The Chronicle of Neurology + Psychiatry (Canada) Oct. 2010

C o n t r o v e r s y i n p a i n m a n a g e m e n t

First opioid guidelinelacks maximum dosen Critics say the dosage should be lower,

those who drafted the guideline say clinical

experience suggests otherwise

Welcome to Chronicle, version 2.0

WE’RE BACK: IN PRINT, and coming soon to your mobilephone, Twitter account, iPad and what-have-you. You’llfind that the re-booted edition of THE CHRONICLE is

more than just a pretty face. Read all about us on page 2

©V

kra

sko

uski|

Dre

am

stim

ea

ge

ncy

Atypical antipsychotic approved for use ..............................6

Friedreich’s ataxia linked to DNA damage ........................11

Migraine’s relationship to depression ..............................14

Camada’s National Newspaper of the CNS Sciences n October 2010

Introducing Chronicle Vitae, the special section of The

Chronicle that puts you in touch with your peers, and helps

you make the most of your own time. This issue: Dr. Adrian

Owen signs on from Cambridge, UK, as the new Canadian

Research Excellence Chair. See page 26

by Josh Long,Assistant Editor, The Chronicle

GUIDELINES FOR PAIN

management are diffi-cult to find. The start

of the Canadian Guideline forSafe and Effective Use ofOpioids for CNCP (ChronicNon-Cancer Pain), says asmuch: “through the countlesshours of re-search, writing,reviewing, revising, discussingand debating that culminated

in this Canadian guideline, thenotion of a common groundat times seemed elusive.”

If this is true among thephysicians who manage chron-ic pain, it is also true amongphysicians concerned of a risein opioid overdoses, and thosewho endure chronic painthemselves.

“We are not opposed toguidelines where they areappropriate, but feel strongly

S t r o k e a n d d e p r e s s i o n

In stroke rehab, a little can go a long wayby Josh Long,Assistant Editor, The Chronicle

EVEN LOW-LEVEL DEPRESSION–so low as to slip through the cracks of tradi-tional depression screening–may hinder stroke recovery, says a study fromthe University of Sydney. By the same token, a low-level exercise program

can lessen depression symptoms and improve stroke recovery, says a study pre-sented at the first bi-annual Canadian Stroke Congress.

For some time, depression has been known to inhibit stroke recovery, notedMaree Hackett, PhD., a senior lecturer at the University of Sydney, and seniorresearch fellow at the George Institute for Global Health, in Australia.

S c h i z o p h r e n i a

New antipsychotic has fewer side effectsARIPIPRAZOLE HAS A MORE POSITIVE WEIGHT GAIN PROFILE and abetter impact on cholesterol and diabetes risk than similar drugs,according to doctors who have prescribed it. It is even less asso-ciated with sexual dysfunction. See page 10

—please turn to page 8


C l i n i c a l n e w s

Nasal deliveryof the first-ever

ADHD-ADDprodrughas sameabsorptionrate asoral form

ADHD medication usually

comes in the form of stimu-

lants with a potential for abuse.

But new research

strongly suggests lisdex-

amfetamine may carry reduced

risk. That’s because when

ingested nasally, this prodrug

does not cause d-amphetamine

levels to rise any higher than

when taken orally, which might

eliminate a possible avenue for

abuse. —please turn to page 22

sept issue20-mitch_09-20-10.qxd:sept issue20-mitch_09-20-10.qxd 21/09/10 1:54 PM

Trap Editor

Page is trapped with Trap Editor 6.0.71 Copyright 2008 Heidelberger Druckmaschinen AG http://www.heidelberg.com You can view actual document traps, with the free Trap Editor (Viewer), a Plug-In from the Prinect PDF Toolbox. Please request a PDF Toolbox CD from your local Heidelberg office in order to install it on your computer. Settings: Width: 0.088 mm = 0.250 pt Printorder: Cyan / Magenta / Yellow / Black / Step Limit: 25.0% Common Density Limit: 0.50 Centerline Trap Limit: 100% Trap Color Scaling: 100.0% Image to Object Trapping: yes Image to Image Trapping: no Black Width Scaling: 100.0% Black Color Limit: 95.0% Overprint Black Text: 12.0 pt Overprint Black Strokes: no Overprint Black Graphics: no

PRISTIQ is indicated for the symptomatic relief of major depressive disorder. The short-term effi cacy of PRISTIQ (desvenlafaxine succinate extended-release tablets) has been demonstrated in placebo-controlled trials of up to 8 weeks. The most commonly observed adverse events associated with the use of PRISTIQ (at an incidence 5% and at least twice the rate of placebo) were nausea (22%), dizziness (13%), hyperhidrosis (10%), constipation (9%), and decreased appetite (5%). PRISTIQ is not indicated for use in children under the age of 18. PRISTIQ is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs, including linezolid, an antibiotic) or in patients who have taken MAOIs within the preceding 14 days due to risk of serious, sometimes fatal, drug interactions with selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI) treatment or with other serotonergic drugs. These interactions have been associated with symptoms that include tremor, myoclonus, diaphoresis, nausea, vomiting, fl ushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, rigidity, autonomic instability with possible rapid fl uctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Based on the half-life of desvenlafaxine succinate, at least 7 days should be allowed after stopping desvenlafaxine succinate and before starting an MAOI.PRISTIQ is contraindicated in patients demonstrating hypersensitivity to desvenlafaxine succinate extended-release, venlafaxine hydrochloride or to any excipients in the desvenlafaxine formulation. Concomitant use of PRISTIQ with products containing venlafaxine is not recommended.Recent analyses of placebo-controlled clinical trial safety databases from selective serotonin reuptake inhibitors (SSRIs) and other newer antidepressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicide ideation and behaviour over that of placebo. The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profi les among the drugs in the class. There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type events that include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression and depersonalization. In some cases, the events occurred within several weeks of starting treatment. Rigorous clinical monitoring for suicide ideation or other indicators of potential for suicide behaviour is advised in patients of all ages, especially when initiating therapy or during any change in dose or dosage regimen. This includes monitoring for agitation-type emotional and behavioural changes. Patients currently taking PRISTIQ should NOT be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose, rather than an abrupt cessation is recommended.Reference: 1. Wyeth Canada. PRISTIQ Product Monograph, August 2009.Product Monograph available upon request.

© 2010 Wyeth CanadaMontreal, Canada H4R 1J6

PRISTIQ®

® Wyeth, owner, now a part of Pfi zer Inc.

CountCount on on

forfor powerful powerful symptom symptom relief relief

The Chronicle of Neurology & Psychiatry was born in1996, smack in the middle of what was called theDecade of the Brain.

That year, entirely by coincidence, marked the firsttime a biological brain, belonging to world chess championGarry Kasparov, would be bested by silicon intelligence, inthe form of an IBM machine known as Deep Blue.

One of the era’s most frequently cited articles fromthe scientific literature was published in 1996 in theBritish Medical Journal, under the title, “Evidence BasedMedicine: What It Is and What It Isn’t.” The lead author,Sackett of Oxford, elaborated, earnestly, if imprecisely:“Evidence based medicine is not ‘cookbook’ medicine.”

Among the lay public, perhaps a greater stir was causedby the civil trial of Mr. O.J. Simpson, the professional ath-lete, which was just getting underway in Santa Monica,Calif.

Twelve years later, The Chronicle of Neurology &Psychiatry placed its belongings in a storage unit andwent on an extended sabbatical leave. In many ways,during the intervening dozen years, the world hadbecome a very different place from the one we entered.

The DSM-IV, still new in ’96, was alreadyabout to give way to DSM-V, an early version ofwhich is currently posted to the World Wide Web athttp://www.dsm5.org.

Along with that, the phrase “posted to the web”had become a lingua franca term, now that the tech-nological spawn of Deep Blue had confidently takenup residence everywhere. Data was multiplying inthe smart phone attached to your belt-loop or inyour purse, percolating in the dashboard of your car,leaching into in the very air we breathe (courtesy ofa development some in the IT department were call-ing “cloud computing.”)

Correspondingly, the typical reaction of the biologicalbrain, in response to the problematic events of 2008, wasto reel. These occurrences included the global financial cri-sis and cascading bankruptcies of many of the planet’sbedrock commercial institutions.

A plot to blow up the Printemps department store inParis was foiled, and the forgotten ruins of an entire ancientcity in Peru were uncovered. Premier Charest was re-elected;Governor Blagojevich was arrested. And just to serve as asecond nostalgic bookend to the epoch, O.J. Simpsonreturned to public attention, this time when he was sen-tenced to a jail term of 33 years after a misunderstandingwith some sports memorabilia collectors in a Las Vegashotel room, a dispute in which firearms played a role.

Whether you happen to be based in an academic cen-tre, or practice in the community, it seems likely yourresponse to these developments was not unlike ours: Itseemed to be the right time to take a break. That respitenow ends, with the publication of this edition.

During our pause, we entertained the usual self-directed questions that anyone is expected to grapple with,

while the sabbatical clock ticks. Who are we? What are wedoing here? What is the point of what we do?

We’ll share our answers below.Who are we? The Chronicle is an independent Canadian

clinical news service, serving medical specialists, oralhealth practitioners, and the life sciences industry. Weare content creators: experienced tellers of storiesabout clinical medicine.

What are we doing here? The Chronicle is here to serve asa conduit for the best, and most interesting, ideas inthe CNS sciences. We connect the minds whichdevise and shape these concepts with those who maywish to apply them in practice, for the purpose ofimproving the lives of their patients. The delivery sys-tems we use are (as the IT department annoyinglysays) “multi-platform.” That means we will apply a

variety of technologies toward the purpose ofknowledge-exchange: print, interactive, broad-cast, and whatever happens to evolve in the daysahead. (Speaking of which, please see thenotices in this issue regarding the “GreenEdition” of The Chronicle, ideal for the iPad.)What is the point of what we do? TheChronicle aspires to bring you essential informa-tion that can be accessed easily in a convenientform. We hope to punch several large holes insome of the silos that separate the CNS subspe-cialties. Our emphasis will be on the intersec-tions of the mind sciences, by which we don’trefer exclusively to co-morbidities. We will payparticular attention to current findings of how— to pick one random example — inflammato-ry disease may relate to mood disorder, whichmay in turn relate to early-onset dementia.

This is not, however, a journal of theory;The Chronicle will continue to be all about PracticalTherapeutics. Our editors will seek to save you time, byproviding a brief summarized overview of the month’sdevelopments in the neurosciences, along with clearlyidentified links to additional information sources. Thosesources may be documentary, or in the form of multime-dia exercises or lectures, to enhance your understanding ofthe specialties. In concert with our Editorial Board, wewill play a leadership role in prompting discussion, pro-moting discovery, encouraging open-mindedness, andshedding light on best practices. We recognize that theendpoint is behavior change, and that an important divi-dend received through that process is a sense of pleasure.

It’s already a tremendous pleasure, simply being withyou again. We invite you to give us hell whenever youthink we’ve got things wrong. We trust that you won’t hesi-tate to let us know, in no uncertain terms, should we evercommit the offense of wasting your time. Please share yourthoughts on any of the material in this issue. Sabbaticalsare fine, but, you know, it is surely great to be back.

The Chronicle of Neurology & Psychiatry is published six times annually by the proprietor, Chronicle Information Resources Ltd., with officesat 555 Burnhamthorpe Rd., Ste. 306, Toronto, Ont. M9C 2Y1 Canada. Telephone: 416.916.2476; Fax. 416.352.6199. E-mail: [email protected].

Contents © Chronicle Information Resources Ltd., 2010, except where noted. All rights reserved worldwide. The Publisher prohibitsreproduction in any form, including print, broadcast, and electronic, without written permissions. Printed in Canada. Mail subscriptions: $72 peryear in Canada, $125 per year in all other countries. Single copies: $12 per issue (plus 13% HST)

Canada Post Canadian Publications Mail Sales Product Agreement Number 40016917The Publisher certifies that advertising placed in this publication meets Revenue Canada requirements for tax deductibility.Volume 13, Number 1, published October 2010

ISSN 1209-0565

Chronicle 2.0belongs to whatwe will categorizeas the ‘post-O.J.Simpson era’”


Trap Editor


TheThe colour colour of of relief reliefinin major major depressive depressive disorder disorder11

See prescribing summary on page 19

CountCount on on

forfor powerful powerful symptom symptom relief relief

epressive nlafaxine trated in

with the the rate

erhidrosis

e of 18. e oxidase

patients e to risk selective nephrine otonergic toms that fl ushing,

euroleptic ility with changes

nd coma. st 7 days nate and

nstrating d-release, nlafaxine ontaining

l safety (SSRIs)

of these ted with

ncreased lacebo. s well as

usions on ss. There SRIs and

adults, akathisia, ggression ed within

or other advised therapy egimen. nal and

NOT be nuation

made to nt drug,

abrupt


Trap Editor


Denitrol cUnivBeha“F

ing mwomC

and

OnsaihohoSUPPcatespatiefaciled bComandInstiO

accestertiaaccothe f“W

menwas latedlessmanLondIn

patienessatricequagivenwasacceinco“I

stroneffecbe imice sfromsaiddirecHeaMid

4n October 2010

Genetic researchers give mice OCDsymptom similar to trichotillomania

De

Obsessive compulsive disorder, or

OCD, may soon be better understood

and researched, now that scientists

may have found a way to inflict labo-

ratory rats with the condition, said a

recent article (SciBX; May 16,

2010; 3(18)).

According to the article titled

“Mouse model of obsessive-compul-

sive disorder,” mice exhibited exces-

sive grooming, during inactivation of

Slitrk5, an OCD symptom comparable

to the human behavioral disorder, tri-

chotillomania, that causes people

to pull out hair, said author

Francis S. Y. Lee, MD, PhD,

associate professor, Department

of Psychiatry and Department of

Pharmacology, Weill Cornell

Medical College, New York City, told

Medscape Psychiatry.

He writes: "It seems to be not

exactly like trichotillomania. Tricho-

tillomania [individuals] will actually

groom others, but these mice will only

groom themselves.”

—More information:

http://ow.ly/2ETTC

Neurology EditorRichard Gladstone,

MD, FRCPCPsychiatry Editor

J. J. Warsh, MD, FRCPCEditor, Innovation in the Mind Sciences

Roger S. McIntyre,MD, FRCPC

Editorial DirectorR. Allan Ryan

Senior Associate EditorLynn Bradshaw

Assistant EditorJosh Long

PublisherMitchell Shannon

Sales DirectorPeter M. Stamp

Production and CirculationCathy Dusome

ComptrollerRose Arciero

s Altelier:This figurative sculpture depicts

a patient from the former Toronto

Hospital for the Insane (now

CAMH.) The creator of this

sculpture and five others, from

the Workman Arts Project of

Ontario, selected six patients

from the 2000 book by Geoffrey

Reaume, Remembrance of

Patients Past: 1870-1940, to

depict in the form of sculptures.

The exhibit was shown at the

CAMH Queen Street site during

the Nuit Blanche festival last

year. The exhibition was called

“inSanity: The Story Behind the

Wall.”

s Quick-start guide to The Chronicle, October 2010:Depression: Atypical antipsychotic approved for MDD (page 6)Pain: First Canadian opioid guideline has no maximum dose (page 8)Schizophrenia: Newly approved antipsychotic has fewer side effects(page 10)Movement disorders: Antibiotic lessens movement disorder symtoms(page 12)Migraine: Depression screening should follow migraine diagnosis (page14)ADHD: Nasal delivery of ADD prodrug no more addictive than oral(page 22)

©Im

age

court

esy

of

Jere

my

Burg

in/F

lickr


Trap Editor


Denicontinized tobacco may be an effective way to con-trol cravings for the addictive substance, says a DalhousieUniversity study published in the March issue ofBehavioural Pharmacology (2010; 21(2):144-152).

“Findings suggest that DT is effective in acutely reduc-ing many smoking abstinence symptoms, especially inwomen,” said the study.

Called “The effects of nicotine, denicotinized tobacco,and nicotine-containing tobacco on cigarette craving,

withdrawal, and self-administration in male and femalesmokers,” the study included smokers four groups ofsmokers with equal numbers of males and females. Theywere then given one of the following: nicotine inhalers,placebo inhalers, nicotinized tobacco, or denicontinizedtobacco. They were then asked to use their assigned prod-uct, after which they assessed their cravings using visualanalogue scales and brief questionnaires, and were permit-ted to smoke a cigarette of their preferred brand.

The participants who were given denicotinized tobac-co and nicotinized tobacco associated the experience with“increased satisfaction and relaxation.”

Though both the nicotinized and deni-cotinized inhalers were found to be effectiveat delaying the subjects’ next cigarettes, only the tobacco,both nicotinized and denicotinized, reduced the numberof cigarettes the subjects smoked.

—More info at http://ow.ly/2EU6y

Ontario programsaid to reduce homelessness afterhospital discharge SUPPORT STAFF AND HOUSING ADVO-cates help reduce homelessness inpatients discharged from psychiatricfacilities, says a joint study conduct-ed by CAMH in London, Ont.,Com munity Services in London,and the Lawson Health ResearchIns titute.

Of the 243 individuals whoaccessed this service at both acute andtertiary sites, only three were homeless,according to a press release issued bythe facility.

“We determined the cost of imple-menting and maintaining the programwas less than the increased costs associ-ated with housing individuals in home-less shelters,” said Ross Fair, generalmanager, Community Services City ofLondon.

In the first phase of research, 14patients with no history of mental ill-ness were discharged from the psychi-atric hospital and divided into twoequal groups. One was a control groupgiven the usual level of care. The otherwas provided intervention includingaccess to a housing advocate andincome support staff.

“It is our hope that throughstrong community partnerships,effective programs and resources canbe implemented across multiple serv-ice sectors to help in the transitionfrom hospital to a permanent home,”said Michael Petrenko, executivedirector of the Canadian MentalHealth Association LondonMiddlesex.

—More information:http://ow.ly/2EUoP

a

TWO NEWLY DISCOVERED FACTORS

suggest damage may continue tooccur long after a first stroke even inyounger adults, says a study out ofthe Hopital Notre-Dame in Mont -real presented at the Canadian StrokeCongress.

“When younger people come inwith a first stroke, they may alreadyhave signs of pre-existing damage intheir brains,” said lead investigator, Dr.Alexandre Poppe. “They are at higherrisk of having a second stroke.”

This is due to leukoaraiosis andsilent brain infarcts (SBI), two fac-tors found to increase risk of strokein people aged from 18 to 50. Asthese conditions may be asymo-tomatic, Dr. Poppe said patients whohave had a stroke should receive anMRI scan.

“A CT scan alone is often insuffi-cient to pick up the brain changescaused by covert brain infarcts,” hesaid, “With an MRI you can actuallytell how old the lesions are. You can seeif they occurred before the stroke.”

ANTI-COAGULANT THERAPIES HAVE

saved many stroke patients, but anew device could save more still, saida University of Calgary researcher.

“This unique new procedure isreally quite miraculous,” said Dr.Mayank Goyal, the director of theSeaman MR Research Centre at theUniversity of Calgary, while present-ing his work at the Canadian StrokeCongress.

The Penumbra System, whichDr. Goyal said can save an hour oftime loosening the clot, is still beingtested in several stroke treatmentcenters across Canada.

“It requires years of training to beable to do this,” said Dr. Goyal. “Itplaces enormous demands on theinterventionalist, on the imagingspecialists, and on the emergencyteam that gets the patient to a desig-nated stroke care facility. Teamworkis key for success.”

He said there to 30 and 40 physi-cians across Canada qualified to usethe Penumbra system.

More risk for strokepatients under 50

Robot loosens clotsfaster than thinners

—Read these and other Canadian Stroke Congress abstracts in Stroke: Journal of the American Heart Association at http://nn.nf/838h

© I

ma

ge

co

urt

esy o

f L

ori B

arr

on

/Ca

na

dia

n S

tro

ke

Ne

two

rk

October 2010 n 5

Denicotinized tobacco could assist in smoking cessation: Dalhousie study

edul-es-of

bletri-plehorhD,entofell

old

notho -allynly

on:TC

“The human brain starts working the moment you are born and never stops

until you stand up to speak in public.” —George Jessel

T o p o f t h e m o n t hT o p o f t h e m o n t h

nn Newfoundland will be funding thestudy of the controversial multi-ple sclerosis therapy previouslyoffered by Dr. Zamboni in Italy.The announcement was madeby Newfoundland HealthMinister Jerome Kennedy, aftera meeting with provincial andterritorial counterparts. None ofthe counterparts were preparedto launch similar studies, but didsay they would be willing toaccelerate trials if research haspromising results. —More infoat http://ow.ly/2FjNT

n n The associate dean of learningand rural initiatives at theUniversity of Calgary medschool, Dr. Doug Myhre, said agroup of students have startedlearning rural medicine inLethbridge. “Earlier exposure torural medicine and rural commu-nities is great for students whoget to learn in that clinical set-ting,” Dr. Myhre told theLethbridge Herald. One studentcalled it a ‘fantastic idea’ thatwould provide her hands onskills and “a chance to focus onpatients.” Lethbridge is thefourth largest city in Alberta,with a population of 86,659. —More info at http://ow.ly/2FjPN

O n t h e w e bO n t h e w e b

n n Google has introduced additionalfeatures that allow patients totrack stress, sleep quality, bloodpressure and exercise. The appli-cation also allows patients totrack their chronic illnesses in theform of a progress journal, andstore advanced directives withinstructions should the patient beunable to communicate theirwishes during emergency or endof life care. —See it athttp://health.google.com

e 8)

ms

age

al

DDeevveellooppmmeennttss ffrroomm tthheeCCaannaaddiiaann SSttrrookkee CCoonnggrreessss


Trap Editor


I n

A pn A

LUni23,0

fromUniv

servemedOntaLong

In 19contsionpsycRwaabsothereall ojust treat

“It’s you’rthe rdoinamocom

part bly dlinesorgainkli

Canence

Whetheynot btheythinkI thilocatthereincrelosseillne

exaction

by Pauline Anderson, Correspondent, The Chronicle

QUETIAPINE FUMARATE EXTENDED RELEASE is the firstatypical antipsychotic to be approved in Canada foradults with major depressive disorder (MDD) who

have not found other antidepressant drugs effective.The approval of the antipsychotic for the treatment of

MDD represents a welcome addition to the pharmaceuticaltools available to treat one of the most common psychiatricdisorders, said Dr. Tom Janzen, a primary care physician spe-cializing in mental health at Regional Mental Health Care inLondon, Ont.

The availability of this therapy givesphysicians a much-needed option fortreatment resistant patients, especiallyconsidering the success rate associatedwith current antidepressants is “muchless” than 100%, said Dr. Janzen. “Theaddition of new treatment options iswelcome as many of our patients con-tinue to suffer with symptoms today.”

This is especially true since patientswith depression have such varied symp-toms. “Depression presents with many different faces andmore and more physicians are targeting the symptoms of thedepressive episode as opposed to treating all depression asthe same entity,” said Dr. Janzen.

Quetiapine fumarate extended release is particularly use-ful in patients who are bothered by sleep disturbances andanxiety, said Dr. Janzen. “It gives them that early relief ofanxiety which is often extremely beneficial.”

This new drug has a different side effect profile thanother antidepressant medications. Whereas sexual and gas-trointestinal side effects are issues with SSRIs and SNRIs, forquetiapine fumarate extended release the concerns are seda-tion, lipid abnormalities, metabolic syndrome and diabetes,said Dr. Janzen.

Weight gain is a side effect of both quetiapine fumarateextended release and SSRIs and is highly variable. “I havesome patients who take [quetiapine fumarate extendedrelease] and have not had any weight gain while others havehad significant weight gain,” said Dr. Janzen, who addedthat adverse events and weight gain are extremely variable.

Before he gives patients a prescription for quetiapinefumarate extended release, Dr. Janzen will obtain a baselinemetabolic profile. “I need to know their cholesterol and glu-cose levels as well as their weight and BMI prior to initiatingthe treatment.” He then monitors these parameters duringthe treatment.

Some psychiatrists may feel uncomfortable managingpatients at high risk for metabolic syndrome or glucoseintolerance. “They may not be as comfortable managingsome of these metabolic parameters as primary care physi-cians are. These are issues that most primary care physicianswill see and manage every day.” said Dr. Janzen.

Dosing depends on whether the drug is used to treat psy-chosis or depression. Doses for psychosis range from 600 to800 mg a day and for anxiety and depression, probably 150to 300 mg a day, said Dr. Janzen.

Adherence rates might improve with this new drug, Dr.Janzen said, “once people get well and recover from theiracute depression, adherence is dictated by the convenienceof the medication, and part of the convenience is arounddosing; once daily dosing is much better tolerated.”

Results from six trials that assessed the efficacy and safetyof quetiapine fumarate extended release showed that thedrug was statistically superior to placebo in the reduction ofdepressive symptoms, although there is no evidence that thedrug is superior to other antidepressants.

MDD will affect about an estimated 8% of Canadians atsome time in their life. About 38% of Canadians living withMDD indicate that they seek treatment for their conditionfrom a primary care professional.

Quetiapine fumarate extended release is also approved byHealth Canada for the treatment of schizophrenia, bipolarmania, and bipolar depression in adult patients.

