2016 BSMC syllabus - Friday - Therapeutics Education Collaboration

Transcription

27th Annual
Best Science Medicine Course
Formerly the Drug Therapy Decision Making Course – 25 years
May 6th and 7th, 2016
Fairmont Waterfront Hotel Vancouver, B.C.
FRIDAY Syllabus
Presented by
The Therapeutics Education Collaboration, The St. Paul’s Hospital Department of Family and Community Medicine
In Cooperation with the
Department of Family Medicine, University of British Columbia
COURSE DIRECTORS
Drs. James McCormack and Robert Rangno
COMMITTEE MEMBERS
Drs. Rita McCracken and Tracey Monk
"It is an art of no little importance to administer medicines properly; but it is an art of much greater and more difficult acquisition to know when to suspend or altogether omit them."
Philippe Pinel 1745‐1826
The New Therapeutic Commandments Thou shalt 1. Have no aim except to help patients according to their goals 2. Always seek knowledge of the benefits, harms, and costs of treatment 3. If all else fails consider watchful waiting 4. Honour balanced sources of knowledge 5. Treat according to level of risk and not to level of risk factor 6. Not bow down to treatment targets 7. Honour thy elderly patient 8. Not pile one treatment upon another 9. Diligently try to find the best treatment for the individual 10. Start with the lowest dose possible Written by R Lehman, J McCormack, T Perry, A Tejani, J Yudkin Best Science Medicine Course 2016
FACULTY
Course Committee
Co-Chairs:
Bob Rangno, Emeritus Prof., Medicine, Pharmacology, UBC & PHC
James McCormack, Prof., Pharmaceutical Sciences, UBC
G. Michael Allan, Prof., Family Medicine, University of Alberta
& Director, Evidence and CPD Program, Alberta College of Family Physicians
Committee:
Rita McCracken, Clin. Assist. Prof., Medicine and Associate Head, Family Medicine, PHC
Tracy Monk, Clin. Assist. Prof., Medicine, UBC
Guest Faculty
Alan Cassels, Adj Prof., Human and Social Development, University of Victoria
Mike Kolber, Assoc. Prof., Family Medicine, University of Alberta
Tina Korownyk, Assoc. Prof., Family Medicine, University of Alberta
Dee Mangin, Assoc. Prof., Family Medicine, McMaster University, Hamilton, Ontario
Local Faculty
Ric Arseneau, Clin. Assoc. Prof., Medicine, UBC, PHC & BCWH
Jason Crookham, Clin. Instructor, Medicine, UBC
Kit Fairgrieve, St. Paul’s Hospital Goldcorp Addiction Medicine Fellow, PHC
Peter Loewen, Asst. Prof., Pharm. Sciences, UBC & VGH
Natasha Press, Clin. Assoc. Prof., Medicine, Infectious Diseases, UBC & PHC
Kam Shojania, Clin. Prof., Medicine, Head, Rheumatology, UBC & PHC
Aaron M Tejani, Clin. Asst. Prof., Pharmaceutical Sciences, UBC
BCWH – BC Women’s Hospital
PHC – Providence Health Care
UBC – University of British Columbia
VGH – Vancouver General Hospital
BSMC
BEST SCIENCE MEDICINE COURSE
27th Annual Best Science Medicine Course
Formerly The Drug Therapy Decision Making Course – 25 years
Friday, May 6, 2016
07:00 Registration (Muffins & Coffee)
Chairs – Bob Rangno and James McCormack
“I’ve Got The Music In Me”
08:00 Welcome
08:10 “Everybody’s Talking At Me”
08:30 “The Bare Necessities” of evidence-based practice
and how to “Rule The World”
Bob Rangno
Bob Rangno and James McCormack
Mike Allan and James McCormack
“Start Me Up”
08:50
09:10
09:20
09:40
10:10
10:20
Do we need to prevent “Bad Blood” with prophylactic antibiotics?
Questions
Stopping SSRIs – “I Can’t Fight This Feeling”
Stories from the Cochrane Collaboration – “Everyday I Write the Book”
Questions
Refreshment Break
“Hurts So Good”
10:40 CentralSensitivitySyndromes(CSS)–“DoYouFeelLikeIDo?"
11:00 Osteoarthritiscanbe“BadTo The Bone”
11:20 Questions
11:30 Concussionsandwhattodowhenyou“Bang yourHead”
11:50 Questions
12:00 Lice Treatment - "I've Got You Under My Skin"
12:10 Lunch
Natasha Press
Dee Mangin
Alan Cassels
Ric Arseneau
Mike Allan
Jason Crookham
Mike Kolber
“Bad Case Of Loving You”
13:00 Male and female sexual dysfunction – can we create “Paradise By The Dashboard Light?”
Tina Korownyk
13:20 Moisturizers and anti-aging creams, can they change the fact that we are “Born This Way”
James McCormack
13:40 There is no “Black Or White” when it comes to drug interactions
Dee Mangin
14:00 Questions
14:20 Refreshment Break
“Helter Skelter”
14:40
15:00
15:20
15:40
16:00
COPD treatments – “All I Need Is The Air That I Breathe”
Antidotes for anticoagulants – are they a case of “Take The Money And Run”?
Polymyalgia rheumatica – relieving “The King Of Pain”
Questions
Adjourn
Mike Allan
Peter Loewen
Kam Shojania
Bob Rangno, James McCormack and Mike Allan
“Whoa-oh-whoa,
Listen To
The Music”
The Doobie Brothers
Welcome!!
“I Got
The Music
In Me”
Kiki Dee band
Robert Rangno, MSc, MD
Professor Emeritus
Medicine and Pharmacology, UBC, Vancouver, BC
James McCormack, BSc (Pharm), PharmD
Professor
Faculty of Pharmaceutical Sciences, UBC, Vancouver, BC
Please let the world,
or at least your world,
know about the course
and what you’ve learned
#bsmc2016
@medmyths
G. Michael Allan, MD, CCFP
Professor
University of Alberta, Edmonton, Alberta
You can find a pdf of the handouts at
http://therapeuticseducation.org/dtc
therapeuticseducation.org
medicationmythbusters.com
“I Can See Clearly Now”
Johnny Nash
DisclosureofCommercial
Support
LearningOutcomeObjec8veSlide
Tobeabletolookatpublishedstudyresultsandteaseoutthe
rela8vebenefit,theabsolutebenefitedtheNNT/NNH
Thisprogramhasreceived
NOfinancialsupportfromANYBODY
JM - Entire salary comes through the UBC Faculty of
Pharmaceutical Sciences - also some legal/
educational work
BR - retired from UBC
MA – U of A & Alberta Health - (Alberta College of
Family Physicians, etc)
We have received no honorarium or research
money from the drug industry in the last 25 or so
years
iOS apps (iPad/iPhone) KidneyCalc
and MyStudies - mystudies.org
Premium podcast subscription Best Science (BS)
Medicine podcast - therapeuticseducation.org
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Bob Rangno, James McCormack and Mike Allan
Have no aim except to help patients according to their
goals
2. Always seek knowledge of the benefits, harms, and
costs of treatment
3. If all else fails consider watchful waiting
4. Honour balanced sources of knowledge
5. Treat according to level of risk and not to level of risk
factor
6. Not bow down to treatment targets
7. Honour thy elderly patient
8. Not pile one treatment upon another
9. Diligently try to find the best treatment for the individual
10. Start with the lowest dose possible
1.
A lot of
bullshit
Relevant
and
useful
information
I
JUST
KNOW
Systematic review/
meta-analysis
RCT
Which is either
A)purposeful
B)based in ignorance
Cohort
Case Control
Case Report
“Expert” Opinion
BEST AVAILABLE EVIDENCE PYRAMID
Need different evidence for different questions
The Bullshit Asymmetry
Recovered Data
2013
The amount of energy needed to refute
bullshit is an order of magnitude bigger
than to produce it.
2016
CHD mortality
Randomized controlled trials of
replacing saturated fat with vegetable
oil rich in linoleic acid (corn oil)
RECOVERED DATA
Blinded RCT
9,423 (M/F) - 4 years
458 (M) - 3 years
36 hard (non-surrogate) outcomes were
reported
1 outcome showed a statistically
significant difference in combined
cardiovascular events 0.86 (0.77-0.96)
CHD mortality
“the totality of evidence no longer provides support for the
traditional diet-heart hypothesis”
If true - 1% absolute reduction in risk
CD002137
James McCormack and G. Michael Allan
The “Bare Necessities”
The “Numbers”
Surrogate markers/
thresholds
The Numbers
Low doses
Shared decision making/
values and preferences
Sources of information
Polypharmacy/
Polytesting
Relative Risk and Absolute Benefit
Intensive therapy
Standard therapy
Relative risk
Relative risk
95% CI
nonfatal myocardial infarction or nonfatal
stroke or death from cardiovascular
causes
6.9
7.2
0.95
0.80-1.05
Death (%)
5
4
1.25
1.01-1.50
Non-fatal MI (%)
3.6
4.6
0.8
0.6-0.9
Non-fatal stroke (%)
1.3
1.2
1.1
0.75-1.50
CHF (%)
3
2.4
1.2
0.95-1.50
Primary outcome (%)
5 is 25%
greater than 4
RR - 1.25
The CI represents a
plausible range of
values for the effect
but not a probability
of its magnitude
25% relative increase
1.25 minus1.00 = 0.25
1.01minus1.00 = 0.01
1.50 minus1.00 = 0.50
5%-4% = 1%
1% = 1/100
NNH = 100
Baseline Risk of a heart attack = 50% over 5 years
RR - Relative benefit = 0.8 or 20% reduction
With Treatment = 40%
Absolute difference = 10%
NNT = 10
Baseline Risk of a stroke = 2% per year
RR - Relative benefit = 0.25 or 75% reduction
With Treatment = 0.5%
Absolute difference = 1.5%
NNT = 67
Baseline risk of cancer = 10% lifetime
RR - Relative harm = 2.5 or 150% increase
With Treatment = 25%
Absolute difference = 15%
NNH = 7
20 “NEGATIVE” STUDIES IN A ROW
LIPIDS
Surrogate markers/
thresholds
AIM-HIGH, HPS2-THRIVE (niacin) BLOOD PRESSURE
ALTITUDE (aliskiren)
ACCORD (fibrates)
VALISH,
AASK, ACCORD
dalOUTCOMES (dalcetrapib)
ME Hg)
O
C
(aggressive
BP lowering)
m
T
STABILITY (darapladib)
OU 140m
G
s
E
v
R
Hg
YES nefit
PADIABETES
EM 20mm tatins o GENERAL
be
s
en
T (1VADT
(irbesartan/afib)
3 - suACTIVE
r
N
ACCORD, ADVANCE,
I
E
SPR HOP d pres CRESCENDO (rimonabant)
(aggressive A1c lowering)
bloo
VISTA-16 (varespladib)
BUT
ROADMAP (olmesartan)
ORIGIN (insulin)
SAVOR-TIMI 53 (saxagliptin) 182,000+
EXAMINE (alogliptin)
patients
ALECARDIO (aleglitazar)
!!
FIN
Y!!!
L
L
A
European Association for the Study of
Diabetes conference in Stockholm, Sweden
Sept 2015
“The packed conference hall listened intently as the
investigators announced the results of the primary
outcome (a composite of cardiovascular mortality,
non-fatal myocardial infarction, and non-fatal stroke),
showing superiority of the drug over placebo, and
burst into impromptu applause when
strong effects were shown”
www.thelancet.com/diabetes-endocrinology November 2015
EMPA-REG OUTCOME
3.1yr - 63 y/o, 71% male, 100% prev CVD, A1c 8.1%
All deaths
CVD
(%)
death (%)
Death from
cardiovascular causes,
nonfatal myocardial
infarction, or nonfatal
stroke (%)
Genital
infections (%)
Empagliflozin
5.7
3.7
10.5
6.4
Placebo
8.3
5.9
12.1
1.8
RR
ARR
NNT/NNH
31
2.6
39
38
2.2
45
14
1.6
61
260
4.6
22
NEJM 2015;DOI: 10.1056/NEJMoa1504720
SPRINT
HOPE-3 CHOLESTEROL
3.3yr - 68 y/o, 64% male, 17% prev CVD, 140/78 mmHg, statin 44%
All deaths
(%)
Myocardial infarction,
acute coronary
syndrome, stroke,
heart failure, or death
from cardiovascular
causes (%)
Acute kidney
injury or acute
renal failure(%)
Serious
syncope
(%)
Intensive
(120mmHg)
Regular
(140 mmHg)
3.3
5.2
4.4
2.3
4.5
6.8
2.6
1.7
RR
35
24
41
25
ARR
NNT /NNH
1.2
85
1.6
62
1.8
56
0.6
173
5.6yr - 66 y/o, 54% male, 0% prev CVD,
138/82mmHg, Total chol 5.2/200
All deaths
(%)
Total MI
(%)
Death from
cardiovascular causes,
nonfatal myocardial
infarction, nonfatal
stroke, resuscitated
cardiac arrest, heart
failure, or
revascularization (%)
Muscle
symptoms (%)
Rosuvastatin
Placebo
5.3
5.6
0.7
1.1
4.4
5.7
5.8
4.7
RR
ARR
NNT/NNH
No
statistical
diff
35
0.4
263
24
1.4
73
24
1.1
91
NEJM 2016
NEJM 2015
HOPE-3 BP
Pre-Med/Pre-Pharmacy
5.6yr - 66 y/o, 54% male, 0% prev CVD,
138/82mmHg, Total chol 5.2/200
All deaths
(%)
Total
stroke
(%)
Cardiovascular death, nonfatal
myocardial infarction, nonfatal
stroke, resuscitated cardiac arrest,
heart failure, revascularization, or
angina with objective evidence of
ischemia (%)
Symptomatic
hypotension,
dizziness, lightheadedness (%)
Candesartan/
HCTZ
5.4
1.2
5.3
3.4
Placebo
5.5
1.5
5.7
2.0
RR
ARR
NNT/NNH
No statistical differences
67
1.4
73
NEJM 2016
=
PRESUMPTUOUS
Definition - too confident especially in a
way that is rude : done or made without
permission, right, or good reason
DPP-4 inhibitors lower A1c by 0.3-0.8% but they do
not modify CVD or mortality
Adverse events were generally uncommon, but a
risk of pancreatitis remains possible, and saxagliptin
increased hypoglycemia (~1 in 50) and heart failure
(~1 in 150)
Normal (20-25) to overweight (25-30) BMI
carries the lowest risk of mortality
~25 appearing lowest (in elderly ~27.5)
Mortality increases when BMI is below “lownormal” (BMI <20) and obese (BMI ≥30), more
at the extremes
When to Measure/Re-measure
Bone density
Cholesterol
If pt would consider
If pt would consider treatment
treatment one time
one time measurement
Before
measurement
translate cholesterol into
treatment
translate T-score into 1010-year CVD risk
year fracture risk
“fire and forget”
approach
After
treatment
Don’t bother as the test Don’t bother because all you
just isn’t precise enough can do is raise the statin dose
- that decision should be
based on magnitude of CVD
reduction not cholesterol
Blood pressure
Easy to measure BUT
many, many repeat
measurements unless
VERY high
Low doses
“fire and forget”
approach????
A sample of RCT Evidence
6.25 mg hydrochlorothiazide
first marketed at 50 to 200 mg daily
6.25 mg captopril
25 mg PO TID is still a commonly recommended initial starting
dose for hypertension
25 mg sildenafil (Viagra)
effective dose for erectile dysfunction
25 mg sumatriptan (Imitrex)
works as well as100 mg
5 mg daily fluoxetine (Prozac)
similar effects to those seen at 20 mg and 40 mg daily
0.25 mg ezetimibe (Ezetrol)
1/40th of the recommended initial starting dose provides 50% of
the LDL lowering effect
15 mg elemental iron daily
as effective for anemia in the elderly as 50 mg and 150 mg with a
lower incidence of side effects
150 mg daily bupropion (Zyban)
0.5 mg BID varenicline (Champix)
produces the same rate of smoking cessation at one year as 300
mg daily (1.0 mg BID)
10 mg atorvastatin
produces 2/3 of the effect on cholesterol as that seen with an 80
mg (8-fold increase) dose
200 mg ibuprofen (Motrin)
as effective as 400 mg for migraine headache
25 mg ranitidine (Zantac)
as effective as 125 mg for heartburn relief
1.8 mg colchicine
as effective as 4.8mg for acute gout with less adverse events
low-dose (~20mg/day) isotretinoin improves
acne similar to conventional dosing
low-dose may reduce common side effects
(chapped lips, dry skin, epistaxis) by 16-35%
may be associated with increased relapse rates
(~20%) particularly with severe acne
% reduction in LDL cholesterol
60
45
Shared decision making/
values and preferences
30
10mg
20mg
40mg
80mg
15
0
Rosuvastatin
Atorvastatin
Simvastatin
Pravastatin
It’s all about figuring out
The Chance
WITH NO TREATMENT
Recommended approaches
•
•
•
VS
•
The Chance
WITH TREATMENT
•
•
GENERAL SUGGESTIONS - these are “relative”
use percentages or natural
frequencies(numerator/denominator)
use absolute terms
add bar graphs or icon arrays
use incremental risk format with icon arrays in
the same array
avoid use of NNTs
if use relative risks add baseline risks
Ann Intern Med 2014;161:270-80
Conditions requiring risk
assessment
The main ones are hypertension,
cholesterol, glucose/diabetes,
osteoporosis/BMD, atrial fibrillation, cancer
Can Fam Physician 2007;53:1326-27
5 Canadian Guidelines for blood pressure, cholesterol,
glucose, and bone density
Figure out risk
Then figure out benefit
Include harm and costs and inconvenience
197 PAGES - 90,000 Words
99
(0.1%)
words - relevant to patients’ values and preferences
Risk of future illness
CVD risk/benefit
(most people don’t benefit despite a lifetime of treatment)
Assume a person’s lifetime risk of CVD is that of a male
with two CVD risk factors - roughly 50% (NEJM 2012;366:321-9)
Assume that with multiple risk factor modification we
can reduce that risk relatively by 60% (VERY optimistic)
Sources of information
Risk goes from 50% ➡ 20%
30% of individuals BENEFIT
70% DO NOT despite a LIFETIME of treatment
A FEW USEFUL PLACES Cochrane Library
thennt.com
AHRQ treatment options
University of Laval decision box
Best Science (BS) Medicine Podcast
Tool For Practice
Therapeutics Initiative
RxFiles
My Studies
Centre for Evidence Based Medicine (UK)
Prescrire
Ottawa Hospital Decision Aids
Less is More Medicine
http://www.therapeuticcommandments.org
Golden Pill Award
Major therapeutic
advance
Clear advantage
Modest
improvement
2011
0
0
2012
0
0
0
2
2013
0
0
2014
2015
1
cholic acid (hereditary bile acid
deficiency)
1
meningococcal conjugate vaccine
(infant immunization)
3
imatinib (ALL
artesunate (malaria)
sofosbuvir (HepC) conjugate vaccine
(infant immunization)
0
abiraterone (prostate CA)
boceprevir (Hep C)
1
propranolol (severe infantile
hemangioma)
1
sodium phenylbutyrate coated
granules (urea cycle disorders)
2
permethrin (scabies)
ketoconazole HRA (endogenous
Cushing’s syndrome)
Prioritize the medications
Polypharmacy/
Polytesting
a)Will it Reduce Symptoms?
Is it actually helping?
b)Will it Reduce the Risk of Future Illness?
Is the size of the effect big enough to justify the
potential side effects, costs and inconvenience?
c)Will it Cause Harm?
Are any of their symptoms being caused by their
medication?
MEDSTOPPER
DON’T: Seven Deadly (PHE) Sins
1) Review of Systems (Mike’s rule)
2) Screen for depression (or virtual anything)
3) Urinalysis, CBC, LFT, creatinine, any biomarker, etc
4) Chest x-ray, ECG, virtual anything
5) Cholesterol or sugar in “young” (<40) healthy
6) Other time wasters: like waist circumference - or even
mention metabolic syndrome.
7) Don’t recommend Vitamins, ASA, low salt, etc
canadiantaskforce.ca
medstopper.com
What do Normal Backs Look Like
33 studies (3110 pts, no Hx of any back pain) of CT/MRI findings.
Anti-CCP, with ~96% specificity and ~14 positive
likelihood ratio, is good for assisting with the
diagnosis of RA
Anti- CCP is present in only 1⁄4 to 1⁄2 of patients
before or at diagnosis, so a negative test does
NOT rule out RA
can also predict more aggressive joint erosion
AJNR Am J Neuroradiol. 2015 Apr;36(4):811-6
Variability in glucose measurements
Seasonal variation
0.2-0.5%
Higher in winter
Am J Epi 2004;161:565-74
The A1c Test
and Diabetes
National Diabetes
Information Clearinghouse
We Are All Individuals
Every patient is an “n of 1” study
Every treatment is an experiment
Natasha Press
Faculty/Presenter Disclosure
Do we need to prevent “Bad Blood” with prophylactic antibiotics? Natasha Press
Division of Infectious Diseases
St. Paul’s Hospital
May 6, 2016.
Disclosure of Commercial Support
• Potential for conflict of interest: none
• Mitigating Potential Bias:
• I will not be discussing any products from companies from whom I have received commercial support
Endocarditis prophylaxis guidelines
• Timeline:
• 1955: first AHA (American Heart Association) guidelines recommend penicillin
• 2007: AHA limits prophylaxis to highest‐risk patients undergoing highest‐risk procedures
• 2008: UK recommends no endocarditis prophylaxis
• Faculty: Natasha Press
•
•
•
•
•
Relationships with commercial interests:
Grants/Research Support: none
Speakers Bureau/Honoraria: Pfizer, Merck
Consulting Fees: none
Other: Advisory board (Pfizer)
Objectives
• When to use prophylactic antibiotics:
• 1. Cardiac indications
– To prevent endocarditis
• 2. Orthopedic indications
– To prevent prosthetic joint infection
Evolution of endocarditis prophylaxis
• Rationale for antibiotic prophylaxis before dental procedures: Eliminate bacteremia that could cause endocarditis
• No firm scientific evidence to support this
• Daily activities cause transient bacteremia
• No randomized control trial – cost, numbers, medicolegal issues
• Pro: prevents cases of infective endocarditis
• Con: unproved, expensive, potentially harmful
Natasha Press
AHA 2007: Highest risk patients
1. Prosthetic heart valves • mechanical and tissue
2. Prior history of Infective endocarditis
3. Cardiac transplant valvulopathy (leaflet pathology and regurgitation)
4. Congenital heart disease – Unrepaired cyanotic
– Repaired with prosthetic material within 6 months
– Repaired with residual defects at site of prosthetic device
Non‐dental procedures
• Respiratory procedures: Incision/biopsy of respiratory tract mucosa
– e.g. tonsillectomy, bronchoscopy with biopsy
• No prophylaxis for:
– GU procedures
– GI procedures
– Skin/MSK procedures
– (unless procedure is in ongoing infection)
Who should get prophylaxis?
• Patient with an implantable cardiac defibrillator undergoing dental root canal
AHA 2007: Highest risk procedures
• Dental: Manipulation of gingival tissue or oral mucosa
• Not for:
– Routine cleaning
