intelligent prescribing - mm3 admin€¦ · taylor, santosh & swanson (2002) submitted...

Optimizing Medication Treatments in ADHD

Dr Dave Coghill

Intelligent Prescribing

Source Consultant AdvisoryBoard

Stock Equity

>$10,000

SpeakerResearch

Lilly X X X

Janssen/McNeil

X X X

UCB X X

Shire X X X

Medikinet/ Flynn

X X

NHS: HTAMHRN

XX

• Severe, pervasive, disabling?

• Problems at home?• Problems at school?

• Persistent after treatment?

• Comorbid problems?

Home CBT

Liaison+ self-instruction

Medication

Taylor, Santosh & Swanson (2002) submitted

Treatment Decisions

ADHDResponse to Stimulants

0

10

20

30

40

Best Response(Percent)

Dextroamphetamine Methylphenidate Equal response to either stimulant

Meta-analysis of within-subject comparative trials evaluating response to stimulant medications

36%

26%

38%

Greenhill et al. JAACAP 1996;35:1304.

About 70% of patients respond to methylphenidate, 70% respond to amfetamineand overall 95% respond to one or the other

Response Analysis: LYBI (≥40% Reduction in ADHD RS Total Score)

Respondersto ATX

Nonrespondersto ATX Total

Responders to OROS® 76 24 100

Nonrespondersto OROS 29 35 64

Total 105 59 164

p<.001, Fisher’s exact test

Patients with at least one week on ATX

About 40% of patients who do not respond to stimulants, do respond to atomoxetine

NICE 2006

• The decision regarding which drug to use should be based on the following: – the presence of comorbid conditions (for example, tic disorders, Tourette’s syndrome, epilepsy)

– the different adverse effects of the drugs

– specific issues regarding compliance for example problems created by the need to administer a mid‐day treatment dose at school

– the potential for drug diversion and/or misuse

– the preferences of the child/adolescent and/or his or her parent or guardian.

NICE 2008• Methylphenidate should be the first‐line drug used in pharmacological treatment of ADHD as this has the largest evidence base.

• Atomoxetine is useful as a second‐line drug for those who do not respond to, or have problems with, methylphenidate, and as a first‐line agent in some instances.

• Antipsychotics are not recommended in the treatment of ADHD.

Attention deficit hyperactivity disorder: Diagnosis and management of ADHD in children, young people and adults - NICE guideline Draft for consultation, January 2008

NICE 2008

• When prescribing methylphenidate for the treatment of children or young people, modified release (MR) preparations should be considered for; – Convenience

– Improving adherence

– Reducing stigma (because the child does not need to take medication at school)

– Reducing the problems schools have in storing and dispensing a controlled drug

– Because of its smoother pharmacokinetic profile.


NICE 2008

• Atomoxetine is generally used as a second‐line treatment, but may be considered as a first‐line treatment in the following circumstances: – Comorbid tics or Tourette’s disorder

– Comorbid anxiety disorder

– Comorbid stimulant substance misuse.


Initiating Treatment

• Psychoeducation• Focussing on desired outcome and target symptoms

• Importance of using standardised ratings and recording baseline information

• Methylphenidate titration strategies– Forced dose– Single dose trials– Starting with long‐acting preparations

• Atomoxetine titration strategies

Psychoeducation

• About the disorder and treatment options

• About the specific pharmacological interventions and important issues associated with their use

• What is and is not known

• Time to response• “paracetamol” model

• Beliefs about medication

• Fears about addiction

The process of pharmacotherapy

• Assessment, diagnosis, target symptoms

• Choose medication– Algorithm approach– Baseline measurements

• Determine starting dose, initial target dose and how to get there– Look at the literature– Take advice– “Start low go slow” but not to slow

• When reach initial target dose wait expected length of time for therapeutic response to occur– Remember that different effects take different times– Adverse events often arise earlier than therapeutic effects

Target Symptoms and Problems

• Core ADHD symptoms

• Behaviour in the home

• Classroom behaviour

• Academic functioning

• Peer group relationships

• Associated symptoms – rage, oppositionality etc.