Asked to comment on the new drug, Dr. Irvin Wolkoff, aToronto psychiatrist, said that although he hasn’t yet pre-scribed it, he’s “pleased” to have a medication from a differ-ent class than the SSRI and SNRI antidepressants to use inthe treatment of depression.

“I am prepared to consider [quetiapine fumarate extendedrelease] for patients who are intolerant of, or receive no ben-efit from, first-line treatment with SSRI preparations.”

Non-proprietary and brand name of therapy: Quetiapine fumerate(Seroquel XR, AstraZeneca).

Atypical antipsychotic approved for MDD in Canadan Quetiapine fumarate extended release capsule an alternative for some patients

Quarter of fathers have postpartum depression, says an AMA studyFathers are also afflicted by postpartumdepression, said a study in the Journal ofthe American Medical Associ-ation, (May2010; 303(19):1961-1969).

“Paternal depression also showed amoderate positive correlation with mater-nal depression,” the authors of the meta-study wrote in their conclusion.

The results found that the rate of post-partum depression for males is twice therate of depression in the overall popula-

tion, 10.4%, over a period of six monthsafter child birth, and rises to 25.6%between three and six months.

James Paulson, PhD, co-author of thestudy, clinical psychologist and associateprofessor of pediatrics at Eastern VirginiaMedical School in Norfolk, Va. told theMontreal Gazette the stress associatedwith a new child may be the cause of post-partum depression in women, rather thanhormones.

John Oliffe, RN, MEd, PhD, professorat the University of British Columbia, andalso co-author, told the Gazette of Mont -real a sharp increase in the rate of depres-sion for males between three and sixmonths after the birth of the child may bebecause that is around the time wherefathers return to work and then have to jug-gle the stress of raising a family with theresponsibilities associated with their jobs.

The Globe and Mail (May 18, 2010)

provided first hand accounts of fatherswith postpartum depression, explaininghow fathers would be uniquely affected.Chris Hale, whose wife also had postpar-tum depression. The 37-year-old said thelowest point of his ordeal was when hiswife called him at work to ask him to comehome, because she was afraid she wouldhurt their daughter.

—More information:http://ow.ly/2FoGH

6 n October 2010

Dr. Tom Janzen


Trap Editor


I n c o n v e r s a t i o n

A psychiatrist reflects on his (unplanned) career in the Canadian Forcesn A conversation with Lt.-Col. Rakesh Jetly, a military psychiatrist with over two decades in the service

Lt.-Col. Rakesh Jetly, MD, is a military psychiatristcurrently a senior medical advisor in theCanadian Forces.

In 1994, he was deployed to Rwanda as part of theUnited Nations humanitarian mission that treated23,000 people.

Upon his return, he applied for postgraduate fundingfrom the Canadian Forces, and in 1996 returned to theUniversity of Toronto to begin psychiatric training.

He’s an officer in the Order of Military Merit. He hasserved 21 years in the military, starting as a general dutymedical officer and flight surgeon at CFB Borden inOntario. He spoke with CHRONICLE assistant editor JoshLong.

In 1994, you deployed to Rwanda as part of Canada’scontribution to the Untied Nation's humanitarian mis-sion. How did that experience shape your view ofpsychiatry in the CF?Rwanda was a phenomenal experience. [...] It was anabsolute privilege to go there. [...] When we arrived,there were body parts everywhere, mass graves, danger,all of the things you find in a war zone. But the soldiersjust did their job. They just looked after people. Wetreated 23,000 people while we were there.

I remember I came back and my boss said to me,“It’s great that you’re back, but there’s nothing thatyou’re going to do that’s going to compare to that forthe rest of your career.” Because the stuff that we weredoing there, the amount of infectious disease, theamount of trauma, nothing back in-garrison care wouldcompare to what we did.

We were there as part of the Canadian Forces, notpart of the overall UN mission, and I saw how incredi-bly difficult it was for the soldiers working on the front-lines. I saw the incredible amount of work that anorganization like ours was able to do, but I also got aninkling of the price.

I did not have the intention of staying in theCanadian Forces for my entire career, but this experi-ence changed everything.

When Canadian Forces members return from tourthey’re sent to a third location decompression site-not back home or somewhere in the war theatre–sothey can have a chance to relax. What role do youthink that plays in the incidence of PTSD cases?I think there’s a risk of overstating the impact of thirdlocation decompression on mental illness. I also thinkthere’s a risk of understating it. If somebody has had anincredibly difficult tour, and they’ve experienced hugelosses, five days in Cyprus will most likely not preventillness.

I think the really important goal of the program isexactly what it is called–it’s decompression, it’s a transi-tion time. The level of satisfaction [with decompres-

sion] is huge. If you can imagine Kandahar, and I’vebeen there twice, you’ve got to carry your weapon allthe time except when you’re in the shower or the gym.In decompression, you’re out of uniform and you're notin battlemind anymore. You're getting some briefingsand you're getting some education.

Being in a place like Cyprus where you can have abeer with your friends, you can toast lost comrades, thechaplains have a little service for the people that diedduring the rotation, maybe you need to let loose a lit-tle. So, the idea of transitioning back toward real lifeoccurs during those few days. It doesn’t do the wholejob. The education that we provide as mental healthprofessionals during decompression specifically targetsthe gaps. For instance, [participants] get a chance todiscuss parenting and challenges that may happen whenthey come home.

What are other common ailments military psychia-trists find in their patients?Our soldiers suffer from all of the other illnesses thatmembers of Canadian society suffer. With depressionpushing nearly 20 per cent of lifetime prevalence insociety, CF members suffer from depression, sufferfrom OCD, suffer from panic, suffer from all these dif-ferent mood and anxiety disorders. In theatre, we saw afair amount of trauma-related illness–the acute stressdisorder, post-traumatic stress disorder–but a lot of the

cases that we saw were depression, difficulties on thehome front, these types of things.

We have to, in a very timely way, provide care, thebest care possible and then really make very good assess-ments as to whether or not ill and injured personnel aresafe to continue in the Canadian Forces.

How do you make people comfortable enough to talkabout these issues?I say quite often that these are treatable illnesses. If [asoldier] is suffering from a psychological illness andcomes forward for care, the first objective I or any of thepeople that work within mental health have is to keep[him or her] in uniform. People that have [PTSD] havegone back to Kandahar, they have deployed and sailedagain.

But the most important thing that I say, and I lookpeople in the eye when I say this, is there's no 100 percent guarantee [when we treat] any illness. But untreat-ed, the illness is going to cause problems. It shows up atwork. It shows up in family life. The best chance some-body has of retaining a meaningful career within theCanadian Forces is to have treatment. People aren't thatsuccessful at hiding it all.

How has your view of the Canadian Forces approachto psychiatric issues changed?In 2000, I remember chairing one of the meetings onmental health, and I said, “We’ve got our work cut outfor us.” Since, it has completely turned around. Wehave risen to the occasion and implemented a compre-hensive pre- and post-deployment program that is theenvy of our allies. Three to six months after comingback, every single soldier that returns is administered apost-deployment screening. If any mental difficultiesare flagged, soldiers get an interview with a mentalhealth professional. On periodic health exams, whenCF personnel have their annual medical, specific men-tal health questions are now always asked.

[Now,] I could be the psychiatrist in-theatre and itwould now be typical to have [people in leadershiproles] walk-in and say, “Hey doc, would you mind see-ing some of my guys, they’ve gone through rough stressthese last couple of weeks, and I just want to make surethey’re OK.” So, it’s a very caring chain if command.[...]We’ve also asked our soldiers specific questions like,“Would you think less of somebody if they were seek-ing mental health care?” We asked 2,500 soldiers a cou-ple of years ago, and the positive was seven per cent.And if you asked that question of employers in the pri-vate sector, it’d probably be much higher than that. Sothe idea of stigma really isn’t as big a problem anyore.It’s never going to be gone, but it’s really not an over-whelming problem.

October 2010 n 7


PRISTIQ®


ineine

glu-inging

ingoseingysi-ans

psy-0 to150

Dr.heirnceund

fetythe

n ofthe

s atwithion

byolar

ff, apre-fer-e in

deden-

te

rsg

d.r-esed

n:H

Lt-Col. Rakesh Jetly, MD‘The experience changed everything’


Trap Editor


Opn Gby JoAssist

Slist.

contmed

currepain agemto th

said cliniopio

couldopio

compnary

Ira

US

W

8 n October 2010

these are premature and relate more to addiction medicinethan pain medicine,” said Barry D. Ulmer, executive directorof the Chronic Pain Association of Canada, in an opinion arti-cle written for THE CHRONICLE OF NEUROLOGY & PSYCHIA-TRY (see page 18).

On the other side of the conflict are those concerned thelack of a maxi-mum dose may bea deficit in theguidelines. Dr.Irfan Dhalla is apharmaceu-ticalpolicy researcherat St. Michael’sHospital in Tor -onto and authorof the Canadian Med-ical Association Journal study, “Pre -scribing of opioid analgesics and related mortality beforeand after the introduction of long-acting oxycodone,” (Dec.8, 2009; 181(12)), and he is a physician concerned of thelack of a maximum dose.

Dr. Dhalla said a major issue he had with the guidelinewas the amount of opioid equivalent defined as a watchfuldose. Within the guideline, a watchful dose is defined as thedose which “requires careful reassessment of the pain and ofrisk for misuse, and frequent monitoring with evidence ofimproved patient outcomes.”

At 200 mg, Dr. Dhalla said the watchful dose is too high,and that studies had shown patients get a good result after120 mg of opioid equivalent.

“One could make a case that’s where a physician shouldbe watchful,” said Dr. Dhalla.

As well, Dr. Dhalla said, the guidelines should include amaximum dose, which the guideline does not include. Thissuggestion is a point of contention for Dr. Norman Buckley,a member of the national advisory panel that helped draft

the guidelines.Of doses

approaching andexceeding 200 mg,Dr. Buckley said,“everybody whotreats chronic painrealizes that thereare also a numberof patients, whowe think are gen-

uine, who take doses much greater than that and appear tohave benefits from the increased dose.”

Dr. Buckley is the chair of the department of anesthesiaat McMaster University’s Michael G. DeGroot School ofMedicine in Hamilton.

Dr. Buckley said he stands by the guidelines as they are,particularly by the decision to omit a maximum dose.

This is because, Dr. Buckley said, there is a differencebetween what exists in published studies, and what physi-cians find through clinical experience.

“Part of that problem may be that the published studiesare of relatively short duration and the clinical experience islong duration,” said Dr. Buckley, who also said most studiesdon’t look further than six months, a length of time that hisclinical experience far exceeds.

“I’ve been seeing patients that I’ve been caring for, forover ten years for example. That may drive some of the dif-ference between what clinicians may experience or believe,and what’s published information.”

Both Drs. Buckley and Dhalla said pain studies are limit-ed to six months, but Dr. Dhalla said physicians should waituntil there are more studies before they prescribe high dosesof opioids owing to the danger of overdoses, whereas Dr.Buckley said this is only evidence there is insufficient longterm research being conducted.

Dr. Buckley expressed a concern as well, that some aremisinterpreting the deliberate choice of words, that 200 mgis a watchful dose rather than a maximum dose, since con-fusing the two could cause problems for physicians whowould prefer to avoid insurance bureaucracy.

“The greatest anxiety about the guidelines was the factthat people were already starting to get notes from insurancecompanies,” he said, “for example, saying ‘the recentCanadian guidelines suggested the maximum dose for 200mg, we’re not going to pay for our client’s medication beyondthat, please advise how you’re going to deal with this.’”)

While Dr. Buckley said this is a legitimate clinical ques-tion, he also said responding to inquiries such as these thiscan add to an already heavy workload.

“To create another letter to send to the insurance compa-ny, it takes time and it’s just another aggravation,” he said.

—What’s your view concerning the new guideline?Contact The Chronicle at [email protected]

First Canadian opioid guideline has no maximum dose

P a i n n e w s

n A survey from the Pain Society ofCanada found 85% of participantsin their study were afflicted withmoderate to severe pain for the lastthree months prior to the survey. Inaddition, 30% of the participants inthe study said they experiencedpain daily, or a few days a week,meeting the definition of chronicpain. In all, 55% of respondents didnot seek treatment from a healthcare provider, and of those who didseek treatment, 31% were dissatis-fied with the treatment. Most ofthose with pain treated their painsymptoms with over-the-countermedication, but one in six respon-dents said they turned to alcohol,illegal drugs, or non-prescribedmedications to cope with their pain.

O n t h e w e bn The science blog Respectful Insolence

published a scathing review of anacupuncture study that some say isproof of the efficacy of acupuncture.“The study actually shows quite a bitof interesting biochemistry behindthe pain response,” said the psy-donymonomous author, Orac, whosaid he is a physician-scientist pos-sessing both an MD and a PhD butdoes not reveal his name out of con-cern patients would see this blog atthe top of Google searches.“Unfortunately, what it doesn’t showis that ‘acupuncture works,’ despiteall the whining about ‘arrogance’from the study’s lead investigator. Allit shows are two things: (1) that achemical called adenosine isreleased when needles are stuckinto the skin of mice and twisted and(2) that adenosine decreases thepain response.”—Read RespectfulInsolenceat http://nn.nf/445h

—continued from page 1

Opioid related deaths on the riseAccording to the Canadian Medical Association Journalstudy “Prescribing of opioid analgesics and related

mortality before and after the introduction of long-acting

oxycodone,” opioid-related deaths

are on the rise (Dec. 2009; 181

(12): 891–897).

Dr. Dhalla and colleagues

report that the number of annual

deaths related to oxycodone use in

Ontario increased about five-fold

between 1999 and 2004 and that

there was a 41% increase in all

opioid-related deaths from prescription and illegal opi-

oids, said the study.

“We know that in Ontario, 300 to 400 deaths are

related to opioids each year,” said Dr. Dhalla, lead

author of the study. “Most of these deaths are acciden-

tal. Others have shown that the risk of harm increases

when higher doses are used. So I think physicians

ought to be very reluctant to prescribe high-dose opi-

oids. From a safety standpoint, it makes sense to me to

be conservative.” Of the deaths studied, 66.4% were

within a month of the patient’s latest visit to a physician.

—This CMAJ study is availableat http://nn.nf/446h

Everybody who treats chronic painrealizes that there are also a numberof patients who we think are genuinewho appear to have benefits from theincreased dose

Dr. NormanBuckley

DDrr.. IIrrffaann DDhhaallllaa


Trap Editor


Opioid guideline may provide relief to pain patients on wait listn GPs hesitant to take on pain maintenance plans contribute to wait period for chronic pain clinics, say guideline’s authorsby Josh Long,Assistant Editor, The Chronicle

SUPPORTERS HOPE THE Canadian Guideline for Safe and Effective Use of Opioidsfor CNCP (Chronic Non-Cancer Pain) may reduce the wait for chronic painclinics and prevent patients from deteriorating on what can be a lengthy wait

list.“On every given day, a third of my day is taken up doing maintenance, and that

contributes to the one year waiting list to get in here,” said Dr. Norman Buckley,medical director of the Pain Management Centre at Hamilton Health Sciences.

He said that means he would have time to see one-third more patients than hecurrently does, if other physicians were willing take these patients and maintain theirpain management plans already developed for them at multidisciplinary pain man-agement clinics like his own. But because not enough do, he said, “that contributesto the one year waiting list to get in here.”

“If a management plan includes opioids some family doctors won’t do that,”said Dr. Buckley. Out of a desire to control the size of their own wait lists, some painclinics will refuse patients who do not have a family physician willing to prescribeopioids as part of a management plan.

“One of the anxieties in the past for physicians was that one of the ways youcould come to the attention of your college disciplinary committee is by prescribingopioids in a way that attracts attention for some reason,” Dr. Buckley said.

He also said such fears are unfounded.“Most commonly, that’s because somebody has made a complaint or you had a

complication in your practice and that’s how you get to the attention of a discipli-nary committee. Then the review of your practice tends to focus on how well you’ve

kept records or what your decision-making process is.”Manon Choinière, PhD, a professor at the Université de Montréal said she hears

a lot of preconceptions as a clinical researcher. “I’m always amazed by the amount of preconceived ideas, that people and even

MDs have about opioids. Of course, you have to be careful and of course there is apotential for abuse, but so many patients are suffering in a useless manner becausethese people have their preconceived ideas.”

Dr. Choinière is a lead author of “The Canadian STOP-PAIN project,” a two-part study published in the Canadian Journal of Anesthesia (June 2010; 57(6):530-8).

Chief among these “preconceived ideas,” Dr. Choinière said, is what she calls anexaggerated fear of malingering.

“It does happen that the patient says they have more pain than they do in real-ity,” Dr. Choinière said. “But very often we will penalize eighty per cent of the pop-ulation with chronic pain because we are afraid they are malingering.”

Whatever makes family physicians reluctant to prescribe opioids, both she andDr. Buckley say it contributes to a growing problem: a wait list. Dr. Choinière said

I’m ... amazed by the amount of precon-ceived ideas, that people and even MDshave about opioids... so many patients aresuffering in a useless manner because thesepeople have their preconcieved ideas

October 2010 n 9

Dr. Manon Choinière

IranIran A report in the Canadian Medical AssociationJournal (May 18, 2010; 182 (8):768-773) findsevidence supporting the idea that botuliniuminjections may provide relief to patients with ten-nis elbow. Iranian scientists out of the ImamKhomeini Hospital Complex, affiliated with theTehran University of Medical Sciences, injected48 tennis elbow patients with botulinium.Although the injections reduced levels of strengthin the patients’ muscles, pain was reduced as well.S.M. Javad Mortazavi, PhD, an assistant profes-sor at the Rafsanjan University of MedicalSciences and the study’s principal author, said thelocation of the injection should be “as close aspossible to the neuromuscular junction plates toensure proper paralysis of the muscles.”

—Read this article in the Canadian MedicalAssociation Journal at http://nn.nf/384hhttp://nn.nf/384h

USAUSA People with arthritic knee pain can find relief bywearing flatter and more flexible shoes according toa study in the journal of Arthritis Care and Research(July 2010; 62(7):903-906) “[Such] shoes mayreduce the complications associated withosteoarthritis in the joints,” the study’s authorsreported. “Footwear with flat and flexible solesrestore the pressure to the bottom of the foot, andover time reduce the damage to the knee and, as aresult, can help stop the development ofosteoarthritis,” said Dr. Najia Shakoor, an authorof the study. The study came to this conclusionafter the facilitators analysed the gait of 31 peoplewith symptoms of osteoarthritis. The patients wereasked to walk in various types of shoes. The resultsshowed that the pressure of the knee joints of thosewho wore clogs and stability shoes was 15% high-er than those who wore flat walking shoes, flip-flops, or walked barefoot.

—Read this article in Arthritis Care and Research at http://nn.nf/380hhttp://nn.nf/380h

Scotland Scotland A study characterizing chronic induced bonepain, the most common form of pain in patientswith cancer, was published online in the journal,Support Care Cancer (August 1, 2010). “Worstpain most accurately reflects the characteristics ofpain flares and functional impairment.Breakthrough pain is often unpredictable, suddenonset and short duration,” the authors wrote. Datawas also collected using the McGill PainQuestionnaire, the Brief Pain Inventory, and abreakthrough pain questionnaire. “Patients withbreakthrough pain had higher total BPI interfer-ence scores,” said the study, “than those with nobreakthrough pain; median (IQR); 35.0 (2.5-44.7) vs. 18.5 (5.5-26.7), p < 0.01.” In all, 48% ofpatients had breakthrough pain. The most com-mon words to describe the pain were annoying,gnawing, aching, and nagging.

—Read this article in Support Care Cancer athttp://nn.nf/622hhttp://nn.nf/622h

Sweden Sweden A cross-sectional, correlation study out ofStockholm evaluates the outcome of patientsundergoing lumbar fusion surgery. “This studyhighlights the strong influence and mediation rolesof psychological factors on pain, mental health,fear of movement/(re)injury, disability andHRQOL [health related quality of life] in patientsscheduled for lumber fusion,” the study’s authorswrote, published in Physiotherapy (Sept. 2010;96(3):213-221). The study followed 107 chronicback pain patients scheduled for lumbar fusion sur-gery, and the effectiveness of the surgery was meas-ured by multiple questionnaires and scales thatcompared the mobility, disability, and level of painafterward against the measures that were estab-lished before surgery. “Pain catastrophising signifi-cantly mediated the relationship between painintensity and mental health. Control over pain sig-nificantly mediated the relationship between men-

tal health and functional disability,self-efficacy and pain outcomeexpectancy significantly mediated therelationship between mental health andHRQOL, and self-efficacy also significantly medi-ated the relationship between pain intensity, fear ofmovement/(re)jury and functional disability.” Themodel developed from these factors explained 28%of the variation in mental health, 30% of variationin fear of movement and injury or aggravation ofan initial injury, 52% of the variation in function-al disability, and 42% of the variation in HRQOL.

—Read this article in Physiotherapy athttp://nn.nf/619hhttp://nn.nf/619h

AustraliaAustralia The Sydney Morning Herald (May 13, 2010)reports on a video game has been been shown toprovide nonpharmacological pain relief, say thegame’s inventors. “Virtual reality is unusually effec-tive at distracting patients from their pain,” saidHunter Hoffman, PhD, a psychiatrist at the HumanInterface Technology Laboratory at the University ofWashington. Dr. Hoffman and a computer scientist,Dave Patterson, PhD, are the inventors ofSnowWorld, which uses virtual reality in head-mounted displays in which players shoot snowballsat penguins. Its been used to treat burns victims bydistracting them from their physical condition.“Patients using SnowWorld are reporting largereductions in pain–typically 35 to 50 per cent–dur-ing daily debriding and physiotherapy sessions,” saidDr. Hoffman. “Brain scans also show large reduc-tions of arousal in the pain regions of the brain whenpatients are playing the game.” Albert Rizzo ofVirtual Reality Psychology Lab has adapted thisapproach to use virtual reality to help ex-servicemencope with PTSD. The project receives funding fromthe U.S. National Institute of Health and the PaulG. Allen Family Foundation.

—Read this article in the Sydney MorningHerald at http://nn.nf/299h http://nn.nf/299h

W o r l d w i d e d e v e l o p m e n t s i n p a i n m a n a g e m e n tW o r l d w i d e d e v e l o p m e n t s i n p a i n m a n a g e m e n t


uld

e ahisley,raft

sesandmg,aid,

whoainereber

whoen-to

esiaof

are,

nceysi-

diese isdieshis

fordif-ve,

mit-waitosesDr.ong

aremgon-

who

factnceent200ond

ues-his

pa-d.ne?org


Trap Editor


Specia

Dmenmorely simof Apape

VaVAS

witscleApr74:

preor latedof scle

YOU

expefor aThisUBCNeur292(

withlongdecrereduonseauth

for ptheir

delayined the authintermildshou

consrosisand Dam

—S

Doidedel


AN ANTIPSYCHOTIC DRUG newly approved for the treat-ment of schizophrenia and bipolar disorder has amore positive weight gain profile and a better impact

on cholesterol and diabetes risk than other similar drugs,according to doctors who have prescribed it.

Aripiprazole, a dopamine partial agonist, has a mechanismof action that differs from other atypical antipsychotics, said Dr.Ruth Baruch, psychiatrist and medical director, communityprograms, Toronto East General Hospital. “It causes fewer sideeffects like increased levels of cholesterol, triglicerides or bloodsugars, so it doesn’t contribute as much to some of the metabol-ic problems compared to other medications.”

Dr. Baruch stressed the importance of regularly moni-toring patients taking this therapy.

The patients who will gain weight on aripiprazole areprobably between five to 10%, said Dr. Roger S. McIntyre,an associate professor of psychiatry andpharmacology at the University of Tor -onto and head of the Mood Dis ord ersPsychopharmacology Unit, UniversityHealth Network, Toronto. This, he said,compares to clinically significant weightgain–7% increase from baseline– foundin 20 to 50% in patients taking otheratypical antipsychotic drugs.

“Weight gain causes discontinuation of medication inabout two thirds of patients,” noted Dr. Baruch. Some of herpatients with schizophrenia who had gained weight withanother atypical antipsychotic lost some of their weight afterswitching to aripiprazole.

Other advantages of this new drug, said Dr. Baruch, is thatit causes less sexual dysfunction than some other medications,and it may also help improve social skills. “It helps somepatients think clearly and interact and has a good effect on theircognitive function, so they can concentrate and focus better.”

Dr. Baruch believes aripiprazole is a good choice forpatients with a first episode of psychosis. “These patients arevery vulnerable to side effects, more so than other patients,”she said. “The adherence rates of first episode patients tendsto be very poor and they will discontinue medications veryquickly.” Dr. Baruch has also had “excellent” results with thetherapy in patients with bipolar 1 disorder (acute mania ormixed episodes).

Dosing for patients with depression–5 to 10 mg aday–is lower than the 20 to 30 mg a day used to treatpatients with schizophrenia or mania, noted Dr. Baruch.

A drawback of this new drug, however, is that the opti-mal dosing is not as easy to predict as with some other ther-apies, said Dr. McIntyre, “The dosing in some patients canbe a little challenging. For some other agents, you can pre-dict the right dose for most patients pretty easily.”