– Anaesthetic injection through tissue
– Placement of orthodontic appliances
• Single‐dose amoxicillin 2g • cephalexin 2g, azithromycin 500mg, clindamycin 600mg
Cases
• Who should get antibiotic prophylaxis?
• Patient with an implantable cardiac defibrillator undergoing dental root canal
• Patient with a bioprosthetic aortic valve replacement undergoing dental root canal
•
•
•
•
NO
NO prophylaxis for patients with ICD or pacemakers
Not a high‐risk patient
(prosthetic valve, previous IE, transplant valvulopathy, congenital heart)
Natasha Press
• Patient with a bioprosthetic aortic valve replacement undergoing dental root canal
•
•
•
•
YES
High‐risk patient
High‐risk procedure
(gingival tissue, periapical, oral mucosa)
• Pediatric patient with recently repaired congenital heart disease (prosthetic material used) undergoing tonsillectomy
Current recommendations • Pediatric patient with recently repaired congenital heart disease (prosthetic material used) undergoing tonsillectomy
• YES
• High‐risk patient
• Congenital heart disease – Unrepaired cyanotic
– Repaired with prosthetic material within 6 m
– Residual defects at prosthetic device
• High‐risk procedure
– Incision/biopsy of respiratory tract mucosa
UK Before and After Study:
5 years later
• In Canada: we follow the AHA guidelines
• In UK: no endocarditis prophylaxis since 2008
• Retrospective before and after study: • Change in antibiotic prescribing
• Change in rates of endocarditis
Thornhill MH et al. BMJ 2011; 342:d2392
UK Before and After Study
• Change in rates of endocarditis
– Significant increase in endocarditis
• Change in antibiotic prescribing:
– 419 cases more than expected (95% CI 95‐743)
– Single‐dose of amoxicillin or clindamycin
– Suggests 66 extra deaths (95% CI 15‐117)
– 88 % decrease
– NNT: 1 in 277 – 277 prescriptions to prevent one case of endocarditis
Thornhill MH et al. British Dental Journal; 28 (11) June 2015
Thornhill MH et al. British Dental Journal; 28 (11) June 2015
Lancet 2015; 385: 1219
Natasha Press
Adverse events to prophylaxis
• Amoxicillin:
Let’s do what Canada does! Prophylaxis for high‐risk patients!
– NO fatal adverse reactions in 35 years
– Very safe (safer than we thought!)
• Clindamycin:
– 1 fatal reaction every 3 years (C. difficile)
– We need a different alternative to amoxicillin
We will not be influenced by the colonies!
Thornhill M et al. J Antimicrob Chemother 2015
UK Updated Guidelines (2015)
Follow‐up for AHA guidelines
• No increase in endocarditis (VGS) since 2007
• No antibiotic prophylaxis
• Amoxicillin 2 g
• Good oral health
• Clindamycin 600 mg
• Cephalexin 2g
Fine Print: “The application of the recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient”
Orthopedic devices
• Azithromycin or clarithromycin 500 mg
Mayo Clin Proc 2015: 90(7); 874.
Orthopedic devices
• No prophylaxis for dental procedures
• Low rate of late prosthetic joint infections (1‐2%) • Paucity of data to support/refute prophylaxis
• Antibiotic prophylaxis debate • “Recommendations for Antibiotics in Patients with Joint Prosthesis Are Irresponsible and Indefensible”. J Can Dent Assoc. 2009;75 (7).
• New in 2013
• Canadian Dental Association Position Statement “routine antibiotic prophylaxis is not indicated for dental patients with total joint replacement”.
• Similar to American Dental Association (ADA)/American Academy of Orthopedic Surgeons (AAOS) Natasha Press
• Patient with multiple prosthetic joints Who should get prophylaxis?
• Patient with multiple prosthetic joints undergoing root canal on every tooth
undergoing root canal on every tooth
• NO
• No antibiotic prophylaxis for patients with prosthetic joints undergoing dental procedures
Final case
• Patient with prosthetic joints do not require antibiotic prophylaxis prior to:
– Dental procedures
– GI procedures
– Urologic procedures
Final case
• Patient with prosthetic aortic valve and total knee replacement undergoing:
• 1. excision of a suspicious nevus
• 2. skin biopsy of an area of cellulitis
Final case
• Patient with prosthetic valve and total knee replacement undergoing:
• Patient with prosthetic valve and total knee replacement undergoing:
• 1. excision of a suspicious nevus
• NO prophylaxis
• 2. skin biopsy of an area of cellulitis
• YES prophylaxis, but not amoxicillin!
• Cover skin pathogens likely to cause bacteremia and endocarditis
Natasha Press
Conclusions
• 1. Cardiac indications:
• We follow AHA 2007 guidelines: Amoxicillin to patients at highest risk undergoing high‐risk procedures
• UK has abandoned prophylaxis because of lack of evidence
• 2. Orthopedic indications:
• Everyone agrees no prophylaxis required
References
•
•
•
•
•
•
•
•
Wilson W et al. Prevention of infective endocarditis. Guidelines from the American Heart Association…Circulation 2007;116:1736‐54
Thornhill M et al. Impact of the NICE guideline recommending cessation of antibiotic prophylaxis for prevention of infective endocarditis: before and after study. BMJ 2011; 342 d2392
Thornhill M et al. NICE and antibiotic prophylaxis to prevent endocarditis. British Dental Journal; 28 (11) June 2015
Thornhill M et al. Incidence and nature of adverse reactions to antibiotics used as endocarditis prophylaxis. J Antimicrob Chemother 2015.
Dayer M et al. Incidence of infective endocarditis in England, 200‐13, a secular trend, interrupted time‐series analysis. Lancet 2015; 385: 1219.
DeSimone DC et al. Incidence of Infective Endocarditis Due to Viridans Group Streptococci…Inpatient Sample. Mayo Clin Proc. 2015; 90(7); 874‐81.
2013 CDA Position on Dental Patients with Prosthetic Joint Replacement. J Can Dent Assoc 2013;79 d126 Watters W 3rd et al. Prevention of orthopaedic implant infection in patients undergoing dental procedures. J Am Acad Orthop Surg March 2013 ; 21:180‐189.
Conclusions
• ID, cardiologists, dentists, orthopaedic
surgeons… agree:
• 1. Excellent dental hygiene
• 2. Antimicrobial stewardship
Dee Mangin
CFPC CoI Templates Slide 1
I Can’t Fight this Feeling:
Stopping SSRIs
• Faculty/Presenter: Dee Mangin
• Relationships with commercial interests:
• No funding gifts or food from drug or diagnostic industries
• Consulting Fees: I have occasionally provided expert witness reports for the plaintiff in class action legal cases taken against pharmaceutical companies. Any fees are donated to an independent patient drug side effect information and reporting website RxISK.org
Dee Mangin
David Braley Nancy Gordon Chair in Family Medicine
Learning objectives
• Understand the issues around prescribing of antidepressants • Understand the strengths and weaknesses of the evidence around long term maintenance treatment to prevent depression recurrence
• Have evidence to inform shared decision making (conversations with patients!) around discontinuation vs continuation of maintenance SSRIs (Absolute risk difference, NNT, NNH, NNTrial…..)
• Learn practical approaches to tapering and stopping SSRIs
Where’s the harm?
•
•
•
•
•
•
•
•
•
•
•
Increased bleeding risk
Increased risk of falls in seniors
Serotonin syndrome in combination with other drugs
Drug interactions
Sleep disturbance
Reduced bone density
Reduced emotional reactivity
Tolerance to effects (“Poop out”)
Sexual dysfunction
Accidental pregnancy exposure
……………
Summary of The Problem
• Many guidelines for primary care recommend maintenance treatment with SSRIs in certain patients: • There is little evidence to support this but it is driving widespread SSRI use
• There are increasing reports of adverse effects of long term use
Examining the evidence base
• Meta‐analysis of maintenance treatment after initial response to SSRIs show relapse rate 41% on placebo vs 18% on active treatment
• Absolute difference 23% NNT 4‐5
Geddes et al Lancet 2005
Dee Mangin
What we know about publication bias in studies of acute treatment
is likely to apply to studies of long term use as well
With permission of Dr Erick Turner 2010
With permission of Dr Erick Turner 2010
Benefit (trial)
Trial design flaws
outcome
threshold
• Almost all trials before need for tapering known
• Many short duration or still during the acute treatment phase
• Outcome measures inadequate (‘return of symptoms’)
• No trials in primary care population where 90% of prescription occurs
Benefit (attenuated)
harm
Low Severity / risk high
Trial Patients
Patients in Practice
Primary Care S condary Care
Kend ck Hega ty Glasz ou BMJ 2008 Oct 24 337
Current maintenance treatment recommendations
‘3 or more episodes’
‘additional risk factors for recurrence (e.g. ongoing psychosocial stressors)’
‘patient preference’
‘comorbid conditions’
Antidepressant Cessation Trial
• Multicentre double blinded placebo controlled RCT of long term maintenance SSRI vs gradual withdrawal to placebo in primary care
• 18 month follow up • Primary outcome: occurrence of moderately severe depression • standard DSM based diagnosis based on the interviewer administered MADRS
• validated cutpoint = 24 (100% agreement with clinician rating)
‘In many patients…….. treatment will be required indefinitely’
American Psychiatric Association
Australasian Clinical Trials Registry 2008
ACTRN12608000613303
Dee Mangin
Was there any harm in trying?
Source population
• Secondary outcomes:
• At 18 months a comparison of:
interviewer and patient reported mood, overall quality of life and functioning, overall psychological distress / symptoms, social and occupation functioning…..
• Depression diagnosed and treated in primary care • On treatment with fluoxetine for at least 12 months (15 months or greater) as maintenance to prevent recurrence of acute depression
• Currently in remission
Who took part?
Results: Primary Outcome
• 33% (419/1273) responded to a mailed invitation to participate
People want to try stopping
• Randomised to Placebo masked taper over 4 weeks if 20 mg (longer if higher dose) vs Continuation at current dose
• Absolute difference in recurrences 12.8% (96% CI 3.4%‐22.3%, p=0.005)
23.3% depression recurrences in the taper arm 10.5% depression recurrences in the continuation arm • Most dated their depression onset back to at least 5 years previously
• The majority of the difference: 6‐16 weeks after taper
• Most had had multiple episodes
• No difference in subthreshold symptoms (‘not so well’)
Summary
What happened next:
Were patients worse off for trying to stop?
Maintenance antidepressants prevent an episode of depression in the subsequent 18 months in 12 8% of patients. NNT (18 months) is 8
7/8 patients taking long term medication experience no benefit For every 16 taking medication one is unable to discontinue because of intolerable withdrawal symptoms. (NNH 16) It seems reasonable to trial withdrawal NNTrial = 2
On measures of interviewer and patients reported mood, overall quality of life and functioning, overall psychological distress / symptoms, social and occupation functioning…..
No suggestion of poorer outcomes at 18 months for those who trial discontinuation
Dee Mangin
Domains of withdrawal symptoms
Observations
Somatic
• disequilibrium (e.g. dizziness, ataxia, vertigo),
• gastrointestinal symptoms (e.g. nausea, vomiting) • flu‐like symptoms (e.g. fatigue, lethargy, myalgia, chills) • sensory disturbances (e.g. parasthesiae, electric shock sensations)
• sleep disturbances (e.g. insomnia, vivid dreams) Psychological
• Given the mean number of long term medications older patients take in most developed countries is 7, evidence is needed about the effects of continuation vs discontinuation • Pragmatic discontinuation trials are ideal for assessing drug effectiveness and safety, against a background of short term industry trials subject to bias
• The high response rate of eligible patients for this trial carried out in routine practice indicates significant patient desire for such trials of discontinuation in a ‘safe’ setting. • anxiety/agitation, irritability and bouts of crying
Do sometimes result in a change in depression rating scale scores
(i.e. they look like the original indication)
From Discontinuation Emergent Signs and Symptoms Scale
How to stop
Leaping into the void….
• Little evidence to guide best way to stop SSRIs
• Evidence that some have more significant discontinuation symptoms than others (paroxetine, venlafaxine): an important consideration when you are choosing a treatment to start
• Various approaches advocated
(evidence free) practical suggestions
• Switch to longer half life (as with benzos: NO EVIDENCE THIS IS HELPFUL) • Taper off (seems rational but no evidence for rate of taper) • Alternating days: unhelpful especially with shorter half life drugs P‐E‐T
1 Preparation
2 Engagement • Explain to the patient that stopping can be easy or more difficult
• Patients on antidepressants for longer may need a longer taper:
• Let patients know they will be no worse off for trying to discontinue
• Suggest they engage family and friends as supports
• Optimise non pharmacological management options
• On them for months – take weeks to stop
• On them for years – take months to stop
• Prepare the patient for discontinuation effects, and reassure them they (especially unusual sensations) are not harmful or life threatening
• Rare but important: Warn specifically about emergent suicidal ideation and akathisia and what to do Dee Mangin
3 Taper
Taper ‐ monitoring
• All SSRIs need tapering (yes fluoxetine too)
• A test drop in dose of say 10% may signal the required rate of taper
• Put control of the taper rate in the patients hands
• Suggest:
Have a clear plan about • If 10% is OK try dropping by 25% steps
• If not stay at 10% or less increments
• Some patients have trouble with the final drop – if this appears to be happening suggest an exponential decay rather than linear drop (e.g. halve or quarter the previous dose each time) • For those needing smaller increment drops you can tablet split or get a liquid preparation (find a compounding pharmacy near you) • If the patient cannot afford compounding, most SSRIs can be dissolved and a proportion of the resultant (well shaken) liquid can be calculated (Consult a pharmacist near you to confirm solubility)
• Some people may not be able to discontinue completely and the lowest dose required to control discontinuation symptoms will minimise harms ( “Dose size does matter” McCormack, J) •
•
•
•
What to monitor
Who will monitor How often
What the agreed criteria for considering restarting are going to be • patients will feel more reassured about trialling a taper if it is framed as ‘pause and monitor’ knowing they can restart. This is one of patient’s expressed fears about deprescribing of any medication. Alan Cassels
CFPC CoI Templates: Slide 1
The Cochrane
Collaboration
“Everyday I write the book”
 Faculty/Presenter: Alan Cassels
Alan Cassels,
Best Science Medicine Course
The Fairmont Waterfront, Vancouver BC
May 6, 2016
 Relationships with commercial interests:
 Grants/Research Support: CIHR Knowledge Translation grant (Medstopper)
 Speakers Bureau/Honoraria: None
 Consulting Fees: DECA Consulting; Quizzify.com;
 Other: Book royalties: Agio Publishing; Greystone Publishing
Twitter: @akecassels
 Potential for conflict(s) of interest:
 Alan Cassels has received (or will receive) funding from Agio Publishing and Greystone
Publishing whose product(s) are being discussed in this program.
Mitigating Potential Bias
 I have no commercial interest (shares, research consultancies, etc) and am not dependent on the success or failure of the pharmaceutical industry (Selling Sickness), the medical screening industry (Seeking Sickness) or the Cochrane Collaboration.  I don’t expect you to purchase any of my books, nor do I expect you to recommend them to your patients.  My books are available on Amazon, in libraries and the discard pile of your local bookstore. 27th Annual Best Science Medicine Course: Slide 4
Learning Outcome Objective Slide
I expect attendees to my lecture will learn something about the origins and creation of the Cochrane Collaboration so that when they Google “Cochrane Library” they will be able to search a vast storehouse of systematic reviews on almost all areas of healthcare. Elvis Costello
“I'm a man with a mission in two or three
editions,
And I'm giving you a longing look.
Everyday, everyday, everyday I write the
book…”
“Don't tell me you don't know
the difference,
Between a lover and a
fighter.
With my pen and my electric
typewriter…”
Alan Cassels
Archie Cochrane
(1909-1988)
“How can we have a
rational health service
if we don’t know which
of the things being
done are useful and
which are useless or
possibly even
harmful?”
Sir Iain Chalmers
“People don’t need
islands unconnected to
any continent, they want
something that tells them:
‘What does it mean?’”
Effectiveness and Efficiency: Random Reflections on Health Services, 1972
“Humans
need clean,
clear health
information
like they need
clean, clear
water.”
The Cochrane
Collaboration
(under
construction)
What determines if a
healthcare
intervention ‘works’?
Alan’s water fountain
--Sir Muir Gray
Who is Cochrane?
People asking hard
questions and
questioning
answers
http //vancouverisland ctvnews.ca/video?clipId=766895
Alan Cassels
What the heck does this
symbol mean?
Systematic Reviews.
• Each line is one trial (the shorter the
line, the more certain the result);
• The vertical line indicates the position if
the two treatments compared in the
trials had similar effects;
• A line touching the vertical line, means
that that particular trial found no clear
difference.
• The diamond represents their combined
results.
• The diamond to the left of the vertical
line indicates that the treatment is
beneficial.
• If the diamond is to the right of the line
would show that the treatment did more
harm than good.
“The notion of systematic
review — looking at the
totality of evidence — is
quietly one of the most
important innovations in
medicine over the past 30
years.”
Goldacre, B. Forward to Evans I, Thornton H, Chalmers I, et
al. Testing Treatments Better Research for Better
Healthcare. 2nd edition. London Pinter & Martin; 2011.
Who is out there
producing gold standard
evidence?
“Like all great ideas, it’s
so simple and obvious
that it just had to be
done.”
Page 37.
p. ix
Kay Dickersin
What kinds of
questions has
Cochrane
tackled?
Was High Dose
Chemotherapy with
Autologous Bone
Marrow Transplantation
HDC/ ABMT beneficial
to treat breast cancer?
p.4
Alan Cassels
Peter Gøtzsche
What is the
effectiveness of
mammography
screening?
How many do you have to screen to save a single life?
Lives saved: 1 in 2,100 women False positives: 690 in 2100
You have high blood pressure:
How low do you need to go?
Alan Cassels
The
SPRINT TRIAL:
“Aiming lower
saves more lives
when it comes to
controlling blood
pressure…”
Cochrane Hypertension Group
Patricia Crowley
For premature infants
do steroids work to
prevent respiratory
distress and save
lives?
p.76
There are REAL human costs resulting from failure to perform
systematic, up-to-date reviews of RCTs of health care: The case of
steroids and prematurity.
• First RCT in 1972.
• By 1991, seven more trials had been reported,
• Corticosteroids reduces the odds of the babies of
these women dying from the complications of
immaturity by 30 to 50 per cent.
• Patricia Crowley published her systematic review
in1989.
• Up to then most obstetricians didn’t realize that the
treatment was so effective.
• Tens of thousands of premature babies have
probably suffered and died unnecessarily (and
needed more expensive treatment than was
necessary).
Tom Jefferson
Do people need to get
a flu shot every year?
Does it make sense for
governments to be
stockpiling billions of
dollars worth of
antivirals?
Alan Cassels
What do we mean when we say flu vaccines ‘work?’
 Flu vaccines are effective in reducing infection and in slightly reducing absence from work in adults, but there is no evidence that they reduce transmission, hospitalization, pneumonia, or death.
 There is poor‐quality evidence from cohort studies that vaccines are effective in elderly people living in institutions, but there is little good‐quality evidence for the elderly population in general.

