ADHD MEDICATION IN ADHD- Facts & Fears. ADHD-Fears & Facts. Overview of talk. Impact of AD/HD. Problem with nerve connections in AD/HD

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1 ADHD MEDICATION IN 2007 ADHD- Facts & Fears Overview of talk Fears raised Facts as known Things we don t know Medications Treatment options FEARS & FACTS P Concannon ADHD-Fears & Facts ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD) Prevalence: 3-5% All countries Males >> Females DSM-IV Criteria Subtypes: Inattentive, H-I, Combined. Behaviour problems Impact of AD/HD Pre-school Adolescent Adult School-age Behavioural disturbance Academic problems Problems socialising Self-esteem issues Academic problems Difficulty with social interactions Self-esteem issues Drug, injuries, crime Problems with jobs Self-esteem issues Relationship problems Injury/accidents Substance abuse Disorders that can co-exist with AD/HD Problem with nerve connections in AD/HD Conduct disorder Anxiety Learning difficulties Step 1 Neurotransmitter Release Noradrenaline Dopamine Nerve Impulse Depression AD/HD Alone 30% Oppositional Defiant Tics Fine Motor Aspergers Step 2 Chemical bridge Step 3 Reuptake molecule (DAT) Receptors 1

2 Stimulants: Short & Long Term Use Do they work in AD/HD? >150 papers on short term efficacy. Males and Females. Different racial backgrounds. Different subtypes of AD/HD. Medication isn t New! To see a single daily dose of [amphetamine] produce a greater improvement in school performance than the combined efforts of a capable staff working in a most favorable setting would have been all but demoralizing to the teachers had not the improvement been so gratifying from a practical viewpoint." --Charles Bradley, MD Am J of Psychiatry,1937 PARENTAL CONCERNS I understand that the science regarding my son's medication is telling me stay on the medication. The big question is: " where are the long term scientific studies telling me that I am doing the right thing." What's going to happen to him in the long run. How is his brain chemistry being affected? Where is the science? mother of ADHD child Fears & Facts FEARS Over-used. Loses Effectiveness. Stunts Growth. Causes Deaths. Leads to Drug Addiction. Causes Tics. Damages the Developing Brain. A Ritalin Epidemic! Fear & Facts-Medicine Use FEAR: Over-Use of Stimulants Media reports 35,000 NSW ChiIdren & Adolescents on Stimulants. FACT: Number is 16,000 Number increased in the 90s Now 1% of 5-16yr olds NO increase since 2000! Reference: NSW Dept... of Health 2

3 Fears & Facts- Effectiveness FEAR: Loses its effect with time. FACT: Ongoing positive effects demonstrated in many studies up to 5 years and anecdotally throughout childhood and adolescence. Stimulants- Short & Long Term Use Long Term Efficacy Studies Methylphenidate 2 years: MTA (n=579), Wilens (n=240) & Abikoff (n=103). 5 years: Charach (n=79). Dexamphetamine 2 years: McGough (n=560). MTA 36 month F/U 3 Trajectory groups for MPH effects over the 36 months in responders. Grp1(34%): Initial small change with gradual continuing improvement. Grp 2 (52%): Good response that continued. Grp 3 (14%): Good response that dissipated with time. Fears & Facts-Age Effect FEAR: Stimulants are only effective in school-aged children. FACT: They work just as well in preschoolers, adolescents and adults ie the whole life spectrum. The oldest stimulant user in NSW is in his late 70s! Medication Effectiveness in Pre-Schoolers PATS (JAACAP Nov 06) 303 subjects 3-5.5yrs. Short term(5wks) & Long term (40wks). 8 phase, 70 week trial. Significant in symptoms but < school-age. Mean daily dose: 14mg S-Es: 30% mod-severe, 11% withdrawn. Stimulants in Adolescence Many brands of MPH and DEX approved for use in adolescents: USA,Europe, Aust. Based on research evidence. Effect size is equal to that seen in school-aged children. 3