Another potential disadvantage is that in 10 to 20% ofpatients, particularly those with a mood disorder, the thera-py can be associated with akathisia, said Dr. McIntyre. “Thiscan be quite serious and patients will stop medicationbecause of it. It can be extremely uncomfortable and can alsocan sow the seed for a more serious movement disorder lateron, with ongoing exposure.”

Insomnia might be another side effect seen in somepatients taking this drug while in others it might cause som-nolence, added Dr. Baruch. One of the biggest drawbackswith the therapy, however, is its cost. At press time, it is notcovered by provincial health plans.

Dr. Baruch believes that more advocacy on the part ofpatients, families, doctors, and communities might helpspeed the process of getting this and other new drugs includ-ed in provincial drug formularies. “We need as many choic-es as possible in schizophrenia and in bipolar disorderbecause some medications work in some patients and otherswork in other patients,” said Dr. Baruch.

Andrew Morrison, a spokesperson for the Ministry ofHealth and Long-term care, said that at press time the drughad yet to be approved for inclusion in formularies. hesaid“It’s difficult to pin a timeframe on that, there’s a lot ofscientific research that needs to take place.”

Meanwhile, the Canadian Expert Drug Advisory Comm -ittee (CEDAC) has recommended against covering aripipra-zole: “based on a CDR systematic review of twelve randomizedcontrolled trials, efficacy outcomes, such as the Positive andNegative Syndrome Scale scores, were similar between aripipra-zole and less expensive antipsychotic agents. The average dailycost of treatment with aripiprazole is more than the cost ofrisperidone and most other antipsychotic agents.”

Aripiprazole is approved in Canada for schizophreniaand bipolar disorder, said Dr. McIntyre.

Non-proprietary and brand names of therapy: aripiprazole(Abilify, Bristol-Myers Squibb Company)

People with schizophrenia often havecognitive deficits that may be aided bycognitive rehabilitation, said Raquel E.Gur, MD, PhD, at the 163rd annualAmerican Psychiatric Association meet-ing in New Orleans.

Cognitive exercises that strengthenmental flexibility, attention, abstrac-tion, spatial memory, face memory andemotion identification would be partic-

ularly applicable given impairments inboth accuracy and speed in cases ofschizophrenia, Dr. Gur said.

Exercises like these may be used totreat these conditions in at risk adoles-cents, said Dr. Gur, as they oftenencounter these difficulties long beforethey develop psychosis, as do firstdegree biological relatives of peoplewith schizophrenia.

These relatives may share the cogni-tive deficits of those with schizophreniabut not the symtoms associated withthe condition itself, indicating the pos-sibility that the relatives have learnedcompensate for these deficits throughcognitive training.

—See the American Psychiatric Association videos at

http://ow.ly/2Fkpm

10 n October 2010

Treating cognitive deficits may prevent initial schizophrenia symptoms

T h i s J u s t I n

n Schizophrenia patients benefittedmore from maintenance therapythan from intermittent drug treat-ment, said a randomized drug trial inGermany. “Based on our findings,patients should be advised to furthermaintain antipsychotic treatment forat least two years, given the other-wise noticeable higher risk forrelapse,” lead author Dr. WolfgangGaebel from Heinrich-Heine-University, Duesseldorf, toldReuters Health by email. The studycompared a second year of mainte-nance treatment against stepwisedrug discontinuation and targetedintermittent treatment in 44 patientswho had completed 12 months ofantipsychotic therapy. There wereno relapses in the maintenancegroup but 19% in the intermittentdrug treatment group did relapse.Dr. Gaebel said this regimen maynot work for patients who have diffi-culty adhering to a drug plan.

Newly approved antipsychotic has fewer side effectsn Aripiprazole could lead to better adherence in patients with schiziophrenia as it has

a smaller mpact on weight gain profile, social skills, and fewer sexual side-effects

Dr. Roger McIntyre

Ann R


Trap Editor


Special to The Chronicle

DISCOVERY OF AN antibiotic’s capac-ity to improve cell function in lab-oratory tests is providing move-

ment disorder researchers with leads tomore desirable molecules with potential-ly similar traits, according to Universityof Alabama scientists co-authoring apaper publishing in the journal Disease

Models & Mechanisms (2010 Mar–Apr;3(3-4): 194–208).

“It’s our hope that this discoveryserves as the impetus for a proper clinicaltrial to evaluate the potential of drugslike ampicillin for early-onset torsiondystonia,” said Guy Caldwell, PhD,associate professor of biological sciencesat The University of Alabama. Dystoniais, like Parkinson's disease, a movement

disorder. Combined, this class of diseasesaffects millions worldwide. People withearly-onset dystonia have one good copyof the gene DYT1, and one problematiccopy, in their DNA. These genes containthe information to make a protein calledtorsinA.

“When proteins go bad, they oftencause disease, but they always have a nor-mal function in our cells,” Dr. Guy

Caldwell said. “We looked to find mole-cules—not necessarily that reversed themutated form of the protein - but insteadenhanced the normal activity of the pro-tein, thereby overcoming the deficiencycaused by the mutant.”

The UA researchers discovered thatampicillin, a common antibiotic of thepenicillin group, serves to activate torsinA,

by Pippa Wysong, Correspondent, The Chronicle

RESEARCHERS HAVE FOUND an increased level of DNAdamage in people who have Friedreich’s ataxia(FRDA), and believe there is a signature of gene activ-

ity that may show severity of disease. The finding sheds lighton some of the mechanisms behind neurodegeneration inthe disease, and could provide clues for new types of bio-markers for tracking disease progression and the effectivenessof treatments.

FRDA is an inherited neurodegenera-tive disease that affects about one inevery 40,000 live births worldwide. It iscaused by a mutation in a gene on chro-mosome 9 that codes for the frataxinprotein. The protein helps regulate thelevel of iron within cells, and is neededfor mitochondria to function.

“Having too much iron in the mito-chondria would be sort of like smokingin a TNT factory. It’s just a really badthing,” said Bennett Van Houten, PhD,professor of pharmacology and chemicalbiology at the University of PittsburghSchool of Medicine. Van Houten said itsets the stage for greater oxidative dam-age to occur.

In people with FRDA, the frataxin protein isn’t made insufficient quantities to do its job. Too much iron contributesto damage to DNA which, in turn, eventually adverselyaffects the patient’s nerve and muscle cells.

For the study, researchers analysed gene activity in bloodsamples from children with FRDA in the U.S., and com-pared it to samples from healthy controls. They also analysedblood samples from an adult population with FRDA, andadult controls, from France. DNA damage, in general, is

common. It occurs as a result of day-to-day exposure to ion-izing radiation, radon, UV light, as well as oxidative damage.In healthy people, the damage tends to be repaired.Researchers took into account what normal patterns ofDNA damage looks like in healthy people.

Looking at gene activity patterns associated with DNAdamage, it was found that the FRDA patients had far greateramounts of DNA damage than healthy controls, in both thepediatric and adult cohorts.

“We found gene expression signatures thatcorrelated with frataxin levels, age of diseaseonset, and a standardized measure of patientdisability,” Dr. Van Houten said. In otherwords, a gene expression signature for DNAdamage specific to patients with the disease.

Generally, it is hoped the research willlead to biomarkers that can be used to notonly determine the severity and stage of dis-ease, but also to help determine whethertreatment is working or needs to be changed.

There was also evidence suggesting oxida-tive stress might be an important underlyingcause of the pathophysiology of the disease.Based on this, it might be possible to use thefindings to help find some form of anti-

oxidative treatment that could slow down the rate of DNAdamage. Part of the trick is targeting the right place in thecell.

“We believe that underlying pathophysiology of the dis-ease is through oxidative stress that can cause DNA damage,and that DNA damage could lead to cell death. And we havea gene signature that would suggest the severity of diseasecould be tracked … and you could [potentially] develop anassay where you could look at these genes and see if thepatients who are being treated are benefiting from treat-ment,” he said.

Friedreich’s ataxia linked to gene on chromosome 9n University of Pittsburgh study reports that FRDA patients have greater DNA damage

Dr. Bennett Van Houten

October 2010 n 11

Vascular comorbidity linked to risk of disability in MSVASCULAR COMORBIDITY is associatedwith rapid progression of multiplesclerosis, says a study released in theApril issue of Neurology (2010;74:1041-1047).

“Vascular comorbidity, whetherpresent at symptom onset, diagnosis,or later in the disease course, is associ-ated with a substantially increased riskof disability progression in multiplesclerosis,” said the study, which

included 8,983 patients with MSenrolled in the North AmericanResearch Committee on MultipleSclerosis. Patients with vascularcomorbidities at diagnosis had morerisk of ambulatory disabilities. (hazardratio [HR]/condition for early gaitdisability 1.51; 95% confidence inter-val [CI] 1.41-1.61).

—Read this Neurology studyonline at http://nn.nf/448h

YOUNGER PATIENTS WERE FOUND TO

experience significantly longer delaysfor a multiple sclerosis diagnosis.This was found in a double-cohortUBC study published in the Journal ofNeurological Sciences (May 15, 2010;292(1-2):57-62).

“Younger at onset patients or thosewith PPMS exhibited significantlylonger delays (p<0.001). Delaysdecreased over the 20+ year period, butreductions varied by clinical course,onset age and sex,” wrote the study’sauthors.

It also found an increase in delaysfor patients more severely disabled ontheir first clinic visit.

“The relationship between referraldelay and initial disability was exam-ined by multiple ordinal regression inthe BCMS cohort,” said the study’sauthors, who concluded that if earlyintervention when disability levels aremild in MS, then these extended delaysshould be addressed.

The subjects of the study studyconsisted of adult-onset multiple scle-rosis patients from British Columbia,and the clinic-based Hospital Notre-Dame in Quebec.

—Read this Journal of NeurologicalSciences study at http://nn.nf/450h


Parkinson’s disease linked to anxiety A quarter of patients with Parkinson's disease were diagnosed with anxiety disor-ders,said a study in the September/August issue of Movement Disorders,(2010:25(7):838-845).

“The severity but not the duration of [Parkinson’s disease] was positively relat-ed to anxiety. [Parkinson’s disease] patients with postural instability and gait dysfunc-tion symptom clustering were more likely to experience anxiety than tremor-dominantpatients,” the study’s authors wrote, neither lateralization of Parkinson's disease, norlevodopa dosage were found to have no relationship with anxiety, but fluctuatingdyskinesias was found to increase the risk. Anxiety disorders were found to decrease with age.

—Read this Movement Disorders study online at http://ow.ly/2FjRy

Double cohort study identifies diagnosisdelays in MS

g aeat

pti-her-canpre-

ofera-hisionalsoater

mem-cksnot

ofelpud-oic-der

hers

ofrughe of

m -pra-zedandpra-aily

of

nia

e

ogni-reniawithpos-rnedough

rican os at kpm

Antibiotics reduce symptoms in patients who have movement disordersn Rise of d-amphetamine levels for nasally ingested prodrug identical for oral route


Trap Editor


(Clostridium Botulinum Neurotoxin Type A [150 kD], free from complexing proteins)XEOMIN® is indicated for blepharospasm, cervical dystonia of a predominantly rotational form (spasmodic torticollis) and post-stroke spasticity of the upper limb.

Merz Pharma Canada Ltd. wishes to inform physicians of the Merz Pharma Canada Ltd. wishes to inform physicians of the This new program is designed to make it easier for This new program is designed to make it easier for patients in need of XEOMINpatients in need of XEOMIN®® by paying up to 20% of the by paying up to 20% of the total prescription costs.total prescription costs.

For more information contact your Merz Pharma Canada For more information contact your Merz Pharma Canada representative, call us at 1-866-RxHelp4 (1-866-794-3574) representative, call us at 1-866-RxHelp4 (1-866-794-3574) or go to www.iTrialRx.com

Advantage Program –XEOMIN® Patient Assistance Plan

New

Gum chewing reduces choking hazard in patients with Parkinson’s diseaseA study released in the April issue ofNeurology has found that chewing gum canParkinson’s patients with difficulty swallow-ing. (2010; 74: 1203-1207)

The study, conducted in theMovement Disorders Clinic at the LondonHealth Sciences Centre, Ont., found swal-

lowing frequency increased during gumchewing over baseline in Parkinson’spatients.

The study included 20 participantsstudied across three tasks, each five min-utes in duration. Repertory and laryngealsignals were recorded using PowerLab,

and the frequency of swallow events werecalculated afterwards.

The findings may help patients forwhom a failure to swallow is a vital concernthat can pose a choking hazard.

—Online at http://nn.nf/451h

12 n October 2010

which, in its normalform, appears to pro-

tect cells from stresses, such as protein misfolding—a problemknown to impact various movement disorders.

Using a nematode animal model designed to evaluatetorsinA activity, the UA lab rapidly screened through hun-dreds of compounds to identify those that were most effec-tive at enhancing torsinA’s normally protective function.

“From there, we collaborated with researchers atHarvard and UAB to validate our findings in human patientcells and mice,” said Kim Caldwell, PhD, associate professorof biological sciences also at the University of Alabama.

“In human dystonia patient cells, ampicillin was effica-cious and restored the patient cells back to the normal func-tion,” Dr. Kim Caldwell said. “And, the drug restored normalmovement to mice that were genetic mimics of dystonia.”

Collaborators in the University of Alabama-led studywas Xandra O. Breakefield, PhD, and her colleagues atHarvard and Yuqing Li, PhD, and his colleagues at theUniversity of Alabama at Birmingham. Songsong Cao, PhD,a former doctoral student in the Caldwell Lab, is the study’slead author; two UA doctoral students, Alexander J.Burdette and Pan Chen; and one former UA student, AmberClark Buckley, are among the co-authors.

Furthermore, the research shows ampicillin enhancesthe capacity of torsinA to protect, within animal models, theneurons which produce dopamine from dying. The death ofthese neurons in human brains leads to the hallmark symp-toms of Parkinson’s disease.

In a statement accompanying the paper, the researcherscaution against the long-term use of an antibiotic in diseasetreatment.

“We have taken ampicillin and used that as a base struc-ture to find things that work like ampicillin but which aren’tampicillin,” Guy Caldwell said. “Finding molecules that are

not antibiotic and still have the capacity to activate torsinAhas been an ongoing effort of our lab, and we have someexciting leads in that direction.”

UA filed patents covering the use of antibiotics andother novel chemicals as activators of torsinA for treatmentof dystonia and other diseases, including Parkinson's disease.The University has also entered into a collaborative researchand licensing agreement with QRxPharma, a clinical stagepharmaceutical company, to identify, develop and commer-cially exploit new torsinA activator drugs.

The UA/QRxPharma research program is directed at re-engineering existing drug therapies for new clinical applica-tions and identifying new drug candidates for uses includingthe treatment of dystonia, Parkinson's disease and other neu-rological disorders.

The project exemplifies, the researchers said, how dis-ease model systems can be used to accelerate the develop-ment of gene and drug discovery and bring pharmaceuticalsmore quickly to the clinical trial stage.

Bringing a drug that does not already have FDAapproval from the research and development stage to apatient takes an estimated 12 years and $800 million dollars,said Dr. Kim Caldwell. By evaluating the potential of mole-cules already pre-screened for toxicity and that have FDAapproval provides a potentially quicker route to clinical tri-als.

“What we were hoping to do was circumvent a lot of thecost in bringing pharmaceutical help to dystonia patients,”Dr. Kim Caldwell said.

The research was supported by the Bachmann-StraussDystonia and Parkinson Foundation, Dystonia MedicalResearch Foundation, the Jack Fasciana Fund for DystoniaResearch and the National Institutes of Health.

Copyright Med Page Today, LLC. All rights reserved. Reprinted withpermission. www.medpagetoday.com

ComissutimeAnd

Signolut

(T

On F

Antibiotic lessens movement disorder symptomscontinued from page 11—


Trap Editor


sewere

s forncern

451h

nAme

ndentse.ch

ageer-

re-ca-ng

eu-

is-op-als

DAa

rs,le-

DAri-

hes,”

usscalnia

ith

Introducing the greenChronicleComing soon: A bimonthly electronic supplement to The Chronicle with original multimedia content in everyissue. Optimized for iPad, and readable on your computer, e-reader and electronic device. Interactive, real-time news, opinion and education in the CNS sciences, with two intriguing value-added features: It’s free.And no trees were harmed in the preparation of this journal.

Sign up for your free subscription now at www.greenchronicle.tk, and be among the first to receive the rev-olutionary greenChronicle. And while you’re at it, why not follow us on Twitter and Facebook?

Your device. Our content.(This could be the ultimate word-association.)

On Facebook: Chron Neuropsych On Twitter: CNSChronicle


Trap Editor



EMERGING RESEARCH GIVES FURTHER CREDENCE to thetheory that migraine headache may be geneticallylinked to depression.

The study in Neurology, (Jan. 2010; 74: 288-294) involved2,652 subjects who took part in the larger ErasmusRucphen Family genetic isolate study. All partici-pants are adult descendants of 22 couples who livedin a community in a southwest section of theNetherlands from the 1850s to the 1900s.

The total study sample, 360 subjects hadmigraines, including 151 who had migraine withaura, and 977 had depression. About 25% of thosewho had migraine also had depression, compared toonly 13% of those without migraine. Heritabilityestimates were 0.56 for all migraine, 0.77 for migraine with-out aura, and 0.96 for migraine with aura.

Gisela M. Terwindt, MD, PhD, a study author and aprofessor at Leiden University Medical Center in theNetherlands, said results suggest common genetic pathwayspartly underlie both depression and migraine, particularly

migraine with aura, rather than one disorder being the con-sequence of the other.

Dr. Noah L. Rosen, director of North Shore HeadacheCentre, assistant professor at Albert Einstein University,New York, who is board certified in both neurology andpsychiatry, agrees the study suggests a common cause.

“People have traditionally said, ‘well, you’redepressed so you get headaches, or you getheadaches so it makes sense that you’re depressed,’”he said. “This study shows very nicely ... that itgoes in both directions.”

Although the study had a “fairly large cohort ofa genetically distinct group of people” compared toearlier population studies that also found a geneticlink between migraine and depression, it does notrepresent a “great leap forward,” he said. Only 25%

of people in the study with migraine have depression, so themajority don’t have this condition. “That’s double what it is inthe general population, but it’s still a minority.”

This suggests there a significant enough comorbidity towarrant screening, said Dr. Rosen, “this absolutely says thatthis is common enough that it should be screened for whenyou have a patient with migraine, especially migraine withaura. By not diagnosing the problem, you’re going to haveless chance of successfully treating your patient.”

Whether treating depression in a patient with migrainewill reduce the number of headaches is unclear, said Dr.Rosen. “But even if you’re not going to decrease the frequen-cy of headache, you’ll help patients by addressing this prob-lem and making sure they get into treatment.”

He also said neurologists and primary care physicianswho are uncomfortable treating depression in patients withmigraine should refer them to a headache center, psychia-

trist, or psychologist. Physicians should not only be

screening for depression in headachepatients but for pain conditions inpatients with depression, said Dr.Murray W. Enns, professor and head,department of psychiatry, Universityof Manitoba, Winn ipeg. “In eitherspecialist’s office–the psychiatrist or

Depression screening should follow migraine diagnosisn About 25% of patients with migraines also have depression, says Neurology study

Adverse experiences linked to migraineYouths who experience “adverse childhood experiences” aremore likely to experience headaches as adults, a studyreports out of the Kaiser Health Plan in San Diego. The studydefined adverse childhood experiences as abuse of an emo-tional, physical or sexual nature, witnessing domestic vio-lence, growing up with mental illness in the home, havingmembers of the household incarcerated or abusing drugs,and experiencing divorce or separation.

“Each ACE increased the chance of frequent headache,and as the number of ACEs increased, so did the risk of fre-quent headache. This ‘dose-response’ relationship’ suggeststhat ACEs may contribute to the development and frequencyof severe headaches later in life,” Dr. Gretchen E. Tietjen, partof the University of Toledo College of Medicine team that con-ducted the research said. Those who had eight or more of anyone of these experiences were more likely to experience fre-quent headaches and migraines. Dr. Tietjen presented herfindings at the American Headache Society’s 52nd Annualmeeting in Los Angeles. —please turn to page 19

Naproxen and acetaminophen may beeffective treatment for migraines, saystwo studies in the journal Headache.

The authors of “Meta-Analysis ofthe efficacy and safety of naproxen sodi-um in the acute treatment of migraine,”(May 2010; 50(5):808-818), wrotenaproxen sodium is superior placebos.

“The available evidence suggeststhat naproxen sodium is more effectivebut may cause more adverse events thanplacebo in the acute treatment of moder-ate to severe migraine. It is effective inreducing headache intensity, rendering

pain-free at two hours and improvingmigraine-associated symptoms.”

A randomized placebo controlledstudy, in the same issue of Headache,(May 2010: 50 (5):819-833), conclud-ed: “acetaminophen 1000 mg, a nonpre-scription drug, is an effective and well-tolerated treatment for episodic andmoderate migraine headache.”

The studies conclude naproxen andacetaminophen effectively decreased oreliminated pain and reduced migrainerecurrence and migraine-associatedsymptoms to a degree defined as a ‘desir-

able outcome’ of migraine therapy by theInternational Headache Society (IHS).”Naproxen, which in the first study wasshown to reduce headache intensity,pain, and symptoms within 2 hours oftaking it is a non-prescriptive alternativeto migraine-treating triptan drugs likefrovatriptan and lacks the side effects oftriptan drugs. Acetomin ophen is also alow cost non-prescriptive pain reliever.

—Read these original studies in Headache at

http://nn.nf/440h

Non-prescription painkillers may be enough migraine relief

DDrr.. NNooaahh RRoosseenn

Dr. Murray EnnsDr. Murray Enns

14 n October 2010

“Imendeprthesedeprcoffedeprwe’reing athat day f

Tassisrecovmethsion deprsaid progings survthression negaand Strok481)

IncompHealgle qState

Tto 28meetdeprfeelinwortthouHackery, b

Shmonpatietionnbasisphyswhicing.”

Shfor a

“Nfor asomethousaid

“Ient treatple ameethaveand

Ifidentreattalkipress

Dnatio

—co

A l


Trap Editor


on-

cheity,

and

u’regetd,’”t it

t ofd toeticnot5%thes in

y tohathen

withave

ineDr.en-ob-

answithhia-

beche

inDr.ad,sityheror

19

y theHS).”

wasnsity,rs ofativelike

ts oflso a

ver.ginal he at 440h

“It sounds like a trite com-ment possibly, but we usedepression interchangeablythese days, with ‘I’m feelingdepressed’ or ‘I didn’t have acoffee this morning, I’m feelingdepressed,’ and that’s not whatwe’re talking about. We’re talk-ing about persistent symptomsthat are happening almost everyday for at least two weeks.”

The challenge for physiciansassisting patients in strokerecovery, is that traditionalmethods for diagnosing depres-sion may not pick up low-leveldepression, which Dr. Hackettsaid can still slow or hinderprogress. She made these find-ings in a study called “Strokesurvivors who score belowthreshold on standard depres-sion measures may still havenegative cognitions of concern”and published in the journal,Stroke (March 2010; 41(3):478-481).

In the study, participantscompleted a 28-item GeneralHealth Questionnaire and a sin-gle question from the PresentState Examination.

The study concluded that upto 28% of the patients did notmeet the study criteria ofdepression, but did experiencefeelings of hopelessness, andworthlessness, as well as suicidalthoughts, all of which Dr.Hackett said can hinder recov-ery, but may go undiagnosed.

She suggested long-termmonitoring for patients, wherepatients may be given a ques-tionnaire to answer on a regularbasis, and then return to theirphysician for reassessment,which she calls “watchful wait-ing.”

She said this may not be easyfor all physicians.

“Now that’s a really hard jobfor a hospital doctor, but it’ssomething a GP can do eventhough they’re all very busy,”said Dr. Hackett.

“If the symptoms are persist-ent that’s when you look attreatment. But some of the peo-ple are people that might notmeet criteria for depression whohave feelings of worthlessnessand suicidal thoughts.”

If persistent symptoms areidentified, she said, there aretreatments available includingtalking therapies and antide-pressants.

Dr. Hackett said a determi-nation as to which treatment

option is most effective dependson whether the patient isalready depressed, or maybecome depressed, becausetalking therapies have notyet been found to be help-ful to already depressedpatients.

“We don’t have any evi-dence to show that on their

own, they are useful to someonewith alreadyd i a g n o s e ddepression,” shesaid, “and theconverse is truefor prevention.We’ve shownthat talkingtherapy can pre-

vent depression.” And vice-versa, antidepres-

sants, she said, are effective attreating depression, but not atpreventing depression inpatients recovering from stroke.They can also have unpleasantside effects that may outweighthe benefits.

Another finding in Dr.

Hackett’s study was that olderpatients who were dependent indaily living were more likely tosay they had negative thoughts.