 A 2007 systematic review of 274 influenza vaccine studies found:
 Industry‐funded studies were published in more prestigious journals and cited more than other studies independently from methodological quality and size.  Studies funded from public sources were significantly less likely to report conclusions favourable to the vaccines.  Generally reliable evidence on influenza vaccines is thin but there is evidence of widespread manipulation of conclusions and spurious notoriety of the studies. 
T Jefferson C Di Pietrantonj M G Debalini A Rivetti V Demicheli Relation of study qua ity concordance take home message funding and impact in studies of influenza vaccines: systematic review BMJ. 2009; 338: b354. Published online 2009 February 12. http //www ncbi nlm nih gov/pmc/articles/PMC2643439/?tool pubmed
Jefferson TO Rivetti D Di Pietrantonj C Rivetti A Demicheli V. Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD001269. http://www.ncbi.nlm.nih.gov/pubmed/17443504
Alan vs Perry
Alan Cassels, flu agent provacateur
“the
Why does some vaccine research rise to the top?
science is on my side”
Sir Ian Chalmers
Dr. Perry Kendall, flu aficionado
“the science is on our side”
Shouldn’t we be absolutely rigorous about the science?
Sir Iain Geoffrey Chalmers
By Ju ia Fullerton-Batten, 27 Feb
2006 – National Portrait Gallery
“Be careful of reading health books.
You may die of a misprint.”
--Mark Twain
What is the question to which
you’d like a Cochrane-level
answer?
cassels@uvic ca
@AKEcassels
(250) 361-3120
Feedback and criticism: cassels@uvic ca
Ric Arseneau
CENTRAL SENSITIVITY SYNDROMES:
“DO YOU FEEL LIKE I DO?”
FACULTY/PRESENTER DISCLOSURE
๏ Faculty/Presenter: Ric Arseneau
Ric Arseneau, MD FRCPC MA(Ed) MBA FACP CGP
Clinical Associate Professor
Division of General Internal Medicine
St. Paul's Hospital & BC Women’s Hospital
Director of Program Planning
Complex Chronic Diseases Program
University of British Columbia
๏ Relationships
with commercial interests:
๏ None
DISCLOSURE OF COMMERCIAL SUPPORT
MITIGATING POTENTIAL BIAS
๏
This program has received NO financial support.
๏Treatment
๏
This program has received NO in-kind support.
๏
Potential for conflict(s) of interest:
๏
None
LEARNING OUTCOME OBJECTIVE
Participants should be able to:
1. Identify clinical presentations that should include CSS in the
differential
2. Name the predisposing, precipitating, and perpetuating factors for
these conditions
3. Explain to patients the basic physiology involved in these conditions
4. Access physician and patient resources to manage these conditions
recommendations are approved by the
Clinical Advisory Committee at the Complex Chronic Diseases Program, BC Women’s Hospital, UBC
Ric Arseneau
501534
MEDICALLY
UNEXPLAINED
SYMPTOMS
2013
HPQ0010.1177/1359105313501534Journal of Health PsychologyStenhoff et al.
Article
Understanding medical students’
views of chronic fatigue
syndrome: A qualitative study
IS IT REAL ?
Journal of Health Psychology
2015, Vol. 20(2) 198–209
© The Author(s) 2013
Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/1359105313501534
hpq.sagepub.com
Alexandra Laura Stenhoff, Shireen Sadreddini,
Sarah Peters and Alison Wearden
Medicalization ?
Malingering ?
Psychiatric ?
Abstract
Chronic fatigue syndrome receives little attention in the medical curriculum. This study explores UK medical
students’ knowledge of and attitudes towards chronic fatigue syndrome. Semi-structured interviews (average
length 22 minutes) were conducted with 21 participants (7 females and 14 males) in years 3 (n = 4), 4 (n
= 11) and 5 (n = 6) of their studies. Inductive thematic analysis taking a realist perspective produced three
themes: limited knowledge, influences on attitudes and training needs. Students acquired their knowledge
and attitudes largely from informal sources and expressed difficulty understanding chronic fatigue syndrome
within a traditional biomedical framework. Incorporating teaching about chronic fatigue syndrome into the
medical curriculum within the context of a biopsychosocial understanding of illness could encourage more
positive attitudes towards chronic fatigue syndrome.
Free-association exercise with housestaff
Keywords
beliefs, chronic fatigue syndrome, health education, models, qualitative methods
4 OVERLAPPING GROUPS
Pain
Fatigue
Unexplained
Symptoms
Sleep Dysfunction
Noncardiac Chest Pain and Fibromyalgia
CENTRAL SENSITIVITY SYNDROMES
Fig. 1. Central sensitization syndromes share a common etiologic mechanism of central
sensitization and frequently present with overlapping epidemiologic, clinical, and psychological features. (Adapted from Yunus MB. Role of central sensitization in symptoms beyond
muscle pain, and the evaluation of a patient with widespread pain. Best Pract Res Clin Rheumatol 2007;21:481–97; with permission.)
Introduction
Chronic fatigue syndrome, also named myalgic and Hotopf, 2005) and often results in substanencephalomyelitis (CFS/ME), is a debilitating tial impairment and high levels of health-care
condition affecting 0.2–0.4 per cent of the UK use (McCrone et al., 2003). Indeed, it has been
population (CFS/ME WG, 2002). It is charac- shown that CFS/ME intrudes into more life
terised by severe, disabling fatigue, not domains (i.e. work, recreation and health), and
explained by other medical conditions, and pre- to a greater degree, than other chronic illnesses
sent for 6 months or more, usually in conjunction with other symptoms (Fukuda et al., 1994;
Sharpe et al., 1994). In the absence
of labora- B. University
of Manchester, UK
Muhammad
Yunus, MD
tory tests or blood tests, diagnosis is made based
on history and exclusion of other possible Corresponding author:
Alexandra Laura Stenhoff, University of Manchester, 11
causes
for the fatigue (National Institute for Macintosh Mills, 4 Cambridge Street, Manchester
Semin Arthritis Rheum 36:339-356
Health and Clinical Excellence (NICE), 2007). M15GG, UK.
CFS/ME has an uncertain prognosis (Cairns Email: [email protected]
Fibromyalgia and Overlapping Disorders:
The Unifying Concept of Central Sensitivity Syndromes
Downloaded from hpq.sagepub.com at University of British Columbia Library on September 12, 2015
277
M.B. Yunus
Semin Arthritis Rheum 36:339-356
Figure 2 Simplified suggested biopsychosocial mechanisms for CS and CSS with interacting factors. ANS, autonomic nervous
system. The relationship between central sensitization and CSS may be bidirectional; chronicity of CSS may accentuate central
sensitization.
Ric Arseneau
CENTRAL SENSITIVITY SYNDROMES
The 3 P’s
Predisposing
๏ Precipitating
๏ Perpetuating
๏
PRECIPITATING
๏ Precipitant vs. “Cause”
๏ Stressor
๏ Physical
๏ Psychological
๏ Infectious
๏ Forest Fire Analogy
๏ ? Lightning strike
๏ ? Camp fire
๏ ? Cigarette
๏ ? Arson ๏ Can’t go back and “undo” or “fix”
๏ Deal with the problem - now
PREDISPOSING
๏Genetic predisposition
๏ Twin studies
๏ Identical - 50%
๏ Fraternal - 25%
๏ Family members
๏Childhood
PRECIPITANT / STRESSOR
Physical
Psychological
Infectious
๏
๏
๏
๏ Trauma (PTSD)
๏ “Burn out”
๏ Other
๏ Viral
๏ Bacterial
๏ Other
Car accident
Surgery
Other injury
PERPETUATING...
NIH Public Access
Author Manuscript
J Behav Neurosci Res. Author manuscript; available in PMC 2011 January 18.
Published in final edited form as:
J Behav Neurosci Res. 2009 January 1; 7(2): 1–17.
trauma
Poor Sleep
Over-exertion
Reduced Activity
Depression
Anxiety
Stress
Kindling and Oxidative Stress as Contributors to Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome
L. A. Jason1,*, N. Porter1, J. Herrington1, M. Sorenson1, and S. Kubow2
DePaul University
1
2
McGill University
KINDLING THEORY: UPREGULATION
๏
Prolonged stimulation of the limbic-hypothalamic-pituitary axis
๏ High-intensity
๏ Chronically
๏
stimulation
repeated low- intensity stimulation Exceeds “threshold limits”
๏ Resulting
in persistent hypersensitivity / low activation threshold
firing ๏ Spontaneous
๏
Neuroplastic changes
Ric Arseneau
PAIN PATHWAY
CHRONIC
PAIN
Sensitization
&
Amplification
CHRONIC PAIN: SENSITIVITY SHIFT
!
PAIN 154 (2013) S10–S28
www.elsevier.com/locate/pain
Review
Glia and pain: Is chronic pain a gliopathy?
Ru-Rong Ji a,⇑, Temugin Berta a, Maiken Nedergaard b
a
b
Department of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC, USA
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Rochester, Rochester, NY, USA
๏ Opioids
๏ Glial
and gliopathy
health
๏ Low
Dose Naltrexone (LDN)
๏ PEA
(palmitoyethanolamide)
bs_bs_banner
FIBROMYALGIA
Pain Medicine 2013; 14: 895–915
Wiley Periodicals, Inc.
MUSCULOSKELETAL SECTION
Original Research Article
Excessive Peptidergic Sensory Innervation of
Cutaneous Arteriole–Venule Shunts (AVS) in the
Palmar Glabrous Skin of Fibromyalgia Patients:
Implications for Widespread Deep Tissue Pain
and Fatigue
Phillip J. Albrecht, PhD,*,† Quanzhi Hou, MD PhD,*,†
Charles E. Argoff, MD,‡ James R. Storey, MD,§
James P. Wymer, MD PhD,‡ and Frank L. Rice, PhD*,†
Conclusions. The excessive sensory innervation
to the glabrous skin AVS is a likely source of severe
pain and tenderness in the hands of FM patients.
Importantly, glabrous AVS regulate blood flow to the
skin in humans for thermoregulation and to other
tissues such as skeletal muscle during periods of
increased metabolic demand. Therefore, blood flow
dysregulation as a result of excessive innervation to
AVS would likely contribute to the widespread deep
pain and fatigue of FM. SNRI compounds may
provide partial therapeutic benefit by enhancing
the impact of sympathetically mediated inhibitory
modulation of the excess sensory innervation.
๏ Excessive
sensory innervation to A-V shunts ๏ Blood
flow dysregulation ๏ Symptoms Ric Arseneau
EPIDEMIOLOGY OF FIBROMYALGIA
Clinical Review & Education
Clinical Crossroads
Fibromyalgia
A Clinical Review
Daniel J. Clauw, MD
•
•
After OA
•
2% to 8% of the population
•
Treatment
Almost all women
Cost
Grades
of Recommendations
General
Newer criteria: symptom based and do not require tender points
•
•
Clinical
Reviewreview
& Education
Clinical Crossroads
1:
Systematic
of randomized
trials or n-of-1 trial
2: Randomized trial or (exceptionally) observational studies with dramatic effect
3: Non-randomized controlled cohort/follow-up study
4: Systematic review of case-control studies,
historically controlled studies
Table. Summary of Treatment Guidelines34
5: Opinion
Diagnostic criteria (1990): chronic widespread pain with tender points
•
Centralized pain state
therapies
Graded exercise36
Cognitive behavioral
therapy (CBT)37
Low
principles of
of
Incorporate principles
self-management including
including aa
self-management
approach
multimodal approach
Adverse Effects
Aerobic exercise has been best
studied but strengthening and
stretching have also been shown
to be of value
Fibromyalgia
Fibromyalgia
1A
Worsening of symp
when program is b
rapidly
Low
Pain-based CBT programs have
been shown to be effective in
one-on-one settings, small
groups, and via the Internet
1A
Most CAM therapies have not
been rigorously studied
1A
No significant adve
effects of CBT per s
patient acceptance
poor when viewed
“psychological” int
Generally safe
34
Table. Summary of Treatment Guidelines34
Details
Evidence
Level
Low
Clinical Review & Education Clinical Crossroads
Cost
Details
A:recommendations
Consistent level 1 studies
B: Consistent
level 235or 3 Low
studies or extrapolations
level of
1 studies
1A
Patient education
Incorporatefrom
principles
including a
C: Level 4 studies or extrapolations fromself-management
level 2 or 3 studies
multimodal approach
D: Level 5 evidence or troublingly inconsistent or inconclusive studies of any level
Consensus
Nonpharmacological
Female:Male ratio of 2:1
Treatment
General
recommendations
Patient education35
1547
Level of evidence
Second most common “rheumatic” disorder
•
JAMA April 16, 2014 Volume 311, Number 15
Evidence
Evidence
Level
Level
Adverse Effects
Effects
Adverse
Complementary
and
Variable
Trusted(Patient(Resources:(
Clinical
Pearls
Clinical
Pearls
alternative
medicine
Fibromyalgia((
38
(CAM) therapies
UpToDate)
1A
1A
Followinginitial
initialdiagnosis,
diagnosis,spend
spendseveral
several
Following
CFIDS)&)Fibromyalgia)Self7Help)
visits(or
(oruse
useseparate
separateeducational
educational
visits
Pain)BC)
sessions)to
toexplain
explainthe
thecondition
conditionand
andset
set
sessions)
treatmentexpectations
expectations
treatment
Headache
Central ME|FM)Society)of)BC)
nervous
Several types of CNS neusystem (CNS)
rostimulatory therapies have
Nonpharmacological
ME/FM)Action)Network)
neurostimulatory
been effective in fibromyalgia
therapies
therapies39
and other chronic pain states
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Ric Arseneau
www.bcwomens.ca/health-professionals/professional-resources/complex-chronic-disease
COMPLEX CHRONIC DISEASES PROGRAM
Fibromyalgia and Chronic Pain in
Related Disorders
Clinical Protocol
Date: Dec 25, 2015
Clinical Protocol: Fibromyalgia and Chronic Pain in Related Disorders
PREAMBLE
The recommendations below are supported by strong evidence (level A) unless stated
otherwise
We have added practical “tips”
The drugs are presented in the order (more or less) to try them
The actual order of use will depend on prior treatment, patient preference, etc.
Look for “two fors” (drugs that benefit two or more problems)
Provide patient with information/dose adjustment handout
Given the different mechanisms of action, patients often end up on 2 or more drugs
Patients with ME/CFS may need to be titrated more slowly, and may not tolerate higher doses
of medications
It is expected that physicians would educate themselves about these drugs beyond the outline
provided below
The treatments described below may occur one-on-one or in a group setting depending on
resources
•
•
•
•
•
•
•
•
•
•
1. PATIENT EDUCATION
Level A evidence
Incorporated into multiple offerings (e.g., handouts, web-based resources)
Incorporated into core group: Living with Complex Chronic Diseases
“Family and Friends” evening session
•
•
•
•
2. PHYSICAL ACTIVITY
•
•
•
Level A evidence
Offered in group setting and individual sessions with PT and OT
Tai-Chi and mild Yoga
o Suggested
o Offerings in community rather than CCDP
3. SLEEP
•
•
Sleep disturbance is a major component of FM and pain
See sleep protocol for details
4. DIET
•
•
Emerging evidence; some RCT data
Offered in group setting and individual sessions with dietitian
5. ALTERNATIVE AND COMPLEMENTARY THERAPIES
•
Some agents have a strong theoretical rational and early evidence
o Co-enzyme, D-Ribose 5 g, magnesium Malate, NADH, Vitamin D
5.1 Co-enzyme Q
• 200 mg TID
Page 1
G. Michael Allan
Osteoarthritis can be Bad to the Bone
• Faculty/Presenter: G. Michael Allan
–
–
–
–
G. Michael Allan
Professor & Director of EBM, Dept of Family Med, U of A
Director of Evidence and CPD, Alberta College of Family Physicians
Grants/Research Support: Not applicable
Speakers Bureau/Honoraria: Not applicable
Consulting Fees: Not applicable
Other:
– Employed by University of Alberta, Alberta Health
– Non-profit sources including Alberta College of Family
Physicians, TOP, IHE, CADTH, etc.
Activity
Learning Objectives
• >10 sys revs, focus on last 5 yrs & Cochrane
– Largest 60 RCTs with 8218 patients2
– Overall quality moderate
We will review and learn about Osteoarthritis
Knee Osteoarthritis
•Non-Pharmaceutical Management
Outcome2
– Exercise, Braces, Taping
•Pharmaceutical Management
– Acetaminophen, Topical NSAIDs, Oral NSAIDs (including
Cox-2’s), Opioids, Glucosamine & Chondroitin, Intraarticular injections (steroid or hylanuronan product)
Short-Term
Long term (2-6 months)
SMD
Scores (0-100)
SMD
Scores
Pain
0.49 (0 39-0 59)
44 vs 32 (Ex)
0.24 (0.140.35)
6 pts better
Function
0 52 (0 39-0 64)
38 vs 28 (Ex)
0.15 (0.040.26)
3 pts better
Quality of Life
0 28 (0.15-0.40)
43 vs 47
Hip similar: estimated NNT 6. Maybe slightly better long-term?3
•NSAID risks (including Cox-2 anti-inflammatories)
1) Cochrane 2008; 4: CD004376. 2) with update 2015 Jan 9;1:CD004376. 3) Cochrane 2014; 4: CD007912. 4)
BMJ 2013;347:f5555 doi: 10.1136/bmj.f5555. 5) Arthritis Rheumatol. 2014;66(3):622-36. 6) BMC Musculoskeletal
Disorders2011,12:123. 7) Cochrane 2007; 4: CD005523. 8) Arch Phys Med Rehabil 2012;93:1269-85. 9 ) Clin
Rehabil. 2013;27:1059-71. 10) J Rheumatol 2009;36:1109–17
Acetaminophen: First do no harm
Activity
• Acetaminophen (≤10 RCTs, 1712 pts)1,2
• Types of exercise: Generally no diff
– Pain, SMD ≤ 0.2 (0.02-0.41)
– Pain NNT=16 (any pain relief)2
– But mean pain score diff=3 (from 54/100)4
– Example effect on Pain: Quad strengthening (SMD 0.29);
Lower limb strengthening (0.53); strength & aerobic
(0.40); walking (0.48); Other (0.32).1
– Subtle diff not consistent5,9 (e.g. Quad > lower limb5)
• Others6 (3-7 RCTS, 1336-2355 pts): short-medium
term pain/disability 1.7-3.7/100
• Aquatic exercise: 0.26- 0.68 pain,7,4 0.34 function4
– 10 RCTs, aquatic vs Land: No diff in any outcome6
• Effect Size small and NNT poor for a pain
• Likely Supervised & more often better (e.g 3/wk)5
• No more research required (had enough by
– In most comparative studies, acetaminophen the
least effective3-5 & likely not be meaningful4,6
• But harm (except LFTs) similar to placebo1,2,4,6
2002)4
1) Cochrane 2008; 4: CD004376. 2) with update 2015 Jan 9;1:CD004376. 3) Cochrane 2014; 4: CD007912. 4)
BMJ 2013;347:f5555 doi: 10.1136/bmj.f5555. 5) Arthritis Rheumatol. 2014;66(3):622-36. 6) BMC Musculoskeletal
Disorders2011,12:123. 7) Cochrane 2007; 4: CD005523. 8) Arch Phys Med Rehabil 2012;93:1269-85. 9 ) Clin
Rehabil. 2013;27:1059-71. 10) J Rheumatol 2009;36:1109–17
1.
