1. No category

The Presidential Plenary:
“Pain Management”
Stefan J. Friedrichsdorf, MD, FAAP
Medical Director, Department of Pain Medicine, Palliative Care & Integrative Medicine,
Children's Hospitals and Clinics of Minnesota, Minneapolis/St. Paul, MN
Associate Professor of Pediatrics, University of Minnesota Medical School
[email protected]
Twitter: @NoNeedlessPain
Pain after burn injury:
Multifactorial
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Acute Pain
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Tissue damage, repetitive trauma
Procedural Pain
Dressing changes, Intravenous access
Neuropathic Pain Portilla AS1, Bravo GL, Miraval FK, Villamar MF, Schneider JC, Ryan CM, Fregni F J Burn Care Res. 2013
Jan-Feb;34(1):e48-52. A feasibility study assessing cortical plasticity in chronic neuropathic pain following burn injury. xxJ Schneider JC1, Harris
NL, El Shami A, Sheridan RL, Schulz JT 3rd, Bilodeau ML, Ryan CM
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Psycho-spiritual-spiritual Pain
Chronic Pain
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Pain can persist after healing Dauber et al. Chronic persistent pain after severe burns. A survey of 358 burn
survivors. Pain Med 2002; 3:6-17.
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n=358; burns covering an average of 59% of their bodies
12 years laster: 52% of respondents reported ongoing burn-related pain
Discuss the four WHO-principles of acute pain management & review
concept of multimodal analgesia
Review the evidence for importance of managing procedural pain (from
IV access to dressing changes): topical anesthesia, positioning, and
distraction (& sucrose if <12 months) plus/minus sedatation
Appreciate high prevalence of neuropathic pain in patients with burn
injuries and discuss a step-by-step treatment approach
Today’s Presentation
✤
Part 1: Acute Pain
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Part 2: Procedural Pain
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Part 3: Neuropathic Pain
Pediatric Pain - Status Quo
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Under treatment of pain in
children
Parents expect pain to be relieved
Forgeron PA, Finley GA, Arnaout M. Pediatric pain prevalence and parents' attitudes at a
cancer hospital in Jordan. J Pain Symptom Manage. 2006; 31(5):440-8.
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Parents’ greatest distress: failing to
protect their child from pain
Tiedeman, M.
(1997). Anxiety responses of parents during and after the hospitalisation of their 5 - to -11 year
old children. Journal of Pediatric Nursing, 12(2), 110-119. Melnyk BM. Intervention studies
involving parents of hospitalized young children: an analysis of the past and future
recommendations. J Pediatr Nurs. 2000 Feb;15(1):4-13.
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Assumption: everything possible is
done
Anand’s neonatal surgery studies
Pediatric Pain - Status Quo
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USA: adults receive more than
two - three times as many
analgesic doses as children
(with identical diagnoses)
(1) Eland JM,
Anderson JE: The experience of pain in children. In: Jacox A (ed). Pain: a source
book for nurses and other health care professionals. Boston: Little Brown & C0;
1977:453-78 (2) Beyer JE, DeGood DE, Ashley LC, Russell GA. Patterns of
postoperative analgesic use with adults and children following cardiac surgery.
Pain. 1983 Sep;17(1):71-81. (3) Schechter NL, Allen DA, Hanson K. Status of
pediatric pain control: a comparison of hospital analgesic usage in children and
adults. Pediatrics. 1986 Jan;77(1):11-5.
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The younger children are, the
less likely they receive
appropriate analgesia
Broome ME, Richtsmeier
A, Maikler V, Alexander M. Pediatric pain practices: a national survey of health
professionals. J Pain Symptom Manage. 1996 May;11(5):312-20.; Nikanne E,
Kokki H, Tuovinen K. Postoperative pain after adenoidectomy in children. Br J
Anaesth. 1999 Jun;82(6):886-9.
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Compared to adults, pediatric
patients receive fewer and/or
incorrectly dosed analgesics in
daily routine
2002;18:262-269.
Ellis JA, et al. The Clinical Journal of Pain.
Inappropriate Analgesia: Why
Bother...?
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Children with persistent pain suffer
more physical symptoms in adult
life, more anxiety and more
depression
Development Study
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1946 Medical Research Council and 1958 National Child
Inadequate analgesia for initial
procedures in children diminishes
effect of adequate analgesia in
subsequent procedures
Weisman SJ, Bernstein B,
Schechter NL: Consequences of inadequate analgesia during painful procedures in children.
Arch Pediatr Adolesc Med 1998. 152:147-9
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NICU: increased morbidity &
mortality
Anand KJ, Barton BA, McIntosh N, Lagercrantz H, Pelausa E, Young
TE, et al. Analgesia and sedation in preterm neonates who require ventilatory support: results
from the NOPAIN trial. Neonatal Outcome and Prolonged Analgesia in Neonates. Arch
Pediatr Adolesc Med. 1999 Apr;153(4):331-8
Trauma & post-traumatic stress
disorder (PTSD)
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US soldiers after serious injury: Use
of morphine during trauma care
reduces risk of subsequent
development of PTSD
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Holbrook TL, Galarneau MR, Dye
JL, Quinn K, Dougherty AL. Morphine use after combat injury in Iraq and post-traumatic
stress disorder. The New England journal of medicine. 2010 Jan 14;362(2):110-7.
