how to assess and prioritize treatments: using evidence-based medicine to choose effective...
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How to Assess and Prioritize Treatments: Using Evidence-Based
Medicine to Choose Effective Treatments for Autism and ADHD
Dan Rossignol, MD FAAFPInternational Child Development Resource Center
321-259-7111 www.icdrc.orgAutism One / Autism Canada 2009 Conference
October 31, 2009
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Disclosures:Disclosures:I have received funding for two studies on I have received funding for two studies on hyperbaric treatment in children with autism hyperbaric treatment in children with autism from the International Hyperbarics Association from the International Hyperbarics Association but I have no commercial or financial but I have no commercial or financial relationships with chamber manufacturers. relationships with chamber manufacturers.
With all treatments and recommendations, With all treatments and recommendations, please consult with your child’s physician please consult with your child’s physician before implementation. before implementation.
The use of every treatment in individuals with autism is “off-label” except for
risperidone for the treatment of irritability
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ADHD AspergerSyndrome
PDD-NOS Autism
Autism Spectrum
Underlying pathophysiology
Psychologically / Behaviorally defined
Communication Stereotypicalbehaviors
Socialinteraction
???
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Autism: Pathophysiology Cerebral hypoperfusion Inflammation
– Cerebral– Gastrointestinal
Dysbiosis Mitochondrial dysfunction Oxidative stress Impaired glutathione production Environmental toxicant exposures
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Study Descriptive Terms
Prospective: planned ahead of time Randomized: participants assigned to a
group by random allotment Double-blind: Neither participants nor
researchers know group assignment Placebo-controlled: A placebo is given to
one group of participants Cross-over: placebo group crosses over
and gets treatment
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Placebo Effect
As high as 30-37% in several studies in children with autism
Points to need for double-blind, placebo-controlled studies
However, also need to treat children now, and cannot always wait for these types of study
Need to evaluate the risk/benefit ratio of each treatment
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Evidence-based Medicine: Strength of Evidence (Efficacy)
A: Supported by at least 2 prospective randomized controlled trials (RCTs) or 1 systematic review
B: Supported by at least 1 prospective RCT or 2 nonrandomized controlled trials
C: Supported by at least 1 nonrandomized controlled trial or 2 case series
D: Troublingly inconsistent or inconclusive studies or studies reporting no improvements
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Caveat
Double-blind, placebo-controlled studies can cause you to lose sight of the individual patient– e.g., DMG: 2 negative double-blind placebo-
controlled studies in autism (however, dose in studies lower than we typically use). DMG is ranked #17 by parents on ARI list. Some children manifest good improvements with DMG, including speech.
– e.g., Secretin
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http://clinicalevidence.bmj.com/ceweb/about/knowledge.jsp
CaveatCaveatOver 50% of what is done in medicine is “off-label”
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Example of Study: A in Autism
Melatonin: 2 randomized, double-blind, placebo-controlled studies demonstrating improvement in the amount of time to fall asleep, number of nighttime awakenings, and length of sleep compared to both baseline and to placebo.
Garstang and Wallis, 2006 Child Care Health Dev 32(5):585-9 Goodlin-Jones et al., 2009 J Clin Sleep Med 5:145-150
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Garstang and Wallis, 2006 Child Care Health Dev 32(5):585-9
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STEPSSTEPS
SSafety: has it been studied in children?afety: has it been studied in children?
TTolerability: what are the side effects?olerability: what are the side effects?
EEfficacy: does it work?fficacy: does it work?
PPrice: how much will it cost?rice: how much will it cost?
SSimplicity: how easy is it to do?implicity: how easy is it to do?
