive crisis (especially when MAOIs are combined with certain tyramine-containing foods or prohibited drugs); induction of mania; rare activation of suicidal ideation; seizures; hepatotoxicity

63

Chapter 8: MAOIs - Tips and Pearls

FIGURE 8.2. Dosing and safety information for tranylcypromine.

Tranylcypromine: Tips and Pearls

Therapeutics


Approved for:Major depressive episode without melancholia



Contraindicated in patients with any cardiac impairment


Should not be used in patients with history of hepatic impairment or in patients with abnormal liver function tests

Dosing Tips


Dosage Range:30 mg/day in divided doses

Tips:Orthostatic hypotension, especially at high doses, may require splitting into 3–4 daily doses; patients receiving high doses may need to be evaluated periodically for effects on the liver



64

The MAO Handbook

FIGURE 8.3. Dosing and safety information for isocarboxazid.

Isocarboxazid:Tips and Pearls

Therapeutics


Approved for:Depression



Contraindicated in patients with congestive heart failure or hypertension; any other cardiac impairment may require lower than usual adult dose; patients with angina pectoris or coronary artery disease should limit their exertion


Contraindicated

Dosing Tips



Tips:Orthostatic hypotension, especially at high doses, may require splitting into 4 daily doses; patients receiving high doses may need to be evaluated periodically for effects on the liver; little evidence to support efficacy below 30 mg/day



65

Chapter 8: MAOIs - Tips and Pearls

FIGURE 8.4. Dosing and safety information for selegiline.

Selegiline (Transdermal):Tips and Pearls

Therapeutics

Mechanism:MAO-A and MAO-B inhibitor in the brain and relatively selective MAO-B inhibitor in the gut

Approved for:Major depressive disorder



May require lower than usual adult dose; observe closely for orthostatic hypotension

No dose adjustment necessary for transdermal administration in patients with mild to moderate renal impairment

No dose adjustment necessary for transdermal administration in patients with mild to moderate hepatic impairment

Dosing Tips

Formulations:Transdermal patch: 20 mg/20 cm2 (6 mg/24 h), 30 mg/30 cm2 (9 mg/24 h),40 mg/40 cm2 (12 mg/24 h)

Dosage Range:6 mg/24 h–12 mg/24 h

Tips:Transdermal patch contains 1 mg of selegiline per 1 cm2 and delivers approximately 0.3 mg of selegiline per cm2 over 24 hours; at 6 mg/24 hours (transdermal), dietary adjustments are not generally required; dietary modifications to restrict tyramine intake from foods are recommended for doses above 6 mg/24 hours (transdermal); because of residual drug in the patch after 24 hours of administration, discard used patches in a manner that prevents accidental application or ingestion by children, pets, or others


Hypertensive crisis was not observed with transdermal patch in clinical trials; theoretically, at high doses, can cause induction of mania, seizures; rare activation of suicidal ideation

66

The MAO Handbook

FIGURE 8.5. Dosing and safety information for moclobemide.

Moclobemide:Tips and Pearls

Therapeutics

Mechanism:Reversible, selective inhibitor of MAO-A

Approved for:Not approved in United States


Not generally recommended for use during pregnancy, especially during first trimester

Cardiac impairment may require lower than usual adult dose; patients with angina pectoris or coronary artery disease should limit their exertion

Use with caution in patients with renal impairment

Plasma concentrations are increased in patients with hepatic impairment; may require one-half to one-third of usual adult dose

Dosing Tips

Formulations:Tablets: 100 mg scored, 150 mg scored


Tips:At higher doses, moclobemide also inhibits MAO-B and thereby loses its selectivity for MAO-A, with uncertain clinical consequences; taking moclobemide after meals may minimize the chances of interactions with tyramine; may be less toxic in overdose than tricyclic antidepressants and older MAO inhibitors; clinical duration of action may be longer than biological half-life and may allow for twice-daily dosing in some patients or even once-daily dosing at low doses


Hypertensive crisis (especially when MAOIs are combined with certain tyramine-containing foods or prohibited drugs); induction of mania; rare activation of suicidal ideation; seizures

67

y MAO inhibitors still play a role in modern psychopharmacology

y Distinct and understandable pharmacological mechanisms account for MAOIs and their:

— Therapeutic actions

— Serotonin syndrome/toxicity

— Sympathomimetic drug interactions

— Dietary tyramine interactions

y Dispelling the myths about these older agents and learning the truth—as well as the pharmacology behind it—can allow clinicians to confidently integrate these agents into clinical practice for patients who do not respond to first-line treatment

Summary

68

The MAO Handbook

69

Azzaro AJ, VanDenBerg CM, Ziemniak J, Kemper EM, Blob LF, Campbell BJ. Evaluation of the potential for pharmacodynamic and pharmacokinetic drug interactions between selegiline transdermal system and two sympathomimetic agents (pseudoephedrine and phenylpro-panolamine) in healthy volunteers. J Clin Pharmacol 2007;47(8):978-90. Bortolato M, Chen K, Shih JC. Monoamine oxidase inactivation: from pathophysiology to therapeutics. Adv Drug Deliv Rev 2008;60:1527-33. Gillman PK. Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors. J Clin Psychopharmacol 2011;31:66-74.

