Transcript Pain Management in Pediatrics

Pharmacological Approaches
to Pain Control
Robert J. Kuhn, Pharm.D
Kentucky Hospital Association Endowed
Professor, Division of Pharmacy Practice
and
Pediatric Pulmonology
Colleges of Pharmacy and Medicine
University of Kentucky
Objectives
• Apply the six rules of management for pediatric
pain control
• Discuss practical aspects of therapy in
neonates, infants and children
• Discuss the dosing of PCA in pediatric patient
and general guidelines for use in children
• Evaluate the use of ambulatory outpatient pain
medication for post-operative patients
• Evaluate and calculate the dosing of opoids in
children with cancer for long term pain relief
• www.childcancerpain.org
Why is pediatric pain
management inadequate?
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Fixed IM dose of narcotic is prescribed
Exaggerated concern about side effects
Delegation of pain treatment
Lack of positive reinforcement
Belief that children do not feel pain
Inadequate knowledge
Problem with pain measurement
Barriers to Pain Management:
Myths
Myth
-Young infants do not feel
pain
-Children easily become
addicted to narcotics
-Children tolerate pain
better than adults
-Children are unable to tell
you where they hurt
Truth
-The central nervous system of a
26-week old fetus experiences
nociception (Anand, 1998)
-Less than 1% of children treated
with opiods develop addiction
-Children’s tolerance for pain
increases with age
-Children can express and identify
pain with the use of proper
pain assessment scales
Barriers to Pain Management:
Myths
Myth
-Children become
accustomed to pain or
painful procedures
-Children will tell you when
they are experiencing pain
-Children’s behavior reflects
their pain intensity
Truth
-Children’s anxiety and
perception of pain increases
-Not always. Ex: fear of
another injection or
hospitalization, lack of
adequate communication
skills or knowledge
-Children experiencing pain
may be active and playing
“normally”; unique coping
skills
Assessment of Pain
• Accurate assessment is a challenge
• Essential to determine effective treatment
• Usually done based on the subjective
clinical assessment of the MD/RN or both
• Use of standardized objective, validated,
reliable method to assess distress
Pain Intensity Ratings
NCCN Practice Guidelines in Oncology. Pediatric Cancer Pain
Pain Intensity Ratings
NCCN Practice Guidelines in Oncology. Pediatric Cancer Pain
Approaches to Effective
Therapy
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Anticipate and prevent pain
Logical sequence for drugs used
Adequate and regular dosing
Appropriate route of administration
Non-Pharmacologic
Management
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Allow for uninterrupted sleep if possible
Provide familiar toys
Give ready access to parent/caregiver
Age-appropriate pre-procedure teaching
Neonatal Pain Control
• 24% solution of Sucrose
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Release of endorphins
Dramatic improvement of pain scores
Standard of care in NICU
2-4 milliliters
May be used prior to painful procedurese.g. circumcision, venipunture
• Sweet-ease and Ora-sweet
Six Rules for Pain
Management of the Pediatric
Patient
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4)
5)
6)
Know the onset of action of the drug
Know when the peak effect will occur and be ready
to monitor
Know the duration of action of the drug
Calculate equipotent doses based on the patient’s
requirement and adjust
Expect and anticipate tolerance: switch or increase
the dose
Angel of Mercy Rule: if on narcotics >24 hrs, start
an osmotically active laxative
NSAIDS and Acetaminophen
Drug
Dose
Acetaminophen 10 – 15 mg/kg
orally/rectally
every 4 – 6
hours
Formulations
Comments
tablet, chew tab, lacks antidrops, suspension, inflammatory
& suppository
activity
Ibuprofen
5 – 10 mg/kg
tablet, chew tab,
orally every 6 – suspension, &
8 hours
drops
Naproxen
5 – 10 mg/kg
tablet, delayed
orally every 8 – release tablet &
12 hours
suspension
delayed
release tabs
given twice
daily
Salicylates
(aspirin)
10 – 15 mg/kg
orally/rectally
every 4 – 6
hours
Reye’s
syndrome
tablet, chew tab,
& suspension
Ketoralac
NSAID used for short term (<5 days)
management of moderate to severe pain
• At equianalgesic doses, considered to have
less post-op N/V than morphine
• Opioid sparing
• Dose: 0.5 mg/kg IV/IM every 6 - 8 hours
(max dose of 60 mg) for 48 - 72 hours
• Disadvantages: cost & side effect profile
General Rules for Narcotics
(excluding neonates and special dosing forms)
Route
• IV administration
• SC or IM
• Oral
• Patch
Peak effect
• 3-5 minutes
• 20-30 minutes
• 60 minutes
• 8-16hours
Opoids
• “Gold standard”: morphine
• At low doses, analgesia usually occurs w/out loss of
consciousness
• Agents differ w/ regard to adverse effects
– CV effects: greatest w/ naturally occurring agents
(i.e. morphine)
• venodilation  decreased BP in hypovolemic
pts
• better alternative: synthetic agents (i.e.