6-16 year-olds (n=24) with acute
burns: Children receiving higher
doses of morphine had greater
reduction in PTSD symptoms over 6
months
Saxe G, Stoddard F, Courtney D, Cunningham K, Chawla N, Sheridan R,
et al. Relationship between acute morphine and the course of PTSD in children with burns.
Journal of the American Academy of Child and Adolescent Psychiatry. 2001 Aug;40(8):915-21.
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Children (n=48) with injury that led
to hospital treatment: Morphine was
associated with lower levels of
PTSD at follow-up 6 months later
Nixon
RD, Nehmy TJ, Ellis AA, Ball SA, Menne A, McKinnon AC. Predictors of posttraumatic stress
in children following injury: The influence ofappraisals, heart rate, and morphine use.
Behaviour research and therapy. 2010 Aug;48(8) 810-5.
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12- to 48-month-old (n=70) children
with acute burns admitted to major
pediatric burn center: Management
of pain with higher doses of
morphine associated with
decreasing number of symptoms of
PTSD in months after major trauma.
Stoddard FJ, Jr., Sorrentino EA, Ceranoglu TA, Saxe G, Murphy JM, Drake JE, et al.
Preliminary evidence for the effects of morphine on posttraumatic stress disorder symptoms
in one- to four-year-olds with burns. J Burn Care Res. 2009 Sep-Oct;30(5):836-43.
Myths and Barriers to Using
Opioids?
Assumptions #1: Addiction
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Addiction → a chronic relapsing
condition characterized by
persistent, compulsive dependence
on a behaviour or substance despite
adverse consequences
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Tolerance does NOT equal
addiction
Withdrawal → distressing
symptoms occur if opioids
discontinued or tapered too fast (or
opioid antagonist given)
Beware of “Pseudo-addiction”
Tolerance → Decrease in drug effect
as result to prior exposure to the
drug (for analgesia and/or adverse
effect)
Assumptions #2: Over-Sedation
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Misconception that goal of opioid
use is to sedate
✤
Patients/Parents do NOT have to
choose between poor pain control or
over sedation
Goal is to provide excellent
symptom control (pain, dyspnea)
while maintaining function
Over sedation / Drowsiness /
desaturation is occasionally
experienced after opioid initiation
or dose increase
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Good analgesia: decrease dose
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Poor analgesia: opioid rotation
Common Opioid Assumptions
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✤
✤
Addiction
✤
Over Sedation / Respiratory
Depression
Maxwell LG. PAIN MANAGEMENT FOLLOWING
MAJOR INTRACRANIAL SURGERY IN PEDIATRIC
PATIENTS: A PROSPECTIVE COHORT STUDY IN
THREE ACADEMIC CHILDREN’S HOSPITALS Pediatric
Critical Care Medicine: May 2014 - Volume 15 - Issue
4_suppl - p 77. Abstracts of the 7th World Congress on
Pediatric Critical Care
Ileus / Gut hypomobility /
Constipation
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Medication “Too strong”
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Masking symptoms:
✤
Abdominal Pain
✤
Ranji SR, Goldman LE, Simel DL,
Shojania KG. Do opiates affect the clinical evaluation of patients with abdominal
pain? JAMA 2006: 296:1764-74
Opioids after major cranial
surgery in children do NOT
result in altered mental status
nor respiratory depression
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As always... Think first
(compartment syndrome?)...
analgesia second... Masking
symptoms
How Do We Manage Acute Pain in
Children?
No Needless Pain
Multimodal Analgesia
WHO guidelines on the pharmacological treatment
of persisting pain in children with medical illnesses
http://whqlibdoc.who.int/publications/2012/9789241548120_Guidelines.pdf
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Dosing at regular intervals (“By the Clock”)
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Adapting treatment to the individual child (“With the Child”)
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Using the appropriate route of administration (“By the appropriate
route)
Using a two-step strategy (“By the Analgesic Ladder”)
WHO Principle 1: Dosing at Regular
Intervals
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When pain is constantly present,
analgesics should be administered,
while monitoring side-effects, at
regular intervals
✤
PRN (as needed) only:
May take several hours &
higher opioid doses to relieve
pain
✤
“By the clock” and NOT as an “as
needed” (or “PRN”) basis
Results in cycle of
undermedication and pain,
alternating with periods of
overmedication and drug
toxicity
✤
Regular scheduling ensures a
steady blood level, reducing the
peaks and troughs of PRN (“as
needed”) dosing
American Pain Society: Principles of Analgesic Use in the
Treatment of Acute Pain and Cancer Pain 2008. 24-27
PRN = Patient Receives Nothing
WHO Principle 2: Adapting
Treatment to the Individual Child
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Treatment should be tailored to
the individual child and opioid
analgesics should be titrated on
an individual basis
At analgesic dosing: no
sedation expected
Dose of strong opioids: only
the sky is the limit
✤
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The effective dose is what
relieves the pain
✤
Effective dose must be
adjusted to child’s needs
✤
Assess response frequently
Pain Scales
✤
Different children may
respond differently to same
dose
Look for opioid-induced
side effects and toxicity
✤
Switching Opioids
Differences between opioids in the balance between analgesic crosstolerance level and the level of cross-tolerance to adverse effects can be
exploited to clinical advantage.