Forced Dose Titration ‐ Dundee

• 4 week titration with weekly dose increments• Baseline and weekly monitoring conducted by nurses• Standardised forms and assessments

– 10 item Connors‐P & Connors‐T– ADHD‐RS ‐ clinician scored– CGI‐S & CGI‐I – clinician scored– Side effects – may be better rated as “other symptoms”

• End of titration – Dr and nurse joint visit

Maximum Benefit – Minimum Dose

Other symptomsNot

presentPresent but

not impairing

Present and impairing

Present and severely impairing

Write note↓

Insomnia or trouble sleeping 0 1 2 3Nightmares 0 1 2 3Drowsiness 0 1 2 3Nausea 0 1 2 3Anorexia (Less hungry than other children)

0 1 2 3

Stomach-aches 0 1 2 3Headaches 0 1 2 3Dizziness 0 1 2 3Sad/unhappy 0 1 2 3Prone to crying 0 1 2 3Irritable 0 1 2 3Thoughts of self-harm 0 1 2 3Suicidal ideation 0 1 2 3Euphoric/unusually happy 0 1 2 3Anxious 0 1 2 3Tics or nervous movements 0 1 2 3“Spaced-out” / “Zombie-like” 0 1 2 3Less talkative than other children 0 1 2 3Less sociable than other children 0 1 2 3

Forced Titration

0

2

4

6

8

10

ADHD‐RSHyp/Imp

ADHD‐RSInatt

CTRS CGAS Low Mood Irritability

Baseline

5mg tds

10mg tds

15mg tds

20mg tds

Single dose trials of MPH

• 5mg on weekend/holiday morning. Parents introduce cognitively demanding task 1 hour later, observe general effect

• 10 mg on another weekend/holiday morning• (15mg on another in teenagers)

Parents draw conclusion as to tolerance and likely effect. If favourable can discuss with prescriber, extend to mornings only during school week with e.g. CTRS‐R, comparing a.m. vs p.m.

Two models for introducing atomoxetine

1. Traditional0.5 mg/kg/day for 7 days, then 1.2 mg/kg/day

2. “German”7‐14 days each of 10 mg, 18, mg, 25 mg and so on following capsule size aiming for 1.2 mg/kg/day

In both instances hang on at 1.2 mg/kg/day for at least 8 (preferably 12) weeks before either giving up or

increasing dose

Monitoring ongoing treatment

• Teamwork

• Coherent and consistent protocols

• Routine measurement

• Identification of “other problems”

• Remember the importance of concordance and adherence

Team Treatment

• Multimodal treatments are often the most appropriate, and one person generally can not do it all

• The team must be mutually supportive

• Don’t underestimate the role/task of the pharmacotherapist

Measurement

• Clinical improvement– Diagnostic specific symptoms– Associated symptoms– Global measures

• Combine observer rated and patient rated measures but don’t assume they measure the same things

USE APPROPRIATE VALID INSTRUMENTS AT APPROPRIATE TIMES

Continuing Care – Dundee Protocol

• Regular follow up appointments by doctor and nurse, particularly at the outset of treatment and for those with complex comorbidity

• Main aims are – to monitor medication– Identify “other problems” which require further assessment / treatment

• The continued routine use of standardised– Data capture proforma– Assessment tools

• ADHD‐RS• CGI‐S & CGI‐I• Side effects

• Teacher Conners before each appointment

• Record weight, height and BP at least six monthly

OPTIMISING TREATMENT WITH LONG ACTING STIMULANT PREPARATIONS

If...If ...you are going to start an extended‐

release stimulant preparation how

do you decide which one to use?