fentanyl- CHEST WALL RIGIDITY IN INFANTS
Disadvantages to Opioid
Administration
• Side effects at equipotent doses
– N/V, pruritus, miosis, constipation, urinary
retention, seizures
– dose-dependent respiratory depression
• “Ceiling effect” with codeine and at higher
doses other oral forms- oxycodone
• Risk for pain cycling with prn administration
• IM administration should be avoided
– erratic absorption and ineffective analgesia
– denial of pain to avoid a “shot”
Initial PCA Dosage in Children
• Opioid naïve children
– Morphine 0.02 mg/kg/hr with boluses of
0.02 mg/kg q 15 mins
– May use equianalgesic doses of
hydromorphone or fentanyl
– Titrate to desired effect
NCCN Practice Guidelines in Oncology. Pediatric Cancer Pain
Codeine in the Spotlight
http://www.fda.gov/Drugs/DrugSafety/ucm313631.htm
Codeine in the Spotlight
• Usual dose: 0.5 – 1 mg/kg/dose every 4 – 6h
(max: 60 mg/dose)
• “Ultra – rapid metabolizing”
– Convert up to 75% more codeine to morphine than
extensive metabolizers
Prevalence of Ultra-Rapid
Metabolizers
Population
UM Genotypes/Phenotypes
(↑ Activity)
Prevalence %
(UM/Total n)
African/Ethiopian
UM (active duplicate genes)
29% (35/122)
African American
UM (three active duplicate
genes)
3.4% (3/87)
6.5% (60/919)
Asian
UM (active duplicate genes)
1.2% (5/400)
2%
Caucasian
UM (three active duplicate
genes)
3.6% (33/919) 6.5% (18/275)
Greek
CYP2D6*2xN/UM
6.0% (17/283)
Hungarian
UM (active duplicate genes)
1.9%
Northern European
UM (active duplicate genes)
1-2%
Pharmacogenomics Recap
The study of genetic factors that influence the variability
in drug response among patients
Polymorphisms exist on:
Drugmetabolizing
enzymes
Am J Health-Syst Pharm 2011.68:143-50.
Drug
transporters
Drug targets
Pharmacogenomics: Prodrug
Population with Disease
Non-Responders
Responders
High Toxicity Risk
Kennedy et al. PSAP VII.
Low Toxicity Risk
Pharmacogenomics: Active Drug
Population with Disease
Non-Responders
High Toxicity Risk
Kennedy et al. PSAP VII.
Responders
Low Toxicity Risk
Metabolism of Codeine
Norcodeine
Codeine
Codeine-6 glucuronide
CYP2D6
Morphine
Morphine-3glucuronide
Morphine-6glucuronide
Clinical Pharmacology & Therapeutics 2011. 1-6.
Normorphine
Codeine Phenotypes and
Genotypes
Likely Phenotype
Genotypes
Examples of Diplotypes
Ultrarapid metabolizer
(~1-2% of patients)
Carry more than 2
functional alleles
Clinical Pharmacology & Therapeutics 2011. 1-6.
*1/*1/*1, *1/*2/*2
Codeine Phenotypes and
Genotypes
Likely Phenotype
Genotypes
Examples of Diplotypes
Ultrarapid metabolizer
(~1-2% of patients)
Carry more than 2
functional alleles
*1/*1/*1, *1/*2/*2
Extensive Metabolizer
(~77-92% of patients)
Carry 2 functional or
reduced function alleles,
Carry 1 functional allele
with a nonfunctional or
reduced function allele
*1/*1, *1/*2, *2/*2, *1/*41,
*1/*4, *2/*5, *10/*10
Clinical Pharmacology & Therapeutics 2011. 1-6.
Codeine Phenotypes and
Genotypes
Likely Phenotype
Genotypes
Examples of Diplotypes
Ultrarapid metabolizer
(~1-2% of patients)
Carry more than 2
functional alleles
*1/*1/*1, *1/*2/*2
Extensive Metabolizer
(~77-92% of patients)
Carry 2 functional or
reduced function alleles,
Carry 1 functional allele
with a nonfunctional or
reduced function allele
*1/*1, *1/*2, *2/*2, *1/*41,
*1/*4, *2/*5, *10/*10
Intermediate metabolizer
(~2-11% of patients)
Carry 1 reduced and 1
nonfunctional allele
*4/*10, *5/*41
Clinical Pharmacology & Therapeutics 2011. 1-6.