4 Fears & Facts- Cardiac FEAR: Stimulants cause unexplained deaths FACTS: No increase unless at risk due to underlying heart problem. Stimulants & Cardiac Toxicity(1) I want the physicians hand to tremble a little before they write the prescription for the drug (stimulants) Dr.Steven Nissen FDA Drug Safety and Risk Management Advisory Committee Stimulants & Cardiac Toxicity (2) Recent History 2005: Health Canada temporarily banned Adderal (Dexamph). Feb 2006: FDA proposed black box for MPH. March 2006: FDA Pediatric Advisory Board rejected the recommendation but endorsed the development of an educational brochure for parents re: ADHD medications. July 2006: RACP parental guide includes the statement: The available data suggests the risk is slightly lower in children taking stimulants. August 2006: FDA directs additional text for drug insert: Misuse of amphetamines may cause sudden death and serious cardiovascular adverse effects. Stimulants & Cardiac Toxicity (3) 25 Cases of sudden death (SD) on stimulants in USA between children/adolescents (7-MPH,12-Dex). 3-4 million child/adol on stimulants Estimated SD risk- -General:0.6-6/100,000 per yr. -Stimulants:0.4/100,000 per yr. Stimulants & Cardiac Toxicity (4) Australian Experience TGA :since 1980, side-effects reports of 113 on MPH & 57 on Dex. 400 cases of Serious adverse effects (included nausea, lack of efficacy). Only 15% of those on MPH were actually classified as serious including2 Sudden Deaths. Stimulants & Cardiac Toxicity(5) 3 ISSUES 1. Is there evidence of causality. 2. Is there evidence for biological plausibility that treatment with stimulants produces dangerous cardiovascular outcomes. 3. What s the balance of risk i.e.the morbidity and mortality of untreated ADHD. 4

5 Stimulants & Cardiac Toxicity (6) Evidence of Association with CVS Risk? 1.Small but significant Increase in pulse/bp (CF exercise) - >2000 children: Syst (2-4mm), Diast (1-3mm),HR(3-5/min) yr olds over 12m: none above 95thP. 2. ECG: no change in PR, QRS or QT/QTc. - >300 controlled trials (N>5000)- No Sudden Deaths reported.? Effect of long term small increase in BP. Stimulants & Cardiac Toxicity (7) Evidence of causality Sudden Death: risk in Childn & Adolests General populatn: 0.6-6/100,000 per yr. Stimulants: 0.4/100,000 per yr. Structural cardiac defects found in 12/19- abnormalities similar to SD characteristics in general population. Many important factors not recorded. CF Paracetamol risk in same period:2464 episodes and 103 deaths! Stimulants & Cardiac Toxicity (9) SUMMARY- Risk Analysis The available data do not seem to warrant major changes in our current treatment of ADHD with stimulants. Balanced against the paucity of convincing data on adverse cardiovascular effects of stimulants are the morbidity and mortality associated with not treating the disorder appropriately. Stimulants remain among the most effective and safe intervention for ADHD Wilens et al 3 rd Sept 06 Fears & Facts-Growth FEAR: Stunts Growth. FACT: Stimulants can lead to a short term decline in growth rates. Long term studies needed. Studies show varied results. At worst it may lead to a loss of 3 cms in ultimate height. Stimulant medication effect on growth Remains a controversial issue despite numerous studies. Difficult to study. Potential mechanisms for suppression include: Appetite suppression. Altered CNS growth factors ( Dopamine effect on Pituitary gland). Direct effect on cartilage. Altered hepatic growth factors. Growth & Stimulants-Review of literature- Poulton 2005 Overview of growth of height studied 29 studies reviewed from Medline (Sep 04) -22 in children,6 in late adolescent/adults and 1 in childrn/adults Varying study design, growth parameters and doses. 9 of the 22 studies results consistent with statistically significant growth attenuation. 2 studies showed rebound growth. 5

6 Ht velocity SDS P < 0.01, **P < 0.001, Student's t-test, 2-tailed (compared to normative data ADHD & Stimulants - at 5 yrs (P Concannon- unpublished) Subjects with M60 data WTPCT BMIPCT HTPCT Percentile n=15 0 BL M6 M12 M18 M24 M30 M36 M42 M48 M54 M60 WTPCT BMIPCT HTPCT MTA-36 Month F/U As a group larger than average 7-9yr old at baseline. Non-medicated continued >average growth. MPH group showed average growth of 2cm and 2.7kg less than non-mph. Fear & Facts- Drug Abuse FEAR: Will lead on to Drug abuse. FACT: Studies show the opposite i.e. Treatment for ADHD lessens the chance of subsequent substance abuse problems. Meta-analysis of 6 ADHD studies on Substance Abuse (Adolescence/adulthood substance abuse outcome data on people who were diagnosed ADHD as children) 674 medicated vs 360 unmedicated subjects Wilens 2003 Review of Studies-Wilens 2003 Results: Untreated ADHD subjects twice as likely as treated subjects to develop SUD. Follow-up into adolescence showed a greater protective effect (OR 5.8) than studies that followed subjects into adulthood (OR 1.4) Results could not be accounted for by any single study or by publication bias. 6