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STEPS: Melatonin
Safety: two double-blind studies showing safety in children with autism
Tolerability: very little side effects Efficacy: Double-blind studies showing
improvements compared to placebo Price: less than $30 per month Simplicity: pill taken at bedtime
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DOEs versus POEMs DOE: Disease Oriented Evidence
– Example: Cholesterol pill lowers my cholesterol by 50 points
– Example: Flecainide– Example: MB12 increases glutathione
POEM: Patient Oriented Evidence that Matters– Example: Cholesterol pill makes me live longer,
or prevents a heart attack or stroke– Example: MB12 improves speech
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Ideal Treatment
Backed by Strength of Evidence: A Safe Tolerable Efficacious Cheap Simple, in-home treatment POEM: Outcome matters to child/parent
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Treatment Options: Know Your Reason for Treatment
Based upon symptoms– e.g., inattention: pycnogenol, zinc,
carnitine, iron, omega-3 fatty acids
Based upon laboratory testing– e.g., oxidative stress: pycnogenol,
carnitine, CoQ10
Based upon probabilities– e.g., most children with autism have low
glutathione: MB12, folinic acid, pycnogenol
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Modified CGI – ParentalModified CGI – ParentalAutism Research InstituteAutism Research Institute
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ActiveTreatment Maintenance
Chelation
Anti-inflammatories
Antioxidants
HBOT
Supplements
Methyl B12
IVIG
GFCF diet
IV Chelation
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McCracken et al., 2002 N Engl J Med 347(5):314-21
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Eikeseth et al., 2007 Behav Mod 31(3):265-78
25/7 20/6
ABA Therapy
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Rossignol, 2009 Annals Clin Psych, in press
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Medications
A: Acetylcholinesterase inhibitors– rivastigmine, donepezil, galantamine
B: Alpha-2 adrenergic agonists– Clonidine, guanfacine
B: Anti-inflammatory medications– Spironolactone, pioglitazone, minocycline,
IVIG, ACTH, prednisone, pentoxifylline
C: Glutamate antagonists– Amantadine, memantine, lamotrigine
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Overall Autistic Behavior
A: Acetylcholinesterase inhibitors, music therapy
B: Alpha-2 adrenergic agonists, HBOT, vision therapy
C: Carnosine, piracetam, B6/Mg, GFCF diet, cyproheptadine
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Speech/Communication
A: Acetylcholinesterase inhibitors, music therapy
B: Carnitine, Tetrahydrobiopterin (BH4), Alpha-2 adrenergic agonists, HBOT
C: Carnosine, B6/Mg, Omega-3 fatty acids, piracetam, GFCF diet, Cyproheptadine, Famotidine, Glutamate antagonists, Auditory Integration Therapy, Neurofeedback
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Stereotypy
A: Naltrexone B: Vitamin C, alpha-2 adrenergic
agonists C: Omega-3 fatty acids, B6/Mg,
cyproheptadine, famotidine, glutamate antagonist, auditory integration training, massage
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Social Interaction
A: Acetylcholinesterase inhibitors, naltrexone
B: Carnitine, tetrahydrobiopterin, HBOT, oxytocin
C: Carnosine, B6/Mg, GFCF diet, Famotidine, Glutamate antagonists, massage, neurofeedback
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Attention/Concentration
A: Omega-3 fatty acids (ADHD), Pycnogenol (ADHD), zinc (ADHD), acetylcholinesterase inhibitors, nicotine, music therapy
B: Carnitine, zinc, alpha-2 adrenergic agonists
C: Omega-3 fatty acids, glutamate antagonists, Iron (if deficient, ferritin < 30), phosphytidylserine
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Hyperactivity
A: Eliminate food coloring, additives and dyes; acetylcholinesterase inhibitors, naltrexone
B: Carnitine, alpha-2 adrenergic agonists
C: Omega-3 fatty acids, magnesium, chelation, glutamate antagonists, AIT, massage
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Sleep
A: Melatonin B: Carnitine, alpha-2 adrenergic
agonists C: Multivitamin, Omega-3 fatty acids D: Iron, 5-HTP
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Irritability/Aggression
A: Risperidone, Acetylcholinesterase inhibitors, naltrexone (esp. self-injury)
B: Alpha-2 adrenergic agonists, anti-inflammatory medications
C: Glutamate antagonists, auditory integration therapy
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Eye contact
A: Acetylcholinesterase inhibitors, music therapy
B: Tetrahydrobiopterin, HBOT C: Omega-3 fatty acids, famotidine
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Coordination
A: Pycnogenol B: Carnitine, Vision therapy C: Omega-3 fatty acids
Tryptophan deficiency (5-HTP or TP) GI-related
Toe-walking
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Supplements with Antiseizure Activity
Taurine Vitamin B6 / P5P Magnesium Omega-3 fatty acids GABA DMG L-Carnosine
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Rossignol, 2009 Annals Clin Psych, in press
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Rossignol, 2009 Annals Clin Psych, in press
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Rossignol, 2009 Annals Clin Psych, in press
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Rossignol, 2009 Annals Clin Psych, in press
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Rossignol, 2009 Annals Clin Psych, in press
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Rossignol, 2009 Annals Clin Psych, in press
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Typical Supplement Doses Vitamin C: 100 mg/kg/day CoEnzyme Q 10: 5-10 mg/kg/day Acetyl-L-Carnitine: 50-100 mg/kg/day L-Carnosine: 200-400 mg twice a day Pycnogenol: 1 mg/kg/day (often higher) MB12 injections: 75 mcg/kg every 1-3 days Folinic acid 400 mcg twice a day Omega-3’s: DHA and EPA ~800 mg/day each Zinc 20-150 mg/day Melatonin: 1-6 mg 30 mins before bedtime
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Typical Med Doses: Use Only Under Physician Supervision
Clonidine 0.1-0.2 mg at bedtime Guanfacine 0.25-1 mg 3 times a day Donepezil 2.5-5 mg at bedtime Galantamine 2-8 mg twice a day Spironolactone 1-3 mg/kg/day Pioglitazone 15-30 mg/day Memantine 5-10 mg bid Lamotrigine 3-5 mg/kg/day
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Summary: Where to start?
Sleep / Melatonin / 5-HTP Multivitamin Omega-3 fatty acids Anti-oxidants Methyl B12 (SC injections) Diet, at least organic and eliminate food
colorings and preservatives, GFCF Digestive enzymes / probiotics