This makes sense to JocelynHarris, PhD., a post-doctoralresearcher at the TorontoRehabilitation Institute and an

October 2010 n 15

INDICATIONS AND CLINICAL USESchizophrenia: ABILIFY (aripiprazole) is indicated for the treatment of schizophrenia and related psychotic disorders. In controlled clinical trials, ABILIFY was found to improve both positive and negative symptoms. ABILIFY has been shown to be more effective than placebo in maintaining clinical improvement for up to 26 weeks.Bipolar Disorder: ABILIFY is indicated for the acute treatment of manic or mixed episodes in Bipolar I Disorder. ABILIFY may be used as acute monotherapy or cotherapy with lithium or divalproex sodium when there is an insuffi cient acute response to these agents alone. The physician who elects to use ABILIFY for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.Geriatrics (≥ 65 years of age): ABILIFY is notindicated in elderly patients with dementia. (See WARNINGS AND PRECAUTIONS – Serious Warnings and Precautions and Special Populations). The safety and effi cacy of ABILIFY in patients 65 years of age or older has not been established. Caution should be used when treating geriatric patients. Pediatrics (<18 years of age): Safety and effi cacy of ABILIFY in pediatric and adolescent patients have not been established. ABILIFY is not indicated for the treat-ment of pediatric and adolescent patients.CONTRAINDICATIONSABILIFY is contraindicated in those patients with a known hypersensitivity to this drug or the excipients of the product. For a complete listing, see DOSAGE FORMS, COMPOSITION and PACKAGING in the Supplemental Product Information section.

WARNINGS AND PRECAUTIONSFor complete information on warnings and pre-cautions, please also consult the Supplemental Product Information section.

General: Body Temperature Regulation: Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ABILIFY for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving con-comitant medication with anticholinergic activity, or being subject to dehydration) (see ADVERSE REACTIONS).Cardiovascular: Orthostatic Hypotension: ABILIFY may be associated with orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. ABILIFY may induce orthostatic hypotension, tachycardia, dizzi-ness, and sometimes syncope, especially at the initiation of treatment. The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of patients on oral ABILIFY (n=2096) included (ABILIFY incidence, placebo incidence): orthostatic hypotension (1.1%, 0.4%), postural dizziness (0.5%, 0.3%), and syncope (0.4%, 0.5%). The risk of orthostatic hypotension may be reduced by more gradual titration to the target dose. The incidence of a signifi cant ortho-static change in blood pressure (defi ned as a decrease in systolic blood pressure 20 mmHg accompanied by an increase in heart rate 25 bpm when comparing standing to supine values) for oral ABILIFY was not statis-tically different from placebo (ABILIFY incidence, placebo incidence): 4.6%, 3.0%. ABILIFY should be used with caution in patients with known cardiovascular disease (e.g., history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medi-cations). Patients with a history of clinically signifi cant cardiovascular disorders were excluded from clinical trials.Dependence/Tolerance: ABILIFY has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence.Endocrine and Metabolism: Hyperglycemia and Diabetes Mellitus: As with some other antipsychotics, exacerbation of pre-existing diabetes and hyperglycemia have been reported rarely and diabetic ketoacidosis and diabetic coma including some fatal cases, have been reported very rarely during the use of ABILIFY (see ADVERSE REACTIONS). Assessment of the relationship between atypical antipsychotic use and glucose abnor-malities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confound-ers, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not com-pletely understood. However, epidemiological studies which did not include ABILIFY suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because ABILIFY was not marketed at the time these studies were performed, it is not known if ABILIFY is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treat-ment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discon-tinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are

starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Neurologic: Neuroleptic Malignant Syndrome (NMS): Neuroleptic malignant syndrome is a potentially fatal symptom complex that has been reported in association with antipsychotic drugs, including ABILIFY. The manage-ment of NMS should include 1) immediate discontinua-tion of all antipsychotic drugs including ABILIFY and other drugs not essential to therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specifi c treatments are available. There is no general agreement about specifi c pharmacological treatment for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential re-introduction of therapy should be very carefully considered. The patient should be carefully monitored, since recurrence of NMS has been reported.Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome is highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug prod-ucts differ in their potential to cause tardive dyskinesia is unknown. ABILIFY should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY, drug discontinuation should be considered. However, some patients may require treatment with ABILIFY despite the presence of the syndrome.Seizure/Convulsion: As with other antipsychotic drugs, ABILIFY should be used cautiously in patients with a his-tory of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.Potential for Cognitive and Motor Impairment:Because ABILIFY may cause somnolence, and impair motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery, including motor vehicles, until they are reasonably certain that ABILIFY therapy does notaffect them adversely. Psychiatric: Suicide: The possibility of a suicide attempt is inherent in psychotic illnesses and bipolar disorder, and close supervision and appropriate clinical management of high-risk patients should accompany drug therapy. Special Populations: Pregnant Women: There are no adequate and well-controlled studies in pregnant women. It is not known whether ABILIFY can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. In animal studies, ABILIFY demonstrated developmental toxicity, including pos-sible teratogenic effects in rats and rabbits. ABILIFY should be used during pregnancy only if the potential benefi t outweighs the potential risk to the fetus. Labor and Delivery: The effect of ABILIFY on labor and delivery in humans is unknown. Nursing Women: ABILIFY was excreted in milk of rats during lactation. It is not known whether ABILIFY or its metabolites are excreted in human milk. It is recommended that women receiving ABILIFY should not breast-feed. Pediatrics (< 18 years of age):Safety and effi cacy in children under the age of 18 years have not been established. ABILIFY is not indicated for the treatment of pediatric and adolescent patients. Geriatrics (≥ 65 years of age): Geriatric patients

THERAPEUTIC CLASSIFICATION: Antipsychotic

Pr

Tablets, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg and 30 mg

Serious Warnings and Precautions: Increased Mortality in Elderly Patients with Dementia: Elderly patients with dementia treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of thirteen placebo-controlled trials with various atypical antipsychotics (modal duration of 10 weeks) in these patients showed a mean 1.6-fold increase in the death rate in the drug-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovas-cular (e.g., heart failure, sudden death) or infec-tious (e.g., pneumonia) in nature (see WARNINGS AND PRECAUTIONS – Special Populations, Use in Elderly Patients with Dementia).


A little depression inhibits recovery, a little exercise reduces depression

Dr. Maree Hackett—please turn to next page


Trap Editor


o c c u p a t i o n a ltherapist whosaid stroke recov-ery patientsshould be en -couraged to par-ticipate even inlow key dailyactivities thatmay includeeverything from a walk throughthe park, to simple socializa-tion.

She presented part of herPhD study, called the “Role ofactivity in the reduction ofdepressive symptoms poststroke,” at the Canadian StrokeCongress in June, concludingthat even low to moderate phys-ical activity can be beneficial.

The abstract which was inStroke, said the study used datafrom 103 people out of a multi-site randomized controlledintervention trial. The experi-mental group included 53 peo-ple, and the control group 50people. The experimental groupwas asked to participate in theGraded Repetitive ArmSupplementary Program(GRASP), a low intensity exer-cise program that focuses onarm and hand function.

Throughout the study, facili-tators measured the patients’depressive symptoms using theCenter for EpidemiologicalStudies Depression Rating Scale(CES-D). Upper limb measureswere also collected through theChedoke Arm and HandInventory, the Motor ActivityLog, and grip strength tests.Post-intervention, group differ-ences were analysed using ananalysis of covariance.

This study concluded “a lessintense exercise program canhave a positive effect on ratingsof depressive symptoms duringinpatient rehabilitation,” andthat this may improve theresults of rehabilitation.

“Aerobic exercise positivelyimpacts mood and depressivesymptoms post-stroke,” shesaid. “But the problem is thatan aerobic exercise would bedefined as cycling, fast-pacedwalking, walking on a treadmillwith incline, things that getyour heart rate up quite a bit,”which can be difficult for somein stroke rehab, Dr. Harris said.

“About thirty per cent ofindividuals who have had astroke may not be able toachieve aerobic capacity espe-cially in the early stages after thestroke,” she said, largely due tolower limb deficits. “Their

mobility won’t allow them tocycle or walk quickly,so this is an alternativemethod to still be ableto improve mood aswell as recover move-ment and, can maybebe more inclusive.”

She said despite thisdifficulty, patients instroke should be asactive as safely possi-

ble.

“Any activity, even social orrecreational, that requires thatthey be moving, interactingwith others, that’s what I wouldprescribe. I think it’s one of thebest medicines that we can use,that’s not pharmacological, topromote health,” she said.

Dr. Michael D. Hill,Spokesperson for the Heart andStroke Foundation, said thereare many simple options a fam-ily physician might consider for

patients on the wait list forstroke rehabilitation, particular-ly patients with relatively minorstrokes permitted to go homefrom the hospital.

“Usually when you’re talkingabout a patient who is now intheir GP’s office after having astroke,” he said, “it’s a relativelymild event in so far as they’renot disabled enough to requirenursing care. That means theycan do some stuff. Usually they

can walk, they can do someactivity, so the encouragementis really to do those things.Walk. If your right arm is weak,get on and use it. Make sureyou’re trying to use two handswith your knife and fork, put abib on so that if you spill yourfood it’s ok. You want to justkeep at it.”—The GRASP exercise routine

developed by Dr. Harris isonline at http://ow.ly/2FlMb

16 n October 2010

generally have decreased cardiac, hepatic and renal func-tion, and more frequent use of concomitant medication. The presence of multiple factors that might increase the pharmacodynamic response to ABILIFY, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitor-ing during the initial dosing period for elderly patients. Use in Elderly Patients with Dementia: Studies of elderly patients with Alzheimer’s disease have suggested that there may be a different tolerability profi le in this population compared to younger patients with schizo-phrenia (see WARNINGS AND PRECAUTIONS – Serious Warnings and Precautions). The safety and effi cacy of ABILIFY in the treatment of patients with Alzheimer’s dis-ease have not been established. If the prescriber elects to treat such patients with ABILIFY, vigilance should be exer-cised. Overall Mortality: Elderly patients with dementia psychosis treated with atypical antipsychotic drugs showed increased mortality compared to placebo in a meta-analysis of 13 placebo-controlled trials of various atypical antipsychotic drugs. In three placebo-controlled studies of ABILIFY in elderly patients with Alzheimer’s disease (n=938; mean age: 82.4 years; range: 56-99 years), the rate of death in ABILIFY-treated patients was 3.5%, com-pared to a rate of 1.7% in the placebo group during or within 30 days after termination from the double-blind phase of the studies. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sud-den death) or infectious (e.g., pneumonia) in nature. ABILIFY is not indicated for the treatment of patients with dementia (see Serious Warnings and Precautions).Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including ABILIFY. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. ABILIFY and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia (see ADVERSE REACTIONS). Safety Experience in Elderly Patients with Alzheimer’s Disease: The safety and effi cacy of ABILIFY in the treatment of patients with dementia have not been established. If the prescriber elects to treat such patients with ABILIFY, vigilance should be exercised, particularly for the emergence of diffi culty swallowing or exces-sive somnolence, which could predispose to accidental injury or aspiration (see WARNINGS AND PRECAUTIONS – Serious Warnings and Precautions).Use in Patients with Renal Impairment: No dosage adjustment is required in subjects with renal impairment.Use in Patients with Hepatic Impairment: No dosage adjustment is required in subjects with hepatic impairment.ADVERSE REACTIONSFor complete information on adverse reactions, please also consult the Supplemental Product Information section. Adverse Drug Reaction Overview: ABILIFY was evalu-ated for safety in 13,543 patients who participated in multiple-dose, clinical trials in schizophrenia, bipolar disorder, major depression, dementia of the Alzheimer’s type, Parkinson’s disease, and alcoholism, and who had approximately 7619 patient-years of exposure to oral ABILIFY and 749 patients with exposure to ABILIFY injection. A total of 3390 patients were treated with oral ABILIFY for at least 180 days and 1933 patients treated with oral ABILIFY had at least 1 year of exposure.Short-Term, Placebo-Controlled Trials of Patients with Schizophrenia: The following fi ndings are based on a pool of fi ve placebo-controlled trials (four 4-week and one 6-week) in which ABILIFY was administered orally in doses ranging from 2 to 30 mg/day. Adverse EventsAssociated with Discontinuation of Treatment: Overall,

there was little difference in the incidence of discon-tinuation due to adverse events between ABILIFY-treated (7%) and placebo-treated (9%) patients. The types of adverse events that led to discontinuation were simi-lar between the ABILIFY and placebo-treated patients.Commonly Reported Adverse Events: The only com-monly observed adverse event associated with the use of ABILIFY in patients with schizophrenia (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) was akathisia (placebo 4%; ABILIFY 8%).Short-Term, Placebo-Controlled Trials of ABILIFY in Patients with Bipolar Mania: The following fi ndings are based on a pool of 3-week, placebo-controlled, bipolar mania trials in which ABILIFY was administered orally at doses of 15 or 30 mg/day. Adverse Events Associ-ated with Discontinuation of Treatment: Overall, in patients with bipolar mania, there was little difference in the incidence of discontinuation due to adverse events between ABILIFY-treated (11%) and placebo-treated (10%) patients. The types of adverse events that led to discontinuation were similar between the ABILIFY and placebo-treated patients. Akathisia, the most com-mon adverse event leading to discontinuation in theABILIFY group, led to withdrawal of 2% of ABILIFY-treatedpatients and 0.3% of patients on placebo. Commonly Reported Adverse Events: Commonly reported adverse events associated with the use of ABILIFY in patients with bipolar mania (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) are: akathisia (13% for ABILIFY [n=917] and 4% for placebo [n=753]), sedation (8% and 3% for ABILIFY and placebo, respecti-vely), restlessness (6% and 2% for ABILIFY and placebo,respectively), and extrapyramidal disorder (5% and 2% for ABILIFY and placebo, respectively). DRUG INTERACTIONSOverview: Drug-Drug Interactions: Potential forOther Drugs to Affect ABILIFY: Aripiprazole is not a sub-strate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation. This sug-gests that an interaction of aripiprazole with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. Both CYP3A4 and CYP2D6 are responsible for aripiprazole metabolism. Agents that induce CYP3A4 (e.g., carbamazepine) could cause an increase in arip-iprazole clearance and lower blood levels. Inhibitors of CYP3A4 (e.g., ketoconazole) or CYP2D6 (e.g., quinidine, fl uoxetine, or paroxetine) can inhibit aripiprazole elimina-tion and cause increased blood levels. Approximately 8% of Caucasians lack the capacity to metabolize CYP2D6 substrates and are classifi ed as poor metabolizers (PM), whereas the rest are extensive metabolizers (EM). CYP2D6-metabolizing capacity should be considered when ABILIFY is co-administered with drugs that in-hibit CYP2D6. Potential for ABILIFY to Affect Other Drugs: ABILIFY is unlikely to cause clinically important pharmacokinetic interactions with drugs metabolized by cytochrome P450 enzymes. In in vivo studies, 10-mg/day to 30-mg/day doses of ABILIFY had no signifi cant effect on metabolism by CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin), and CYP3A4 (dextromethorphan) substrates. Addition-ally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro. Due to its α1 adrenergic receptor antagonist activ-ity, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.To report suspected side effects: By toll-free telephone: 1-866-234-2345By toll-free fax: 1-866-678-6789Online: www.healthcanada.gc.ca/medeffectBy email: [email protected]

DOSAGE AND ADMINISTRATIONDosing Considerations: The effi cacy and safety of ABILIFY, at doses greater than 30 mg/day, have not been established.Schizophrenia: Usual Dose in Adults: The recom-mended starting and target dose for ABILIFY is 10 or15 mg/day administered on a once-a-day schedule without regard to meals. Doses in the range of 10 to 30 mg/day have been established as effective in clinical trials. However, greater effi cacy has not been demonstrated at doses higher than 10 mg/day. Dosage increases, if needed, should only be made after 2 weeks, the time needed to achieve steady state. The maximum daily dose should not exceed 30 mg/day. Patients should be maintained on the lowest effective dose that provides optimal clinical response and tolerability and should be periodically reassessed to determine the need for maintenancetreatment. Switching from Other Antipsychotics: There are no systematically collected data to specifi cally address switching patients with schizophrenia from other antipsychotics to ABILIFY or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsy-chotic administration should be minimized.Bipolar Disorder: Usual Dose in Adults: The recom-mended starting dose for ABILIFY as acute monotherapy or as cotherapy with lithium or valproate is 15 mg given once a day, without regard to meals. The dose can be increased to 30 mg/day based on clinical response. Patients should be treated with the lowest effective dose that provides optimal clinical response and tolerability. The maximum daily dose should not exceed 30 mg/day.Dosing Considerations in Special Populations:Pediatric (< 18 years of age): Safety and effi cacy of ABILIFY in pediatric and adolescent patients have not been established. ABILIFY is not indicated for the treatment of pediatric and adolescent patients.Geriatric (≥ 65 years of age): Safety and effi cacy of ABILIFY in the treatment of schizophrenia and Bipolar I Disorder in patients 65 years of age or older have not been established. Given the greater sensitivity of this population, a lower starting dose may be considered when clinical factors warrant (see WARNINGS AND PRECAUTIONS – Special Populations, Geriatrics).Patients with hepatic impairment: No dosage adjust-ment is required for patients with hepatic impairment. Patients with renal impairment: No dosage adjust-ment is required in patients with renal impairment.Gender: No dosage adjustment is required for female patients as compared to male patients.Smoking status: No dosage adjustment is required for smokers (see DRUG INTERACTIONS – Drug Lifestyle Interaction). Refer to DRUG INTERACTION section for dosage adjustment in patients taking ABILIFY concomi-tantly with strong CYP3A4 inhibitors (such as ketocon-azole or clarithromycin), with potential CYP2D6 inhibitors (such as quinidine, fl uoxetine, or paroxetine) or with potential CYP3A4 inducers (such as carbamazepine). Missed Dose: If a patient misses a dose by a few hours, the patient should be advised to take their dose as soon as he/she remembers. If most of the day has passed, he/she should be advised to wait until the next scheduled dose. Patients should be advised to not take 2 doses of ABILIFY at once.STORAGE AND STABILITYStore tablets at 15° to 30°C.

—continued from previous page

Dr. Jocelyn Harris

half ic wamontimewaitimenmech

ate,

—co

PartWARNDepenwithdrclinicaobservthis limdivertecarefucloselyincreaGenitoABILIFto be dmost thetic HemaIn casconsidNeuroof NMautonoand caphokinat a dincludeand unOther cholinepatholTardivhood tthe toincreaafter refor estpartialtreatmsymptcess. Tof the be resresponpotentwho dtreatmfor conSeizuwith oThere seizurePotendrugs,SomnoABILIFSpecipharmclearaadult sin the pharmsimilarPRECAADMINschizoaged 6subjecUse iIncludistudiedemen(e.g., patienresponwith A(see WSafetyplaceb(n=93adversat leaslence (urinary0%, AUse inin patinot behistorydiagnoAND PGenderazoleapparehowevand wRace:the efevaluakineticLactosand 1respecglucosADVERAdverwith Astabiliznoncofl exibleing ex

Op


Trap Editor


omementings.

weak,sureands

put ayourjust

utineris isFlMb

of een

m-or

out ave ver, ses ed,

d to not on cal ally nce

no ess her ant ate ent nia, ate sy-

m-apy ven be se. ose lity. ay.ns:of

not the

of ar I not his red ND

st-

st-

ale

red tyle for

mi-on-ors

with

urs, oon he/led

s of

half of all patients on pain clin-ic wait lists may have to wait sixmonths, or more. In the mean-time, said Dr. Choinière, thosewaiting for chronic pain treat-ment have no adequate copingmechanisms.

“At first they are so desper-ate, they try traditional medi-

cine, they try alternative medi-cine, they try all kinds of treat-ment until someone refers themto a pain clinic,” she said.“Quite often, the patient willpay more money in the firstcouple of years, than if theyhave the pain for six years.”

The impact of these wait-ing lists is more than just the

pain the chronic pain patientendures, said Dr. Buckley. Thelonger the wait, the more thepatients deteriorate physically,professionally, and socially.

“The more their personalfunctioning deteriorates,” saidDr. Buckley, “the more theybecome physically less ablebecause they restrict their phys-

ical activities because of painand therefore they become pro-gressively deconditioned.”

QUALITY OF LIFEDr. Choinière said the addedstress of enduring pain mayaffect patients’ jobs as well attheir relationships with theirfamilies, which can result in

depression and make it moredifficult to rehabilitate apatient.

“Sleep habits, that’s anoth-er problem. Very often thepatients have very poor qualityof sleep,” said Dr. Choinière,“the poorer the sleep the morepain they have the day after, andthe more pain they have the lessgood quality of sleep they havethe next day.”

Dr. Choinière said opioidscan play an essential role inmultidisciplinary pain manage-ment by allowing the patient anopportunity to learn other, non-pharmacological techniques tomanage their pain.

“If you have a very intensepain, and you’re trying to teachthe patient relaxation, if the painis too intense, forget about it,”said Dr. Choinière. “The patientwon’t be able to concentrate andto learn the techniques.

That’s why, she said, opi-oids are often a necessary part ofa pain management strategy.

“You need to relieve thepain with medication to someextent so you can teach the per-son how to relax,” she said.

Dr. Chris Spanswick, theCalgary Health Region’s painprogram medical leader, said theguideline may be an importantstep toward addressing theseconcerns. He said aside frommaintenance plans, the guide-line outlines a responsibility onthe part of physicians to pre-scribe opioids when the situa-tion calls for it.

“There’s a nice little sectionthat addresses the issue of physi-cians who refuse to open theirprescription pad,” he said.

“There’s a second sectionthat says it’s inappropriate notto prescribe opioids when theyprove to be efficacious.”

Dr. Spanswick said outsideof opioid use, physicians shouldtreat the whole patient, and notjust the pain. That often meanscognitive behaviour therapy totreat the psychological symp-toms that often accompany thepain.

“A reduction in pain is notpromised in these programs,”said Dr. Spanswick, referring tocognitive behaviour therapy,“but a reduction of pain verycommonly occurs.”

—The entirety of theCanadian Guideline for Safeand Effective Use of Opioids

for CNCP (Chronic Non-CancerPain) is available at

http://www.nn.nf/9302


October 2010 n 17

Part B – Supplemental Product InformationWARNINGS AND PRECAUTIONSDependence/Tolerance: In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ABILIFY misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).Genitourinary: Priapism: Rare cases of priapism have been reported with ABILIFY. This adverse reaction, as with other psychotropic drugs, did not appear to be dose-dependent and did not correlate with the duration of treatment. The most likely mechanism of action of priapism is a relative decrease in sympa-thetic tone.Hematologic: Infrequent cases of leukopenia have been reported with ABILIFY. In case of symptoms of infection, WBC count and differential count should be considered.Neurologic: Neuroleptic Malignant Syndrome (NMS): Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phos-phokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.), and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anti-cholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.Tardive Dyskinesia: The risk of developing tardive dyskinesia and the likeli-hood that it will become irreversible increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, thereby, may possibly mask the underlying pro-cess. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. Seizure/Convulsion: In short-term, placebo-controlled trials of patients treated with oral ABILIFY, seizures/convulsions occurred in 0.1% (3/2096) of patients. There were confounding factors that may have contributed to the occurrence of seizures in some of these patients. Potential for Cognitive and Motor Impairment: Like other antipsychotic drugs, ABILIFY has the potential to impair judgment, thinking, or motor skills. Somnolence was a commonly reported adverse event in patients treated with ABILIFY in clinical trials.Special Populations: Geriatrics ( 65 years of age): In formal single-dose pharmacokinetic studies (with ABILIFY given in a single dose of 15 mg), ABILIFY clearance was 20% lower in elderly ( 65 years) subjects compared to younger adult subjects (18 to 64 years). There was no detectable age effect, however, in the population pharmacokinetic analysis in schizophrenia patients. Also, the pharmacokinetics of ABILIFY after multiple doses in elderly patients appeared similar to that observed in young, healthy subjects. (see WARNINGS AND PRECAUTIONS – Serious Warnings and Precautions and DOSAGE AND ADMINISTRATION – Geriatrics). Placebo-controlled studies of oral ABILIFY in schizophrenia or bipolar mania did not include suffi cient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Use in Elderly Patients with Dementia: Cerebrovascular Adverse Events, Including Stroke in Elderly Patients with Dementia: In placebo-controlled clinical studies (two fl exible dose and one fi xed dose study) of elderly patients withdementia, there was an increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in ABILIFY-treated patients. In the fi xed-dose study, there was a statistically signifi cant dose response relationship for cerebrovascular adverse events in patients treated with ABILIFY. ABILIFY is not indicated for the treatment of patients with dementia (see WARNINGS AND PRECAUTIONS – Serious Warnings and Precautions). Safety Experience in Elderly Patients with Alzheimer’s Disease: In three, 10-week, placebo-controlled studies of ABILIFY in elderly patients with Alzheimer’s disease (n=938; mean age: 82.4 years; range: 56-99 years), the treatment-emergent adverse events that were reported at an incidence of 3% and ABILIFY incidence at least twice that for placebo were lethargy [placebo 2%, ABILIFY 5%], somno-lence (including sedation) [placebo 3%, ABILIFY 8%], and incontinence (primarily, urinary incontinence) [placebo 1%, ABILIFY 5%], excessive salivation (placebo 0%, ABILIFY 4%), and lightheadedness (placebo 1%, ABILIFY 4%).Use in Patients with Concomitant Illness: Clinical experience with ABILIFY in patients with certain concomitant systemic illnesses is limited. ABILIFY has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from pre-marketing clinical studies (see WARNINGS AND PRECAUTIONS, Cardiovascular – Orthostatic Hypotension).Gender: Cmax and AUC of aripiprazole and its active metabolite, dehydro-aripip-razole, are 30 to 40% higher in women than in men, and correspondingly, the apparent oral clearance of aripiprazole is lower in women. These differences, however, are largely explained by differences in body weight (25%) between men and women. No dosage adjustment is recommended based on gender.Race: Although no specifi c pharmacokinetic study was conducted to investigate the effects of race on the disposition of ABILIFY, population pharmacokinetic evaluation did not demonstrate important race-related differences in the pharmaco-kinetics of ABILIFY. No dosage adjustment is recommended based on race.Lactose: ABILIFY tablets contain lactose (70 mg, 67 mg, 62 mg, 57 mg, 124 mg and 187 mg for the 2 mg, 5 mg, 10 mg, 15 mg, 20 mg and 30 mg tablets, respectively). Patients with rare hereditary problems of galactose intolerance or glucose-galactose malabsorption should not take ABILIFY. ADVERSE REACTIONSAdverse Drug Reaction Overview: The conditions and duration of treatment with ABILIFY (monotherapy or adjunctive therapy with antidepressants or mood stabilizers) included (in overlapping categories) double-blind, comparative and noncomparative open-label studies, inpatient and outpatient studies, fi xed- and fl exible-dose studies, and short- and longer-term exposure. Adverse events dur-ing exposure were obtained by collecting volunteered adverse events, as well as

results of physical examinations, vital signs, weights, laboratory analyses, and ECG. Adverse events were recorded by clinical investigators using terminology of their own choosing. In the tables and tabulations that follow, MedDRA dictionary terminology has been used to classify reported adverse events into a smaller number of standardized event categories, in order to provide a meaningful estimate of the proportion of individuals reporting adverse events. The stated frequencies of adverse events represent the proportion of individuals who reported at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the fi rst time or worsened while receiving therapy following baseline evaluation. There was no attempt to use investigator causality assessments; i.e., all events meeting the defi ned criteria, regardless of investigator causality are included. Adverse Events Reported at an Incidence of 2% or More Among ABILIFY-Treated Patients and Greater than Placebo in Short-Term, Schizophrenia and Bipolar Mania Placebo-Controlled Trials: Table 1 enumerates the pooled incidence, rounded to the nearest percent, of treatment-emergent adverse events that were reported during acute therapy (up to 6 weeks in schizophre-nia and up to 3 weeks in bipolar mania), including only those events that were reported in 2% or more of patients treated with ABILIFY (doses 2 mg/day) and for which the incidence in patients treated with ABILIFY was greater than the incidence in patients treated with placebo in the combined dataset.