7 Fear & Facts- Tics FEAR: Stimulants Causes Tics. FACT: Can do but More often doesn t effect or bring on. Do stimulants cause/worsen tics? Answer: unequivocally YES in 70s &80s Bradley (1950) reported tic-like motor activity with amphetamine. Mattson (1968) described DEX-induced involuntary movements. Golden (1974) reported MPH induced TS. Contraindication to stimulants included family history of Tics. Confusing Situation Individual children may show considerable fluctuation in frequency and severity of their tics during treatment. This may represent the natural course of their tics. Onset of tics is around the same time as stimulants are started i.e. 5-10yrs old. *Example of 8 yr old. Tourette s Study Group 2002 Multi-centre randomised double blind clinical trial 136 children with ADHD and chronic TD Randomised into 1) Clonidine 2) MPH 3) Clonidine and MPH 4) Placebo 8 week period Tourette s Study Group 2002 Worsening of tics: 20% in MPH 26% in clonidine alone 22% in placebo Conclusion: Prior recommendation to avoid MPH in ADHD+TD children was unsupported. Study Review-Palumbo 2004 Pooled data from 3 placebo controlled studies of IR MPH and OROS MPH (Concerta) and 2 open label studies of Concerta (9m and 2yrs). Incidence of tics emergency was non-significant across all 3 treatment groups Concerta: 4.0% MPH: 2.3% Placebo: 3.7% 7

8 SUMMARY Group data do not support that MPH results in exacerbation of motor or vocal tics. Long term MPH treatment seems to be safe and effective for the management of ADHD in children with mild/moderate tic disorder. Fears & Factsdeveloping brain FEAR: Damages the Developing Brain. FACT: Evidence inconclusive but suggests not. Sensitive Periods Stages during maturation when environmental conditions( including drug exposure) influence development for a limited time by fine tuning connections and function. Susan Anderson, Trends in Pharmacological Sciences, May 05 Problems with Current Rat Studies using Stimulants 1. High dose of drug. 2. Given IV not oral ie high levels. 3. Healthy rats- not humans 4. No ADHD rats. Studies looking at long-term effects of stimulants on the developing brain are yielding contradicting evidence. Currently there is little of concern. There is work that suggests that MPH improves the developing brain and that any effects may not just be negative, Chromosome (gene) Study The only human chromosomal study done in children before and after 3 months on MPH reported minor chromosomal aberrations. This was a preliminary study but reminds us that ongoing research is required.. 8

9 Life Events & Developing Brain We need to remember that all environmental exposures whether they be drug or life events potentially impact on the growing brain. Examples are seen in deprived children who have attachment issues. Adverse experiences due to ADHD symptoms will also influence the immature brain. Ritalin LA Sprinkles within capsule 6-7hrs duration. Onset minutes Can be sprinkled On jam etc. Can t use portion of the sprinkles Concerta hr preparation Onset minutes- smooth release PBS MPH Overcoat Tablet Shell Laser-Drilled Hole MPH Compartment #1 MPH Compartment #2 Push Compartment Atomoxetine ( Strattera ) Nor-Adrenaline Re-uptake Inhibitor 24hour action. Not a Stimulant -GPs can prescribe. Effect builds up over several weeks Once/day dose. $150/month or PBS. Side-effects similar to stimulants- no tics. suicidal thoughts and liver inflammation reported. Which Medication? MPH and DEX-many studies and known side-effects. Effective in >80% of ADHD. Strattera ( Atomoxetine )- last 5 yrs. Studies so far don t show same effect on attention.? Useful when anxiety, substance abuse and if no response to stimulants. Others eg Clonidine, SSRIs when above don t help. Daily Struggle for ADHD Child & Carers TIME OF DAY -TASK Before school - Get ready for school Assembly -Not disrupt AM Session -Attend,do work,not disrupt Lunch -Play co-operatively PM Session -As for AM After School -Do homework, Activities Bed -Settle for bed IR Ritalin Ritalin LA Concerta Strattera 9

10 Cost of Medications MPH, DEX and most long acting forms are PBS Authority. (Paediatricians/Psychiatrists only). Strattera is PBS authority when stimulants are contra-indicated. (GPs can prescribe). Ritalin LA- soon on PBS. Medication Holidays Period off medication. If growth issues. To assess maturation of ADHD symptoms. Give chance to practice behavioral treatment -? Resistant adolescent. If care-givers feel has lost it s effect. How long will he need medication? The medicine is continued as long as the person needs it - maybe life-long. In many cases maturity enables the person to employ strategies to control the symptoms. We have trials off the medicine at regular intervals to assess whether it s still needed. IT S NOT THE END OF THE WORLD, IT S JUST ATTENTION DISORDER Dr Sam Goldstein in his video to AD/HD adolescents 10