Switching opioids can possibly achieve a more favorable balance
between analgesia and adverse effects, hence the rationale for trial of a
different opioid in the event of toxicity or inadequate analgesia.
Lawlor P (2001) Dose Ratios Among Different Opioids. In: Bruera E, Portenoy RK (ed) Topics in Palliative Care Vol 5; Oxford
University Press, pp 247-76
Analgesia
Side effects
Side effects
Analgesia
Pain Assessment
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Patients simultaneously may experience different qualities, including
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Nociceptive Pain
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Somatic Pain
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Visceral Pain
Psycho-social-spiritual Pain (“Total Pain”)
and/or Neuropathic Pain
and/or Chronic Pain
Be creative when measuring pain: a single pain score often will not be enough:
Regular (!) Pain Assessment
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One-dimensional self-report
scores
Multi-dimensional rating scores
Route of Administration
i.v. / s.c.
i.m.
nebulization?
Analgesic
Drugs
transmucosal
oral
transdermal
intranasal
(MAD
device)
sublingual
suppository
WHO Principle 4:
Using a Two-Step Strategy
WHO Step 1
Mild Pain
Ibuprofen
and/or
Acetaminophen
(Paracetamol)
Other NSAIDs?
Cox-2 Inhibitor?
Citius, Altius, Fortius...?
✤
Ibuprofen salts: fast-acting
formulations
✤
Moore, R.A., et al., Faster, higher, stronger? Evidence
for formulation and efficacy for ibuprofen in acute pain. Pain, 2014. 155(1): p. 14-21.
✤
✤
produced significantly better
analgesia over 6h, fewer remedications than standard
formulations
200-mg fast-acting ibuprofen
(NNT 2.1; 95% confidence
interval 1.9-2.4) was as
effective as 400 mg standard
ibuprofen (NNT 2.4; 95% CI
2.2-2.5), with faster onset of
analgesia.
✤
More rapid absorption,
faster initial pain reduction,
good overall analgesia in
more patients at the same
dose, and probably longerlasting analgesia, but with
no higher rate of patients
reporting adverse events.
However, earlier onset
preferred in other pain
condition, such as chronic
nociceptive or neuropathic
pain?
Peloso, P.M., Faster, higher, stronger: to the gold medal podium?
Pain, 2014. 155(1): p. 4-5.
Nociceptive Pathways & Primary Sites of Action of Analgesics
Thalamus
o
eur
dN
2n
n
Aδ
or
C
r
e
fib
Acetaminophen
(Paracetamol)
NSAIDs
Injury
Brain Regions that Modulate Pain
and Emotion
Somatosensory Cortex
Both
Pain
Insular Cortex
Isnard J, Magnin M, Jung J, Mauguiere F, GarciaLarrea L. Does the insula tell our brain that we are in
pain? Pain. 2011 Apr;152(4):946-51.
Prefrontal Cortex
Thalamus
Hippocampus
Anterior Cingulate Cortex
Apkarian AV, et al. Eur J Pain. 2005;9:463-484; Casey KL, Tran TD. Cortical mechanisms
mediating acute and chronic pain in humans. In: Cervero F, Jensen TS, eds. Handbook of
Clin Neurology. 2006:159-177; Charney DS, Nestler EJ, Bunney BS, et al, eds.
Neurobiology of Mental Illness. 2nd ed. 2004; Schweinhardt P, et al. Curr Opin Neurology.
2006;19:392-400
Amygdala
Slide with Permission: Barry Cole, Bob Dworkin, Roy Freeman, Charles Argoff, Howard
Fields
WHO Principle 4:
Using a Two-Step Strategy
WHO Step 1
Mild Pain
Ibuprofen
and/or
Acetaminophen
(Paracetamol)
Other NSAIDs?
Cox-2 Inhibitor?
WHO Step 2
Moderate to Severe Pain
Morphine
or
fentanyl,
hydromorphone,
oxycodone,
methadone
Morphine Pharmacokinetics
✤
✤
„A principle of pharmacokinetics teaches us that unless the
drug reaches the site of action, it cannot be expected to exert
its dynamic effect.