Table 1: Treatment-Emergent Adverse Events in Short-Term, Placebo-Controlled Trials in Patients with Schizophreniaa and Bipolar Maniab

Treated with Oral ABILIFYPercentage of Patients Reporting Eventc

System Organ Class ABILIFY Placebo Preferred Term (n=1843) (n=1166)Eye Disorders Blurred Vision 3 1Gastrointestinal Disorders Nausea 15 11 Constipation 11 7 Vomiting 11 6 Dyspepsia 9 7 Dry Mouth 5 4 Toothache 4 3 Abdominal Discomfort 3 2 Stomach Discomfort 3 2General Disorders and Administration Site Conditions Fatigue 6 4 Pain 3 2Musculoskeletal and Connective Tissue Disorders Musculoskeletal Stiffness 4 3 Pain in Extremity 4 2 Myalgia 2 1 Muscle Spasms 2 1Nervous System Disorders Headache 27 23 Dizziness 10 7 Akathisia 10 4 Sedation 7 4 Extrapyramidal Disorder 5 3 Tremor 5 3 Somnolence 5 3Psychiatric Disorders Agitation 19 17 Insomnia 18 13 Anxiety 17 13 Restlessness 5 3Respiratory, Thoracic, and Mediastinal Disorders Pharyngolaryngeal Pain 3 2 Cough 3 2a 926 ABILIFY-treated patients and 413 placebo-treated patients.b 917 ABILIFY-treated patients and 753 placebo-treated patients.c Events reported by at least 2% of patients treated with oral ABILIFY, except events which had an incidence equal to or less than placebo.

An examination of population subgroups did not demonstrate a difference in the incidence of adverse events based on age, gender, or race.Short-Term, Placebo-Controlled Trial of Adjunctive Therapy in Patients with Bipolar Mania: In a placebo-controlled trial of patients with bipolar mania who were already tolerating either lithium or valproate as monother-apy, ABILIFY was administered orally for 6 weeks at doses of 15 or 30 mg as adjunctive therapy with lithium or valproate. The adverse events reported in that study were generally similar to the adverse events listed in Table 1 from clinical trials in which ABILIFY was used as monotherapy. Akathisia and tremor were reported more frequently when ABILIFY was used as adjunctive therapy. Akathisia was reported in 19% of patients treated with ABILIFY as adjunctive therapy compared to 5% of patients who received placebo as adjunctive therapy. In the lithium subgroup, the incidence of akathisia was 28% in patients treated with ABILIFY as adjunct and 4% in patients treated with placebo. In the valproate subgroup akathisia was reported in 12% of patients treated with ABILIFY as adjunctive therapy compared to 6% treated with placebo as adjunctive therapy. The incidence of tremor was 9% for patients treated with ABILIFY as adjunctive therapy and 6% for patients who received placebo as adjunctive therapy. Other commonly reported adverse events in this trial were insomnia 8% vs. 4% and extrapyramidal disorder 5% vs 1%, in ABILIFY-treated patients and placebo-treated patients, respectively.Discontinuation rates due to adverse events were 12% for patients treated with adjunctive ABILIFY compared to 6% for patients treated with adjunctive placebo. Akathisia, the most common adverse event leading to discontinua-tion in the ABILIFY group, led to withdrawal of 5% of ABILIFY-treated patients and 1% of patients on placebo.Dose-Related Adverse Events: Dose response relationships for the inci-dence of treatment-emergent adverse events were evaluated from four trials in patients with schizophrenia comparing various fi xed oral doses (2, 5, 10, 15, 20, or 30 mg/day) of ABILIFY to placebo. This analysis, stratifi ed by study, indicated that the only adverse event to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence [including sedation]; (incidences were placebo, 7.4%; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%). In two clinical trials in patients with bipolar mania comparing fi xed doses of 15 or 30 mg of oral ABILIFY to placebo, no dose response relationship for treatment-emergent adverse events was found.Extrapyramidal Symptoms: Table 2 provides the percentage of patients reporting treatment-emergent extrapyramidal symptoms in short-term placebo-controlled trials.

1p < 0.012p < 0.053p 0.001

In a long-term (26-week), placebo-controlled trial of schizophrenia, data on the Simpson-Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyski-nesias) did not show a difference between ABILIFY and placebo.Weight Gain: In 4- to 6-week trials in schizophrenia, there was a slight difference in mean weight gain between ABILIFY and placebo patients(+0.7 kg vs. -0.05 kg, respectively) and also a statistically signifi cant differ-ence in the proportion of patients meeting a weight gain criterion of 7% of body weight [ABILIFY (8%) compared to placebo (3%)]. In 3-week trials in bipolar mania, the mean weight gain for ABILIFY and placebo patients was 0.1 kg vs. 0.0 kg, respectively. The proportion of patients meeting a weight gain criterion of 7% of body weight was ABILIFY 2% compared to placebo 3%. In the 6-week trial in mania in which ABILIFY or placebo was used as adjunctive therapy with either lithium or valproate, the mean weight gain for ABILIFY and placebo patients was 0.6 kg vs. 0.2 kg, respec-tively. The proportion of patients meeting a weight gain criterion of 7% of body weight with adjunctive ABILIFY was 3% compared to adjunctive placebo 4%. In a long-term (26-week) placebo-controlled study of ABILIFY,a categorization of patients with schizophrenia at baseline on the basis ofbody mass index [BMI <23 (“low”); 23–27 (“normal”); > 27 (“high”)] revealed mean weight losses in patients treated with ABILIFY and patients on placebo (“low” BMI, -0.5 kg weight loss in both treatment groups; “normal” BMI, mean weight loss of -1.3 kg in ABILIFY-treated patients and -0.6 kg in placebo-treated patients; “high” BMI, mean weight loss of -2.1 kg in ABILIFY-treated patients and -1.5 kg in placebo-treated patients). In a long-term (52-week) study of ABILIFY and haloperidol, a categorization of patients with schizophrenia at baseline on the basis of BMI revealed the greatest mean weight gain in patients with low BMI compared to normal or overweight patients in both groups (patients with “low” BMI, mean weight gain 2.6 kg in ABILIFY-treated patients and 1.5 kg in haloperidol-treated patients; “normal” BMI, a mean weight gain of 1.4 kg in ABILIFY-treated patients and 0.2 kg in haloperidol-treated patients; “high” BMI, weight loss of -1.2 kg in ABILIFY-treated patients and -0.8 kg in haloperidol-treated patients). In both studies, the highest incidence of clinically signifi cant weight gain (>7% of body weight) was in patients with a low BMI (<23) compared to normal (23-27) or overweight patients (>27).ECG Changes: Between group comparisons for a pooled analysis of placebo-controlled trials in patients with schizophrenia or bipolar mania, revealed no signifi cant differences between oral ABILIFY and placebo in the proportion of patients experiencing potentially important changes in ECG parameters. ABILIFY was associated with a median increase in heart rate of 2 beats per minute compared to no increase among placebo patients.Additional Findings Observed in Clinical Trials: Adverse Events in Long-Term, Double-Blind, Placebo-Controlled Trials: The adverse events reported in a 26-week, double-blind trial comparing oral ABILIFY andplacebo in patients with schizophrenia were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higherincidence of tremor [8% (12/153) for ABILIFY vs. 2% (3/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity(8/12 mild and 4/12 moderate), occurred early in therapy (9/12 49 days), and were of limited duration (7/12 10 days). Tremor infrequently led to discontinuation (<1%) of ABILIFY. In addition, in a long-term(52-week), active-controlled study, the incidence of tremor for ABILIFY was 5% (40/859). A similar adverse event profi le was observed in a long-term, 26-week placebo-controlled study in bipolar mania.Other Adverse Events Observed During the Pre-marketing Evaluation of Oral ABILIFY: Following is a list of MedDRA terms that refl ect treatment-emergent adverse events as defi ned in the introduction to the ADVERSE REACTIONS section reported by patients treated with oral ABILIFY at multiple doses 2 mg/day during any phase of a trial within the database of 13,543 patients. All events assessed as possible adverse drug reactions have been included. In addition, medically/clinically meaningful events, particularly those that are likely to be useful to the prescriber or that have pharmaco-logic plausibility, have been included. Events already listed in Tables 1– 3 or other parts of the ADVERSE REACTIONS section have been excluded. Although the events reported occurred during treatment with ABILIFY, they were not necessarily caused by it. Events are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following defi nitions: frequent adverse events are defi ned as those occurring on 1 or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in less than 1/100 but at least 1/1,000 patients; rare events are those occurring in less than 1/1,000. Blood and Lymphatic System Disorders: Infrequent:leukopenia, neutropenia, thrombocytopenia. Cardiac Disorders: Infrequent:bradycardia, palpitations, cardiopulmonary failure, myocardial infarc-tion, cardio-respiratory arrest, atrioventricular block, extrasystoles, sinus tachycardia, atrial fi brillation, angina pectoris, myocardial ischemia; Rare:atrial fl utter, supraventricular tachycardia, ventricular tachycardia. Endocrine

Table 2: Percentage of Patients Reporting Treatment-Emergent Extrapyramidal Symptoms in Short-Term Placebo-Controlled Trials Percentage of Patients Reporting Event Schizophrenia Bipolar Mania Bipolar Mania Monotherapy Cotherapy ABILIFY Placebo ABILIFY Placebo ABILIFY PlaceboEPS-related AEs(excluding akathisia) 14 14 16 8 15 8Akathisia-relatedevents 8 4 13 4 19 5

Table 3: Mean Change from Baseline to Endpoint Score on the SAS, Barnes Akathisia Scale and AIMS from Short-Term Placebo-Controlled Trials Mean Change from Baseline to Endpoint Score Schizophrenia Bipolar Mania Bipolar Mania Monotherapy Cotherapy ABILIFY Placebo ABILIFY Placebo ABILIFY PlaceboSAS -0.06 -0.08 0.503 -0.01 0.731 0.07Barnes 0.08 -0.05 0.213 -0.05 0.302 0.11AIMS -0.441 -0.02 -0.02 -0.06 0.08 -0.10* A negative score indicates improvement.

Table 3 provides the mean change from baseline to endpoint score on the Simpson-Angus Rating Scale (for EPS) (SAS), Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesia) (AIMS) from short-term, placebo-controlled trials.

Opioid guideline intended to reduce wait for pain management: authors


Trap Editor


by Barry Ulmer,Executive Director, Chronic PainAssociation of Canada

It is well establishedchronic pain is a majorhealth care problem

largely ignored in the healthcare field and by those mak-ing health care policy deci-sions.

As patients we can attest tothis as we continue to be stig-matized, marginalized and often

simply ignored. The recently released

Canadian Guideline for Safeand Effective Use of Opioids forCNCP (Chronic Non-CancerPain) reinforces this and raisesanother barrier to the treatment

and management of pain.As pain sufferers we are fun-

damentally opposed to theimplementation of this guide-line and urge all to come for-ward and speak-up.

We feel strongly they are pre-

mature and relate more toaddiction medicine than painmedicine.

They reinforce the manybiases and attitudes that pre-vail aboutthe use ofopioids.

We areconcernedt h i sguide-linein its pres-ent formin not an effective tool andwill have the consequence ofdenying access to appropriatecare of people with chronicpain.

The document itself is fartoo cumbersome and willencourage doctors to drop theirpain patients as they becomeoverwhelmed by additionalpaperwork through time spenton credentialing and documen-tation that will be required toprescribe opioids.

The increased testing onlyreinforces the belief that thesemedicines should be reserveduntil one’s final days.

NOT FOR EVERYONENo other health condition hasso many restrictions in receivingappropriate care as in pain man-agement. We realize pain med-ication is not for everyone, butfor some it is one piece of thepuzzle that allows an individualto be a productive part of socie-ty.

By attempting to includespecific doses or equivalencesthey have opened the doorwider to insurers to stop payingfor medication, to increasedhealth care costs for the patientand increased costs to ourhealth care system in general.

There is no clear guidelineabout the dosages of morphineequivalents when other opioidsare used. In order for the guide-line to be clear, they would haveto specify the maximum dosefor each opioid that is used.

This in itself invites prob-lems as the dosing equivalentsin fact vary greatly from patientto patient. Expecting primarycare physicians to be able tokeep track of the guideline foreach opioid will lead to theeasier option of simply avoid-ing the use of these medica-tions altogether.

18 n October 2010

Barry Ulmer

Chronic Pain Association of Canada calls for more education on opioid usen The executive director of the Chronic Pain Association says physicians should have more education rather than a guideline

—please turn to next page

Disorders: Infrequent: diabetes mellitus (including blood insulin increased, carbohydrate tolerance decreased, diabetes mellitus non-insulin-dependent, glucose tolerance impaired, glycosuria, glucose urine, glucose urine pres-ent), hyperglycemia, hypoglycemia, polydipsia; Rare: diabetic ketoacido-sis, diabetic hyperosmolar coma. Eye Disorders: Infrequent: photophobia, diplopia, eyelid edema, photopsia. Gastrointestinal Disorders: Infrequent:gastroesophageal refl ux disease, dysphagia, swollen tongue, esophagitis; Rare: pancreatitis. General Disorders and Administration Site Conditions: Frequent: asthenia, peripheral edema, pyrexia, irritability, chest pain; Infrequent: feeling jittery, face edema, thirst, angioedema; Rare: hypothermia. Hepatobiliary Disorders: Rare: hepatitis, jaundice. Immune System Disorders: Infrequent: hypersensitivity. Injury, Poisoning, and Procedural Complications: Frequent: fall; Infrequent: self-mutilation; Rare: heat stroke. Investigations: Frequent: weight decreased, creatine phosphokinase increased; Infrequent: hepatic enzyme increased (increased ALT, increased AST), blood glucose increased, blood prolactin increased, blood urea increased, electrocardio-gram QT prolonged, blood creatinine increased, blood bilirubin increased; Rare: blood lactate dehydrogenase increased, glycosylated hemoglobin increased, gamma-glutamyl transferase (GGT) increased.Metabolism and Nutrition Disorders: Frequent: decreased appetite; Infrequent: hyperlipidemia, anorexia, hypokalemia, hyponatremia. Musculo-skeletal and Connective Tissue Disorders: Frequent: arthralgia; Infrequent: muscle rigidity, muscular weakness, muscle tightness, mobility decreased; Rare: rhabdomyolysis. Nervous System Disorders: Frequent: coordination abnormal; Infrequent: speech disorder, dyskinesia, parkinsonism, dystonia, memory impairment, cogwheel rigidity, cerebrovascular accident, convul-sion, hypokinesia, tardive dyskinesia, hypotonia, myoclonus, hypertonia, akinesia, bradykinesia; Rare: Grand Mal convulsion, choreoathetosis, neu-roleptic malignant syndrome. Psychiatric Disorders: Frequent: suicidal ideation; Infrequent: aggression, loss of libido, suicide attempt, hostility, libido increased, anger, anorgasmia, delirium, intentional self-injury, com-pleted suicide, tic, homicidal ideation; Rare: catatonia, sleepwalking. Renal and Urinary Disorders: Infrequent: urinary incontinence, urinary retention, polyuria, nocturia. Reproductive System and Breast Disorders: Infrequent: menstruation irregular, erectile dysfunction, amenorrhea, breast pain; Rare: gynaecomastia, priapism. Respiratory, Thoracic, and Mediastinal Disorders: Frequent: nasal congestion, dyspnea, pneumonia aspiration. Skin and Subcutaneous Tissue Disorders: Frequent: rash (including erythematous, exfoliative, generalized, macular, maculopapular, papular rash; acneiform, allergic, contact, exfoliative, seborrheic dermatitis, neurodermatitis, and drug eruption), hyperhydrosis; Infrequent: pruritus, photosensitivity reaction, alopecia, urticaria. Vascular Disorders: Frequent: hypertension; Infrequent: hypotension, syncope. Abnormal Hematologic and Clinical Chemistry Findings: A between-group comparison for 3- to 6-week, placebo-controlled trials in patients with bipolar mania and schizophrenia revealed no differences between the ABILIFY and placebo groups in the proportions of patients experiencing clinically important changes in most routine serum chemistry, hematology, or urinalysis parameters (including changes in prolactin, fasting glucose, triglyceride, HDL, LDL and total cholesterol measurements). Similarly, there were no differences in the incidence of discontinuations for changes in serum chemistry, hematology, or urinalysis. In a long-term (26-week), placebo-controlled trial there were no clinically important differences between the ABILIFY and placebo patients in the mean change from base-line in prolactin, fasting glucose, triglyceride, HDL, LDL, and total cholesterol measurements. Higher percentages of elevated creatine phosphokinase were observed in ABILIFY-treated patients compared to placebo-treated patients in short-term and long-term clinical trials. The most common AEs that were temporally associated with elevated CPK levels were musculoskeletal stiffness, myalgia, chest pain, fall, and muscle rigidity.Post-Market Adverse Drug Reactions: The adverse reactions presented below were reported during the post-marketing use of ABILIFY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Investigations: Very rare: Weight increased, blood glucose fl uctuation. Skin and Subcutaneous Tissue Disorders: Very rare: Allergic reaction (e.g., anaphylactic reaction, angioedema, laryngospasm, oropharyngeal spasm). Gastrointestinal Disorders: Very rare: Diarrhea.DRUG INTERACTIONSDrug-Drug Interactions: Ketoconazole and Other CYP3A4 Inhibitors: Coadministration of ketoconazole (200 mg/day for 14 days) with a15-mg single dose of ABILIFY increased the AUC of aripiprazole and its active metabolite by 63% and 77%, respectively. The effect of a higherketoconazole dose (400 mg/day) has not been studied. When ketocon-azole is administered concomitantly with ABILIFY, ABILIFY dose should be reduced to one-half of its normal dose. Other strong inhibitors of CYP3A4 (itraconazole) would be expected to have similar effects and require similar dose reductions; weaker inhibitors (erythromycin, grapefruit juice) have not been studied. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the ABILIFY dose should be increased. Quinidine and Other CYP2D6Inhibitors: Coadministration of quinidine (166 mg/day for 13 days), a potent inhibitor of CYP2D6, with a 10-mg single dose of ABILIFY increased the AUC of aripiprazole by 107% but decreased the AUC of its active metabolite, dehydro-aripiprazole, by 32%. The dose of ABILIFY should be reduced to one-half of its normal dose when quinidine is administered concomitantly with ABILIFY. Concomitant administration of other signifi cant inhibitors of CYP2D6, such as fl uoxetine or paroxetine, would be expected to have similar effects and, therefore, should be accompanied by similar dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy,the ABILIFY dose should be increased. Carbamazepine: Coadministra-tion of carbamazepine (200 mg BID), a potent CYP3A4 inducer, with ABILIFY(30 mg QD) resulted in an approximate 70% decrease in Cmax and AUC values of both aripiprazole and its active metabolite, dehydro-aripiprazole. When carbamazepine is added to ABILIFY therapy, the dose of ABILIFY should be doubled. Additional dose increases should be based on clinical evalu-ation. When carbamazepine is withdrawn from the combination therapy, the ABILIFY dose should be reduced.Drugs having no clinically important interactions with ABILIFY: Famotidine: Co-administration of ABILIFY (given in a single dose of 15 mg) with a 40-mg single dose of the H2 antagonist famotidine, a potent gastric acid blocker, decreased the solubility of aripiprazole and, hence, its rate of absorption. The Cmax of aripiprazole and dehydro-aripiprazole, was reduced

by 37% and 21%, respectively. The extent of absorption (AUC) of aripiprazole and dehydro-aripiprazole, was reduced by 13% and 15%, respectively. No dosage adjustment of ABILIFY is required when administered concomitantly with famotidine. Valproate: When valproate (500-1500 mg/day) and ABILIFY (30 mg/day) were co-administered, at steady state the Cmax and AUC of aripiprazole were decreased by 25%. No dosage adjustment of ABILIFY is required when administered concomitantly with valproate. When ABILIFY (30 mg/day) and valproate (1000 mg/day) were co-administered, at steady state there were no clinically important changes in the Cmax or AUC of valproate. No dosage adjustment of valproate is required when administered concomitantly with ABILIFY. Lithium: A pharmacokinetic interaction of ABILIFY with lithium is unlikely because lithium is not bound to plasma proteins, is not metabolized, and is almost entirely excreted unchanged in urine. Co-administration of therapeutic doses of lithium (1200-1800 mg/day) for 21 days with ABILIFY (30 mg/day) did not result in clinically important changes in the pharma-cokinetics of aripiprazole or its active metabolite, dehydro-aripiprazole (Cmax

and AUC increased by less than 20%). No dosage adjustment of ABILIFY is required when administered concomitantly with lithium.Co-administration of ABILIFY (30 mg/day) with lithium (900 mg/day) did not result in clinically important changes in the pharmacokinetics of lithium. No dosage adjustment of lithium is required when administered concomitantly with ABILIFY. Lamotrigine: Co-administration of 10 to 30 mg daily oral doses of ABILIFY for 14 days to subjects with bipolar I disorder had no effect on the steady-state pharmacokinetics 100 to 400 mg once daily lamotrigine, a UDP-glucuronosyltransferase 1A4 substrate. No dosage adjustmentof lamotrigine is required if ABILIFY and lamotrigine are administered concomitantly. Dosing recommendations for lamotrigine should be followed closely if valproate is also to be administered. Venlafaxine: Co-administration of 10 to 20 mg daily oral doses of ABILIFY for 14 days to healthy subjects had no effect on the steady-state pharmacokinetics of venlafaxine and O-desmethylvenlafaxine following 75 mg once daily venlafaxine XR, a CYP2D6 substrate. No dosage adjustment of venlafaxine is required if ABILIFY is administered concomitantly with venlafaxine. Escitalopram: Co-administration of 10 mg daily oral doses of ABILIFY for 14 days to healthy subjects had no effect on the steady-state pharmacokinetics of 10 mg once daily escitalopram, a substrate of CYP2C19 and CYP3A4. No dosage adjustment of escitalopram is required if ABILIFY and escitalopram are administered concomitantly. Dextromethorphan: ABILIFY at doses of 10 to 30 mg per day for 14 days had no effect on dextromethorphan’s O-dealkylationto its major metabolite, dextrorphan, a pathway dependent on CYP2D6activity. ABILIFY also had no effect on dextromethorphan’s N-demethylation to its metabolite 3-methyoxymorphan, a pathway dependent on CYP3A4activity. No dosage adjustment of dextromethorphan is required whenadministered concomitantly with ABILIFY. Warfarin: ABILIFY 10 mg per day for 14 days had no effect on the pharmacokinetics of R- and S-warfarinor on the pharmacodynamic end point of International Normalized Ratio,indicating the lack of a clinically relevant effect of aripiprazole on CYP2C9 and CYP2C19 metabolism or the binding of highly protein-bound warfarin. No dosage adjustment of warfarin is required when administered con-comitantly with ABILIFY. Omeprazole: Co-administration of ABILIFY (10 mg per day for 15 days) and a single 20-mg dose of omeprazole, a CYP2C19substrate, had no effect on the pharmacokinetics of omeprazole in healthy subjects. No dosage adjustment of omeprazole is required when administeredconcomitantly with ABILIFY. Lorazepam: Co-administration of oral lorazepam (2 mg) and oral ABILIFY (15 mg) to healthy subjects (n=24 males; ages 18-43 years old) did not result in clinically important changes in the pharmacokinetics of either drug. No dosage adjustment of either drug is required when they are administered concomitantly. However, the intensity of sedation was greater with the combination as compared to that observed with ABILIFY aloneand the incidence of orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone (see WARNINGS AND PRECAUTIONS).Drug-Food Interactions: ABILIFY can be administered with or without food. Drug-Herb Interactions: Interactions with herbal products have not been studied.Drug-Laboratory Interactions: Interactions with laboratory tests have not been identifi ed. Drug-Lifestyle Interactions: Alcohol/CNS Drugs: Given the primary CNS effects of ABILIFY, as with most psychoactive medications, combination use of ABILIFY with alcohol or other CNS drugs with overlapping undesirable effects such as sedation, should be avoided. Smoking: Aripiprazole is metabolized by multiple pathways involving the CYP2D6 and CYP3A4 enzymes but not CYP1A enzymes. Thus, no dosage adjustment is required for smokers.OVERDOSAGEHuman Experience: In clinical studies, no deaths were associated with accidental or intentional acute overdosage of ABILIFY alone. In clinical trials, in the patient taking the largest confi rmed amount of ABILIFY, 1080 mg, ingested with alcohol, the only symptom reported was vomiting. In postmar-keting experience, there is a single case of death that was possibly associated with accidental or intentional acute overdosage of ABILIFY alone. The patient ingested 900 mg of ABILIFY, was hospitalized in the intensive care unit for 10 to 14 days and died. The patient’s medical history included excessive alcohol use, although it is unclear whether alcohol was present at the time of overdosage. In the patient taking the largest confi rmed amount of ABILIFY, 1680 mg, the only symptoms reported were vomiting, fatigue, and dizziness. In addition, a report of non-fatal accidental overdose with ABILIFY alone (up to 195 mg) in a 2.5 year old child has been received. Vomiting, somnolence, lethargy, transient loss of consciousness and CNS depression were reported for this patient. Other potentially medically important signs and symptoms that have been observed during overdose included blood pressure increase and tachycardia. In the patients who were evaluated in hospital settings, there were no reported observations indicating clinically important adverse change in vital signs, laboratory assessments, or electrocardiogram.Management of Overdosage: No specifi c information is available on the treatment of overdose with ABILIFY. Management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxy-genation and ventilation, and management of symptoms. The possibility of multiple drug involvement should be considered. Therefore, cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Following any confi rmed or suspected overdose with ABILIFY, close medical supervi-sion and monitoring should continue until the patient recovers. Charcoal:

In the event of an overdose of ABILIFY, an early charcoal administration maybe useful in partially preventing the absorption of aripiprazole. Administrationof 50 g of activated charcoal, one hour after a single 15-mg oral dose of ABILIFY, decreased the mean AUC and Cmax of aripiprazole by 50%.Hemodialysis: Although there is no information on the effect of hemodialysis in treating an overdose with ABILIFY, hemodialysis is unlikely to be useful in overdose management since ABILIFY is highly bound to plasma proteins. For up-to-date information on the management of a suspected drug overdose, contact the regional Poison Control Centre.ACTION AND CLINICAL PHARMACOLOGYMechanism of Action: The mechanism of action of aripiprazole, as with other drugs having effi cacy in schizophrenia and bipolar disorder is unknown. However, it has been proposed that the effi cacy of aripiprazole may be mediated through a combination of partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors; how-ever, the clinical relevance of these interactions has not been established. Actions at receptors other than D2, 5-HT1A, and 5-HT2A may explain some of the other clinical effects of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic α1 receptors). The clinical relevance of these receptor interactions with aripiprazole is unknown.DOSAGE FORMS, COMPOSITION AND PACKAGING2 mgEach green, modifi ed rectangle tablet imprinted with “A-006” and “2” con-tains: aripiprazole 2 mg. Non-medicinal ingredients: cornstarch, hydroxypro-pyl cellulose, lactose monohydrate, magnesium stearate, and microcrystal-line cellulose. Coloring agents: FD&C Blue No. 2 Aluminum Lake and Iron Oxide Yellow. Bottles of 30 tablets and blister packs of 100 tablets.5 mgEach blue, modifi ed rectangle tablet imprinted with “A-007” and “5” contains: aripiprazole 5 mg. Non-medicinal ingredients: cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Coloring agents: FD&C Blue No. 2 Aluminum Lake. Bottles of 30 tablets and blister packs of 100 tablets.10 mgEach pink, modifi ed rectangle tablet imprinted with “A-008” and “10” contains: aripiprazole 10 mg. Non-medicinal ingredients: cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Coloring agents: Iron oxide red. Bottles of 30 tablets and blister packs of 100 tablets.15 mgEach yellow, round tablet imprinted with “A-009” and “15” contains: aripiprazole 15 mg. Non-medicinal ingredients: cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Coloring agents: Iron oxide yellow. Bottles of 30 tablets and blister packs of 100 tablets.20 mgEach white, round tablet imprinted with “A-010” and “20” contains: aripiprazole 20 mg. Non-medicinal ingredients: cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Bottles of 30 tablets and blister packs of 100 tablets.30 mgEach pink, round tablet imprinted with “A-011” and “30” contains: aripiprazole 30 mg. Non-medicinal ingredients: cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Coloring agents: Iron oxide red. Bottles of 30 tablets and blister packs of 100 tablets.Product Monograph available on request. Last revised July 3, 2009.

ABILIFY is a trademark of Otsuka Pharmaceutical Co., Ltd., used under licence by Bristol-Myers Squibb Canada Co.Distributed by Bristol-Myers Squibb Canada2344 Alfred-Nobel, Suite 300, Montréal, Québec H4S 0A4

Pr

Itdoincom“unn

Wworlusinthorpletebut specpossexpewou

Timppatiessenfailuof pto capatieical

Astronguidto hintemissto carea

Tpaintivelresouty ttogethinand actued in

TmortheirWattion—ly min p

Ttimebecalittlepainin syeasietionsthanpainleaveasseshavepaintheir

Tbefopenaof th

curencTh

—co


Trap Editor


e topain

manypre-

ande ofriateonic

s farwill

theircomeonalpent

men-d to

onlytheserved

n hasivingman-med- butf thedualocie-

ludeencesdoorayingasedtientour

al. elinehineioidsuide-havedose.

prob-lentstient

marye toe for

thevoid-dica-

page

It is already clear insurers aredoing this in addition to filingcomplaints against doctors for“unnecessary prescribing.”

We agree that in an idealworld every person in painusing opioids should receive athorough, thoughtful com-plete appropriate evaluation,but it is not clear what a painspecialist is; even if it werepossible to define such anexpert, it is doubtful therewould be enough.

This is a plan that placesimpossible requirements onpatients and prescribers;essentially it is a formula forfailure with a high probabilityof producing further obstaclesto care, subsequently harmingpatients with legitimate med-ical conditions.

As pain patients we feelstrongly the authors of thisguideline, (those that professto have the patients’ bestinterest in mind), havemissed a golden opportunityto create real change in thisarea of medicine.

They would have impactedpain medicine far more posi-tively if they had used theirresources and the obvious abili-ty to bring a strong grouptogether to develop forwardthinking educational programsand then use their influence toactually have them implement-ed into our medical schools.

They would have been farmore productive to combinetheir efforts with those of JudyWatt-Watson, PhD, in educa-tion—something that will real-ly make a difference for peoplein pain.

To write a guideline at thistime is sheer folly simplybecause most practitioners, withlittle or no specific training inpain management and workingin systems that make it mucheasier to treat common condi-tions like high blood pressurethan a complex problem likepain may intend to help, butleave most patients under-assessed and under-treated andhave little clue on how to treatpain, let alone to use opioids intheir endeavours.

This is putting the horsebefore the cart. It is time to stoppenalizing the many for the sinsof the few.

—Unique perspectives oncurrent issues in the CNS sci-ences are always welcome atThe Chronicle. Send yours to

[email protected]

neurologist–the fact that thereis this strong comorbidity sug-gests that screening for theother condition when the firstone is present is important.”

The study is a “reminder”and a “reinforcement” to physi-cians that these disorders oftenco-occur, he said. “It flags for us[psychiatrists] that migraine,especially migraine with aura, is

particularly likely to be associat-ed with depression. It suggeststhat the genetic factors are real-ly important, especially in thecomorbidity of depression andmigraine with aura.”

Though there’s speculationthat genes underlying depres-sion and migraine have some-thing to do with the regulationof serotonin and/or glutaminefunction, the study “doesn’t tellus what those genes actually

are,” said Dr. Enns. “We don’treally know how it translatesinto some kind of physiology. Ifwe knew how it translated intophysiology, that might give usclearer targets for interventionpharmacologically.”

Understanding genetic fac-tors contributing to bothmigraine and depression couldeventually lead to better strate-gies to manage the course ofthese diseases when they occur

together, Dr. Andrew Ahn,University of Florida inGainesville, author of an edito-rial accompanying the study,said in a press release.

“In the meantime,” hewrote, “people with migraine ordepression should tell their doc-tors about any family history ofeither disease to help us betterunderstand the link.”

—Read this Neurologystudy at http://nn.nf/438h

Depression screening should follow migraine diagnosis —continued from page 14

October 2010 n 19

—continued from previous page

Patient Selection CriteriaTherapeutic Category: Antidepressant

Action: Serotonin and Norepinephrine Reuptake Inhibitor (SNRI)

Indications and Clinical Use

Adults: PRISTIQ® desvenlafaxine Extended-Release Tablets is indicated for: the symptomatic relief of major depressive disorder. The short-term effi cacy of PRISTIQ extended-release tablets has been demonstrated in placebo- controlled trials of up to 8 weeks.

Pediatrics (<18 years of age): PRISTIQ is not indicated for use in children under the age of 18. Safety and effectiveness in the pediatric population have not been established (see WARNINGS AND PRECAUTIONS, potential association with behavioural and emotional changes, including self-harm).

CONTRAINDICATIONS• Desvenlafaxine must not be used concomitantly in patients taking monoamine oxidase inhibitors (MAOIs, including linezolid,

an antibiotic) or in patients who have taken MAOIs within the preceding 14 days due to the risk of serious, sometimes fatal, drug interactions with selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI) treatment or with other serotonergic drugs. These interactions have been associated with symptoms that includetremor, myoclonus, diaphoresis, nausea, vomiting, fl ushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, rigidity, autonomic instability with possible rapid fl uctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Based on the half-life of desvenlafaxine succinate, at least 7 days should be allowed after stopping desvenlafaxine succinate and before starting an MAOI.

• Hypersensitivity to desvenlafaxine succinate extended-release, venlafaxine hydrochloride or to any excipients in the desvenlafaxine formulation. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.

SPECIAL POPULATIONSPregnant Women: the safety of desvenlafaxine in human pregnancy has not been established. The extent of exposure to PRISTIQ in pregnancy during clinical trials was very limited. There are no adequate and well-controlled studies in pregnant women. Therefore, desvenlafaxine should be used during pregnancy only if the potential benefi ts justify the potential risks. If desvenlafaxine succinate is used until or shortly before birth, discontinuation effects in the newborn should be considered.

Post-marketing reports indicate that some neonates exposed to SNRIs, SSRIs, or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical fi ndings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding diffi culty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperrefl exia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SNRIs, SSRIs and other newer antidepressants, or, possibly a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see DRUG INTERACTIONS). When treating a pregnant woman with PRISTIQ during the third trimester, the physician should carefully consider the potential risks and benefi ts of treatment.

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Labour and Delivery: the effect of desvenlafaxine on labour and delivery in humans is unknown. PRISTIQ should be used during labour and delivery only if the potential benefi ts justify the potential risks.

Nursing Women: desvenlafaxine (O-desmethylvenlafaxine) is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from PRISTIQ, a decision should be made whether or not to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Only administer PRISTIQ to breastfeeding women if the expected benefi ts outweigh any possible risk.

Pediatric: safety and effectiveness in patients less than 18 years of age have not been established.

Geriatrics (≥65 years of age): of the 3,292 patients in clinical trials with PRISTIQ, 5% were 65 years of age or older. No overall differences in safety or effi cacy were detected between these subjects and younger subjects; however in the short-term placebo-controlled trials, there was a higher incidence of systolic orthostatic hypotension in patients ≥65 years of age compared to all adults treated with desvenlafaxine. For elderly patients, possible reduced renal clearance of desvenlafaxine should be considered when determining dose (see Dosing Considerations, Geriatrics and ACTION AND CLINICAL PHARMACOLOGY, Geriatrics). Greater sensitivity of some older individuals cannot be ruled out.

WARNINGS AND PRECAUTIONS

POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM.

Pediatrics: Placebo-Controlled Clinical Trial DataRecent analyses of placebo-controlled clinical trial safety databases from Selective Serotonin Reuptake Inhibitors (SSRIs) and other newer anti-depressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.

The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliabconclusions on the relative safety profi les among the drugs in the class. Adults and Pediatrics: Additional DataThere are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics anadults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type eveninclude: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some casethe events occurred within several weeks of starting treatment.Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised patients of all ages especially when initiating therapy or during any change in dose or dosage regimen. This includemonitoring for agitation-type emotional and behavioural changes.Patients currently taking PRISTIQ should NOT be discontinued abruptly, due to risk of discontinuation symptom(See WARNINGS and PRECAUTIONS, Discontinuation Symptoms, below). At the time that a medical decision is madto discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose, rather than an abrucessation, is recommended. (See Dosage and Administration). Concomitant Use of PRISTIQ with VenlafaxineSince desvenlafaxine is the major active metabolite of venlafaxine, concomitant use of PRISTIQ with products containinVenlafaxine is not recommended since the combination of the two will lead to additive desvenlafaxine exposure.Monitoring and Laboratory TestsSerum Lipids: increases in cholesterol (total and LDL) and triglycerides were observed in some patients treated widesvenlafaxine succinate in placebo-controlled pre-marketing clinical trials, particularly with higher doses. Measurement serum lipid levels should be considered during treatment.Heart Rate and Blood Pressure: increases in heart rate and blood pressure were observed in some patients in clinical trialparticularly with higher doses. Measurement of blood pressure is recommended prior to initiating treatment and regularduring treatment with desvenlafaxine succinate (see ADVERSE REACTIONS, Vital Sign Changes). Self-Harm: rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised patients of all ages. Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxietagitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessnesshypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially wheinitiating therapy or during any change in dose or dosage regimen. (See WARNINGS AND PRECAUTIONS, POTENTIAASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).PsychiatricMania/hypomania: mania/hypomania may occur in a small proportion of patients with mood disorders who have receivemedication to treat depression, including desvenlafaxine succinate. During phase 2 and phase 3 studies, mania was reportefor approximately 0.1% of patients treated with PRISTIQ. Activation of mania/hypomania has also been reported in a smaproportion of patients with major affective disorder who were treated with other marketed antidepressants. As with aantidepressants, PRISTIQ should be used cautiously in patients with a history or family history of mania or hypomania. NeurologicSeizures: cases of seizures have been reported in pre-marketing trials with PRISTIQ. Desvenlafaxine succinate shoube prescribed with caution in patients with a seizure disorder. Desvenlafaxine has not been systematically evaluated patients with a seizure disorder. Serotonin Syndrome: as with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, maoccur with desvenlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergneurotransmitter systems (such as triptans, serotonin reuptake inhibitors, sibutramine, MAOIs (including linezolid, aantibiotic), St. John’s Wort (Hypericum perforatum) and/or lithium) and with drugs that impair metabolism of serotoniSerotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonominstability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperrefl exiincoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea).If concomitant treatment with desvenlafaxine and other agents that may affect the serotonergic neurotransmitter systesuch as another SSRI, a Selective Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) or a 5-hydroxytryptamine receptagonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiatioand dose increases. The concomitant use of desvenlafaxine with serotonin precursors (such as tryptophan supplementis not recommended (see DRUG INTERACTIONS, Serotonin Syndrome).OphthalmologicNarrow Angle Glaucoma: mydriasis has been reported in association with desvenlafaxine; therefore, patients with raiseintraocular pressure or those at risk of acute narrow- angle glaucoma (angle- closure glaucoma) should be monitore(see ADVERSE REACTIONS). GastrointestinalPotential for Gastrointestinal Obstruction: because the PRISTIQ tablet does not appreciably change in shape in thgastrointestinal tract, PRISTIQ should not be administered to patients with pre-existing gastrointestinal narrowin(pathologic or iatrogenic, such as small bowel infl ammatory disease, “short gut” syndrome due to adhesions or decreasetransit time, past history of peritonitis, cystic fi brosis, chronic intestinal pseudo-obstruction, or Meckel’s diverticulum). Thehave been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of othdrugs in nondeformable controlled-release formulations, and very rare reports of obstructive symptoms associated withe use of nondeformable controlled-release formulations in patients without known gastrointestinal stricture. Due to thcontrolled-release design, PRISTIQ tablets should only be used in patients who are able to swallow the tablets whol(See DOSAGE AND ADMINISTRATION; Recommended Dose and Dosage Adjustment).

ADVERSE REACTIONSThe safety of PRISTIQ in major depressive disorder was evaluated in 3,292 patients exposed to at least one dose of PRISTIQThe most commonly observed adverse reactions (incidence of 5% or greater for the DVS SR pooled 50- to 400-mg doseand incidence higher than placebo) in DVS SR-treated MDD patients in short-term placebo controlled trials were: nauseheadache, dry mouth, hyperhydrosis, dizziness, insomnia, constipation, decreased appetite, somnolence, fatigue, tremoand vomiting, and, in men, erectile dysfunction and ejaculation delayed.

Safety Information

Prescribing Summary


Trap Editor


Two Neurological NovelsSaturdayby Ian McEwan (http://ow.ly/2FkCY)MCEWAN, AS IS HIS CUSTOM, uses rou-tine situations, mundane on the sur-

face, involving theinteractions ofindividuals tomake much largerpoints about thecomplexities ofbeing human. Inthis 2007 novel, hedepicts a middle-aged London neu-rologist whoseordered routine is

disrupted by public demonstrationsagainst the impending Iraq war, and asubsequent motor-vehicle encounterwith an oddly hostile stranger. Whathe’s really describing is the interplay ofbiology, happenstance, and destiny, asthey collide during the end of themodern epoch in Western civilization.“Saturday” is potent and engagingstuff, although not as insightful andnuanced as the very best of McEwan’swork. —Mitchell Shannon

Memory by Donald E. Westlake(http://ow.ly/2FkGm)PUBLISHED FOR THE FIRST TIME thisApril, a year following the author’sdeath, this is not in the mould of pre-

vious Westlakes,which were slicklyexecuted, enter-taining, and com-mercially successfulcrime novels.“Memory” is noneof the above. Setand likely writtenin the early ormid-60s,

“Memory” is a dark, weighty and dis-turbing fictive commentary on cogni-tion impairment, memory and person-ality. Westlake’s offhand prose stylecoats a challenging message, and leavesthe reader with much to think, andperhaps brood, about.” —MS

—What book have you recentlycome across that might be of interest to

your colleagues? Send your shortreviews to: [email protected]

Nov. 26 - 27, 20102nd Conference on Positive Aging

Vancouver, B.C.Contact: Katia Selezeneva ¶ Phone: 604-

822-7524 ¶ Fax: 604-822-4835 ¶ E-Mail: [email protected]

Dec. 3 - 7, 201064th Annual Meeting of the American

Epilepsy SocietySan Antonio, Texas

Contact:Meeting Organiser ¶ Phone: 860-586-7505

E-mail: [email protected]

Dec. 9 - 12, 2010The 7th International Congress on MentalDysfunctions & Other Non-Motor features

20 n October 2010

Adverse Events Reported as Reasons for Discontinuation of Treatment in MDD Clinical TrialsIn the 8-week placebo-controlled, pre-marketing trials for MDD, 12% of the 1,834 patients who received PRISTIQ (50-400 mg/day)discontinued treatment due to an adverse experience, compared with 3% of the 1,116 placebo-treated patients in those trials.At the recommended dose of 50 mg, the discontinuation rate due to an adverse experience for PRISTIQ (4.1%) was similar to the rate for placebo (3.8%) and only 1% of patients discontinued due to nausea.The most common adverse reactions leading to discontinuation (i.e., leading to discontinuation in at least 2% and incidence higher than placebo) of the PRISTIQ-treated patients in short-term trials of up to 8 weeks were: nausea (4%); dizziness, headache and vomiting (2% each). To report adverse events:Wyeth CanadaT 1-800-463-6001F 1-866-463-6001

DRUG-DRUG INTERACTIONSMonoamine Oxidase Inhibitors: desvenlafaxine succinate is contraindicated in patients taking MAOIs. Desvenlafaxine succinate must not be used in combination with a monoamine oxidase inhibitor (MAOI), or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of desvenlafaxine succinate, at least 7 days should be allowed after stopping desvenlafaxine succinate before starting an MAOI (see CONTRAINDICATIONS).

Serotonin Syndrome: as with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with desvenlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, other SNRIs, linezolid [an antibiotic which is a reversible non-selective MAOI], lithium, sibutramine, tramadol, or St. John’s Wort [Hypericum perforatum], with drugs which impair metabolism of serotonin (including MAOIs; see CONTRAINDICATIONS), or with serotonin precursors (such as tryptophan supplements). Serotonin syndrome symptoms may include mental status changes, autonomic instability, neuromuscular aberrations and/or gastrointestinal symptoms (see WARNINGS AND PRECAUTIONS).

If concomitant treatment of desvenlafaxine with an SSRI, an SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of desvenlafaxine with serotonin precursors is not recommended.

Central Nervous System (CNS) Active AgentsThe risk of using desvenlafaxine succinate in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when desvenlafaxine succinate is taken in combination with other CNS-active drugs.

Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when PRISTIQ is initiated or discontinued.

GeneralPRISTIQ is not indicated for use in children under 18 years of age (see WARNINGS AND PRECAUTIONS, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).

Recommended Dose and Dosage AdjustmentInitial Treatment: the recommended dose of PRISTIQ (desvenlafaxine succinate) extended-release tablets is 50 mg once daily, with or without food. In clinical studies, no additional benefi t was demonstrated at doses greater than 50 mg/day. In clinical studies, doses of 50-400 mg/day were shown to be effective, although no additional benefi t was demonstrated at doses greater than 50 mg/day, and adverse events and discontinuations were more frequent at higher doses. If the physician, based on clinical judgment, decides a dose increase above 50 mg/day is warranted for an individual patient, the maximum dose should not exceed 100 mg/day. Patients should be periodically reassessed to determine the need for continued treatment.It is recommended that PRISTIQ be taken at approximately the same time each day. PRISTIQ tablets must be swallowed whole with liquids, and must not be chewed, divided or crushed. The medication is contained within a non-absorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice something that looks like a tablet in their stool. Due to the controlled-release design, PRISTIQ tablets should only be used in patients who are able to swallow the tablets whole.Missed Dose: a patient missing a dose should take it as soon as they remember to. If it is almost time for the next dose, the missed dose should be skipped. The patient should be cautioned against taking two doses concomitantly to “make up” for the missed dose.Discontinuing PRISTIQ: symptoms associated with discontinuation of PRISTIQ, other SNRIs and SSRIs have been reported (see WARNINGS AND PRECAUTIONS, Discontinuation Symptoms and ADVERSE REACTIONS, Discontinuation symptoms). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate. As the lowest dosage strength of PRISTIQ is 50 mg, it is recommended that dose reduction from 50 mg/day should proceed to 50 mg every other day before discontinuation. Dosing ConsiderationsPatients with severe renal impairment and end-stage renal disease: the recommended dose in patients with severe renal impairment (24-hr CrCl <30 mL/min) or end-stage renal disease (ESRD) is 50 mg every other day. Because of individual variability in clearance in these patients, individualization of dosage may be desirable. Supplemental doses should not be given to patients after dialysis (see ACTION AND CLINICAL PHARMACOLOGY, Renal Insuffi ciency).Use in patients with hepatic impairment: no dosage adjustment is necessary for patients with hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY, Hepatic Insuffi ciency).

Geriatrics (≥65 years of age) : no dosage adjustment is required solely on the basis of age; however, possible reduced clearance of PRISTIQ should be considered when determining dose (see ACTION AND CLINICAL PHARMACOLOGY, Geriatrics).