Codeine Phenotypes and
Genotypes
Likely Phenotype
Genotypes
Examples of Diplotypes
Ultrarapid metabolizer
(~1-2% of patients)
Carry more than 2
functional alleles
*1/*1/*1, *1/*2/*2
Extensive Metabolizer
(~77-92% of patients)
Carry 2 functional or
reduced function alleles,
Carry 1 functional allele
with a nonfunctional or
reduced function allele
*1/*1, *1/*2, *2/*2, *1/*41,
*1/*4, *2/*5, *10/*10
Intermediate metabolizer
(~2-11% of patients)
Carry 1 reduced and 1
nonfunctional allele
*4/*10, *5/*41
Poor metabolizer
(~5-10% of patients)
Carry no functional alleles
*4/*4, *4/*5, *5/*5, *4/*6
Clinical Pharmacology & Therapeutics 2011. 1-6.
Alternatives to Codeine/APAP
• Hydrocodone/APAP (tablet, solution)
– Oral solution, 7.5 (hydrocodone) – 500 mg
(APAP)/15mL
– Children and adolescents < 50 kg:
• 0.1 – 0.2 mg/kg every 4 - 6 hours
– Children and adolescents ≥ 50 kg:
• 5 – 10 mg every 4 - 6 hours
– Onset of action: 10 – 20 minutes
– Toxicity in CYP2D6 ultra-rapid metabolizers is
diminished
Alternatives to Codeine/APAP
• Oxycodone/APAP (tablet, solution)
– Oral solution, 5 (oxycodone) – 325 mg
(APAP)/5mL
– Children and adolescents, mild – moderate pain:
• 0.1 – 0.2 mg/kg every 4 - 6 hours (maximum: 50 mg
oxycodone)
– Children and adolescents, severe pain:
• 0.2 mg/kg/dose every 4 – 6 hours (maximum APAP: 90
mg/kg/day or 4000 mg)
– Onset of action: 10 – 15 minutes
– Toxicity in CYP2D6 ultra-rapid metabolizers is
diminished
Alternatives to Codeine/APAP
• Acetaminophen ATC
– Oral solution, 160 mg/5 mL
– Dosing:
• 10 – 15 mg/kg/dose every 4 – 6 hours (Maximum: 4
g/day)
– For less severe pain cases such as
tonsillectomy
– Should be given around the clock to prevent
pain spikes
Opioid Analgesic Comparison
Drug
Onset (min)
Duration (h)
Equianalgesic
I.M. Dose (mg)
Equianalgesic
P.O. Dose (mg)
100 – 130
200
Codeine
IM: 10 – 30
PO: 30 – 60
4–6
Fentanyl
IM: 7 – 15
IV: Immediate
IM: 1 – 2
IV: 0.5 – 1
0.1
---
Hydrocodone
PO: 10 – 20
3–6
---
30 – 45
Hydromorphone
PO: 15 – 30
4–5
1.5
7.5
Morphine
PO (immediaterelease): 15 – 60
IV: ≤ 5
PO (immediate-release),
IV, IM, SubQ: 3 – 5
Extended-release: 8 – 12
10
30
Oxycodone
PO (immediaterelease): 15 – 30
PO: immediate-release: 4 – 5
Controlled release: 12
---
20
Parenteral to Enteral
Conversion
Drug
Conversion
factor (PO to
IV)
Equi-analgesic Dose
IV
Equi-analgesic
Dose PO
Morphine
3:1
0.1 mg/kg/dose IM/IV
every 1 – 4 hours
0.3 mg/kg every 3 –
6 hours
Fentanyl
---
0.5 – 1 mcg/kg every 1
– 2 hours
Meperidine
1:1
1 mg/kg/dose IM/IV
every 3 – 4 hours
Codeine
---
0.5 – 1 mg/kg/dose
every 4 – 6 hours (max
= 60 mg/dose)
---
Oxycodone
---
0.05 – 0.2 mg/kg/dose
every 4 – 6 hours
---
Hydromorphone
5:1
0.015 mg/kg/dose
every 4 – 6 hours
--1 mg/kg/dose every
3 – 4 hours
0.03 – 0.08
mg/kg/dose every 4
– 6 hours
IV to PO Conversion Example
• Example:
– 20 kg patient- 6 year old
– Morphine 2 mg IV q 3 hours- received 3 doses last 24 hours.