With morphine the situation is that when the drug dose not
reach the PATIENT, what hope is there for pain relief?”
Ghooi & Ghooi: Lancet 1998; 325:1625
WHO Principle 4:
Using a Two-Step Strategy
WHO Step 2
Moderate to Severe Pain
WHO Step 1
Mild Pain
Morphine
Intermediate
Step ?
Ibuprofen
and/or
Acetaminophen
(Paracetamol)
or
fentanyl,
hydromorphone,
oxycodone,
methadone
Tramadol
Other NSAIDs?
Cox-2 Inhibitor?
Codeine
Hydrocodone
Current body of evidence
cannot support whether the
main analgesic effect results
from hydrocodone or the
metabolite hydromorphone Singla,
A. and P. Sloan (2013). "Pharmacokinetic evaluation of
hydrocodone/acetaminophen for pain management." J Opioid
Manag 9(1): 71-80.
Inactive Prodrug:
Active Metabolite:
Codeine
Inactive? Prodrug*:
Hydrocodone
Morphine
Active Metabolite:
also
CYP3A4
Cytochrome P450 2D6
Hydromorphone
(Dilaudid®)
Nociceptive Pathways & Primary Sites of Action of Analgesics
Opioids
• Pre-synaptic nerve terminal
â Neurotransmitter release
Thalamus
• Post-synaptic nerve terminal:
Membrane hyperpolarization
o
eur
dN
2n
=> suppress neuronal excitability
n
Aδ
or
C
r
e
fib
Opioids
Acetaminophen
(Paracetamol)
NSAIDs
Injury
Multimodal (Opioid-sparing) Analgesia
Non-Opioids
• Acetaminophen /
Paracetamol
• NSAIDs
Opioids
• Tramadol („weak“)
• Morphine („strong“)
WHO-Principles
• “By the clock”
• “By the child”
• “By the appropriate
route”
• “By the WHO ladder”
Integrative Pain Management
✤
✤
State of the art pain
management in the 21st century
demands that pharmacological
management must be
combined with supportive and
integrative, nonpharmacological therapies to
manage a child's pain.
✤
✤
Cognitive behavioral
techniques (e.g. guided
imagery, hypnosis, abdominal
breathing, distraction,
biofeedback)
Acupuncture, acupressure,
aromatherapy
Physical methods (e.g. cuddle/
hug, massage, comfort
positioning, heat, cold, TENS)
Integrative Pain & Symptom
Management
✤
✤
A Pediatrician’s Top 10 Apps
for Distraction & Pain
Management
http://NoNeedlessPain.org
Nociceptive Pathways & Primary Sites of Action of Analgesics
Periaqueductal
grey (endorphins)
Thalamus
dN
2n
on
eur
ng
di
en ion
sc b i t
De nhi
I
+
Integrative
(non-pharmacological)
therapies
o
Aδ
rC
fib
er
Opioids
Injury
Acetaminophen
(Paracetamol)
NSAIDs
How does this stuff work...?
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✤
✤
Distraction significantly increased the activation of the cingulo-frontal
cortex including the orbitofrontal and perigenual anterior cingulate
cortex (ACC), as well as the periaquaeductal gray (PAG) and the
posterior thalamus.1 Active distraction techniques, such as imagery,
appear to modulate endorphine release in the midbrain, including the
periaqueductal grey and thereby increase activity of descending
inhibiting pathways thereby decreasing nociception from the dorsal
horn resulting in gate pain modulation during distraction.2-4
1.!
Valet M, Sprenger T, Boecker H, et al. Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during pain--an fMRI analysis. Pain. Jun 2004;109(3):399-408.
2.!
Tracey I, Ploghaus A, Gati JS, et al. Imaging attentional modulation of pain in the periaqueductal gray in humans. The Journal of neuroscience : the official journal of the Society for Neuroscience.
Apr 1 2002;22(7):2748-2752.
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3.!
Derbyshire SW, Osborn J. Modeling pain circuits: how imaging may modify perception. Neuroimaging clinics of North America. Nov 2007;17(4):485-493, ix.
✤
4.!
Bingel U, Wanigasekera V, Wiech K, et al. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med. Feb 16 2011;3(70):70ra14.
Multimodal (Opioid-sparing) Analgesia
Non-Opioids
• Acetaminophen /
Paracetamol
• NSAIDs
Opioids
• Tramadol? („weak“)
• Morphine („strong“)
Invasive Approaches
• Regional anesthesia
• Neuraxial anesthesia
- Epidural or intrathecal
- Nerve blocks
- Neurolytic blocks
• [Intraventricular opioids?]
• [Percutaneous cervical
cordotomy?]
Adjuvants
WHO-Principles
• “By the clock”
• “By the child”
• “By the appropriate
route”
• “By the WHO ladder”
Integrative
Therapies
• Massage
• Heat/cold
• Deep Breathing
• Biofeedback
• Hypnosis
• etc.