Ann Rheum Dis. 2004;63:901-7. 2. Cochrane 2006;1:CD004257. 3. Ann Intern Med. 2015;162: 46-54.
4. Euro J Pain 2007;11:125–38. 5. Osteoarthritis Cartilage. 2010;18:476-99. 6. BMJ 2014;350:h1225
G. Michael Allan
Oral NSAIDs: The Balancing Act
Oral NSAIDs: The Balancing Act
• NSAID vs Acetaminophen3
• Traditional NSAIDs vs Cox-2 selective
– No efficacy difference Cox-2 & traditional NSAIDs1
• Meta-analysis2: 23 RCTs, 10,845 pts
– Global improve (pt) = 57% NSAID vs 39% NNT 6
– GI AE: Traditional NSAID, 19% vs 13%, NNH=12
• Withdrawal due to GI AE, 8% vs 4%, NNT 25.
– VA improved 10.1mm or 15.6%. SMD 0.32.
– Exclude run-in bias trials (10 left), SMD 0.23.
• Sys Rev5: 25 RCTs, 9964 pts
– 10.2 better out of 100 (from baseline of 64)
• Network Meta:6 0.33 (celecoxib)- 0.52 (diclofenac)
1. NICE OA Guideline (http://www.rcplondon.ac.uk/pubs/contents/d87b4537-b333-4b8a-a2d8-5e96b7f4b65a.pdf )
2. BMJ 2004; 329 (7478):1317. 3 Cochrane 2006 (1):CD004257. 4. Ann Rheum Dis. 2004;63(8):901-7. 5. Euro J
Pain 2007; 11: 125-38. 6. Ann Intern Med. 2015;162:46-54.
Topical NSAIDs: benefit over risk
• ≥5 Sys Rev, Most recent from Cochrane
– 34 RCTs (7688 pts). RCT quality moderate-good
Duration
% better on
% better on
Topical NSAID Placebo
RR (95% CI)
NNT
2-3 weeks
37%
19%
1 9 (1.6-2.4)
5-6
4-6 weeks
42%
24%
1.7 (1.4-2.1)
6
8-12 weeks
60%
50%
1 2 (1.1-1.3)
10
• Topical = Oral with 15% circulating NSAID level
• Topical NSAID Adverse events
– No diff between Topical NSAID & placebo in systemic or GI
– Local AE: Topical 12.6%vs placebo 7.8%, NNH 21
– Withdrawal due to AE: Topical 5.4% vs Placebo 3.8%, NNH 63
1. BMJ 2004;329(7461):324. 2. J Rheumatol 2006;33:1841–4. 3. www.Bandolier.com March 05. 4. NICE OA
Guideline (http://www.rcplondon.ac.uk/pubs/contents/d87b4537-b333-4b8a-a2d8-5e96b7f4b65a.pdf ) 5. J
Rheumatolo 2004;31(10): 2002-12. 6. Tools for Practice #40, Jan 24, 2011. Cochrane 2012; 9: CD007400.
Chondroitin: More of the Same
• Sys Rev1: 43 RCTs, 9110 pts (9 low risk of bias)
– 20% improvement on WOMAC: NNT 17,
– Pain NNT 4-5 (but my calculation is 10-12)
• Pts prefer NSAIDs (RR 2.34) but more GI AE4
• n-of-1 RCT, Celecoxib vs Acetaminophen5
– 80% no preference in 2 Tx;
– 17% picked Celebrex (5% sure it was better)
– 3% picked Acetaminophen
1. NICE OA Guideline (http://www.rcplondon.ac.uk/pubs/contents/d87b4537-b333-4b8a-a2d8-5e96b7f4b65a.pdf )
2. BMJ 2004; 329 (7478):1317. 3 Cochrane 2006 (1):CD004257. 4. Ann Rheum Dis. 2004;63(8):901-7. 5
Rheumatology 2007;46:135-140
Glucosamine: Harm=0 (? Benefit)
• Sys reviews in last 5 yrs + Cochrane
– 7 Sys rev with 2-25 RCTs (414 - 4963 pts).
• Pain: Results very widely, SMD 0.16 (ns) to 0.51 (sign)
– Some subgroups higher:1-4,7 Rotta brand SMD 1.11 (sign).7
– In larger studies:1 Change in pain scale 0.4 / 10 (Sign).
• Clinically meaningful change=0 9
• Function: Vary by trial duration & assessment tool,
SMD 0.08 (NS) to 0.54 (sign).2,7
• Adverse effects: None.7
• Approximate yearly cost is $60 at 500mg TID.
1) BMJ. 2010; 341:c4675. 2) Int J Clin Pract. 2013; 67:585-94. 3) Arthritis Care Res (Hoboken). 2014 Jun 6. 4)
Osteoarthritis Cartilage. 2010; 18(4):476-99. 5) Rheumatol Int. 2010; 30(3):357-63. 6) Am J Sports Med. 2014
May 27. [Epub ahead of print] 7) Cochrane 2005; (2):CD002946.
Viscosupplementation:
• ≥7 sys revs. Best = Rutjes 2012:1 89 RCTs
– 12,667 patients (mean age 63), ~16 weeks.
• Pain reduced (at 3 months) SMD -0.37 (-0.46, -0.28)
• Heavily dependent on quality markers
• Others find similar: Sys Rev2 (22 RCTs, 4056 pt)
PAIN
Sensitivity
Variable 1 Outcome 1
RCT Size
n<100
0.59 (0.31, 0.88)
Variable 2 Outcome 2
n≥100
Drug Co
Yes
0.52 (0.24, 0.80)
No
0.0 (-0.16, 0.15)
Study year
1990-99
0.89 (0.66, 1.13)
≥2010
0.06 (-0.13, 0.25)
Allocation
Concealment
Unclear
0.67 (0.40, 0.93)
Yes
0.06 (-0.24, 0.37)
0.14 (-0.17, 0.45)
Cochrane 2015; 1: CD005614. Ann Intern Med. 2007;146:580-90.
– MCID benefit (-0.37 = 9mm on 100mm pain scale).
• BUT many issues,
– High quality RCTs (>100 pts, proper randomization, blind
outcome assessor): no meaningful effect on pain/function
– Publication bias: Negative trials less l kely to be
published. 5/6 unpublished studies showed no effect.
• Dropouts due to AE, RR 1.33 (1.01, 1.74)
• Viscosupplementation (1-3 injections) ~$285-500.
1) Ann Intern Med. 2012; 157:180-91. 2) CMAJ 2005;172:1039-43. 3) JAMA 2003; 290:3115-21 4) Cochrane
2006; 2: CD005321. 5) J Fam Pract 2006; 55:669-75. 6) J Fam Pract 2005; 54: 758-67. 7) J Bone Joint Surg
2004; 86:538-45.
G. Michael Allan
Steroid Injection (knee) for OA
• 6 Systematic Reviews: 5-13 RCTs with 207-648 patients.
– Corticosteroid (triamcinolone 20-40mg mostly, then
methylprednisolone 40-120mg & others) vs placebo injections.
• Pain: Using 100 point Visual analog scale, ~54 baseline,4
Steroids reduced pain more than placebo:
– 21-22 points lower at one week,1,2 16.5 points lower at two weeks,3
7.4 points at 3-4 weeks1
• Average ~15 points better between 1-4 weeks4
• Maximal effect may occur at 1.5 weeks4
–
At later time points, difference is non-statistically significant1
– Compared to baseline, pain was reduced 29 points at 3 months.5
1. Can Fam Physician. 2004;50:241-8. 2. Cochrane. 2006;2:CD005328. 3. BMJ. 2004;328:869. 4. Eur J Pain.
2007;11:125-38. 5. Ann Intern Med. 2015;162:46-54. 6. J Am Acad Orthop Surg. 2009;17:638-46.
Opioids
• Sys Rev: 22
RCTs1
(8275 pts) (publication bias)
– Pain: SMD 0.28 (0.20-0.35), 0.7/10
– Function: SMD 0.26 (0.17-0.35), 0.6/10, NNT ~10-12
– AE: Oxycodone (e.g.): Any AE: 87% vs 52%, NNH 3
• Withdrawal due to AE: 32% vs 6%, NNH 4
• 18 RCT2, 4856 pts, (12 wks), SMD 0.58 (0.52-0.64)
– Opioid sub-groups: Strong 0.69 vs weak 0.52
– Withdrawal rates = 7% Placebo, 19% weak opioids
(NNH=9), 31% strong opioids (NNH 5)
– Increased withdrawal confirmed by others.3
• 6 RCTs (1057 pts),4 10.5 /100
1. Cochrane 2014; 9: CD003115. 2. OsteoArthritis & Cartilage 2007;15:957-965
3. Schmerz. 2011;25(3):296-3053. 4. European J of Pain 2007; 11:125–138
Platelet Rich Plasma Injections
Steroid Injection (knee) for OA
• Pain: Reaching pain target or global improvement
– 74-78% steroid vs 45-54% placebo:1-3 NNT 3-5, at 1-4 weeks.1-3
– Results at >4weeks inconsistent: 2 no effect,1,2 one reports NNT 5 at
16-24 weeks.3
• Function and stiffness not reliably changed.5
• Sensitivity mostly unclear (e.g. if steroids vary7) but maybe
– Worse radiographic severity ≈ reduced effectiveness8
– Higher clinical severity ≈ improve effectiveness8
• Joint infection 1/14,000-77,000 with intra-articular injection9
• Maximum frequency ~4/year.10
– RCT injected steroids 4x/year for two years without any harms.
– Cohort of ≥4 injections/year found no harm.
1. Can Fam Physician 2004;50 241-8. 2. Cochrane 2006;(2) CD005328. 3. BMJ 2004;328(7444) 869. 4. Eur J Pain
2007;11 125-38. 5. Ann Intern Med 2015;162 46-54. 6. J Am Acad Orthop Surg 2009;17 638-46. 7. Clin Rheumatol
2014;33 1695-706. 8. Rheumatology 2013;52 1022-32. 9. Am Fam Physician. 2014;90 115-6. 10. TFP
Opioids (Tramadol)
• Tramadol, Sys rev: 11 RCTs, (1939 pts)
– Pain Scale: 8.5 better out of 100.
– Pain (% ≥Mod Improve): RR 1.37 (1.22-1.55),
71%% vs 51%, NNT 5
– Adverse Events: minor 20% vs 8%, NNH 9
• Withdrawal due to AE: 28% vs 12%, NNH 7
• Bottom-Line: Opioids work, NNT ~5-10 but
it’s similar to NSAID and lots of adverse
events (NNH 5-10)
Cochrane 2006; 3: CD005522.
Miscellaneous 1
• 5 sys revs of 2-6 RCTs (257-609 pts).1-5 Best5:
– 50% pain reduction: 43.8% PRP vs 19.3%, NNT 5
– Pain: SMD 0.53 (0.28-0.77) & Function: 1.24 out of 25.
• Highest quality RCT (176 pts) in Meta.6
– At 6 months, 14 outcomes, 1 statistically significant:
– 50% pain reduction: 38.2% PRP vs 24.1% HA, NNT 8
• New Largest, well designed RCT7 with 192 pts
– 33 outcomes (11 outcomes at 2, 6 12 months): No diff.
• Bottom-Line: Likely not effective.
1. Arthroscopy. 2013;29:2037-48. 2. Knee Surg Sports Traumatol Arthrosc. 2013 Nov 26. [Epub ahead of print]
3. Arch Phys Med Rehabil. 2014;95:562-75. 4. PM R. 2015;7:637-648. 5. Br J Sports Med. 2015;49:657-72.
6. Arthroscopy. 2012;28:1070-8. 7. Am J Sports Med 2015 43: 1575
• Acupuncture: 16 RCTs (3498 pts), For pain,
– Vs Sham: SMD 0.28 (0.11-0.45) ≈ 4.5mm out of 100mm.
– Better trials (e.g. good blinding): even less effect
• Ultrasound: 5 RCTs (341 pts), For Pain
– SMD 0.49 (0.23-0.76) ≈ 12 out of 100
– Unreliable: poor quality RCTs (Mean score 0.8 / 8)
• Thermal Therapy: 3 RCTs (179 pts)
– Unreliable: poor, small, diff outcomes (?quad strength)
Cochrane 2010;1:CD001977. Cochrane 2010;1:CD003132. Cochrane 2003;4:CD004522.
G. Michael Allan
Miscellaneous 2
• Transcutaneous electrostimulation:18 RCT (813 pts)
– Pain SMD 0.86 (0.49-1.23); 2.1 / 10
– Poor quality (1.4/8) & bigger studies, SMD = 0.07
• Electromagnetic Field Therapy: 9 RCTs (636pts)
– Pain: 15.1/100 but Function & Quality of Life: No diff
• Braces & Orthoses (insole): 13 RCTs (1356 pts)
– Knee brace: At 12 months, no effect (more quit with brace
due to lack of effect). Shorter, some mixed benefit
– Lateral Wedge Insoles: no effect
1. Cochrane 2009; 4: CD002823. 2. Cochrane 2013; 12: CD003523 3. Cochrane 2015;3:CD004020.
Miscellaneous Summary
•
•
•
•
No: acupuncture, joint lavage, braces or insoles
Very unlikely: Ultrasound, thermal, TENS
Unlikely: Diacerein, ginger.
Maybe (?): electromagnetic field therapy.
Miscellaneous 3
• Diacerein (10 RCTs, 2210 pts): Natural Health Prod2
– Anthraquinone synthesized, interferes with interleukin- 1,
– Pain VAS 8.6mm (1.7-15.6) & Function not sign
– Diarrhea = 37.3% vs 10.2% (NNH 4).
• Ginger: 5 RCTs (757 patients) on 500-1000/d
– Pain SMD 0.30 (0.09-0.50) but allocation concealment:
Yes SMD 0.14 vs unclear SMD 0.42
– Withdrawal due to AE: NNH 15 (Mostly bad taste & GI
upset)
• Joint Lavage: 7 RCTs with 567 patients
– Pain SMD 0.11 (-0.21-0.42) = 3mm to 100mm
– Function SMD 0.10 (-0.11-0.30) = 2mm to 100mm
1. Osteoarthritis Cartilage. 2015;23:13-21. 2. Cochrane. 2010;5:CD007320. 3. Cochrane 2014;2:CD005117.
American Academy of Orthopedic Surgeons CPG
Strong recommendations For
Moderate Recommendations For
Activity.
Weight loss (if BMI >25)*
NSAIDs & Tramadol
Inconclusive Recommendation
Electrotherapeutic modalities
Manual Therapy
Unloader type braces.
Acetaminophen, Opioids, Patches
• Overall: None, at least yet.
Intra-articular corticosteroids
Articular growth factor/plasma-rich protein
• Two Promising therapies based on single RCTs:
Strong Recommendations Against Moderate Recommendations Against
– Prednisone 7.5 mg OD x 6 weeks (lasts 6 more weeks)
– Methotrexate 10-25mg OD x 12 weeks.
J Rheumatol 2014;41;53-59. Ann Rheum Dis. 2014 Mar 27. doi: 10.1136/annrheumdis-2013-204856.
Acupuncture.
Lateral Wedge Insoles
Glucosamine or Chondroitin
Needle Lavage
Hyaluronic
* Insufficient evidence to support: Open Rheumatol J. 2014;8 89-95.
Jason Crookham
Faculty/Presenter: Jason Crookham DO CCFP(SEM) Concussions and what to do when you “bang you head”.
Jason Crookham DO CCFP(SEM) Clinical Instructor UBC
None
Potential for conflict(s) of interest:
None
None
None
1. Describe signs, symptoms and pathophysiology
of concussion
2. Be aware of consensus statement and
management guidelines for concussion
3. Understand the therapeutic goals of concussion
management and limitations of guidelines
4th International Consensus Conference on Concussion in Sport
Zurich, Switzerland
November 1‐2nd, 2012. TRAUMATIC BRAIN INJURY
Glasgow Coma Sca e
5th International Consensus Conference on Concussion in Sport
Berlin, Germany
October 26‐27th, 2016. “Minimal”
Mild
?
Sports concussion
Mod
Severe
Jason Crookham
DEFINITION
INJURY DEFINITION: SPORTS CONCUSSION
1.
Concussion may be caused either by a direct blow to the head,
face, neck or elsewhere on the body with an ‘‘impulsive’’ force
transmitted to the head.
2.
Concussion typically results in the rapid onset of short- lived
impairment of neurologic function that resolves spontaneously.
However in some cases symptoms and signs may evolve over a
number of minutes to hours.
3.
Concussion may result in neuropathological changes but the
acute clinical symptoms largely reflect a functional disturbance
rather than a structural injury and as such, no abnormality is
seen on standard structural neuroimaging studies.
4.
Concussion results in a graded set of clinical symptoms that may
or may not involve loss of consciousness. Resolution of the
clinical and cognitive symptoms typically follows a sequential
course. However it is important to note that in some cases,
post-concussive symptoms may be prolonged.
“Concussion is a brain injury and is defined as a
complex pathophysiological process affecting the
brain, induced by biomechanical forces. Several
common features that incorporate clinical,
pathologic and biomechanical injury constructs that
may be utilized in defining the nature of a concussive
head injury include…”
DETAILED CLINICAL ASSESSMENT
OUTLINED IN SCAT3 AND CHILD SCAT3
NOTE Develop d by CAT3 Subcommittee (M
verson, Johnston McC
GRADUATED RTP PROTOCOL
Rehabilitation stage
Functional exercise at each stage of rehabilitation
Objective of each stage
1 No activity
Symptom limited physical and cognitive rest
Recovery
2 Light aerobic exercise
Walking, swimming or stationary cycling keeping
intensity < 70% MPHR
No resistance training
Increase HR
3 Sport-specific exercise
Skating drills in ice hockey, running drills in soccer No
head impact activities
Add movement
4 Non-contact training drills
Progression to more complex training drills e g
passing drills in football and ice hockey
May start progressive resistance training
Exercise, coordination, and cognitive
load
5 Full contact practice
Following medical clearance participate in normal
training activities
Restore confidence and assess
functional skills by coaching staff
6 Return to play
Normal game play
• 24 hours per step (therefore about 1 week for full protocol)
• If recurrence of symptoms at any stage, return to previous asymptomatic level and
resume after further 24 hr period of rest
uwisse, McCrory, Dvorak Echemendia, Guskiew
Putukian, Raftery, Schneider)
SAME DAY RETURN TO PLAY?
• Unanimously agreed that no RTP should occur
on the day of concussive injury
Jason Crookham
ON-FIELD OR SIDELINE EVALUATION OF ACUTE
CONCUSSION-WHEN A PLAYER SHOWS ANY
FEATURES OF A CONCUSSION
• The player should be evaluated by a physician or other licensed healthcare
provider onsite using standard emergency management principles and
particular attention should be given to excluding a cervical spine injury.
• The appropriate disposition of the player must be determined by the
treating healthcare provider in a timely manner. If no healthcare provider
is available the player should be safely removed from practice or play and
urgent referral to a physician arranged.
• Once the first aid issues are addressed an assessment of the concussive
injury should be made using the SCAT3 or other sideline assessment tools.
Dilemmas in Concussion
Management
•
•
•
•
On field evaluation
In office evaluation
Follow-up
Late Follow-up
• The player should not be left alone following the injury and serial
monitoring for deterioration is essential over the initial few hours
following injury.
• A player with diagnosed concussion should not be allowed to return to play
on the day of injury.
On Field Evaluation
• Witness / injury
report
• SCAT-3
• Monitor for symptoms
• Thinking/Rememberi
ng
• Physical
• Emotional
• Physical / mental rest
48 hours
In Office Evaluation
• Symptom severity
• SCAT 3
• Evaluate for
symptoms better
explanted by
alternative causes
• Introduce Return to
Play guideline
MANAGEMENT
• CORNERSTONE = initial period of rest until
acute symptoms resolve
 Physical Rest
 No training, playing, exercise, weights
 Beware of exertion with activities of daily living
 Cognitive Rest
 No television, extensive reading, video games?
 Caution re: daytime sleep
MANAGEMENT
• Expect gradual resolution within 7-10
days
• Gradual return to school and social
activities that does not result in
significant exacerbation of symptoms
• Proceed through step-wise return to sport
/ play (RTP) strategy
Jason Crookham
2 week follow up
3 month follow up
• Symptom evaluation
• Consider referral to
concussion specialist
• Consider
multidisciplinary team
• Consider specific
symptom
management
• Discuss “significant
exacerbation of
symptoms”
SCAT3 – 4 PAGE LAYOUT
4. Patient
Information
2. Scoring
3. Instructions
1. Sideline
Assessment
Jason Crookham
Mike Kolber
•  Faculty/Presenter(s): Michael Kolber
•  Rela:onships with commercial interests:
“Lice Lice Baby”
–  Pay from University of Alberta and Alberta Health
•  Research and Speaking Fees
Mike Kolber MD, CCFP MSc
University of Alberta Department of
Family Medicine
Winter 2015-‐16
Lice Learning ObjecSves
•  AWer the session, delegates should be able to:
–  Understand epidemiology / transmission of lice
–  Understand how to diagnose lice
–  Learn why older tradiSonal treatments fail and
potenSally more efficacious treatment opSons
–  Explain reasons for failure of therapy
–  Non-‐Profit Sources (Alberta College of Family Physicians,
Towards OpSmized PracSce)
–  No funding from industry
What is Head Lice?
•  6 leg parasiSc insect found on human head
•  Live louse = ½ size of match head
–  Nit (egg) = size of sesame seed
•  AcSve lice, nits: < 5mm from scalp on hair shaW:
(survive on blood: close to food source)
–  Nits >1 cm from scalp = non-‐viable
•  Most developed countries: < 10 per infestaSon
•  Lives only on humans: < 48 hours off host
•  Do not spread diseases
Centers for Disease Control and PrevenSon; 2015.
www.cdc.gov/parasites/lice/head
Lice Epidemiology
•  Found world wide: irrespecSve of:
–  Socioeconomic climate,1,2 cleanliness1
–  Low SE status à ↑ risk of treatment failure
•  Common: ~1 million cases / year CAN
•  Predominantly: Day care, school aged children3
–  5-‐20% of school kids have lice at any Sme4,5
•  Girls > boys: longer hair and sharing
combs6
1Pediatrics 2015;135;e1355-‐65, 2Emerg Infect Dis 2008;14(9) 1493-‐4.
3Center for Disease Control and PrevenSon 2015 available at
www.cdc.gov/parasites/lice/head/treatment.html.
Lice Transmission
Yes -‐ able to transmit
No – Cannot Transmit
•  Sleeping in same bed
•  InSmate play
•  Sharing combs, hats, toques
•  From your dog / cat
•  From non-‐inSmate play
(they do not fly)
•  Toilet seat
Pillows of infected paSents
have live lice 4% of Sme2
Pediatrics 2015;135(5) e1355-‐65. 2Interna2onal Journal of Dermatology 2003,
42, 626–629
Mike Kolber
2 days to mate
Lice Symptoms
•  Many asymptomaSc
•  Scalp itch
Treatment #1
Adult
Female
Louse
–  especially behind ears, worse at night
–  ReacSon to louse saliva in bite (anScoagulant)1
•  Scalp impeSgo à think fungal or lice
Lay eggs
(5-‐10/day)
8-‐9 days
10 days
Treatment #2
Eggs
Hatch
Only mate once (stores sperm)
Untreated, cycle repeats every 21 days
One lice live span 30 days
Pediatrics 2015;135(5) e1355-‐65.
Diagnosing Lice
Teaching Point #1: Only when see live louse
TreaSng Lice: SystemaSc Review
•  Only 20% with nits à acSve lice1
•  Wet combing à superior to visual inspecSon2
–  300 children: 100 had lice (21) or nits (79)
–  21 lice: 6 found via inspecSon, 19 w wet combing
•  Other studies; wet combing 3-‐4 Smes more
likely and 2xs as fast to find lice3,4
Teaching Point #2: Use wet combing to diagnose
1Pediatrics 2001;107 1011-‐5, 2Arch Dermatol 2009;145(3) 309-‐13. 3Epidemiol Infect.
(2008), 136, 1425. 4Pediatric Dermatology Vol. 18 No. 1 9–12, 2001
Treatment Principles
•  Treat only those with live lice
–  Check household contacts /schoolmates when cases
•  Most treatments: topical and OTC
•  Pediculicide (kills lice) but not ovicidal (eggs) à
repeat in 9 days (when eggs hatch)
•  AEs: skin and eye irritant
•  Do not use condiSoner before /aWer treatment
(may ↓ treatment effecSveness)
Ideal Treatment Product
• 
• 
• 
• 
1 applicaSon
Kills louse + nits
No Adverse Effects
Minimal cost
Mike Kolber
Issues with TradiSonal Pediculicides
•  Resistance:
–  98% N. American have genes for resistance to classic
pediculicides
–  Likely why pediculicide studies show ↓ efficacy
•  Need 2 applicaSons
•  Neurotoxin = chemical: “I want natural treatment”
Lice Treatments CANADA 2016
Class
Names
Mechanism
Applica:on
Pros and Cons
Cost
Combing +
Picking
Bug Buster
LiceMeister
Mechanical
Removal
Q 3-‐4 days x 2
weeks
No chemicals
Less effecSve
$
Permethrin Nix, Kwellada Neurotoxic
Leave 10 min
rinse off.
REPEAT 7-‐10 d
Resistance
$$
CI ragweed allergy,
Approved 2 month old
Pyrethrins
R&C
Neurotoxic
Leave 10 min
rinse off.
REPEAT 7-‐10 d
Resistance
$$
Approved > 2 years old
Silicone
DimeScone
Nyda 4%
Hydrin 92%
“suffocates”
Leave x 30 min,
comb then
rinse in 8 hours
High efficacy, ovicidal
Flammable at high %
Silicone-‐
like
Isopropyl
myristrate
(Resultz)
Dissolves
Exoskeleton
2-‐3 applicaSons
7 days apart
Appears beyer than
$$
tradiSonal pediculicide
Use in ≥ 4 years old
$$
J Med Entomol 2014;51 450-‐7.
Price Comparisons of Commonly Prescribed PharmaceuScals Alberta 2016
“Bug BusSng” (Wet Combing)
Not Available, Too Toxic or Too Costly
Product
Reasons to not use
Lindane
AEs (neurotoxicity, marrow suppression, lymphoma)
Banned for agriculture, removed US and CAN1
Malathion (Ovide)
Not available in CAN, organophosphate pesScide
Septra
AnSbioSc stewardship, Stevens Johnson Syndrome
Pyrethrins + piperonyl
butoxide (RID)
Not available in CAN
IvermecSn (oral)
Unavailable in CAN for lice unless Special Access, neurotoxic if
use in < 15kg children, pregnant mothers, cost
IvermecSn (topical)
Cost (200$ / 60 grams), indicated for rosacea
Mobile Heat Units
Unavailable in CAN, cost
1. 
2.
3. 
4. 
Shampoo
CondiSoner and comb wet hair (detangle)
Lice comb: base of hair shaWs
Wipe off comb (lice) at every pass
1Lancet
Oncology 2015, doi.org/10.1016/ S1470-‐2045(15)00081-‐9
CFP 2012; 58 840, N Engl J Med 2010;362 896-‐905, CADTH 2010,
Clinical Evidence 2010 Pediatrics 2006 118 1963
Bug BusSng vs Pediculicides
• 
• 
• 
• 
RCT BB vs malathion or permethrin: 133 UK kids
BB treatment: q 3 days x 12 days, pediculicide once
Cure: 52% BB vs 13% (ARD = 39%, NNT = 3)
Issues:
–  Inadequate comparator: pediculicide once
–  Differing baseline: age, previous infestaSons
–  DifferenSal FU: day 5 pediculicide vs day 15 BB
BMJ 2005; doi:10.1136
Other Bug BusSng Studies
RCT 74 UK children (70% ♀)
•  BB (4xs in 2 weeks) vs malathion (repeated once)
•  Quality: AC, blinded, PP analysis
7 day cure: BB 38% vs 78% malathion: NNH= 3
•  Issues: detecSon based on dry hair inspecSon
Conclusion: Bug Bus:ng Less Efficacious than Pediculicide
Lancet 2000; 356: 540
Mike Kolber
Wet combing added to Pediculicide
•  95 US paSents (kids + adults), all treated w 1%
permethrin (most repeat @ day 8)
•  Randomized to adjunct combing (or not)
•  Day 15 cure: 78% vs 73% combing (NSS)
•  Issues: lice diagnosis: dry or “wet rinsing”
–  Some state “need plasSc (not metal) comb”
J Pediatr 2002; 141 665
DimeScone Evidence
Products
Popula:on
Outcome
No Lice
Results
NNT
DimeScone 4% vs
Malathion 0.5%
(repeated 1 week)1
73 UK aged 1-‐48)
Day 9 AND 14
Dime:cone 70%
Malathion 33%
3
DimeScone 92% vs
Permethrin 1%
(repeated 1 week)2
145 Brazilian children Day 9
Dime:cone 97%
Permethrin 68%
4
DimeScone 4% (once)
Permethrin 1%
(repeated 1 week)3
90 UK children and
adults
Day 9
Dime:cone 80%
Permethrin 36%
3
DimeScone 4%
Phenothrin 0.5%
(repeated 1 week)4
253 UK peds / adults
66% with lice > 3/12
and 50% > 1 year
Day 9 AND 14
DimeScone 70%
Phenothrin 75%
NSS
DimeScone 100%
(cohort study)5
58 US children
Day 14
Dime:cone 97%
NA
1PLoS
ONE 2007; 2: e1127, 2BMC Inf Dis 2008; 8:115, 3BMC Derm 2013;13:5, 4BMJ 2005; 330: 1423 5BMC
Pediatrics 2015; 15:70
DimeScone (Nyda)
Product Monograph
•  Avoid in pregnant women, ok > 2 years
•  Leave x 30 minutes, comb, then let dry
overnight
•  Repeat in 8-‐10 days
•  PotenSally Flammable
Results for Resultz (Isopropyl myristate)
Products
Popula:on
Outcome
Lice Free
Results
NNT
IPM (1-‐3xs 7 days apart)
RID (pyrethrin) 2-‐3xs
(43% used IPM 3 Smes)1
60 paSents
Florida
Day 21
40% IPM
17% RID
5
IPM /cyclomethicone (Full
Marks) vs Permethrin 1%
Each given twice2
168 UK
Day 14
(mostly kids)
82% IPM
19% RID
2
IPM vs Malathion
Each given 3 Smes3
216 kids
54% IPM
42% malathion
NSS
Day 21
Resultz appears superior to pyrethrins / Permethrin
G. Pohl-‐Boskamp GmbH & Co. KG. Product Monograph NYDA DimeScone
100 cSt SoluSon, 50% w/w. September 11, 2012
Approach to Treatment Failures
1.  RepeaSng treatment < 8-‐10 days:
-‐ ie. prior to nits (eggs) hatching)
2. Hair condiSoner use: prevents tx from adhering
3. Pediculicide resistance:
-‐ if suspect resistance à try different product
4. Re-‐infestaSon from close contact
J Cutaneous Medicine Surgery; 2007; 161,
2Pharma J 2009;280 371–375, Clinical Evidence 2015; 01 1703
3Australasian J of Derm (2010) 51, 175–182
What about the clothes, bed sheets?
•  Lice can only survive off scalp ~2 days
–  Only deal with clothes / linens from last 2 days
•  Wash clothes and linens in hot water and dry
hot [or dry clean]
•  For un-‐washables: plasSc bag for 2 weeks
(freeze not necessary)
–  lice / eggs will die (no food source)
Int J Dermatol 2003;42(8) 626, CDC 2015
CDC 2015, J Med Entomol 2014; 51 450-‐7, CFP 2016; 62 (4) 322
Mike Kolber
No-‐nit is Non-‐sense
•  Only 20% eggs à acSve lice
•  No nits = many days off school for no reason
•  Should replace no nits with:
–  “please ensure child treated before coming back”
Pediatrics 2001;107(5) 1011-‐5.
Lice Summary
•  5-‐20% school children have lice
•  Only treat live lice (diagnosis by wet combing)
•  Resistance to tradiSonal tx common
–  Consider: dimeScone, isopropyl myristate
•  Wash clothes, linens from last 48 hours
•  Put non-‐washables in plasSc bag x 2 weeks
•  Tx failures: retreat aWer 9 days, avoid condiSoners,
look for re-‐infestaSon, try different product
Tina Korownyk
Male and Female Sexual Dysfunction
can we create “Paradise By the Dashboard Light?”
• Faculty/Presenter: Tina Korownyk
• Relationships with commercial interests: None
– Grants/Research Support: – Speakers Bureau/Honoraria:
– Consulting Fees: – Other:
Tina Korownyk
• This program has received financial support from University of Alberta in the form of my salary
• This program has received in‐kind support from BS Medicine in the form of travel & accommodation in order to attend this conference.
• I will not let BS Medicine influence my thinking
• Potential for conflict(s) of interest: None
Be aware of effectiveness of various pharmacologic interventions in male & female sexual dysfunction
Increase awareness of possible effects on sexual function of commonly used drugs Can alcohol contribute to poor choices in sex?
• Meta‐analysis of 12 observational studies. • Adjusted analysis: – linear relationship: Alcohol & unprotected sex
– Each 0.1 blood alcohol level = ~3% increase in unprotected sex. • Bottom‐Line: Country says it best
• “I Ain't Never Gone To Bed With An Ugly Man, But I Sure Woke Up With a Few”
Addiction. 2012 Jan;107(1):51‐9. Tina Korownyk
PDE 5 Inhibitors for Erectile Dysfunction
A “Hyposexuality Crisis?”
• Variable incidence of “sexual dysfunction” cited
– 9‐43%1
– Highest values from papers2 with probable conflicts of interest3,4
• 283 College students assessed how frequently they think about sex6:
• The market for a drug that enhances female sexual desire has been to be worth up to $2bn in the U.S.5 (3.2 billion for men by 2019)
(Headache, flushing, runny nose)
Duration
Cost/4 tabs
Sildenafil (Viagra) 100mg
30‐60 mins
4‐5 hours
$50
Tadalafil (Cialis) 20mg
35‐45 mins
24‐36 hours
$80
g
Vardenafil (Levitra) 20mg
30‐60 mins
4‐5 hours
$75
Vardena il (Staxyn) 10 mg
bli
l)
30 60 mins
5 hou s
$43
http://www.health.harvard.edu/mens‐health/which‐drug‐for‐erectile‐dysfunction
Its not the same for females
(Sildenafil)
Efficacy of PDE 5 Inhibitors for ED
NNT = 3‐4
NNH = 5
Onset
) – Males Median 19x/day (Range 1‐388)
– Females 10x/day (Range 1‐140)
1) NEJM 2008;359(19) 2005‐2017. 2) JAMA. 1999;281(6) 537‐44) 3) Spinal Cord. 2011;49(2) 273‐9. 4) J Sex Med. 2009;8 2143‐53. 5) BMJ 2010;341:c5701 6) J Sex Res. 2012 49(1) 69‐77.
Medication
•
•
•
•
2002 RCT1
781pts, FSAD, 4 wk run‐in, PP analysis Pre & postmenopausal women
No difference for any end point
– (two GEQ, sexual event log, the LSC, and the SFQ) • Main AE were headache, flushing, rhinitis, nausea, visual disturbances, and dyspepsia
1) J Womens Health Gend Based Med. 2002;11(4):367‐77.
1) Eur Urol. 2015 Oct 68(4) 674‐80.2 2) Indian J Endocrinol Metab. 2015 Jul‐Aug 19(4) 451‐61
Success in obtaining FDA approval for Female Sexual Dysfunction 1
– 1994 efforts for sildenafil abandoned
– 2004 testosterone patch failed to win approval due to safety concerns.
– 2010 flibanserin withdrawn from development
Leonore Tiefer, associate clinical professor of psychiatry at New York University School of Medicine and Albert Einstein College of Medicine
BMJ 2010;341:c5701
Tina Korownyk
Drugs that Affect Female (and male) Sexual Desire?
Flirting with Flibanserin
• FDA Approved for HSDD Aug 2015 : Previously Rejected 3x – 2 Early RCTS =  satisfying sexual events ~0 8/mo, no  desire
– 2013 RCTs: monthly desire  0 3 out of 6 – Excluded all women taking benzos, sleep aids, narcotics…
SSRIs1
– 13%‐76% report sexual dysfunction
• Any A/E NNH 6, Dizziness 14, Somnolence 15, Nausea 20, Fatigue 42, Serious A/E 100‐334, Syncope 500
• Risks ?worse with Etoh, CYP3A4 inhibitors (OCPs, fluconazole)
Oral Contraceptives2
• 2013 Systematic Review, 36 studies (6 rcts)
– At least one death from Etoh poisoning
– Etoh interaction study =25 healthy volunteers (23 men), – 22% reported increase in desire
– 15% reported decrease in desire
– 64% no change
• 3 more requested by FDA
• Bottom‐Line: 5% change in desire and <1 additional “satisfying” sexual event in 30 days for frequent adverse events.
1) J Psychopharmacol. 2010 Apr 24(4) 489‐96 2) Eur J Contracept Reprod Health Care. 2013 Feb 18(1) 27‐43
Strategies for managing antidepressant induced sexual dysfunction
• Cochrane Sys Review, 23 RCTs, 1886 pts1
• 22 added medications, 1 switched
• Medications that demonstrated benefit:
– Sildenafil (3 rcts)
– Tadalafil (1 rct)
– Buproprion 150mg bid (3 rcts)2
• Unclear effect
– Buproprion150mg qd (2 rcts)
– Switching antidepressants
• Estimates of effect could be affected by unpublished trials
Cochrane Database Syst Rev. 2013 May 31 5:CD003382 2) J Psychopharmacol. 2011 Mar 25(3):370‐8. Do Oral Contraceptives Impact Sexual Function?
• 2612 online questionnaires, female medical students ≤ 30 yrs in German, Austria and Switzerland
• Using FSFI score 26.55 for “at risk sexual dysfunction”:
–
–
–
–
54% using nothing
37% oral hormonal contraceptives
31% non‐oral hormone contraceptives 27% non hormonal contraceptives
• No significant difference in scores for EE doses or progestins
Arch Gynecol Obstet (2015) 292 883–890 Buproprion for Female Sexual Dysfunction?
• 232 women, 29 yrs, HSDD. All failed at least one other tx
– Buproprion SR 150mg/d vs placebo x 12 weeks. • Findings: Significant improvement with buproprion
– 65.3% buproprion responded ‘Definitely yes’ to Global efficacy question vs 4.3% placebo (p=0.001)
– 71.8% in buproprion were definitely satisfied with tx vs 3.7% placebo (p=0.001)
• Limits: One “specialty” site in Iran, + exclusion criteria
• Comments: Impressive numbers, however definite limitations. Most common A/E was headache. • Improvement in some outcomes supported by other trials2 • Side efffects of buproprion may outweigh benefits.
1) BJU Int. 2010 Feb 11. [Epub ahead of print] 2) (J Clin Psychopharmacol 2004;24:339–342) Systematic Review ‐ RCTs
RCTs
Graham
1992
Women seeking help for PMS
Oranratanaphan
2006
OC vs placebo
Placebo
Sexual Desire
YES
Decrease
~15‐20 points VAS over placebo
2 difference OC
NO
Increase
FSFI*
2 different OC
NO
Increase
Increase FSFI from ~29 to 30
Women sterilized COC vs progestin
vs placebo
YES
Decrease
Edinburgh consistent in all measures, trend for Manila
Sabatini
2006
Women in need of OC
2 different OC, vaginal ring
NO
Mean not reported**
40% reported decrease in desire with OC, 12% with VR
Caruso
2011
159 women seeking OCs
2 different OC
NO
Improved in newer OC
SPEQ 0.5 points
Redmond 1999
Re‐analysis of RCT for acne
OC vs Placebo
YES
No effect
Not an outcome of the study
Strufaldi
2010
Women in 1 yr
relationship wanting OC
Graham 1995
Eur J Contracept Reprod Health Care. 2013 Feb 18(1):27‐43
Tina Korownyk
Change in Sexual Interest Scores for OC and Placebo
Is one better than another?
A circular argument
Depends on where you read:
• Vaginal ring better1
• Ultra‐low estrogen (EE < 20μg) reduces sexual desire more than higher estrogen (EE ≥20 μ g)2.
• Post hoc analysis3 CHOICE study
– Biggest risk: depo‐provera, vaginal ring, implant (~30% lacked interest in sex)
– Industry study by makers of OCP, no placebo
J Sex Med 2014;11 471–480 2) Eur J Contracept Reprod Health Care. 2013 Feb 18(1) 27‐43 3) Obstet Gynecol. 2016 Mar 127(3) 563‐72. Psychoneuroendocrinology. 1993 18(4):273‐81
What about Side Effects of 5‐ARIs?
NNH
Decreased Libido
181 ‐ 1673
Erectile Dysfunction
111 ‐ 2003
Ejaculatory Dysfunction
81 ‐ 1673
Composite Cardiac Failure
334 (one trial)*
Gynecomastia
Case reports
Systematic review
NNH
Bottom Line
822
No strong evidence of one being superior. Industry funded papers each cite their drug has less s/es
1) CMAJ. 1996 Nov 1;155(9):1251‐9. 2) Arch Dermatol. 2010 Oct;146(10):1141‐50. 3) J Am Acad Dermatol 1998;39:578‐89. 4) Review of s/es The Dark Side of 5α‐reductase inhibitors’ therapy: Korean J Urol. 2014 Jun;55(6):367‐79
James McCormack
Moisturizers
JamesMcCormack
Norela/onshipswithcommercialinterests
James McCormack, BSc (Pharm), PharmD
Professor
Faculty of Pharmaceutical Sciences, UBC, Vancouver, BC
LearningOutcomeObjec1veSlide
Tobeabletorecommendanevidence-basedmoisturizer
"Preservation of a youthful complexion has been the
goal of aging humans for thousands of years"
Ann Intern Med 2013;158:781-90
289 ads
variety of claims - superiority, scientific,
performance, subjective
OVERALL
Vague 42%
Omission 17%
False 23%
Acceptable 18%
J Glob Fas Mark 2015:6:194-206
James McCormack
AGE and SUN
Most (90%+) changes associated
with skin aging are due to
photoaging from sun exposure
and chronologic aging
•
•
•
•
•
Unregulated terms
These terms can
mean
ANYTHING
or
NOTHING
AT ALL
Dermatologist recommended
Clinically proven
Hypoallergenic
Non-comedogenic
Alcohol-free
24-hour anything
Non-irritating
Repairing
Detoxifying
Contouring
Healing
Dermatologist tested
Dermatologist approved
Proven formula
Chemical free
FDA has no authority to require companies to test
cosmetic products for safety
most cosmetic marketing claims are unregulated, and
companies are rarely, if ever, required to back them up,
even for children’s products
companies are allowed to leave some chemical
ingredients off product labels
“Fragrance” may include any number of the industry’s
3,100 stock chemicals
FDA does not have the resources or authority for premarket approval of cosmetic product labelling
Cosmetic Myths
creams designed for different body parts
expensive creams
hydrating serums
age reversing products
toners
body-firming products
sunscreen > 50 SPF
facial masks
Ingredients essential to all moisturizers
April 2012
7 creams studied