Patient/parent report that pain has been well controlled.
– Ready for discharge. Need Rx for PO oxycodone for home
– Morphine IV: 2 mg x 3 doses/24 hours = 6 mg/day
– Morphine PO:
• Morphine IV: PO = 1:3 (1mg IV-3mg po)
• 16 mg IV = 18 mg PO
– Oxycodone PO:
• Morphine PO:Oxycodone PO = 1.5:1 (30mg Morphine=20mg
oxycodone
• 18 mg PO (morphine) = 12 mg PO (oxycodone)
– Oxycodone solution (5 mg/5mL) 4 mg (4 mL) PO every 6
hours
• 0.2 mg/kg/dose PO every 6 hours
Pharmacist Assessment
• Collect- Total Morphine dose and pain score-6mg IV
morphine and good pain scores
• Assess: Pain well controlled and should not get worsepatient improving
• Plan- Conversion to oral therapy with dose calculations
and outpatient RX- Consider a bowel regimen due to
anticipated side effect: Constipation
• Implement-Fill Rx and counsel patient- palpability
issues?- Start Bowel regimen miralax 1 cap two times a
day
• Follow Up- Call next day and check with patients/parents
• IF sleepy and no pain-lower or stop med- if more pain –
consider increase in dose or reassessment
Parenteral to Enteral
Conversion
Drug
Conversion
factor (PO to
IV)
Equi-analgesic Dose
IV
Equi-analgesic
Dose PO
Morphine
3:1
0.1 mg/kg/dose IM/IV
every 1 – 4 hours
0.3 mg/kg every 3 –
6 hours
Fentanyl
---
0.5 – 1 mcg/kg every 1
– 2 hours
Meperidine
1:1
1 mg/kg/dose IM/IV
every 3 – 4 hours
Codeine
---
0.5 – 1 mg/kg/dose
every 4 – 6 hours (max
= 60 mg/dose)
---
Oxycodone
---
0.05 – 0.2 mg/kg/dose
every 4 – 6 hours
---
Hydromorpho
ne
5:1
0.015 mg/kg/dose
every 4 – 6 hours
--1 mg/kg/dose every
3 – 4 hours
0.03 – 0.08
mg/kg/dose every 4
– 6 hours
Opioid Analgesic Comparison
Drug
Onset (min)
Duration (h)
Equianalgesic
I.M. Dose (mg)
Equianalgesic
P.O. Dose (mg)
100 – 130
200
Codeine
IM: 10 – 30
PO: 30 – 60
4–6
Fentanyl
IM: 7 – 15
IV: Immediate
IM: 1 – 2
IV: 0.5 – 1
0.1
---
Hydrocodone
PO: 10 – 20
3–6
---
30 – 45
Hydromorphone
PO: 15 – 30
4–5
1.5
7.5
Morphine
PO (immediaterelease): 15 – 60
IV: ≤ 5
PO (immediate-release),
IV, IM, SubQ: 3 – 5
Extended-release: 8 – 12
10
30
Oxycodone
PO (immediaterelease): 15 – 30
PO: immediate-release: 4 – 5
Controlled release: 12
---
20
Don’t Forget a Bowel Regimen
Bowel Regimens
Senna liquid (8.8 mg/5mL)
Recommended
with opioid
treatment > 3 days
2 – < 6 years
2.7 – 3.75 mL at bedtime
6 – 12 years
6 – 7.5 mL at bedtime
> 12 years
10 – 15 mL at bedtime
Senna tablets (8.6 mg/tablet)
2 – < 6 years
½ tablet at bedtime
6 – 12 years
1 tablet at bedtime
> 12 years
2 tablets at bedtime
Docusate (liquid 50 mg/5mL, capsule 50, 100,
250 mg)
< 3 years
10 – 40 mg/day divided 1 – 4 doses
3 – 6 years
20 – 60 mg/day divided 1 – 4 doses
6 – 12 years
40 – 150 mg/day divided 1 – 4 doses
Don’t Forget a Bowel Regimen
Bowel Regimens
Recommended
with opioid
treatment > 3 days
Senna + Docusate (Senokot-S tablet, 50 mg
docusate, 8.6 mg sennosides)
2 – < 6 years
½ tablet at bedtime
6 – < 12 years
1 tablet at bedtime
> 12 years,
adults
2 tablets at bedtime (max: 4
tablets twice daily)
Miralax (Polyethylene glycol 3350, 1 capful =
17 g)
> 6 months
0.5 – 1.5 g/kg/day*
* Round to nearest ¼ of cap (i.e. 4.25, 8.5,
12.75, 17g)
Newer Bowel Regimen
Alternative in children
• Polyethyelene Glycol
3500 “aka” Miralax
• Safe to use in
children
• 8.5mg-17gms Two
times a day
• Aggressive Treatment
• Miralax 17gms orally
every 2 hours x 4
doses for severe
constipation
• Sorbitol oral solution
• 70%
• 10-15ml two times a
day
• Great Taste
• Less filling
Pharmacist Assessment
• Collect- Total Morphine dose and pain score-6mg IV
morphine and good pain scores
• Assess: Pain well controlled and should not get worsepatient improving
• Plan- Conversion to oral therapy with dose calculations
and outpatient RX- Consider a bowel regimen due to
anticipated side effect: Constipation
• Implement-Fill Rx and counsel patient- palpability
issues?- Start Bowel regimen miralax 1 cap two times a
day
• Follow Up- Call next day and check with patients/parents
• IF sleepy and no pain-lower or stop med- if more pain –
consider increase in dose or reassessment
Benzodiazepines and Options
• Potential Lethal Combination in childrenMyth or reality
• Benzodiazepines- smooth muscle
relaxants with known respiratory
depressant activity
• Not a pain reliever- no analgesic
properties
• Treating agitation and anxiety in childrenjust like us.