• Alpha-Agonist
• Anticonvulsants
• TCA/Antidepressants
• NMDA-channel blockers
• Na-channel blockers
• Antispasmodics
• Benzodiazepines
• Corticosteroids
• Muscle relaxants
• Radiopharmaceuticals
• Bisphosphonates
• etc.
Today’s Presentation
✤
Part 1: Acute Pain
✤
Part 2: Procedural Pain
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Part 3: Neuropathic Pain
Procedural Pain in Children: From
IV access to dressing change
http://www.cartoonistgroup.com
Procedural Pain Management
5-year Marius requires stitches in ED
2014
Procedural Pain: A call for action
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✤
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What are children most afraid of
coming to our clinical service?
Needle procedures (incl. vaccine
injections) performed in childhood
are a substantial source of distress
It is estimated that up to 25% of
adults have a fear of needles
Guideline statement: management of
procedure-related pain in children
and adolescents.J Paediatr Child Health 2006;42(Suppl
1):S1-29. with most fears developing in childhood Hamilton JG.
Needle phobia: a neglected diagnosis. J Fam Pract 1995;41:169-75
✤
with most fears developing in
childhood Hamilton JG. Needle phobia: a neglected
diagnosis. J Fam Pract 1995;41:169-75
Pain outcomes in a US children’s hospital:
a prospective cross-sectional survey
✤
In past 24 hrs, what was cause of worst pain?
✤ 40% Needle poke
✤ 34% Trauma/injury/other medical
✤ 10 % Surgery
✤ 8% Procedure
✤ 4% Acute illness/infection
✤ 3% Treatment for known disease
✤
Friedrichsdorf SJ, Postier AC, Eull D, Foster L, Weidner C, Campbell F: Pain outcomes in a US children’s hospital: a prospective
cross-sectional survey. Hospital Pediatrics 2015. 5(1):18-26
Procedural pain: A call for action
Pain ratings at 4-6 months routine vaccination higher for circumcised
versus uncircumcised boys Taddio A (1994) Lancet, 344:291-2
✤
Preterm infants: Poorer cognition and motor function associated with
higher number of skin-breaking procedures Grunau RE, Whitfield MF, Petrie-Thomas J, Synnes AR,
✤
Cepeda IL, Keidar A, et al. Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in
preterm infants. Pain. 2009 May;143(1-2):138-46.
Memory of previous painful experience has great influence on pain
experience during subsequent procedures Versloot J, Veerkamp JSJ, Hoogstraten J: Children’s self-reported
✤
pain at the dentist. Pain 2008. 137:389-94
Inadequate analgesia for initial procedures in young children (8 years or
younger) diminishes the effect of adequate analgesia in subsequent
procedures Weisman SJ, Bernstein B, Schechter NL: Consequences of inadequate analgesia during painful procedures in children. Arch
✤
Pediatr Adolesc Med 1998. 152:147-9
Essential Components of
Procedural Pain Management
“Non-Negotiable”
✤ Topical Anesthesia
✤ 0-12 months: Sucrose
✤ Positioning
✤ Distraction (Integrative (non-pharmacological) therapies)
Other Considerations
✤ Possibly other pharmacological approaches
✤ Consider appropriate sedation, if excellent analgesia cannot be
achieved
“Non-negotiable” Components of
Procedural Pain Management in Children
Topical Local Anesthetics
✤
!
To reduce pain at the time of injection, encourage parents to use
topical anesthetics during vaccination of children (grade A recommendation, based on
level I evidence). Taddio A, Appleton M, Bortolussi R, Chambers C, Dubey V, Halperin S, et al. Reducing the pain of childhood
vaccination: an evidence-based clinical practice guideline. CMAJ : Canadian Medical Association journal 2010 Dec 14;182(18):E843-55.
✤
!
Topical anesthetics are considered safe for children of all ages.
However, administration of excessive doses and/or prolonged
application times can lead to serious adverse effects, including
irregular heartbeat, seizures and difficulty breathing www.hc-sc .gc .ca/dhp-mps/
medeff/advisories-avis/public/_2009/emla ametop_pc-cp-eng.php
✤
!
For children undergoing vaccination, there is insufficient
evidence for or against the use of skin-cooling
techniques (vapocoolants, ice, cool/cold packs) to reduce pain at the
time of injection (grade I recommendation, based on conflicting level I evidence).
EMLA versus LMX
✤
EMLA Cream (lidocaine 2.5%
and prilocaine 2.5%) vs Ela-Max
LMX 4% Lidocaine Topical
Anesthetic Cream (1) Koh JL, Harrison
D, Myers R, Dembinski R, Turner H, McGraw T: A randomized,
double-blind comparison study of EMLA and ELA-Max for
topical anesthesia in children undergoing intravenous
insertion. Paediatr Anaesth 2004. 14(12):977-82; (2) Eichenfield LF,
Funk A, Fallon-Friedlander S, Cunningham BB: A clinical study
to evaluate the efficacy of ELA-Max (4% liposomal lidocaine) as
compared with eutectic mixture of local anesthetics cream for
pain reduction of venipuncture in children. Pediatrics 2002.