Garnier, L'Oreal Paris, Lancome Paris,
Olay, Aveeno, Neutrogena
August 2009
13 products studied
Nivea, L'Oreal, Simple Kind to Skin, Olay,
Dr Brandt, Logona, Clarins, Clinique,
StriVectin, Garnier, Boots, Avon, RoC
"After 6 weeks ...
no product
was even slightly
better than the rest,
including the control."
"Simple moisturiser
worked just as
well as more
expensive creams"
80% WATER
10-30% Oils/lipids/fats (emollients) Decreases Evaporation
Typically from plants and animals - PETROLATUM (petroleum
jelly), beeswax, lanolin, mineral oil, shea butter, cocoa butter,
olive oil, coconut oil, sesame oil, squalene
5% Emulsifiers - Allows Oils to Mix with
Water
Beeswax/borax, cetearyl alcohol, polysorbate 60, PEG-150
stearate, steareth-20, lecithin, glyceryl monostearate
0.5% Preservatives
Parabens, phenoxyethanol, MCI/MI
James McCormack
Other ingredients
5% Humectants - Attracts Water
GLYCEROL (glycerin), propylene glycol, butylene glycol,alpha-hydroxy
acids (glycolic acid, lactic acid), urea
1% Silicones
DIMETHICONE
2% Herbal extracts - Most Added with No
Clinical Evidence They Do Anything and often
the reason for allergic reactions
0.2% Fragrance - 100s used
Often the reason for allergic reactions
MOST IMPORTANT
INGREDIENT
Sunscreen!
INGREDIENTS
TOUTED AS
"Antiaging/
antiwrinkle”
retinoids
niacinamide
hyaluronic acid
alpha hydroxy acids
ceramides
Tretinoin overall
Wrinkles are
typically evaluated
(looking at just the doses that worked >0.01%)
APPLYING TO FACE
FOR 6 MONTHS
Retin-A
Avita
Altinac
Tretin-X
Refissa
Renova
Stieva-A
Airol
Atralin
People using
People using
THE ACTUAL
CREAM with TRETINOIN CREAM ALONE DIFFERENCE
using a 9 point scale
"Topical tretinoin
[Retin-A and others]
is considered
the GOLD standard
to treat photoaged skin"
Journal of Cosmetic Dermatology 2015;14:40-6
Average change
from using tretinoin
0.5-1.0
% OF PEOPLE IMPROVED
Investigator’s assessment
75%
40%
Patient’s assessment
85%
60%
Fine wrinkles
65%
35%
Coarse wrinkles
45%
25%
Uneven skin discolouration
70%
45%
35%
25%
30%
20%
25%
% OF PEOPLE HARMED
Redness
30%
5%
Scaling/dryness
55%
20%
Burning/stinging
30%
10%
25%
35%
20%
IN 6
MONTHS
ADAPTATION OF DATA FROM A COCHRANE REVIEW - NUMBERS ROUNDED OFF
Before and after images in adverts
Other “active” ingredients
PRESCRIPTION
tretinoin (Retin-A, Avita, Altinac, Tretin-X, Refissa, Stieva-A, Airol, Atralin)
isotretinoin (Isotrex)
Less well studied but
tazarotene (Tazorac, Avage, Zorac)
likely similar to tretinoin
adapalene (Differin)
NON-PRESCRIPTION - many OTC products
retinol
ceramide
Have less
retinol acetate
niacinamide
effect than
retinyl palmitate tretinoin but
glycolic acid
better tolerated
retinaldehyde
‘lactic acid
James McCormack
BEST EVIDENCE
A Randomised Trial
Any other type of study has too many limitations/biases
Does a cream actually
“WORK” for you?
1) Don’t look at any adverts for moisturizers
50 people
Preferably they aren’t told
which group they are in
2) Start by choosing an inexpensive moisturizer
50 people
PLUS an
“active ingredient
After 3-6 months objectively assess if there is a
difference in “wrinkles” between the groups
3) If you actually want an effect on wrinkles chose one
that contains ingredients shown in well-designed
studies to actually do something
4) Do a patch test - small amount - wait 24 hours and if
no reaction then continue to use it for a few weeks
ALMOST NO CREAMS HAVE THIS TYPE OF EVIDENCE
Does a cream actually
“WORK” for you?
5) If it contains an active ingredient use it very sparingly
at most once a day for a few weeks
6) If after a few weeks you like the way it makes your
skin feel, the texture, the fragrance - USE IT
7) Because even the GOLD standard treatments have
such a small effect you will never be able to
objectively assess the impact
Smiling is the best anti-aging “cream”
Try ones like these first
Are these the best? - no one knows.
But they contain reasonable ingredients.
Notice they come in BIG sizes
Dee Mangin
Dangerous Caring
How good medicines can be bad for your health and how to avoid it
Or: There is no “Black Or White” when it comes to drug interactions
•
Faculty/Presenter: Dee Mangin
•
– No funding gifts or food from drug or diagnostic industries
– Consulting Fees: I have occasionally provided expert witness reports for the plaintiff in class action legal cases taken against pharmaceutical companies. Any fees are donated to an independent patient drug side effect information and reporting website RxISK.org
Dee Mangin
David Braley Nancy Gordon Chair in Family Medicine
Learning objectives
• Understand the scope and importance of drug interaction issues
• Become familiar with some important drug interactions with medicines we prescribe commonly
• Be excited by the possibilities of sniffing out drug interactions
• Not be confused by any talk of enzymes, substrates, inhibitors and cytochromes
The invisible pandemic
• Hospitalisation from inappropriate medication use in older adults estimated at 17% • 70 000 admissions a year in Canada due to preventable drug adverse reactions • Adverse drug reactions 4‐6th most common cause of death (US)
• Rate goes up sharply with the number of drugs taken Breaking News
Prescribing in UTIs – dangerous?
• Cotrimoxazole associated with an increased risk of sudden death when combined with ACE inhibitors and angiotensin receptor blockers
• The mechanism is thought to be a sudden hyperkalemia
• There is also an increased risk when Cotrimoxazole is prescribed with spironolactone, thought to be the same mechanism
• A smaller but significant increased risk was also seen with ciprofloxacin in the ACE/ARB study. Mechanism unclear
• Effect was not seen with nitrofurantoin or norfloxacin
Dangerous Caring
This kills more people every year than
– Breast cancer
– Colon cancer
– Lung cancer
Dee Mangin
ADR Risks in polypharmacy
13% with the use of two medications
58% with five medications
82% with seven or more medications 7
[Patterson 2012]
1000 older adults
• Annual healthcare costs of ADR’s $65,631
• $27,365 of this associated with preventable events – that is $27 million for every million older adults in the community
• Common reason for medical misadventure claims
Reducing patient harms
• The “triple whammy” – ACEI + NSAID + diuretic
• Do you routinely warn your patients about over the counter NSAIDs?
Case One – Sarah, 28y
• Presents after a very odd weekend experience
— Agitation and restlessness
— Sweating, shivering, muscle twitching
— Headache, diarrhoea
• Previous MVA with severe head injury
• On venlafaxine (high dose) and carbamazepine
? What would you ask Sarah?
? What is the provisional diagnosis?
Dee Mangin
Serotonin Toxicity ‐
Is dose related and may include:
Serotonin Toxicity ‐
Is dose related and may include:
Neuromuscular effects
Autonomic effects
Mental status changes
Neuromuscular effects
Autonomic effects
Mental status changes
Hyperreflexia
Tachycardia
Agitation
Hyperreflexia
Tachycard a
Agitation
Clonus
Hyperthermia
Hypomania
Clonus
Myoclonus
Sweating
Anxiety
Myoclonus
Shivering
Flushing
Confusion
Shivering
OLDER ADULTS
Tremor
Mydriasis
Tremor
Mydriasis
Hypertonia/rigidity
[M
Hunter Serotonin Toxicity Criteria
Hypertonia/rigidity
Hypomania
Anxiety
Confusion
[
Drugs with potential for serotonin toxicity when used in combination
•
• SSRIs, SNRIs
•
• Some TCAs
•
• Opioids – especially tramadol
•
• Illicit substances
• Rizatriptan, sumatriptan
• OTC & complementary – St John’s Wort, cough mixtures
Lithium
MAOIs
Buspirone
Isoniazid
Isbister 2007
Case Two – Lucy, 21y • Presented 3/7 ago with skin infection, prescribed erythromycin
• Now feeling unwell – palpitations, light headed
What further information do you need?
What might have triggered this?
• Erythromycin 400mg, two twice daily
• Citalopram 40mg, once daily
Drugs associated with QT prolongation
Antimicrobials
Antidepressants Antipsychotics
Antiarrythmics
Methadone
Dee Mangin
[Owens 2006]
How is QT interval accurately measured?
[adapted from Heist 2005]
How often do you do an ECG prior to prescribing a QT prolonging drug? In at risk patients, assess QTc interval before and after starting/adding/increasing a medicine that may affect QT
The cardiac action potential [Owens 2006]
Drugs withdrawn due to QT prolongation and arrhythmias
• Sibutramine (2010)
• Cisapride (2000) Vanessas Law
• Terfenadine (2010)
Dee Mangin
We are high prescribers of antidepressants
• There is a global increase in antidepressant prescribing
• Most developed countries have prevalence rates of antidepressant prescribing of 10% or more
• One of the drivers of this growth is long term use
Potential for harm:
A year in the life of 18 Family Doctors
Macrolide scripts per Family Doc
Number of patients dispensed a macrolide already on one of the
following drug classes
SSRI/SNRI/ Mirtazapine
TCA‡
SSRI/SNRI/ Mirtazapine + TCA‡
24
21
8
10
1
18
18
14
16
17
6
22
6
11
15
12
1
5
14
5
3
6
6
5
2
5
5
1
9
1
0
2
2
0
2
5
2
0
0
0
1
1
3
3
1
1
1
0
0
0
0
107
82
30
61
31
194
100
64
139
67
25
162
28
36
69
49
14
Ted’s details
Case 3 – Ted, 55y
• Increasing general weakness over past 2 weeks
• Initially had numbness in his hands and difficulty getting dressed
• Fatigued ‐ was unable to walk further than next room
• Increasing unsteadiness and fallen once
What other information would you want?
• Long term conditions:
– Hypertension, hyperlipidaemia, asthma
• Medications: –
–
–
–
–
Cilazapril 5mg/day
‐ Bendrofluazide 5mg/day
Diltiazem CD 120mg/day ‐ Aspirin 100mg/day
Simvastatin 40mg/day
Fluticasone/salmeterol and salbutamol inhalers
Erythromycin (2 weeks prior) for chest infection • Physical exam:
– increasing weakness and numbness
– no specific muscle tenderness
Statin‐induced myopathy
• Uncommon with statins alone
– myalgia 2‐11%
– myositits 0.5%
– rhabdomyolysis < 0.1%
• Dose‐dependent adverse event
• BUT Increased risk if co‐prescribed with drugs that:
– are myotoxic (e.g. fibrates, colchicine)
– increase simvastatin plasma levels (e g. CYP3A4 inhibitors, diltiazem)
• Simvastatin (and atorvastatin) more likely to be affected by CYP3A4 inhibitors than pravastatin or rosuvastatin
Simvastatin‐induced myopathy
Avoid simvastatin with moderate/strong CYP3A4 inhibitors:
(Refer to NZ Formulary or Medsafe Data Sheet for a full list)
– Macrolide antibiotics ‐ erythromycin, clarithromycin
– Grapefruit – Azole antifungals ‐ itraconazole, fluconazole, ketoconazole, posaconazole, voriconazole
– Ciclosporin
– Protease inhibitors (HIV and Hep C antivirals) ‐ e.g. ritonavir
Reduce simvastatin dose with weak CYP3A4 inhibitors:
– Verapamil, diltiazem, amiodarone
– Monitor for muscle toxicity
Dee Mangin
What should you do in all 3 cases?
• Place a patient alert in Medication module How could Ted have been managed better?
• Report to Health Canada (patient can do this via www.rxisk.org which will populate a report form and also has a free interaction checker patients can use):
– If serious, unexpected, concerning, new medicine
– If in doubt, report it!
Consider query builders to look for at‐risk patients
Careful Combinations
There are some uncommon (but potentially life‐threatening) disorders that can occur with combinations of medicines we prescribe freely:
Take home messages (1)
Some uncommon (but life‐threatening) disorders can occur with certain common medicine combinations
• Serotonin toxicity
– High dose or combination serotonergic agents
• Serotonin toxicity
– High dose or combination serotonergic agents
• QT prolongation
– Usually dose related, many medicines associated
– Some patient factors may increase risk
• Myopathy/rhabdomyolysis with statin use
– Dose‐dependent – usually due to combination with medicines that
inhibit statin metabolism
Take home messages (2)
• The risks of polypharmacy can outweigh the benefits of
individual medicines
• A complete and current list of medications is important
• Patients may be taking other medicines
• From other prescribers
• Purchased Over The Counter
• Obtained for recreational use
• Make patients aware of risks of interactions and document
discussions – engage them in checking for interactions /
checking side effects / adverse event reporting
• QT prolongation
– Usually dose related, patient factors may increase risk
– Consider ECG in at risk patients
• Myopathy/rhabdomyolysis with statin use
– Dose‐dependent: usually due to combination with medicines that
inhibit statin metabolism
– Do not use potent CYP3A4 inhibitors with simvastatin
(e g. erythromycin, itraconazole, grapefruit)
G. Michael Allan
COPD Treatments:
“All I need is the Air that I Breathe”
G. Michael Allan
Professor, Department of Family Med, U of A
Director Evidence & CPD Program, ACFP
• Faculty/Presenter: G Michael Allan
–
–
–
–
Grants/Research Support None
Speakers Bureau/Honoraria None
Consulting Fees None
Other None
• N/A
We will review and learn about COPD treatment
• Refer to “Quick Tips” document.
1. Inhaled Medications (outcomes include Exacerbations,
hospitalization and mortality)
•
Short-Acting Bronchodilators, Long-Acting Beta-Agonists,
Long Acting Anticholinergic, Inhaled Corticosteroids,
Combinations
2. Oral Medications and other interventions
•
Theophylline, Corticosteroid, Oxygen, Vaccinations,
Exacerbations
Therapy: Specific Outcomes
After smoking
cessation
• There are many choices of Outcomes
• Focus on Patient Orient Evidence that Matters
– In order: FEV1, St George’s Respiratory Questionnaire
(SGRQ), Exacerbations (Hospitalizations) & Mortality
(Only intervention to
slow ↓ lung function
FEV1 loss from 60ml
/year to 30ml )
• RCT’s that found effect treat mostly
– Symptomatic AND FEV1<60%
– 2011 ACP may consider with 60-80 + Sx
• If mild, start with short acting puffers.
1.. JAMA 2003 290: 2301-2312.
Ann Intern Med. 2007;147:639-653. Ann Intern Med 2011;155:179-191.
G. Michael Allan
The More the Scarier
Drug
Device
Single Agents
Class Dose &
Delivery
(1 month)
Cost
Agent
FEV1
ml
SGRQ
Mean
SGRQ Exacerbation Death
NNT
NNT
Serious AE
Formoterol (Foradil)
Aerolizer
LABA
BID 12μg
$70 (Y)
Indacaterol
149
3.6
9
30
ns
ns
Formoterol (Oxeze)
Turbuhaler
LABA
BID 6-12μg
$65 (Y)
Formoterol
45
2.66
4
ns
ns
Withdrawal (NNT 19)
Salmeterol (Servent)
Diskus
LABA
BID 50μg
$78 (Y)
Salmeterol
101
1.64
15
22
ns
Withdrawal (NNT 15)
Indacaterol (Onbrez)
Breezhaler
LABA
OD 75μg
$69 (Y)
Aclidinium
90
2.3
11
ns
ns
Withdrawal (29‐77)*
Aclidinium (Tudorza)
Genuair
LAMA
BID 400μg
$75 (Y)
Glycopyrronium
Glycopyrronium (Seebri) Breezhaler
LAMA
OD 50μg
$75 (Y)
Umeclidinium
Tiotropium (Spiriva)
LAMA
OD 18μg
$89 (Y)
Handihaler
Tiotropium (Respimat)
Soft Mist
LAMA
OD 5μg
$89 (N)
Umeclidinium (Incruse)
Ellipta
LAMA
OD 62 5μg
$65 ?
Respiratory Research 2013, 14:49. The Lung Association & Lung Association Ontario
http://www.on.lung ca/document doc?id=2231 Tony
Nickonchukhttps://www.lung ca/lung-health/lung-disease/copd/medication
Hospitalization
• LABA2
– TORCH= 32 (may be
exaggerated)
• Same for LABA + steroid
• Tiotropium3,4
– NNT= 25 or 30
• ICS – only one study &
ns
1. NEJM. 2007;356:775-89 3. JG M
2006; 21: 1011-9. 4. Cochrane 2005,
2: CD002876.
Mortality
• LABA+Steroid1 vs
– Placebo NNT 56
– Steroid NNT 44
• Tiotropium: Not
significant1 OR
– Per protocol analysis
NNT=53 (for 4 yrs)4
1. Ann Intern Med. 2007;147:639-653. 2. JGIM
2006; 21: 1011-9. 3. NEJM. 2007;356:775-89. 4.
NEJM. 2008;359:1543-54.
Tiotropium & Mortality
3.32
10
14
ns
Less with drug
4.7‐7.9
ns
ns
ns
ns
Tiotropium
119
2.89
10
16
ns**
Inhaled
Steroids
70
1.22
n.a.
22
ns
Withdrawal (NNT 14)
Many***
* Aclidinium causes Diarrhea NNH 91
** Mortality: Handihaler OR 0.92 (0.80‐1.05) vs Respimat OR 1.47 (1.04‐2.08), NNH 143
*** Inhaled Steroids Oral Candidiasis (NNH 27), Voice change (NNH 34), Bruising (NNH 32), Pneumonia (NNH 30)
Adverse events: Inhaled Steroids
• Fracture
– One RCT showed decreased bone density1
– Meta of RCTs: ~NNH 83-172 over 3 yrs.2
• Pneumonia
– From TORCH: 18.9% vs 12.8% = 6.1% (NNH 17)3
– >4 Meta-analysis find similar (NNH 13-25)4-8
• 47 for Severe pneumonia (1 yr)3
– Date not perfect (many no x-ray, budesonide less, etc)
• Bottom-Line: Over 3 years, both fracture (NNH
~100) & pneumonia (NNH ~30) more common
1) NEJM 2000;343:1902-9. 2) Thorax 2011;66:699-708. 3) NEJM. 2007;356:775-89
4) JAMA. 2008;300:2407-16. 5) Arch Intern Med. 2009;169: 219- 29. 6) Cochrane
2007;4:CD003794. 7) Cochrane 2014;3: CD010115. 8) Lancet 2009; 374: 712–19
So, which puffer first
• Tiotropium vs LABA: 2 publications
• Sys Rev: 22 RCTs (23,309), Mortality:
– Handihaler OR 0.92 (0.80-1.05), 4.9% vs 6.1%
– Respimat: OR 1.47 (1.04-2.08), 2.4% vs 1.7%, NNH 143
• Other Respimat vs Handihaler (Sys Rev)
112
90‐140
mortality2
– Handihaler (UPLIFT, meta, cohorts): ≤ death
– Respimat (Cohort & meta): Increased mortality (dose effect)
– TIOSPIR (2 3 yrs, 17,135): respimat=handihaler; but healthy pop
• Bottom-Line: Avoid tiotropium in respimat or soft
mist inhaler. Use of Tiotropium in handihaler
(classic “spiriva” inhaler) encouraged.
Cochrane Database Syst Rev. 2014;7:CD009285. 2) Pulm Pharmacol Ther. 2014;;28 91-7
– 7384 x1 yr, tiotropium 18ug vs salmeterol 50ug BID1
• Patients with ≥1 exacerbations: 34% vs 39%, NNT 19
– 1207 pts, ½ yr: tiotropium>placebo but salmeterol not2
• LABA/steroid (50/500 BID) vs tiotropium3: 1323 x 2 yrs
– Very high drop-out (39%) but No diff exacerbations or quality of life3
• LABA vs Steroid: Review (7 RCTs, 5997 pts)5
– No difference except Steroids more pneumonia & poss ble
increased mortality (OR 1.17; 0.97 to 1.42)
• Bottom-line: Tiotropium likely best first long-acting
puffer but LABA like salmeterol, not far behind
1) NEJM 2011; 364:1093-103. 2) Thorax 2003;58:399-404. 3) Am J Respir Crit Care Med. 2008;177:19-26. 4)