Stahl SM. Stahl’s essential psychopharmacology. 3rd ed. New York, NY: Cambridge Univer-sity Press; 2008.

Sun-Edelstein C, Tepper SJ, Shapiro RE. Drug-induced serotonin syndrome: a review. Expert Opinion Drug Safety 2008;7(5):587-96.

Wimbiscus M, Kostenkjo O, Malone D. MAO inhibitors: risks, benefits, and lore. Cleveland Clinic J Med 2010;77(12):859-82.

Suggested Reading

70

The MAO Handbook

71

Release/Expiration Dates Print Monograph Released: December 15, 2011Electronic Books Released: January, 2012CME Credit Expires : December 14, 2014. If this date has passed, please contact NEI for updated information.

CME Posttest Study GuidePLEASE NOTE: The posttest can only be submitted online. The posttest questions have been provided below solely as a study tool to prepare for your online submission. Faxed/mailed copies of the posttest cannot be processed and will be returned to the sender. If you do not have access to a computer, contact customer service at 888-535-5600.

1. A 49-year-old man has been taking an MAO inhibitor for the past 5 years to manage his depression. When he and his wife went out to dinner for their 30th anniversary he had two glasses of Chianti and an Italian meal high in cheese content. He began to experience palpitations, sweating, nausea, vomiting and extremely elevated blood pressure. His wife rushed him to the ER, where the doctors asked what medications he is currently taking. Which of the following could be responsible for these symptoms?

A. Oral low-dose selegiline (10 mg/day)B. Transdermal selegiline (6 mg/day)C. Tranylcypromine (30 mg/day)D. A and CE. A, B, and C

2. A 32-year-old man takes an MAO inhibitor for social anxiety disorder and is otherwise healthy. He has a bad cold that is keeping him up at night and wants to know if there is anything he can take to alleviate the cold symptoms. Which of the following would be the safest medication to recommend?

A. Antihistamine without serotonin reuptake inhibitionB. Antihistamine with serotonin reuptake inhibitionC. None of these are safe

3. A 35-year-old woman on an MAO inhibitor experiences a medical emergency requiring immediate surgery. Which of the following can generally be used with caution in this type of situation?

A. BenzodiazepineB. CodeineC. MorphineD. Any of these can be usedE. None of these can be used

4. A 45- year-old man with severely treatment-resistant depression has exhibited a partial response to a MAO inhibitor. Which of the following should absolutely NOT be used as an augmenting agent for this patient?

A. AmitriptylineB. ClomipramineC. NortriptylineD. Protriptyline

CME Posttest and Certificate

72

The MAO Handbook

5. A 54-year-old man with a history of treatment-resistant depression has been successfully treated with a monoamine oxidase inhibitor (MAOI) for the last year. He recently suffered a severe back injury and is in quite a bit of pain. In light of potential interactions with the MAOI, which of the following would be an acceptable pain management option for this patient?

A. MeperidineB. NSAIDC. TramadolD. The patient cannot take any of these medications

6. A 36-year-old man with depression has had three therapeutic trials of serotonin reuptake inhibitors (SRI) with notable improvement. His clinician is now considering switching from his current SRI to an MAO inhibitor. Which of the following is an appropriate switching strategy in this situation?

A. Cross-titrate SRI with MAO inhibitorB. Discontinue SRI, then initiate MAO inhibitorC. Discontinue SRI, then wait five half-lives before initiating MAO inhibitorD. Discontinue SRI, then wait 14 days before initiating MAO inhibitor

CME Online Posttest and CertificateTo receive your certificate of CME credit or participation, complete the posttest and activity evaluation, available only online, by clicking the link found at the end of this electronic book or at www.neiglobal.com/CME (under “Book”). If a passing score of 70% or more is attained (required to receive credit), you can immediately print your certificate. There is no fee for CME credits for this activity. If you do not have access to a computer, contact customer service at 888-535-5600.


http://www.neiglobal.com/WebPosttest.aspx?taction=webposttest&args=PT_AT-BOOK11-MAO

the mao handbook - neiglobal.comcdn.neiglobal.com/content/monographs/2011_mao_handbook.pdf · the...

Documents