109(6):1093-9
✤
Ela-Max LMX: 30 minutes
application as effective as 60
minutes
✤
✤
Analgesia duration:
✤
✤
EMLA application for
preventing pain during IV
insertion in Children
EMLA 1-2 hours vs. LMX 1
hour
Skin time:
✤
EMLA 4 hours vs. LMX 2
hours
EMLA® and Neonates
In neonates, EMLA reduces the
behavioral pain response to
venipuncture but not heel lance
Effective for neonates > 34
weeks gestation for lumbar
puncture Kaur G, Gupta P, Kumar A: A randomized
✤
✤
Taddio A, Ohlsson A, Einarson TR, Stevens B, Koren G: A
systematic review of lidocaine-prilocaine cream (EMLA) in the
treatment of acute pain in neonates. Pediatrics 1998. 101(2):E1
trial of eutectic mixture of local anesthetics during lumbar
puncture in newborns. Arch Pediatr Adolesc Med 2003, 157(11):
Single doses have not been
associated with
methemoglobinemia Taddio A, Ohlsson
✤
A, Einarson TR, Stevens B, Koren G: A systematic review of
lidocaine-prilocaine cream (EMLA) in the treatment of acute pain
in neonates. Pediatrics 1998. 101(2):E1
1065-70
Application of Cream
Cellophane (no Tegaderm®:
hurts at time of removal)
✤
Needle pokes without the pain?
J-Tip in the Emergency Room (CBS 4 Morning News)
J-Tip (Lidocaine)
J-tip: single-use, disposable, carbondioxide-powered, needleless lidocaine
injector
✤
✤
Adults: More pain than s.c. lidocaine
Cooper JA, Bromley LM, Baranowski AP, Barker SG: Evaluation of a needlefree injection system for local anaesthesia prior to venous
cannulation. Anaesthesia 2000. 55(3):247-50
LET Anesthesia
3mL LET-gel: Lidocaine 4%Epinephrine 0.18% -Tetracaine
0.5%
✤
Singer AJ, Stark MJ. Pretreatment of lacerations with lidocaine,
epinephrine, and tetracaine at triage: a randomized double-blind
trial. Acad Emerg Med. 2000 Jul;7(7):751-6.
✤
✤
Sitting upright
✤
Distraction
✤
Topical Anesthesia
✤
“Non-negotiable” Components of
Procedural Pain Management in Children
Sucrose for Children 0-12 months
Reduces pain (PIPP, VAS) and cry during painful procedure, such as
venipuncture Stevens B, Cochrane Database of Systematic Reviews 2004, Issue 3
✤ Role of endogenous opioids - naloxone blunts effect
✤
Effective dose (24%): 0.05 - 0.5 mL (= 0.012 - 0.12 g)
Administration 2 minutes prior to mild - moderately painful procedure
✤ Duration ~ 4 min
✤ Does not prevent development of hyperalgesia Taddio A, Shah V, Atenafu E, Katz J. Influence of
✤
✤
repeated painful procedures and sucrose analgesia on the development of hyperalgesia in newborn infants. Pain. 2009 Jul;144(1-2):43-8.
✤
Breastfeeding
✤ Effective in term infants (superior to sweetening agents) (1) Shah PS, Cochrane
Database of Systematic Reviews 2006, Issue 3 (2) Gray L, Miller LW, Philipp BL, Blass EM. Breastfeeding is analgesic in healthy newborns.
Pediatrics. 2002 Apr;109(4):590-3. (3) Weissman A, Aranovitch M, Blazer S, Zimmer EZ. Heel-lancing in newborns: behavioral and spectral analysis
assessment of pain control methods. Pediatrics. 2009 Nov;124(5):e921-6.
✤
Ineffective in preterm infants? Holsti L, Oberlander TF, Brant R. Does breastfeeding reduce acute procedural pain
in preterm infants in the neonatal intensive care unit? A randomized clinical trial. Pain. 2011 Nov;152(11):2575-81.
Harrison, DM. Be Sweet to Babies (August, 2014). Retrieved from YouTube
http://tinyurl.com/BSweet2newborns
“Non-negotiable” Components of
Procedural Pain Management in Children
Pediatric Positioning in 1985
Positioning
To reduce pain at the time of
injection, do not place children in a
supine position during vaccination
(grade E recommendation, based on
level I evidence). Taddio A, Appleton M, Bortolussi R,
✤
Chambers C, Dubey V, Halperin S, et al. Reducing the pain of childhood
vaccination: an evidence-based clinical practice guideline. CMAJ : Canadian
Medical Association journal 2010 Dec 14;182(18):E843-55.
✤ When feasible, offer choice to child
(parent’s lap?)