Cochrane 2010;5:CD007891. 5) Cochrane 2011;12: CD007033. 6) Ann Intern Med. 2011;155:179-191.
G. Michael Allan
Combo puffers (1+1≈1.1)
Vaccinations
• Guidelines Support use of Influenza yearly
and Pneumococcal q 5-10 yrs.1
Influenza2:
•
Less Exacerbations & Flu
• Pneumococcal4: No proven benefit
(Exacerbation, pneumonia, hospitalization or
mortality) in COPD
1. Can Respir J. 2003 May-Jun;10 Suppl A:11A-65A Can Respir J 2008; 15(Suppl A) 1A
- 8A. 2. Cochrane 2006; 1: CD002733 3. Cochrane 2006;(4):CD001390.
Dual Agents
Agent
FEV1
ml
SGRQ
Mean
Serious AE
90‐160 2.9‐4.1
?
22
53
Pneumonia NNH~70
ICS/LABA vs ICS
50‐110 0.3‐2.8
?
ns
75
none
?
23
ns
Pneumonia NNH~48
70
High withdrawal and very inconsistent results
ICS/LABA vs Tio
Tio/LABA vs either
1.58
70
60‐110
Umeclidinium/
Vilanterol (vs either)
1.61
?
ns
ns
ns
?
16-∞
~42
ns
Withdrawal NNT~19
19-25
ns
ns
Rate down
~0.14-0.26
?
**Pneumonia, local effects, fractures up
Glycopyrronium/
Indacaterol v Tio*
60‐100 2.22.6
~12
Fluticasone +
Vilanterol vs Vil
10‐20
?
?
* Vs Tiotropium or Glycopyrronium
** Increased numbers of Pneumonia, local effects (e.g. thrush) & fractures
Adding Fluticasone/Salmeterol to Tiotropium
• 6 RCTs, 1268 patients, Follow-up 35 weeks
–
–
–
–
Device
Class Dose
Cost
Salmeterol+fluticasone
(Advair)
Diskus
LABA +
ICS
B D 50+ 100,
250, 500μg
$108-127
(Y)
Salmeterol+fluticasone
(Advair)
MDI
LABA +
ICS
B D 25+ 125,
250μg
$63-87
(Y)
Formoterol+budesonide
(Symbicort)
Turbuhaler LABA +
ICS
OD or B D 5 +
100, 200μg
$55
(Y)
Formoterol+Mometasone
(Zenhale)
Breezhaler LABA+
ICS
B D 5 + 50, 100, $58-69
200μg
(N)
Vilanterol+Fluticasone
(Breo)
Ellipta
LABA
+ICS
OD 25 + 100μg
Vilanterol+Umeclidinium
(Anoro)
Ellipta
LABA +
LAMA
OD 25 + 62.5μg $107
(SA)
Indacaterol+Glycopyrronium
(Ultibro)
Breezhaler LABA +
LAMA
OD 110 + 50μg
$153
(SA)
$107
(SA)
Respiratory Research 2013, 14:49. The Lung Association & Lung Association Ontario
http://www.on.lung.ca/document.doc?id=2231 https://www.lung.ca/lung-health/lung-disease/copd/medication
Treating AECOPD (“Lung Attack”)
SGRQ Exacerbation Death
NNT
NNT
ICS/LABA vs Plac
ICS/LABA vs LABA
Drug
Exacerbation: OR 0.73; (0.55-0.96); 31% vs 37%, NNT 18
SGRQ: 4.63 (4.26-5.01); No # provided for ≥4.
Any Adverse Events: OR 1.24 (0.98-1.57), 39% vs 34%,
Serious AE: OR 0.95 (0.58-1.52).
• Oral Steroids1:
– Treatment Failure (return to care) NNT = 9
– Dose ranges from 30-60mg prednisone, 4-14 days.
• Antibiotics2
– Mortality reduction = NNT 8
– Treatment Failure (return to Care) NNT 3
• Abx choice really doesn’t matter 2,3
– In Uncomplicated: 1st Line: Amoxicillin, doxycycline,
Sulpha, 2nd or 3rd generation cephalosporins, extended
spectrum macrolides.
– In complicated: Beta-lactam/beta-lactamase inh bitor,
fluoroquinolone
1. Cocrhane 2005; 1: CD001288. 2. Cochrane 2006; 2: CD004403. 3 Can Respir J.
2003 10 Suppl A:11A-65A
Daily antibiotics or Rolfumilast
• Daily Antibiotic:1 1142 severe, zithro 250mg OD vs placebo
• ≥1 exacerbation: 57% vs 68%, NNT 10
• SGRQ: ≥4 was 43% vs 36%, NNT 15
• 5%  hearing & macrolide res (81% vs 41%) nasopharyngeal
– Erythromycin 250mg BID found similar
– 1157 Moxifloxacin (as 5 days q8 weeks): less effective
• Roflumilast: Meta2 (9 RCTs, 9211 pts) + severe RCT3 (1935)
• Bottom-Line: Adding dual therapy to Tiotropium
will improve COPD quality of life to small level.
For 18 people over ¾ of year, one will avoid an
exacerbation.
European J Internal Med 2014; 25: 491–495
– ≥1 COPD exacerbations : 20.8% vs 24.1%, NNT 31
– Harms: Weight loss (NNH 15 & Weight loss ~2kg x0.5-1 yr),
Diarrhea (NNH 17), Nausea (NNH 34), Headache (NNH 50)
– Severe: ≥1 Exacerbation 39.2% vs 44.7%, NNT 18
• ≥1 exacerbation hospitalization, 15.5% vs 19.7%, NNT 24
Tools for Practice #62, Feb 21, 2012. 2) Cochrane Database Syst
Rev. 2011;(5):CD002309. 3) Lancet 2015; 385: 857–66
G. Michael Allan
Adjunct Measures
• Pulmonary Rehab: (if Sx & FEV1<50%)
– Better SGRQ (6.9) & exercise (walks +44m in 6 min)3
– Hospitalization & mortality trend better but not stat sign.1
• Oxygen: RCTs3 used FEV1 <30% & PaO2 ≤55mmHg
– O2 reduced death (RR 0.61, 0.46-0.82), NNT ~18 x 3 yrs
– TOP4 & Can5: if Sx severe or FEV1<40%, do PaO2
– If PaO2 is ≤55mmHg, then Supplemental Oxygen
• Give 15 or more hr/d to keep PaO2 >60 mm Hg (or sat ≥ 90%)3,5
1) Cochrane Database Syst Rev. 2015;2:CD003793. 2) Ann Intern Med
2007;147:633-8 & 639-53 3) Ann Intern Med. 2007;147: 633-38, & 639-53.
4) TOP COPD CPG. 5) Can Respir J 2008; 15(Suppl A): 1A-8A.
Adjunctive Treatments
• Theophylline1: Very few POEM outcomes
– Exercise tolerance: No diff
– Exacerbations: No diff
• Oral Steroids (in Chronic)2: No POEM
evidence.
• Nutritional supplementation3: No evidence
to support
• Methylxanthines in AECOPD4: No Help
1. Cochrane 2002; 3: CD003902. 2. Cochrane 2005; 3: CD005374. 3. Cochrane 2005;
2:CD000998 4. BMJ. 2003;327:643-8.
Peter Loewen
Antidotes for Anticoagulants
“Take The Money And Run”?
No conflicts of interest.
Dr. Peter Loewen
B.Sc.(Pharm), ACPR, Pharm.D., FCSHP, RPh
University of British Columbia
Vancouver General Hospital
[email protected]
Major Bleeding in AF Trials
Objectives
% per year
5.0
After the session and upon reflection, participants will be
able to:
1.Describe to their patients the probability
and implication of major bleeding with OAC
therapy.
2.Appropriately discuss the relevance of
antidotes to OAC therapy with their patients.
NS
NNT 147
x 1y
NS NNT 308
x 1h
NNT 105
x 1y
2.5
0.0
RE-LY
warfarin
NOAC hi dose
NOAC low dose
ROCKET-AF
ARISTOTLE
NNT 56
x 1y
ENGAGE AF
RE-LY, ROCKET-AF, ARISTOTLE, ENGAGE AF
ICH in AF Trials
% per year
5.0
First 30 days of
warfarin:
“major hemorrhage”
11.8% per person-year
16.7% if CHADS2 > 3
warfarin
NOAC hi dose
NOAC low dose
2.5
0.0
Over the 5-year study
period:
8.7% visited the hospital
for bleeding
HR 0.40
NNH 500 HR 0.31
x 1y
NNH 500
x 1y
RE-LY
HR 0.67
NNH 500
x 1y
ROCKET-AF
HR 0.42
NNT 213
x 1y
ARISTOTLE
HR 0.48
NNT 218
HR 0.3
x 1y
NNT 170
x 1y
18% of those died in
hospital or within 7 days
of discharge
ENGAGE AF
RE-LY, ROCKET-AF, ARISTOTLE, ENGAGE AF
Gomes T, et al. CMAJ. 2013;185(2):E121–7
Peter Loewen
Major Bleeding Case-Fatality
Major Bleeding Case-Fatality
Extracranial Bleeding
Intracranial Bleeding
warfarin
11-20%2
~50%3
rivaroxaban
5-10%2
dabigatran
~9%1
apixaban
?
13 RCTs (n=27,419 treated 6-36 mos, 1121 major bleed in 1034 individuals)
AF & VTE, all NOACs
Case fatality for major bleeding:
1. Majeed A, et al. Circulation 2013;128:2325–32
2. Beyer-Westendorf J, et al. Blood [Internet] 2014;124:955–62
3. Fang MC, et al. Am J Med 2007;120:700–5
NOAC: 7.6%
warfarin: 11%
RR 0.53 (0.43-0.64)
Chai-Adisaksopha C, et al. J Thromb Haemost 2015;13:2012–20
Managing OAC-associated
bleeding
site-specific therapy
endoscopy, neurosurgery,
etc
volume, cryosupernatant
plasma CPD (CSP), FFP,
prothrombin complex
concentrates (PCC), antidote
Holbrook A, CHEST 2012;141:e152S–84S.
Fawole A, et al. Cleve Clin J Med 2013;80:443–51.
HOW DOES Vit.K AFFECT OUTCOMES
IN WARFARIN-ASSOCIATED
MAJOR BLEEDS?
Johansen M, et al. Cochrane Database Syst Rev 2015;7:CD010555.
Peter Loewen
“Serious bleeding, although rare, can occur in your brain or in
your gut. If this happens the doctor can give you an antidote that
reverses the anticoagulation and gets the blood back to normal.”
Palacio AM, et al. Patient Prefer Adherence 2015;9:133–8.
WHAT WOULD AN IDEAL ANTIDOTE DO?
“… if a severe bleeding event does occur, the antidote can be
used to reduce the duration and severity of the bleeding event.”
Ghijben P, et al. Pharmacoeconomics 2014;32:1115–27.
www.praxbind.com
Pollack CV Jr., et al. N Engl J Med 2015;373:511–20.
www.clinicaltrials.gov NCT02104947
Peter Loewen
www.clinicaltrials.gov NCT02329327
Siegal DM, et al. N Engl J Med 2015;373:2413–24.
Managing OAC-associated
bleeding
site-specific therapy
endoscopy, neurosurgery, etc
Restart OAC?
When?
volume, cryosupernatant
plasma CPD (CSP), FFP,
prothrombin complex
concentrates (PCC),
antidote
Restart OAC?
When?
Witt DM, et al. Arch Intern Med. 2012;172(19):1484–91.
Restart OAC?
When?
Restart OAC?
When?
“restarting warfarin after 7 days was not
associated with increased risk of GIB but was
associated with decreased risk of mortality and
thromboembolism compared with resuming after
30 days of interruption.”
Qureshi W, et al. Am J Cardiol. 2013;113(4):662–8.
n=4602 AF patients discharged from hospital following antithromboticassociated GI bleed. 5 years followup.
HR for restarting antithrombotic treatment vs. not restarting
Staerk L, et al. BMJ 2015;16;351:h5876.
Peter Loewen
Restart OAC?
When?
Restart OAC?
When?
Claassen DO, et al. Arch Neurol. 2008;65(10):1313–8.
Restart OAC?
When?
Kuramatsu JB, et al. JAMA 2015;313:824–36.
Restart OAC?
When?
HAS-BLED
HAS-BLED performance based on LRs
strong
moderate
0.43
weak
00.81
moderate
1
1.14
2
2.12
3
3.73
3.36
1.6
4
5
>=2 vs <2
3.34
0.1
Pisters et al. CHEST 2010; 138(5):1093–1100
0.2
strong
1
LR+
>=4 vs. <4
5
10
Loewen P, Dahri K. Ann Hematol. 2011;90:1191–200.
Peter Loewen
Bleeding CPRs - C statistics
clinically
useless
How to HAS-BLED
limited modest clinically
value value
useful
OBRI
Kuijer
Shireman
HEMMOR2HAGES
RIETE
HAS-BLED
ATRIA
Clinician judgement
0.5
0.6
0.7
0.8
Ohman et al. JAMA 2000;284:876-8
Donzé J et al. Am J Med 2012;125:1095–102
How to HAS-BLED
www.acc.org/anticoagevaluator
www.sparctool.com
Kam Shojania
PMR – Polymyalgia Rheumatica
•
•
Faculty: Kam Shojania
Polymyalgia Rheumatica
•
–
–
–
–
–
Grants/Research Support: Indirectly, via faculty: Janssen, BMS, Abbvie, Pfizer, Roche, UCB, Amgen.
Speakers Bureau/Honoraria: Two industry talks last year. Consulting Fees: Two times in the past year Other: UBC salary, Ministry of Health contract for IVIG management. Arthritis Research Centre, CHEOS, Arthritis Society
Investments relevant to this talk: None
Kam Shojania, MD, FRCPC Chief, UBC Division of Rheumatology
• This program has received financial support from Nobody in the form of Nothing.
• This program has received in‐kind support from Nothing in the form of Nobody.
• Potential for conflict(s) of interest:
•
•
•
• I won’t be talking about biologics for PMR because they are off label. In particular, I won’t be discussing Tocilizumab because we very rarely would consider it for PMR. Off label. Don’t do it. None really. Nobody can make money on PMR. Oh wait! There might be a biologic useful for PMR called tocilizumab (made by Roche). Stay tuned for lot’s of ‘CME’ .
1. Don’t use high dose prednisone for PMR. Max 20mg daily. Try 15mg daily for most patients 2. About 10% of PMR may have a normal ESR or CRP. If one is normal, check the other. Consider repeating in a week or two if both normal.
3. Would be rare to have PMR under 60 yo. 3. Infection and malignancy can mimic PMR
4. Fibromyalgia can mimic PMR (what is fibromyalgia? Ask James)
5. All patients will get steroid side effects so consider MTX as a steroid‐sparing agent in PMR. Case 1
• 75 yo man with 1 week of proximal muscle pain and stiffness in the AM. Very fatigued. No features of GCA. • On exam mild tachycardia, reduced shoulder and hip ROM.
• Anemic. WBC 13, elevated neutrophils, CRP 160. • What is the DDx? Kam Shojania
Case 1 continued
• Infection, PMR, vasculitis, malignancy.
• Infection! • If you treat with prednisone you would likely kill him. Case 2
• 59 yo woman with 12 weeks of proximal muscle pain and stiffness in the AM. Very fatigued. Wt gain of 15 lbs. Depressive symptoms.
• On exam tired‐looking and no obvious findings. No joint pain. • Anemic. WBC 8, CRP 12. • What is the DDx? Case 2
• Hypothyroid
• Fibromyalgia
• Depression
• Prednisone 50mg daily would help her quite a bit at the beginning and the CRP would normalize. What is PMR?
• Proximal myalgia of the hip and shoulder girdles associated with morning stiffness (at least 1 hour)
• Etiology is largely unknown
• Associated with HLA‐DR4
• Some series show higher prevalence of antibodies to Adenovirus and RSV
Epidemiology
• Elderly patients, >50 years of age (mostly >60)
– Incidence 52.5/100000
– Prevalence 0.5‐0.7%
•
•
•
•
Females 2:1
White, European (highest rates in Northern Europe)
Some evidence of genetic susceptibility 50% Temporal arteritis patients will have PMR (15% of PMR patients will develop TA)
Clinical Picture
Often previously healthy, >50
Bilateral proximal muscle pain and stiffness
ESR >40, CRP elevation
Prompt response to steroids
Low grade fevers, weight loss
Malaise, fatigue, depression
Difficulty getting out of bed, rising from sitting, performing ADLs
• Rarely can have high spiking fevers
•
•
•
•
•
•
•
Kam Shojania
Exam findings
• Low grade temp
• Muscle strength is NORMAL
• Pain specifically in shoulder and hip girdle despite lack of clinically significant swelling
• Tenderness to palpation and diminished ROM in shoulders and hips
• Can get a transient synovitis (usually knee, wrist, sternoclavicular joints)
Treatment
• Rule out infectious/autoimmune process
–
–
–
–
–
• Low dose prednisone (10‐15mg/d) for 2‐4 weeks. Then can start trying to taper.
• Vitamin D/Calcium
• Steroid sparing agents (MTX usually)
Few points about steroid therapy
• Starting >10mg  fewer relapses, shorter treatment periods than compared to <10mg
• Starting >15mg lead to higher cumulative doses and more steroid adverse affects
• Tapering lead to more successful treatment, fewer relapses, when done slowly (1mg/mo)
Endocarditis
RA
Lupus
Systemic Infection
Myositis
Prognosis ‐ good
• But prednisone is the big problem
• Self limited and most resolve within 1‐3 years, however patients experience significant decrease in quality of life • 50% of patients can often be weaned off all steroids by 2 years
– If relapse, often occurs within 12 months of weaning steroids
• Need to be monitored for GCA
Other differentials to consider
•
•
•
•
•
•
•
Amyloidosis (inflammatory)
Fibromyalgia
Osteoarthritis
Shoulder disorders – bilat rotator cuff
Cervical spondylosis
Parkinson’s Disease
Multiple Myeloma
Tests to order
•
•
•
•
•
ESR (typically >40, sometimes >100), CRP
ANA, RF, Blood cultures
CBC
CK  NORMAL!
No imaging necessary but Xrays should not show erosive disease or osteopenia. – MRI if done will often show bursitis.
• TA biopsy only done if you suspect TA
Kam Shojania
ESR vs CRP? – choose the CRP
ESR
CRP
Watch blood separate in a tube mm/hr
Increases with age and anemia, females, renal disease.
Cheap
Acute phase reactant made by liver.
More specific. More sensitive to change.
Previously more expensive and now cheaper. We often see inappropriate treatment of PMR:
• Prednisone 50mg daily! • Rapid taper and re‐initiation of prednisone: Yo‐yo
• Steroid withdrawal symptoms mimic PMR flare. Also responds to steroids. Taper long and slow. • Rheumatoid arthritis can start out as looking like PMR initially. And often RF, CCP negative in elderly onset RA. If symptoms more to hands/wrists/feet, then reconsider RA as the diagnosis and consider DMARD. Some tips to make you look
good (or at least not bad)
Make sure you look for PMR mimics
right away. Missing infection and
malignancy would not be good.
Review all prednisone S/E verbally and
in writing and chart it.
Do not use NSAIDs
Temporal Arteritis
•
•
•
•
•
•
•
•
Visual loss, Headache
Scalp tenderness
Jaw claudication
CVA
Aortic arch syndrome
Thoracic aorta aneurysm
Dissection
A few rules for PMR
• Start with prednisone 15mg daily (not 50mg). • Taper to 10mg within 4‐8 weeks then by 1mg/month
• A good response to prednisone (90% better in 48h) is a good diagnostic test. • Watch for GCA symptoms. • Follow up every month at least during the 1st year. Perhaps every 2 months in the 2nd year. • Recommend low dose MTX at 10‐15mg PO weekly
• Exercise, fall‐prevention, osteoporosis management including bisphosphonates
Kam Shojania
Medical co‐morbidities!
• Hypertension
• Diabetes
• Osteoporosis
• Obesity
• Cardiovascular risks
• Sleep apnea
When to refer?
• Atypical presentation such as less than 60yo or not responsive to steroids
• Co‐morbidities that make prednisone worrisome.
• Inflammatory arthritis
• Very high inflammatory markers
• Features of GCA
• Early MTX use will reduce prednisone requirements. 27th Annual Best Science Medicine Course
1. Don’t use high dose prednisone for PMR. Max 20mg daily. Try 15mg daily for most patients 2. About 10% of PMR may have a normal ESR or CRP. If one is normal, check the other. Consider repeating in a week or two if both normal.
3. Would be rare to have PMR under 60 yo. 3. Infection and malignancy can mimic PMR
4. Fibromyalgia can mimic PMR (what is fibromyalgia? Ask James)
5. All patients will get steroid side effects so consider MTX as a steroid‐sparing agent in PMR. Bringing Best Evidence to Clinicians:
Combining Evidence and Clinical
Pharmacology to Improve Drug
Therapy
Mark the date: Friday, 29 October 2016
Where: Surrey Memorial Hospital, 13750 96 Ave, Surrey BC
What: Bringing Best Evidence to Clinicians: Combining Evidence and Clinical Pharmacology
to Improve Drug Therapy
Overview
This popular conference put on every year by the UBC Therapeutics Initiative in collaboration
with UBC Continuing Professional Development is designed to provide physicians,
pharmacists, and other health professionals with up-to-date, evidence-based, practical
information on prescription drug therapy. Although primarily aimed at prescribers (MD’s,
NP’s) and pharmacists, this course will appeal to any health professional who wants to learn
and think about the scientific evidence behind what we should or should not be doing with
prescription drugs.
CCCEP and Mainpro M1/MOC Section 1 credits will be available. Note that this conference
is not supported by industry funding.
Comments from last year:

“Excellent, thought-provoking, evidence-based content.“

“Unbiased speakers who strongly believe in practicing evidence-based medicine.“

“Promotes critical thinking and provides powerful messages that will stick with me.“

“Probing questions make you examine your beliefs and how you practice.“

“Always an excellent course.“
Speakers & Topics
What is the Evidence For or Against Using Opioids for Chronic Pain?
Dr. Jason Busse, National Pain Centre, McMaster University; Chair, Canadian Opioid
Guideline Update; Author of forthcoming systematic review on opioids for chronic pain.
Hamilton, ON
Dogma vs. Evidence in Management of Atrial Fibrillation, and Treatments to Prevent
Atherosclerotic Events
Dr. John Mandrola, Cardiac electrophysiologist, endurance athlete, and chief cardiology
correspondent for Medscape. Louisville, KY
Is Evidence Available to Guide Palliative Care?
Dr. Staci Mandrola, Internist, hospice/palliative care physician, and cyclist. Louisville, KY
Guidelines we can trust? Understanding pitfalls, limitations, and conflict of interest in
clinical guidelines
Sarah Burgess, PharmD, Dalhousie University
What do we Now Know about the Benefits/Harms of Drugs for Type 2 Diabetes?
Cait O’Sullivan, PharmD, Provincial Academic Detailing Program and UBC Therapeutics
Initiative
How can you Tell Whether your Patient is Benefiting from Drug Treatment of COPD?
Aaron Tejani, PharmD, UBC Therapeutics Initiative
New Evidence about Hypertension Targets and Statins for Primary Prevention
Dr. James M. Wright, UBC Therapeutics Initiative
Workshops:

Dealing with difficult chronic pain and palliative care

Incorporating evidence about preventive therapies into patient informed consent

Making decisions about anticoagulants for atrial fibrillation or VTE

Difficult hypertension

Practical deprescribing
Registration opening soon at: http://ubccpd.ca/course/BestEvidence2016
Thanks for your questions and discussion.
Thanks for completing your course evaluations.

2016 BSMC syllabus - Friday - Therapeutics Education Collaboration

Transcription

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