Benzodiazepines and Options
cont
• Have I given a CNS sedating drug in the
last two hours?
• Has we changes the rate of the PCA in the
last three to four hours?
• Is the child on any long term medication
that is very sedating? If yes, any changes
in dose recently?
• Is this patient experiencing pain?
Benzodiazepines and Options
cont
• Rule -there is a much better chance that
treating the pain or anxiety is better than
side effects.
• If not, have the antidotes at hand
• Antidotes work in 30 seconds or less if
given IVP?
Topical Approach
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LMX- 4 % topical lidocaine
Indicated for topical administration to intact skin to
provide local anesthesia for minor procedures (IV
cannulation, venipuncture)
Apply generously to site & cover w/ airtight occlusive
dressing 1 hr prior to procedure
SE: local itching, pallor, & erythema
J-Tip- Needless injection with Buffered lidocaine
Inject- pain free for topical anesthesiaOnset of action 1-2 minutes
Duration 30 minutes
Sorting Out Opioid Allergies
• True immunologic opioid allergy is RARE
• Pseudoallergic drug reactions mimic true
immunologic reactions, but are not
immune-mediated  “nonimmune
hypersensitivity reactions or anaphylactoid
reactions”
• Direct stimulation of mast cells  release
of histamine
– Itching, flushing, hives, sweating and mild
hypotension may occur
Sorting Out Opioid Allergies
Opioid
Classification of
Chemical Source
Relative Histamine
Release
Buprenorphine
Semi-synthetic
No data
Codeine
Natural
High
Fentanyl
Synthetic
Low
Hydrocodone
Semi-synthetic
No data
Hydromorphone
Semi-synthetic
Low
Meperidine
Synthetic
High
Methadone
Synthetic
Low
Morphine
Natural
High
Nalbuphine
Semi-synthetic
No data
Oxycodone
Semi-synthetic
Low
Oxymorphone
Semi-synthetic
Low
Managing Opioid Allergies
Pharmacist Assessment
• Collect- Total Morphine dose and pain score-6mg IV
morphine and good pain scores
• Assess: Pain well controlled and should not get worsepatient improving
• Plan- Conversion to oral therapy with dose calculations
and outpatient RX- Consider a bowel regimen due to
anticipated side effect: Constipation
• Implement-Fill Rx and counsel patient- palpability
issues?- Start Bowel regimen miralax 1 cap two times a
day
• Follow Up-Call 12 hour later , rash,itching, pain still
present
Allergy- Duration of Action
• Collect- Patient History-phone call and symptoms
• Assess- True allergy to oxycodone but not to morphine
• Plan: Stop Meds- go to acetaminophen- ibuprofen not
indicated –risk of bleeding
• Methadone-oral option- long acting
• Conversion- Methadone 1:1 with morphine but longer
duration of action dose every 12 hours
• 4mg oxycodone= 4mg methadone but every 12 hours
instead of every 4-6 hours.
Implement:Convert to 4mg of methadone every 12 hours
liquid preparation only 5mg tablets
Follow Up: Patient well controlled on 4mg methadone every
12 hours
Conclusions
• Should adapt more aggressive approach
toward managing acute pain in children
• Available therapeutic options are broad,
safe and effective at adequate doses
• Many new drugs are on the horizon
• Primary endpoint:
“It doesn’t hurt anymore”
Questions