Comfort Positioning
Swaddling, facilitated tucking,
kangaroo care
Skin-to-skin care for procedural pain in neonates
“Non-negotiable” Components of
Procedural Pain Management in Children
Integrative Therapies for Needle
Procedures
Cochrane Review 2013: 39 trials, 3394 children 2-19 years - needleprocedures (immunizations and injections). Uman LS, Birnie KA, Noel M, Parker JA, Chambers CT,
McGrath PJ, Kisely SR. Psychological interventions for needle-related procedural pain and distress in children and adolescents. Cochrane Database of
Systematic Reviews 2013, Issue 10
There is strong evidence that distraction and hypnosis are effective in
reducing the pain and distress that children and adolescents experience
during needle procedures
Promising but limited/no evidence for preparation and information or
both, combined CBT, parent coaching plus distraction, suggestion, or
virtual reality
✤
Integrative Therapies for Needle
Procedures
To reduce pain at the time of
injection among children four
years of age and older, offer to rub
or stroke the skin near injection
site with moderate intensity before
and during vaccination (grade B
recommendation, based on level
II-1 evidence) Taddio A, Appleton M, Bortolussi R,
✤
Chambers C, Dubey V, Halperin S, et al. Reducing the pain of
childhood vaccination: an evidence-based clinical practice guideline.
CMAJ : Canadian Medical Association journal 2010 Dec
14;182(18):E843-55.
Parent coaching: Certain types of
parental behaviours (e.g.,
nonprocedural talk, suggestions
on how to cope, humour) have
been related to decreases in
children’s distress and pain,
whereas others (e.g., reassurance,
apologies) have been related to
increases in children’s distress and
pain. Taddio A, Chambers CT, Halperin SA, et al. Inadequate
✤
pain management during childhood immunizations: the nerve of it.
Clin Ther 2009;31(Suppl 2):S152-67.)
Distraction
Hypnosis in Pediatric Practice: Imaginative Medicine in Action
By Laurence Sugarman, MD
A documentary for child health professionals
Distraction
✤
Reduction of fear and anxiety
Determine if the child wishes to watch or be
distracted
✤
✤
Young children: books, bubbles and pinwheels
✤
Coaching roles for parents
✤
Older children: video games and biofeedback
How many mistakes can you spot?
New York Time 7/2/14: The Price of Prevention: Vaccine Cost
Are Soaring
✤
“Non-negotiable” Components of
Procedural Pain Management in Children
Other
Considerations
(5) (Intranasal) Systemic Analgesia
(6) Sedation
Intranasal Opioid Application
✤
✤
✤
✤
Nasal mucosa richly vascularized
Fenestrated epithelium drains by way of the facial and
sphenopalatine veins
⇒ Avoiding first pass metabolism
Hydromorphone: ER trauma patients - plasma concentration similar to
those after IV administration Wermeling DP, Clinch T, Rudy AC, Dreitlein D, Suner S, Lacouture PG. A multicenter,
✤
open-label, exploratory dose-ranging trial of intranasal hydromorphone for managing acute pain from traumatic injury. J Pain. 2010 Jan;11(1):
24-31.
Intranasal Opioid Application
Drops or spray diluted in normal saline 0.9%
Pharmacokinetic profile similar to i.v. in children
✤ Mucosal Atomization Device (MAD)
✤
✤
http://intranasal.net/deliverytechniques/default.htm
Intranasal Opioid Application
✤
✤
Drops or spray diluted in normal saline 0.9%
Pharmacokinetic profile similar to i.v. in children
RCT
24 children (4-8 years)
✤ Burn dressing changes
✤ Control: oral morphine
✤ Titrated until pain free
⇒ intranasal dose slightly higher (1.4
mcg/kg + 15mcg Q5min)
⇒ pain relief comparable
⇒ safety profile acceptable, no
serious adverse events
✤
✤
Borland ML, Bergesio R, Pascoe EM, Turner S, Woodger S. Intranasal
fentanyl is an equivalent analgesic to oral morphine in paediatric burns
patients for dressing changes: a randomised double blind crossover study.
Burns. 2005 Nov;31(7):831-7.
Intranasal Opioid Application
RCT
32 children (4-8 years)
✤ Postoperative analgesia
✤ Control: i.v. fentanyl
✤ Titrated until pain free
⇒ intranasal dose slightly higher
(1.4 mcg/kg)
⇒ pain relief comparable
⇒ safety profile acceptable, no
serious adverse events Manjushree R, Lahiri A,
✤
✤
Ghosh BR, Laha A, Handa K. Intranasal fentanyl provides adequate
postoperative analgesia in pediatric patients. Can J Anaesth. 2002 Feb;
49(2):190-3.
Case report
Acute pain ER
✤ 48 children (3-12 years)
✤ Dose applied every 5 minutes as
required
✤ Median dose: 1.5 mcg/kg
✤ ⇒ good pain control
✤ ⇒ no side effects
✤
✤
Borland ML, Jacobs I, Geelhoed G. Intranasal fentanyl reduces acute pain
in children in the emergency department: a safety and efficacy study. Emerg
Med (Fremantle). 2002 Sep;14(3):275-80.