Switching Patients to or from a Monoamine Oxidase Inhibitor: at least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with desvenlafaxine succinate. In addition, based on the half-life of desvenlafaxine succinate, at least 7 days should be allowed after stopping desvenlafaxine succinate before starting an MAOI.

Discontinuation of Therapy: a gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. Discontinuation regimens should take into account the individual circumstances of the patient, such as duration of treatment and dose at discontinuation (see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS).

SUPPLEMENTAL PRODUCT INFORMATIONAdverse Reactions in MDD Clinical TrialsPRISTIQ was evaluated for safety in 3,292 patients diagnosed with major depressive disorder who participated in multiple-dose pre-marketing trials, representing 1,289 patient-years of exposure. Among these 3,292 PRISTIQ-treated patients, 1,834 patients participated in 8-week, placebo-controlled trials at doses ranging from 50 to 400 mg/day. Of the total 3,292 subjects exposed to at least 1 dose of PRISTIQ, 1070 were exposed to PRISTIQ for greater than 6 months and 274 were exposed for 1 year.Adverse Reactions Occurring at an Incidence of ≥1% among PRISTIQ-treated Patients in Short-Term Placebo-controlled TrialsThe following adverse reactions (Table 2) occurred at ≥1% and are listed alphabetically by body system. Reported adverse events were classifi ed using a standard MedDRA-based Dictionary terminology.Table 2: Adverse Reactions (≥1% in Any PRISTIQ Group): Percentage of Subjects in Short-Term, Placebo-Controlled MDD Studies

System Organ ClassPreferred Term

PRISTIQ

Placeboa

n=111650 mgb

n=317100 mgb

n=424200 mgb

n=307400 mgb

n=31750-400 mga

n=1834Cardiac disorders

Palpitations 2 1 3 2 3 2Tachycardia 1 1 <1 1 2 1

Ear and labyrinth disorders

Tinnitus 1 2 1 1 2 1

Eye disorders

Mydriasis <1 2 2 6 6 4Vision blurred 1 3 4 4 4 4

Gastrointestinal disordersNausea 11 22 26 36 41 32Dry mouth 8 11 17 21 25 20Constipation 4 9 9 10 14 11Diarrhea 9 11 9 7 5 8Vomiting 2 3 4 6 9 6

General disorders and administration site conditions

Fatigue 4 7 7 10 11 8Chills 1 1 <1 3 4 2Feeling jittery 1 1 2 3 3 2Asthenia 1 1 2 1 1 1

Investigations

Blood pressure increased 1 1 1 2 2 2Weight decreased 1 2 1 1 2 1

Metabolism and nutrition disorders

Decreased appetite 2 5 8 10 10 9

Musculoskeletal and connective tissue disorders

Musculoskeletal stiffness 1 1 <1 1 1 1

Nervous system disorders

Headache 25 20 22 29 25 25Dizziness 6 13 10 15 16 13Somnolence 4 4 9 12 12 9Tremor 2 2 3 9 9 6Paraesthesia 1 2 2 1 3 2Dysgeusia 1 1 1 1 2 2Disturbance in attention <1 <1 1 2 1 1

Psychiatric disorders

Insomnia 6 9 12 14 15 12Anxiety 3 3 5 4 4 4Abnormal dreams 2 2 3 2 4 3Anorgasmia 0 <1 2 2 6 2Libido decreased 1 2 3 3 2 2Orgasm abnormal <1 1 1 1 2 1Nervousness 1 <1 1 2 2 1

Renal and urinary disorders

Urinary hesitation <1 <1 1 2 2 1

Respiratory, thoracic and mediastinal disorders

Yawning <1 1 0 4 3 3

Skin and subcutaneous tissue disorders

Hyperhidrosis 4 10 11 18 21 15Rash 1 1 1 2 <1 1

Vascular disorders

Hot fl ush <1 1 1 2 2 2

MDD=major depressive disorder.a. Includes data from all short-term, placebo-controlled studies including fi xed-dose and fl exible-dose studies.b. Only includes data from short-term, placebo-controlled, fi xed-dose studies.Classifi cations of adverse events are based on the Medical Dictionary for Regulatory Activities (MedDRA).Note: <1% indicates an incidence less than 0.5%, but greater than zero.

Administration

in

Con2

SEXUAL FUNCTTable 3 shows tgroup (8-week,

Table 3: Sexuaof Subjects in S

Preferred Te

Men onlyd

Erectile dysEjaculation AnorgasmiaLibido decreEjaculation Ejaculation Orgasm ab

Women onlyAnorgasmiaLibido decreOrgasm ab

a. Medical Dicb. Includes dac. Only included. Percentage

n=131; DVe. Percentage

n=176; DV

ADVERSE DRUGA total of 3292evaluated in 10were exposed fo

The following lisdose range studi

Adverse reaction Very comm Common: ≥ Uncommon Rare: ≥0.0 Very rare: <

Cardiac disordeEar and labyrinEye disorders: CGastrointestinaGeneral disordewithdrawal syndImmune systemInvestigations:increased, bloodMetabolism andMusculoskeletaNervous systemUncommon: synPsychiatric disoUncommon: depRenal and urinaReproductive sysexual dysfunctioRespiratory, thoSkin and subcuVascular disord* Frequency is c

Ischemic cardiamyocardial infarexperienced theCerebrovascula

Discontinuation MDD clinical triageneral, discontiPRECAUTIONS).

Orthostatic Hypwere detected behypotension in pcannot be ruled Considerations,

ECG Changes: ein clinical trials lQTc, PR, and QRwas observed bestudy was desig

Table 4: Estimawith Different H

Treatment

PRISTIQ 20

PRISTIQ 60

Moxifl oxac(Active con

a. Mean (90%b. The PRISTI


Trap Editor


entaltures

discontinuation desvenlafaxine .

ded whenever ch as duration ).

trials, representing als at doses rangingter than 6 months

es

50-400 mga

n=1834

21

1

44

32201186

8221

21

9

1

251396221

12432211

1

3

151

2

in Parkinson’s Disease (MDPD 2010)Barcelona, Spain

Contact: KENES International ¶ Phone: 41-229-080-488 ¶ Fax: 41-229-069-140

¶ E-mail: [email protected]

Jan. 19 - 21, 2011

Quadricentennial Neuroscience Summit2011: In Celebration of Life in the

NeurosciencesManila, Philippines

Contact: Joseree-Ann S. Catindig, MD ¶Phone: 632-749-9788 ¶ Fax: 632-749-9788 ¶

E-mail: [email protected]

Jan. 28 - 30, 20114th European Neurological Conference

on Clinical Practices (ENCCP) 2011Lisbon, Portugal

Contact: Congress Secretariat ¶ Phone: 41-0-22-533-0948 ¶ Fax: 41-0-22-580-2953


Feb. 16 - 18, 201144th Annual Recent Advances in

NeurologySan Francisco, Calif.

Contact:UCSF Office of Continuing MedicalEducation, 3333 California Street, Room 450 ,San Francisco, CA 94118 ¶ Phone:415-476-4251 / 415-476-5808 ¶ Fax:415-476-0318 /

415-502-1795 ¶ E-mail:[email protected]

Feb. 21 - 22, 20117th Annual Update Symposium on

Clinical Neurology and NeurophysiologyTel Aviv, Israel

Contact: Aryeh Lewis ¶ Phone: 972-2-652-0574 ¶ Fax: 972-2-652-0558


June 20, 2011 - June 22, 2011CyberPsychology & CyberTherapy

ConferenceGatineau, Que.

Contact:Prof. Brenda K. Wiederhold ¶ Phone:1-858-642-0267 ¶ Fax: 1-858-642-0285 ¶ E-Mail: [email protected]

May 17, 2014 - May 22, 201452nd American Society of Neuroradiology

(ASNR 2014) Annual MeetingMontreal, Que.

Contact: ASNR ¶ Phone: 630-574-0220 ¶Fax: 630-574-0661 ¶

E-Mail: [email protected]

—Let us know about upcomingconferences of interest to your col-

leagues. Contact: [email protected]

October 2010 n 21

SEXUAL FUNCTION ADVERSE REACTIONSTable 3 shows the incidence of sexual function adverse reactions that occurred in 1% or more of PRISTIQ-treated MDD patients in the 50 mg dose group (8-week, placebo-controlled, fi xed and fl exible-dose, pre-marketing clinical trials).

Table 3: Sexual Dysfunction Adverse Reactions (≥1% in Men or Women in Any PRISTIQ Group) During the On-Therapy Period: Percentage of Subjects in Short-Term, Placebo-Controlled MDD Studies

Preferred Terma Placebob DVS SR 50 mgc

DVS SR 100 mgc

DVS SR 200 mgc

DVS SR 400 mgc

DVS SR 50-400 mgb

Men onlyd

Erectile dysfunction 1 3 6 8 11 7Ejaculation delayed <1 1 5 7 6 5Anorgasmia 0 0 3 5 8 4Libido decreased 1 4 5 6 3 4Ejaculation disorder <1 0 1 2 5 2Ejaculation failure 0 1 0 2 2 1Orgasm abnormal 0 0 1 2 3 1

Women onlye

Anorgasmia 0 1 1 0 3 1Libido decreased <1 1 2 1 1 1Orgasm abnormal <1 1 1 1 1 1

a. Medical Dictionary for Regulatory Activities (MedDRA) terms.b. Includes data from all short-term, placebo-controlled studies including fi xed-dose and fl exible-dose studies.c. Only includes data from short-term, placebo-controlled, fi xed-dose studies.d. Percentage based on the number of men (placebo, n=403; DVS SR 50 mg, n=108; DVS SR 100 mg, n=157; DVS SR 200 mg,

n=131; DVS SR 400 mg=154; DVS SR 50-400 mg, n=723).e. Percentage based on the number of women (placebo, n=713; DVS SR 50 mg, n=209; DVS SR 100 mg, n=267; DVS SR 200 mg,

n=176; DVS SR 400 mg=163; DVS SR 50-400 mg, n=1111).

ADVERSE DRUG REACTIONS - ALL MDD CLINICAL TRIALS A total of 3292 subjects were exposed to at least 1 dose of PRISTIQ ranging from 50 to 400 mg/day in MDD clinical trials. Long-term safety was evaluated in 1070 subjects in MDD who were exposed to desvenlafaxine succinate for at least 6 months (180 days) and 274 subjects in MDD who were exposed for 1 year (356 days).

The following list is a list of MedDRA preferred terms that refl ect adverse events that have been determined to be adverse drug reactions throughout the dose range studied (50 to 400 mg) during any premarketing MDD trials.

Adverse reactions are categorized by system organ class and listed in order of decreasing frequency using the following defi nitions: Very common: ≥10% of patients Common: ≥1% and <10% of patients Uncommon: ≥0.1% and <1% of patients Rare: ≥0.01% and <0.1% of patients Very rare: <0.01% of patients

Cardiac disorders: Common: palpitations, tachycardia.Ear and labyrinth disorders: Common: tinnitus.Eye disorders: Common: mydriasis, vision blurred.Gastrointestinal disorders: Very common: nausea, dry mouth, constipation; Common: vomiting, diarrhea.General disorders and administration site conditions: Very common: fatigue; Common: asthenia, chills, feeling jittery, irritability; Uncommon: drug withdrawal syndrome.Immune system disorders: Uncommon: hypersensitivity.Investigations: Common: weight decreased, weight increased, blood pressure increased; Uncommon: blood cholesterol increased, blood prolactin increased, blood triglycerides increased, liver function test abnormal.Metabolism and nutrition disorders: Very common: decreased appetite.Musculoskeletal, connective tissue, and bone disorders: Common: musculoskeletal stiffness.Nervous system disorders: Very common: headache, dizziness; Common: somnolence, tremor, disturbance in attention, paraesthesia, dysgeusia; Uncommon: syncope; Rare: convulsion, dystonia.Psychiatric disorders: Very common: insomnia; Common: orgasm abnormal, anorgasmia, anxiety, nervousness, libido decreased, abnormal dreams; Uncommon: depersonalization, hypomania. Renal and urinary disorders: Common: urinary hesitation; Rare: proteinuria.Reproductive system and breast disorders: Common: erectile dysfunction,* ejaculation delayed,* ejaculation disorder,* ejaculation failure*; Uncommon: sexual dysfunction.Respiratory, thoracic, and mediastinal disorders: Common: yawning; Uncommon: epistaxis.Skin and subcutaneous tissue disorders: Very common: hyperhidrosis; Common: rash.Vascular disorders: Common: hot fl ush; Uncommon: orthostatic hypotension.* Frequency is calculated based on men only.

Ischemic cardiac adverse events: in clinical trials, there were uncommon reports of ischemic cardiac adverse events, including myocardial ischemia, myocardial infarction, and coronary occlusion requiring revascularization; these patients had multiple underlying cardiac risk factors. More patients experienced these events during desvenlafaxine treatment as compared to placebo (see WARNINGS AND PRECAUTIONS/Cardiovascular/Cerebrovascular).

Discontinuation Symptoms: adverse drug reactions reported in association with abrupt discontinuation, dose reduction or tapering of treatment in MDD clinical trials at a rate of ≥5% include: dizziness, nausea, headache, irritability, diarrhea, anxiety, abnormal dreams, fatigue, and hyperhidrosis. In general, discontinuation events occurred more frequently with longer duration of therapy (see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS).

Orthostatic Hypotension: Of the 3,292 patients in clinical trials with PRISTIQ, 5% were 65 years of age or older. No overall differences in safety or effi cacy were detected between these subjects and younger subjects; however, in the short-term placebo-controlled trials, there was a higher incidence of orthostatic hypotension in patients ≥65 years of age compared to patients <65 years of age treated with desvelafaxine. Greater sensitivity of some older individualscannot be ruled out. For elderly patients, possible reduced renal clearance of desvenlafaxine should be considered when determining dose (see Dosing Considerations, Geriatrics and ACTION AND CLINICAL PHARMACOLOGY, Geriatrics).

ECG Changes: electrocardiograms were obtained from 1,492 PRISTIQ-treated patients with major depressive disorder and 984 placebo-treated patients in clinical trials lasting up to 8 weeks. No clinically relevant differences were observed between PRISTIQ-treated and placebo-treated patients for QT, QTc, PR, and QRS intervals. In a thorough QTc study with prospectively determined criteria, desvenlafaxine did not cause QT prolongation. No difference was observed between placebo and desvenlafaxine treatments for the QRS interval (see ACTION AND CLINICAL PHARMACOLOGY). A thorough QTc study was designed to assess the potential effect of 200 and 600 mg of PRISTIQ on QT interval prolongation.

Table 4: Estimated and 90% Confi dence Interval for QTc Changes from Time-Matched Baseline Relative to Placebo at Hour 8 after Dosewith Different Heart Rate Correctionsa

Treatment Fridericia’s QT Correction (ms) Population QT Correction (ms)

PRISTIQ 200 mg 1.5(-0.88, 3.88)

3.18(0.87, 5.50)

PRISTIQ 600 mgb -2.43(-4.90, 0.04)

0.98(-1.42, 3.38)

Moxifl oxacin 400 mg(Active control)

10.80(8.44, 13.16)

10.92(8.62, 13.22)

a. Mean (90% confi dence intervals)b. The PRISTIQ doses of 200 and 600 mg were 2 and 6 times the maximum recommended dose, respectively.

Abnormal Hematologic and Clinical Chemistry FindingsSerum LipidsElevations in fasting serum total cholesterol, LDL cholesterol, and triglycerides occurred in the controlled trials. Some of these abnormalities were considered potentially clinically signifi cant (see WARNINGS AND PRECAUTIONS, Serum Cholesterol Elevation and Monitoring and Laboratory Tests, Serum Lipids).

The percentage of subjects who exceeded a predetermined threshold for values of outliers is represented in Table 5.

Table 5: Proportion (%) of Subjects With Lipid Abnormalities of Potential Clinical Signifi cance for All Short-Term, Placebo-Controlled Clinical Trials

PRISTIQ

Placeboa

n=111650 mgn=317

100 mgn=424

200 mgn=307

400 mgn=317

50-400 mga

n=1834Total Cholesterol

Increase ≥1.29 mmol/L and absolute value ≥6.75 mmol/L 2 3 4 4 10 5

LDL Cholesterol

Increase ≥1.29 mmol/L and absolute value ≥4.91 mmol/L <1 1 0 1 2 1

Triglycerides

≥3.7 mmol/L 3 2 1 4 6 3

a. Includes data from all short-term, placebo-controlled studies including fi xed-dose and fl exible-dose studies.

ProteinuriaIn placebo-controlled studies 6.4% of subjects treated with PRISTIQ, had treatment-emergent proteinuria. Proteinuria was usually of trace amounts, and was not associated with increases in BUN or creatinine or adverse events. The mechanism of the enhanced protein excretion is not clear but may be related to noradrenergic stimulation.

Vital Sign ChangesTables 6 and 7 summarize the changes that were observed in placebo-controlled, short-term, premarketing trials with PRISTIQ in patients with MDD.

Table 6: Mean Changes, Vital Signs, at Final On-Therapy for All Short-term, Fixed-dose Controlled Trials

PRISTIQ

Placebo 50 mg 100 mg 200 mg 400 mgBlood Pressure

Supine systolic bp (mm Hg) -1.4 1.2 2.0 2.5 2.1Supine diastolic bp (mm Hg) -0.6 0.7 0.8 1.8 2.3

Pulse rate

Supine pulse (bpm) -0.3 1.3 1.3 0.9 4.1Weight (kg) 0.0 -0.4 -0.6 -0.9 -1.1

At the fi nal on-therapy assessment in the 6-month, double-blind, placebo-controlled phase of a long-term trial in patients who had responded to PRISTIQduring the initial 12-week, open-label phase, there was no statistical difference in mean weight change between PRISTIQ- and placebo-treated patients.

Table 7 provides the incidence of patients meeting criteria for sustained hypertension (defi ned as treatment-emergent supine diastolic blood pressure ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive visits).

Table 7: Incidence (%) of Patients with Sustained Hypertension for All Short-Term Fixed-Dose Clinical Trials

PRISTIQ

Placebo 50 mg 100 mg 200 mg 400 mg

Sustained hypertension 0.5 1.3 0.7 1.1 2.3

DRUG-DRUG INTERACTIONS

Potential for other drugs to affect desvenlafaxine succinate (see also ACTION AND CLINICAL PHARMACOLOGY)

Inhibitors of CYP3A4: CYP3A4 is a minor pathway for the metabolism of PRISTIQ. In a clinical study, ketoconazole (200 mg BID) increased the area under the concentration vs. time curve AUC of PRISTIQ (400 mg single dose) by about 43% and Cmax by about 8%. Concomitant use of PRISTIQ with potent inhibitors of CYP3A4 may result in higher concentrations of PRISTIQ.

Inhibitors of other CYP enzymes: based on in vitro data, drugs that inhibit CYP isozymes 1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19, and 2E1 are not expected to have signifi cant impact on the pharmacokinetic profi le of desvenlafaxine.

Potential for desvenlafaxine to affect other drugs (see also ACTION AND CLINICAL PHARMACOLOGY)

Drugs metabolized by CYP2D6: clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. When desvenlafaxine succinate was administered at a dose of 100 mg daily in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased approximately 17%. When 400 mg of desvenlafaxine was administered (8 times the recommended 50 mg dose), the AUC of desipramine increased approximately 90%. Concomitant use of desvenlafaxine with a drug metabolized by CYP2D6 may result in higher concentrations of that drug.

Drugs metabolized by CYP3A4: in vitro, desvenlafaxine does not inhibit or induce the CYP3A4 isozyme.

In a clinical study, PRISTIQ (400 mg daily) was co-administered with a single 4 mg dose of midazolam (a CYP3A4 substrate). The AUC and Cmax of midazolam decreased by approximately 31% and 16%, respectively. Concomitant use of PRISTIQ with a drug metabolized by CYP3A4 may result in lower exposure to that drug.

Drugs metabolized by CYP1A2, 2A6, 2C8, 2C9 and 2C19: in vitro, desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, and 2C19 isozymes and would not be expected to affect the pharmacokinetics of drugs that are metabolized by these CYP isozymes.

P-glycoprotein transporter In vitro, desvenlafaxine is not a substrate or an inhibitor for the P-glycoprotein transporter.

The pharmacokinetics of desvenlafaxine are unlikely to be affected by drugs that inhibit the P-glycoprotein transporter and desvenlafaxine is not likely to affect the pharmacokinetics of drugs that are substrates of the P-glycoprotein transporter.

Drug-Food InteractionsFood does not alter the bioavailability of desvenlafaxine.

Drug-Herb InteractionsSt. John’s Wort: in common with SSRI's, pharmacodynamic interactions between PRISTIQ and the herbal remedy St. John’s Wort may occur and may result in an increase in undesirable effects (see DRUG INTERACTIONS, Serotonin Syndrome).

Drug-Lifestyle InteractionsEthanol: as with all CNS-active drugs, patients should be advised to avoid alcohol consumption while taking desvenlafaxine succinate.

For complete prescribing information please refer to the Product Monograph.


PRISTIQ®


“A life of pleasure makes even the strongest mind frivolous at last.” - Edward Bulwar-Lytton

Vancouver2nd Conference on

Positive AgingNov. 26 - 27, 2010


Trap Editor


by Pippa Wysong,Correspondent, The Chronicle

ASMALL CLINICAL STUDY investigating the ADHD druglisdexamfetamine dimesylate intranasally shows that,in adult men, the level of activity in the blood is sim-

ilar to that achieved by the capsule version of the drug.Findings suggest the addictive potential of the intranasaltherapy is no greater than the currently available oral form,though there are still questions about the compound’s effec-tiveness for ADHD.

According to an announcement from the drug’s manu-facturer, “this research is important because the route ofadministration of a drug may affect the rate and extent ofabsorption, which in turn may affect the risk of abuse.However, in this study, absorption of [lisdexamfetaminedimseylate] through the nose did not result in a rapid rise ind-amphetamine levels.”

The compound is known to have addictive characteris-tics along with potential for abuse. Lisdexamfetamine is apro-drug form of the compound, and is not converted to d-amphetamine until well after the drug has been taken oral-ly. The oral pro-drug version has been reported to have less

addictive (and less abuse) potential.There can be different rates of onset of activity with

different delivery methods. With some drugs that are nor-mally administered via an oral route, using them in an alter-nate form can have a different effect. For instance smoking,injecting, or inhaling a drug can have a more rapid onset ofaction, or have a different time to maximum plasma con-centration, according to details of the study that were pre-sented in a poster at the annual meeting of the AmericanPsychiatric Association in May 2009.

The study noted that in the U.S. “a recent survey ofadmissions to substance abuse treatment services in 2007

conducted by the Substance Abuse and Mental HealthAdministration, between 5.5% and 9.9% of all stimulantabuse (licit and illicit agents) occurs via inhalation.”

Researchers hoped to find out whether an intranasaldelivery of lisdexamfetamine had a shorter onset of action,and a greater risk for abuse compared to the capsule form.Lisdexamfetamine is long-acting and indicated for the treat-ment of ADHD in children aged six to 12 years, and adults.

The study was a randomized, cross-over study whichenrolled 18 healthy adult men with no history of substanceabuse. They were aged 18 to 65 years, with a mean age of25.1. Subjects were randomly assigned to receive a singlenasal or oral dose of lisdexamfetamine 50 mg, then, at leastseven days later, the subjects were switched to the oppositeregimen.

Findings showed the median time to maximum plas-ma concentration of d-amphetamine was five hours afteroral administration, and four hours after intranasal admin-istration of the drug. Maximum plasma concentration weresimilar being an average of 35.9 ng/mL with intranasaladministration, versus 37.6 ng/mL when administeredorally.

However, the long-term effectiveness of lisdexamfeta-mine in the treatment of ADHDis not known, according to Dr.James Wright, professor of anes-thesiology, pharmacology andtherapeutics, and medicine at theUniversity of British Col umbia inVancouver. He was not part of thestudy, and noted that it is toosmall to affect practice.Additionally, it is not known if thefindings can be extended to pedi-atric or teen populations.

“Generally, for all available treatments for ADHD, theeffectiveness is not there and the long-term benefit-harmratio is not known,” he said.

Studies tend to be short-term, and generally ADHDtreatment is prescribed long-term, Dr. Wright said. “Largemulti-year RCTs assessing CNS stimulants are needed thatfollow treated and untreated cohorts into adulthood.Generally, better benefit and harm evidence is necessarybefore long-term CNS stimulant treatment can be recom-mended,” he said.

Non-proprietary and brand names of therapy: lisdexamfeta-mine dimesylate (Vyvanse, Shire)

Nasal delivery of ADD prodrug no more addictive than oraln Rise of d-amphetamine levels for nasally ingested prodrug identical for oral route

Findings showed that the mediantime to maximum plasma

concentration of d-amphetaminewas five hours after oral

administration, and four hoursafter intranasal administrationF r o m t h e l a y p r e s s

n The New York Times reports on whatmay be a better test for ADHD in“Seeking an Objective Test forAttention Disorder” (May 31, 2010)The article is written by KatherineEllison, who has ADHD. She writesabout her experience sitting throughthe 20-minute test. The test, invent-ed by Harvard psychiatrist Dr. MartinH. Teicher, required Ellison look at ascreen and use a mouse to click onstars that have five or eight points,but not stars with four points. AsEllison performed this task, aninfrared tracking device pointed at areflector affixed to her head meas-ured how long she spent looking atthe testing monitor. Dr. Teicher saidtracking the position of the subject’shead allows the test to detect howhard a person is working to completethe test, and so may identify drugseeking behaviour.