ANSWER

The one that best suits that child at that time

This will depend on pharmacodynamic profile This is determined by:• Methylphenidate or Amfetamine• Proportions IR/ER• Duration of action• Delivery mechanism

Methylphenidate – Concerta XL, Equasym XL / Metadate CD, Medikinet Retard

Duration of action • Equasym XL, Medikinet Retard = 8 hours

• Concerta XL = 12 hours

IR / ER proportions• Concerta XL = 22 / 78 %

• Equasym XL = 30 / 70 %

• Medikinet Retard = 50 / 50 %

Banaschewski T et al., Eur Child Adolesc Psychiatry 2006;15(8):476-495

Pharmacokinetic ProfilesBanaschewski T et al. Eur Child Adol Psych 2006

Ritalin® LA 40 mg = 20mg IR

Equasym® XL 60 mg = 18 mg IR

Concerta® 54 mg = 12 mg IR

Time (h)

0 5 10 150

5

10

15

20

Mean d,l‐m

ethylphe

nidate

plasma levels (n

g/mL)

Bioavailability of different MPH-ER Products

Ritalin® 20 mg BID = 20 mg IR

Gonzalez MA, et al. Int J Clin Pharmacol Ther. 2002;40:175‐184..

Medication 0 – 4 hours- IR

4 – 8 hours 8 – 12 hours

Equasym XL 10mgs 3mgs 7mgs +/- MPH IR

Concerta XL 18 mgs 4mgs 14mgs

Methylphenidate IR 5mgsBD/TDS

5mgs 5mgs 5mgs

Ritalin LA 10mgs 5mgs 5mgs +/- MPH IR



Concerta XL 36mgs 8mgs 28mgs


Methylphenidate IR 10mgs BD/TDS 10mgs 10mgs 10mgs


Concerta XL 45 mgs 10mgs 35 mgs

Equasym XL 40 mgs 12mgs 28mgs +/- MPH IR







Equasym XL 60mgs 18mgs 42mgs



Medication 0 – 4 hours(IR)

4 – 8 hours 8 – 12 hours



Methylphenidate IR 5mgs BD/TDS

5mgs 5mgs 5mgs



XX X

X

X

XX X

X X

Lunchtime

Even after a settled morning seems to be getting into constant bother in playground and at dinner. School observation suggests this is due to breakthrough symptoms rather than any psychosocial probs.

Peers avoiding contact, often kept in at breaktime

Problems at weekend as haingdifficulties at football

Switch from IR MPH to either Concerta to see if helps to manage breakthrough symptoms

XX

X

X

X

XX X

X X

Changing Treatments

• Ensuring optimization of current treatment

• Switching treatment

• Combining different formulations

• Combining different medications

Questions you could ask before changing to a different drug

• Have I titrated properly?• Is this drug/preparation working well at any times during the

day?• Have I got good enough information from school• Are parents and school in agreement about the effects of the

drug?• Am I targeting the right symptoms?• Is there a behavioural explanation for the drug “wearing off”• What else is going on in patients life / family life?• Is the medication working but effects limited by side effects?• Have I missed any comorbidity?• Is the diagnosis right?

European Guidelines Summary of results

IR stimulants ER stimulants Atomoxetine

Efficacy● Effect sizes● Numbers needed to

treat

++++

++++

+++

Efficacy duration + ++ ++

Compliance + ++ (?) ++ (?)

Dosing flexibility ++ + +

Abuse potential ++D-AMP: +++

+ (?) -

Costs - - - - -

European Guidelines Summary of recommendations

• If a child responded to immediate‐release methylphenidate there could be reasons to move them to extended‐release

• If a child had an adverse event on methylphenidate then next step often to move to atomoxetine

• If a child has failed to respond to methylphenidate, the next option may be dexamfetamine or atomoxetine

• Choice of extended‐release preparation will depend on profile of action over time

intelligent prescribing - mm3 admin€¦ · taylor, santosh & swanson (2002) submitted...

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