—Read the New York Timesarticle at http://nn.nf/748f

ADHD may be linked to low level pes-ticide exposure, suggests a joint studyconducted by researchers based at theUniversity of Montreal and HarvardUniversity and published in Pediatrics(June 2010; 125(6):e1270-1277).

Dr. Robin Walker, a member of theCanadian Institute of Child Health and

chairperson of the pediatric health unitfor the Canadian Pediatrics Society, saidthese results are worrisome.

“We’re not talking about acute toxi-city. We’re much more concerned aboutthe impact on the developing organismof low-level, continuous exposure,” shetold the Montreal Gazette.

“Findings support the hypothesisthat organophosphate exposure, at lev-els common among U.S. children, maycontribute to ADHD prevalence,” theauthors wrote, though more research isneeded to confirm causality.

—Read this original study inPediatrics at http://nn.nf/439h

ADHD linked to low-level exposure to pesticides in childhood, say pediatricians

22 n October 2010

Dr. James Wright


lthant

salon,m.at-lts.ch

nceof

gleastite

as-terin-eresal

red

ta-HDDr.es-ndthein

theooce.thedi-

therm

HDrgehatod.arym-

ta-

l

hesist lev-may

” thech is

dy in439h

ns

PRESCRIBING SUMMARY

THERAPEUTIC CLASSIFICATIONMuscle relaxant, peripherally acting agent

INDICATIONS AND CLINICAL USEXEOMIN® is indicated in adults for the symptomatic management of: blepharospasm; cervical dystonia of a predominantly rotational form (spasmodic torticollis); post-stroke spasticity of the upper limb.XEOMIN® as a treatment for focal spasticity has been studied in association with usual standard care regimens and is not intended as a replacement for these treat-ment modalities. XEOMIN® is not likely to be effective at a joint affected by a fixed contracture.XEOMIN® may only be used by physicians with suitable qualifications and proven experience in the application of Botulinum toxin type A and in the use of the neces-sary equipment, e.g. EMG (electromyography).

CONTRAINDICATIONSHypersensitivity to Botulinum neurotoxin type A or to any of the excipients. Gen-eralised disorders of muscle activity (e.g. myasthenia gravis, Lambert-Eaton syn-drome). Presence of infection at the proposed injection site.

SERIOUS WARNINGS AND PRECAUTIONS-

ment of toxin activity that is unique to XEOMIN®

used to describe XEOMIN® activity are different from those used to describe that of other botulinum toxin preparations and the units representing XEOMIN®

activity are not interchangeable with other products. ®

(See DOSAGE AND ADMINISTRATION).

GeneralPatients and caregivers should be advised to seek immediate medical consultation if swallowing, speech, or respiratory disorders arise.In very rare cases severe adverse events like muscle weakness, dysphagia or aspiration pneumonia with a suspected causal relationship to toxin spread have been reported with the use of botulinum toxin. Also very rare cases of adverse events with a fatal outcome have been reported. Patients with a neurological underlying disease or swallowing, speech or respiratory difficulties have an increased risk for these adverse drug reactions and should be treated and supervised very carefully. An anaphylactic reaction may occur rarely after injection of Botulinum neurotoxin

anaphylaxis should be available. Extra caution is required when injecting at sites close to sensitive structures such as the carotid artery and lung apices. XEOMIN® should be used with caution: in patients suffering from amyotrophic lateral sclerosis or other diseases which result in peripheral neuromuscular dysfunction; in targeted muscles which display pronounced weakness or atrophy.

GASTROINTESTINAL

Spasmodic torticollisPatients should be informed that injections of XEOMIN® for the management of spasmodic torticollis may cause mild to severe dysphagia with the risk of aspiration and dyspnoea. Medical intervention may be necessary (e.g. in the form of a gas-

three weeks after injection. Patients with smaller neck muscle mass, or patients who require bilateral injections into the sternocleidomastoid muscles are at greater risk.

-fect of Botulinum toxin as the result of the neurotoxin spread into the oesophageal musculature.

HematologicXEOMIN® should be used with caution if bleeding disorders of any type occur. It should be used with caution in patients receiving anticoagulant therapy.

OPHTHALMOLOGIC

BlepharospasmBecause of the anticholinergic effect of Botulinum toxin type A, XEOMIN® should be used with caution in patients at risk of developing an angle closure glaucoma.In order to prevent ectropion, injections into the lower lid area should be avoided, and

drops, ointments, soft bandage contact lenses, or closure of the eye by patching or similar means.Reduced blinking following XEOMIN® injection into the orbicularis muscle can lead to corneal exposure, persistent epithelial defects and corneal ulceration, especially in patients with cranial nerve disorders (facial nerve). Careful testing of cor-neal sensation should be performed in patients with previous eye operations. Ecchymosis easily occurs in the soft tissues of the eyelid. Immediate gentle pressure at the injection site can limit that risk.

SPECIAL POPULATIONS

Pregnant Women:

unknown. XEOMIN® should not be used during pregnancy unless clearly necessary and unless the potential benefit justifies the risk.

Nursing Women:-

fore, the use of XEOMIN® during lactation is not recommended.

Pediatrics (<18 years of age):No data is available on the use of XEOMIN® in children and it is therefore not currently recommended in this age group.

Geriatrics (>65 years of age):Although clinical studies included a number of patients over the age of 65, no clinical trials specifically designed for elderly patients have been performed. Initial dosing should begin at the lowest recommended dose for the specific indi-cation and be cautiously titrated within the recommended range for optimal patient outcome.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

A are mainly related to the diffusion of Botulinum neurotoxin type A from the tar-get muscle to adjacent muscles. Such undesirable effects are rare, and most are localized in close proximity to the injection site; systemic side effects are un-common. Intramuscular injection into neck muscles for treatment of cervical dystonia occasionally results in transient dysphagia and a general weakness in the

ptosis and diplopia. Intramuscular injections of Botulinum toxin type A for up-per limb spasticity were reported to be commonly associated with local reac-tions like hypertonia, ecchymosis, purpura, pain in shoulder, arm or hand, muscle weakness, bleeding and itching after administration at the injection site.

Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reac-tion rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related ad-verse events and for approximating rates.In the 6 studies conducted to provide data on the safety of XEOMIN® 1082 subjects were treated with trial medications (XEOMIN®, active comparator or placebo). See product monograph for study parameters.

Table 1: Adverse Drug Reactions Reported in 1% of Cervical Dystonia Patients

System organ classPreferred term

Number of subjects (%)

XEOMIN®

N=272

Active Comparator 1 (Botulinum toxin type A-complex)

N=244

Gastrointestinal disorders 24 (8.8) 15 (6.1)

Dysphagia 24 (8.8) 15 (6.1)

Musculoskeletal & connective tissue disorders 9 (3.3) 2 ( 1)

Muscular weakness 4 (1.5) 1 ( 1)

Neck pain 5 (1.8) 1 ( 1)

Powder for solution for injection, 100 LD

Prescribing Summary

Patient Selection Criteria

Safety Information

(Clostridium Botulinum Neurotoxin Type A (150 kD), free from complexing proteins)


Trap Editor


Table 2: Adverse Drug Reactions Reported in 1% of Blepharospasm Patients


Number of subjects (%)

XEOMIN® N=148

Active Comparator 1 (Botulinum toxin type A-complex)

N=152

Eye disorders 12 (8.1) 12 (7.9)

Dry eye 3 (2.0) 0 (0.0)

Eyelid oedema 0 (0.0) 2 (1.3)

Eyelid ptosis 9 (6.1) 7 (4.6)

Vision blurred 0 (0.0) 3 (2.0)

Table 3: Adverse Drug Reactions Reported in 1% of Patients with Post-stroke Spasticity of the Upper Limb (Double-blind Period)


Number of subjects (%)XEOMIN®

N=73Placebo

N=75

Gastrointestinal disorders 0 (0.0) 1 (1.3)

Dysphagia 0 (0.0) 1 (1.3)

General dis. & admin. site conditions 0 (0.0) 1 (1.3)

Injection site pain 0 (0.0) 1 (1.3)

Nervous system dis. 1 (1.4) 0 (0.0)

Headache 1 (1.4) 0 (0.0)

Table 4: Adverse Drug Reactions Reported in 1% of Patients with Post-Stroke Spasticity of the Upper Limb (Open-Label Extension Period)


XEOMIN®

Number of Subjects (%) N= 145

Gastrointestinal disorders

Dysphagia 2 (1.4)

General dis. & admin. site conditions

Injection site pain 4 (2.8)

Musculoskeletal and connective tissue disorders

Muscular weakness 5 (3.4)

Pain in extremity 2 (1.4)

MERZ Canada at 1-866-815-8715.

Drug-Drug Interactions-

biotics or other medicinal products that interfere with neuromuscular transmission, e.g. tubocurarine-type muscle relaxants.

® with aminoglycosides, polymyxins, tetracyclines, linomycin, spectinomycin or any other drugs that interfere with neuro-muscular transmission requires special care. Peripheral muscle relaxants should be used with caution, if necessary reducing the starting dose of relaxant, or using an intermediate-acting substance such as vecuronium or atracurium rather than sub-stances with longer lasting effects. 4-Aminochinolines may reduce the effect of XEOMIN®.

Recommended Dose and Dosage Adjustment

Blepharospasm

treatment session is recommended to be at least every 12 weeks.

patients and in long-term repeat-dose treatment.At repeat treatment sessions, the dose may be increased up to two-fold (as long as

-sidered insufficient – usually defined as an effect that does not last longer than two months. However, there appears to be no additional benefit obtainable from injecting

frequently than every three months.

Spasmodic torticollisIn the management of spasmodic torticollis, XEOMIN® dosing must be tailored to the individual patient, based on the patient’s head and neck position, loca-tion of possible pain, muscle hypertrophy, patient’s body weight, and response to the injection. A suitable sterile needle (e.g. 25-30 gauge/0.30-0.50 mm) is used for injections into superficial muscles, and an e.g. 22 gauge/0.70 mm nee-dle may be used for injections into deeper musculature. An injection volume of approximately 0.1 to 0.5 mL per injection site is recommended.

effect of each treatment generally lasts approximately 3-4 months; however, it may

patients and in long-term repeat-dose treatment.

Post-stroke Spasticity of the Upper LimbReconstituted XEOMIN® is injected using a suitable sterile needle (e.g. 26 gauge/0.45 mm diameter/37 mm length, for superficial muscles and a longer needle, e.g. 22 gauge/0.7 mm diameter/75 mm length, for deeper musculature). An injection volume of approximately 0.2 to 1 mL per injection site is recommended, but it can be exceeded to 1.5 mL in selected cases.

Table 5: Dosage guide for the management of post-stroke spasticity of the up-per limb

Clinical Pattern Muscle

Units

Flexed Wrist (Total) 90

Flexor carpi radialis 50

Flexor carpi ulnaris 40

Clenched Fist (Total) 80

Flexor digitorum superficialis 40

Flexor digitorum profundus 40

Flexed Elbow (Total) 130-190

Brachioradialis 60

Biceps 80

Brachialis 50

Pronated Forearm (Total) 25-65

Pronator quadratus 25

Pronator teres 40

humb-in-Palm (Total) 10-40

Flexor pollicis longus 20

Adductor pollicis 10

Flexor pollicis brevis/ Opponens pollicis 10

different muscles. Initial dosing should begin at the lowest recommended dose for the specif-ic indication and be cautiously titrated within recommended dose range for optimal patient outcome.

is recommended to be at least 12 weeks.

innervation zones can reduce undesirable effects and, at the same time, may reach more intrafusal fibres.

BlepharospasmAfter reconstitution, the XEOMIN® solution is injected using a suitable sterile needle (e.g. 27-30 gauge/0.30-0.40 mm). Electromyographic guidance is not necessary. An injection volume of approximately 0.05 to 0.1 mL is recommended.XEOMIN® is injected into the medial and lateral orbicularis oculi of the upper lid and the lateral orbicularis oculi of the lower lid. Additional sites in the brow area, the lateral orbicularis and in the upper facial area may also be injected if spasms here interfere with vision.

Administration


Injections near the levator palpebrae superioris should be avoided to reduce the oc-currence of ptosis. Diplopia may develop as a result of Botulinum neurotoxin type A diffusion into the inferior oblique. Avoiding medial injections into the lower lid may reduce this adverse reaction.

Spasmodic torticollisIn the management of spasmodic torticollis, XEOMIN® is usually injected into the sternocleidomastoid, levator scapulae, scalenus, splenius capitis, and/

responsible for controlling head position may be involved and therefore require treatment. If difficulties arise isolating single muscles, injec-

mass and the degree of hypertrophy or atrophy are factors to be taken into consideration when selecting the appropriate dose.Multiple injection sites permit XEOMIN® more uniform coverage of the innervated areas

number of injection sites is dependent upon the size of the muscle to be chemically denervated.

increased risk of adverse reactions (in particular dysphagia) when bilateral injec-

Post-stroke Spasticity of the Upper LimbLocalisation of the involved muscles with electromyographic guidance or nerve stimulation techniques may be necessary. Multiple injection sites may allow XEOMIN® to have more uniform contact with the innervation areas of the muscle and are especially useful when larger muscles are injected.

-tient based on the size, number and location of muscles to be treated, the severity of spasticity, and the presence of local muscle weakness. Initial dosing should begin at the lowest recommended dose and be cautiously titrated within the recommended dose range for optimal patient outcome.

Reconstitution

except those mentioned below.XEOMIN® is reconstituted prior to use with sterile unpreserved sodium chloride 9 mg/mL (0.9%) solution for injection. Reconstitution and dilution should be performed in accordance with good clinical practice guidelines, particularly with respect to asepsis.It is good practice to perform vial reconstitution and syringe preparation over plastic-lined paper towels to catch any spillage. An appropriate amount

rubber stopper of the vial is cleaned with alcohol (70%) prior to insertion of the

if the vacuum does not pull the solvent into the vial. Reconstituted XEOMIN® is a clear colourless solution free of particulate matter. XEOMIN® should not be used if the reconstituted solution (prepared as above) has a cloudy appearance or contains floccular or particulate matter.

Table 6: Possible Dilutions of XEOMIN® in the Reconstituted Solution

Solvent added(sodium chloride 9 mg/mL (0.9%)

solution for injection

Resulting dose in units per 0.1 mL

0.5 mL1.0 mL2.0 mL4.0 mL8.0 mL

20.010.0 5.02.5

1.25

Any solution for injection that has been stored for more than 24 hours as well as

reconstituted solution, see SPECIAL HANDLING INSTRUCTIONS

SUPPLEMENTAL PRODUCT INFORMATION

Dosing ConsiderationsUnit doses recommended for XEOMIN® are not interchangeable with those for other preparations of Botulinum toxin.

XEOMIN® may only be used by physicians with suitable qualifications and proven experience in the application of Botulinum toxin and in the use of the necessary equipment, e.g. EMG (electromyography).Reconstituted XEOMIN® is intended for intramuscular injection. After reconstitution, XEOMIN® should be used for only one injection session and for only one patient.

® should be as recommended for the specific indica-tion.

for each patient. A titration of the dose should be performed.A decrease or increase in the XEOMIN® dose is possible by administering a smaller or larger injection volume. Initial dosing should begin at the lowest recommended dose for the specific indication and be cautiously titrated within the recommended range for optimal patient outcome. If no treatment effect occurs within one month after the initial injection, the following measures should be taken:

facility.

injection technique, fixed contracture, too weak antagonist, possible development of antibodies.

performed under the following conditions: 1) dose adjustment with regard to analysis of the most recent therapy failure, 2) EMG-guidance, 3) the recommended minimum interval between the initial and repeat treatment is followed

not been investigated whether secondary non-response due to the development of antibodies is less frequent under XEOMIN® therapy than under treatment with conventional preparations containing the Botulinum toxin type A complex. In cases of non-response, alternative therapies should be considered.XEOMIN® has not been studied in the paediatric population and is therefore not recommended in the paediatric age group until further data become available.Prior to administering XEOMIN®, the physician must familiarise himself/herself with the patient’s anatomy and any alterations to the anatomy due to prior surgical procedures. Extra caution is required when injecting at sites close to sensitive structures

--

ment and in treatment-naive patients for post-stroke spasticity of the upper limb.Clinical effects of XEOMIN® may increase or decrease with repeated injections. Possible reasons for change in clinical effect are different techniques of reconstitution, the chosen injection intervals, the injected muscles and marginally varying toxin activity resulting from the biological testing pro-cedure employed or secondary non-response. Previously akinetic or sedentary patients should be reminded to gradually re-sume activities following the injection of XEOMIN®. XEOMIN® contains albumin, a derivative of human blood. Standard meas-ures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include careful selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medi-cinal products prepared from human blood or plasma are administered, the possibility of transmitting infective

no reports of viral transmissions with albumin manufactured to European Pharmacopoeia specifications by established processes.

Immune

young age at disease onset, and higher total dosage received of Botulinum toxin. Antibody development may lead to treat-

Less Common Clinical Trial Adverse Drug Reactions (<1%) Cervical Dystonia: eye pain, diarrhoea, dry mouth, vomiting, colitis, asthenia, injection site inflammation, injection site tender-ness, skeletal pain, myalgia, headache, tremor, dysphonia, skin rash, erythema, pruritus, sweating increased. Blepharospasm: conjunctivitis, dry mouth, inflicted injury, muscle weakness, paraesthesia, headache, skin rash.Post-stroke Spasticity

Abnormal Hematologic and Clinical Chemistry Findings In all clinical trials, there were no findings indicative of underlying pathological changes as a result of trial medication, both with regard to the incidence of abnormal hematologic and clinical chemistry values and with regard to the mean change in laboratory values for either treatment group.

Post-Market Adverse Drug Reactions ® has been marketed: eye swelling, eyelid

edema, madarosis, vision blurred; injection site reactions; asthenia, fatigue; dysphagia, nausea, abdominal disten-sion; hypersensitivity including allergic dermatitis, skin rash, erythema, drug eruptions, lymphadenopathy, alopecia; dysphonia, cough, dyspnoea, asthma; herpes zoster; muscular weakness, muscle spasm, myalgia, trismus; dysarthria, headache, somnolence; cardiovascular insufficiency, circulatory collapse; abnormal dreams. Side effects related to spread of toxin distant from the site of administration have been reported very rarely (exaggerated muscle weakness, dysphagia, and aspiration pneumonitis with fatal outcome in some cases).

events have been reported following administration of conventional Botulinum toxin type A complex: dysarthria, abdominal pain, hyperhidrosis, anorexia, hypoacusis, tinnitus, radiculopathy, and syncope.

and myocardial infarction, some with fatal outcomes. It remains unclear whether these deaths were induced by conventional preparations containing the Botulinum toxin type A complex or whether these were caused by pre-existing cardiovascular disease. Serious and/or immediate hypersensitivity reactions have been rarely reported, includ-ing anaphylaxis, serum sickness, urticaria, soft tissue oedema, and dyspnoea. Some of these reactions have been reported following the use of conventional Botulinum toxin type A complex either alone or in combination with other agents known to cause similar reactions.

® in clin-ical studies with blepharospasm and cervical dystonia patients. However, these findings were not considered clinically relevant in the opinion of the treating cardiologist and the exact relationship of these events to XEOMIN® is un-known. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

OTHER INTERACTIONS

Drug-Food InteractionsInteractions with food are not relevant.

Drug-Herb InteractionsInteractions with herbal products have not been established.

Drug-Laboratory InteractionsInteractions with results of laboratory tests have not been established.

Drug-Lifestyle Interactions XEOMIN®

the therapeutic and/or adverse effects of XEOMIN®, which may also interfere with the ability to drive and operate machinery. Consequently affected persons should avoid these tasks until their faculties are fully recovered.

OVERDOSAGE:Increased doses of Botulinum neurotoxin type A may result in pronounced neuromuscular paralysis distant from the injec-

exposure. Signs of overdose may include general weakness, ptosis, diplopia, swallowing and speech difficulties, or paralysis of the respiratory muscles resulting in an aspiration pneumonia. In case of an overdose, the patient must be monitored medically for several days. If signs of intoxication appear, hospitalisation with general supportive measures is necessary. Intubation and assisted ventilation will become necessary until improvement if paralysis of the respiratory muscles occurs.

® contains 0.6 ng Botu-

application.® XEOMIN® is a registered trademark of Merz GmbH.

MERZ PHARMA CANADA


What were some of the techniques you used to com-municate with people in a persistent vegetative state?The general grasp was to [have them] imagine doingthings in their head, and that produces activity in thebrain that is very similar to performing those actions.What’s widely typical now is to get them to imagineplaying tennis, get them to imagine waving their armsaround in some way, to hit the ball. When they do thatan area of the premotor cortex lights up, exactly in thesame way it would if they were playing tennis. Anothertechnique that we use is to ask them to imagine mov-ing from room to room in [their] house because whenthey do that, areas of the brain involved in spatial nav-igation light up.

How might other specialists take the research forwardand really make a difference?It opens up lots of broader questions, about conscious-ness, about what it means to be conscious and abouthow we can measure consciousness that certainlyinvites the participation of other specialists. The prob-lem we have in understanding whether a patient in avegetative state is conscious or not is really rather simi-lar [to] the problem that an anesthesiologist might havein trying to know whether a patient that has been anes-thetized is conscious or not. [It] is a very difficult question.

[As well,] there’s an awful lot of research on sleep, we know that most of us thinkthat when we’re asleep were unconscious. But then most of us are familiar with thesituation of having our partner in bed start talking to us and they’re often able toelicit a response when we’re entirely unconscious. So how can we generate a responseto being talked to while we sleep? These are really quite fundamental questions

about the nature of consciousness.Some of the techniques that we’ve been developing and

some of the areas we’ve become interested in through aninterest in brain injury and vegetative states will open upavenues for investigation and these other areas that arerelated to the general question of consciousness.

Another area, though it’s really beyond my area ofexpertise, that I think we’ll be doing some work on whenwe get to Canada is brain-computer interfaces, devices thatare being developed typically for patients with spinal cordinjuries to communicate by moving a cursor on a screenwithout using their hands. I think that would be a tremen-dous achievement and that’s something that I think we cansee in the next ten years.

As a result of your new affiliation with the University ofWestern Ontario, will you be moving to Canada or will youstill be working from Cambridge?Well, we’re moving en masse, which involves a lot of equip-ment and people, and I’m sure it’s going to be worth it.The Canada Research Chair program comes with a sub-stantial amount of funding which means we will be able toset up a streamlined system for investigating the effects ofbrain injury that is, I think far, far, superior to what wecurrently have.

Dr. Owen spoke with CHRONICLE associate editor Lynn Bradshaw.

—Who is making news at your institution, or in your community? Tell TheChronicle, so we can inform our readers. Write us at [email protected]

n Inside Chronicle Vitae, October 2010: Books: Two recent neurological novels briefly noted (page 20)Conferences: Upcoming meetings in the CNS sciences (page 20)

DDDr. Owen obtained his PhD in neuropsychology in Parkinson’sresearch trying to understand why these patients have cogni-tive deficits, and then became a post-doctoral student at the

Montreal Neurological Institute when the field of functional brain imag-ing was burgeoning. In 1996 he discovered a patient in a vegetativestate was consciously aware and able to respond to scientists in thefMRI scanner, an event he calls the highlight of his whole career.

New Canadian Excellence Research Chair from Cambridge

fMRi data shows how patient once assumed to be in avegetative state communicating “yes” and “no” respons-es by changing brain activity. “yes” responses (coded byimaging playing tennis) and “no” responses (coded byimagining moving around the rooms of his house) couldbe decoded accurately in patient based solely on thefMRI responses (lower panel) which were similar to thoseobserved in healthy controls performing the sameimagery tasks (top panel).

“A handful of patience is worth more than a bushel full of brains.” —Dutch proverb

n October 2010

n Dr. Adrian Owen is moving to theUniversity of Western Ontario fromCambridge University in January,to research cognitiveneuroscience andMRI imaging. TheChronicle spoke withhim about hisresearch, and hisplans for the newcenter


Trap Editor


andh ann up

are

a ofwhen

thatcordreen

men- can

y ofyou

uip-h it.sub-le tots oft we

The.org

overb

XEOMIN® is indicated in adults for the symptomatic management of blepharospasm, cervical dystonia of a predominantly rotational form (spasmodic torticollis) and post-stroke spasticity of the upper limb.

Your art,

XEOMIN® science science

(Clostridium Botulinum Neurotoxin Type A [150 kD], free from complexing proteins)

23


Trap Editor



Trap Editor


The Chronicle of Neurology + Psychiatry (Canada) Oct. 2010

Documents

Transcript of The Chronicle of Neurology + Psychiatry (Canada) Oct. 2010