✤
Sedation
If good procedural analgesia not feasible with the “4 Non-Negotiables”,
consider:
(1) Mild sedation: Nitrous gas
Zier, J. L. and M. Liu (2011). "Safety of high-concentration nitrous oxide by
nasal mask for pediatric procedural sedation: experience with 7802 cases."
Pediatric emergency care 27(12): 1107-1112.
or
(2) Moderate/deep sedation (e.g. ketamine, propofol)
Note:
A sedative alone (such as a benzodiazepine) can never be a substitute for
procedural analgesia.
Thanks to Patricia D. Scherrer MD, Medical Director, Sedation Services
Children's Hospitals and Clinics of Minnesota
IV Access Under Nitrous Gas
22 months-old, LMX in place, needed IV for radiologic procedure, history of challenging IV access in the
past
www.cmaj.ca/cgi/content/full/cmaj.101720/DC1
Today’s Presentation
✤
Part 1: Acute Pain
✤
Part 2: Procedural Pain
✤
Part 3: Neuropathic Pain
Pain after burn injury
✤
Multi-factorial involving tissue damage, repetitive trauma and damage
to sensory nerve endings Nedelec et al. Sensory perception and neuroanatomical structure in normal and grafted skin of
burn survivors. Burns 2005 Nov , 31 (7): 817-30.; Norman A, Judkins K. Pain in the patient with burns. Contin Educ Anaesth Crit Care Pain (2004)
4 (2): 57-61.
✤
Neuropathic pain component Portilla AS1, Bravo GL, Miraval FK, Villamar MF, Schneider JC, Ryan CM, Fregni F J
Burn Care Res. 2013 Jan-Feb;34(1):e48-52. A feasibility study assessing cortical plasticity in chronic neuropathic pain following burn injury. xxJ
Schneider JC1, Harris NL, El Shami A, Sheridan RL, Schulz JT 3rd, Bilodeau ML, Ryan CM
✤
Pain can persist after healing Dauber et al. Chronic persistent pain after severe burns. A survey of 358 burn
survivors. Pain Med 2002; 3:6-17.
✤
✤
n=358; burns covering an average of 59% of their bodies
12 years laster: 52% of respondents reported ongoing burn-related
pain
Neuropathic Pain
✤
Pain arising as a direct consequence of a lesion or disease affecting the
somatosensory system (IASP 2008)
✤
✤
Grading System: (1) Definite, (2) Probable; (3) Possible
(…but, not all lesions in the somatosensory system lead to
neuropathic pain)
Neuropathic Pain Assessment
✤
Currently there are no validated
neuropathic pain scales for children <
18 years
✤
✤
✤
Adults
✤
✤
Pain Quality Assessment Scale
(PQAS) - 20 items
http://www.mapi-research.fr/
t_03_serv_dist_Cduse_pqas.htm Jensen,
M.P. (in press). Pain assessment in clinical trials. In D. Carr & H.
Wittink (Eds.), Evidence, outcomes, and quality of life in pain
treatment. Amsterdam: Elsevier.
NPS® Neuropathic Pain Scale 12 items
http://www.mapi-research.fr/
t_03_serv_dist_Cduse_nps.htm
Galer BS, Jensen MP. Development and preliminary
validation of a pain measure specific to neuropathic pain: the
Neuropathic Pain Scale. Neurology. 1997 Feb;48(2):332-8
NSAIDs for Neuropathic Pain
✤
NSAIDs are so widely viewed as
being ineffective for neuropathic
pain that no major guidelines
even mention them in their
algorithm.Attal N, Cruccu G, Baron R, Haanpää M,
✤
NSAIDs are commonly
prescribed for neuropathic pain
Dieleman JP, Kerklaan J, Huygen FJ, Bouma PA, Sturkenboom CJ.
Incidence rates and treatment of neuropathic pain conditions in the
general population. Pain 2008;137:681-8.
Hansson P, Jensen TS, et al. EFNS guidelines on the
pharmacological treatment of neuropathic pain: 2010 revision. Eur J
Neurol 2010;17:1113-e88.
✤
Preclinical and clinical studies
have demonstrated efficacy for
NSAIDs in neuropathic pain
states Vo T, Rice AS, Dworkin RH. Non-steroidal anti-
✤
inflammatory drugs for neuropathic pain: how do we explain
continued widespread use? Pain 2009;143:169-71.; Cohen KL,
Harris S. Efficacy and safety of nonsteroidal anti-inflammatory
drugs
Opioids for Neuropathic Pain
✤
Adult Evidence: Metaanalysis:
Opioids, including tramadol,
have a consistent efficacy in
neuropathic pain Finnerup NB, Sindrup SH,
Jensen TS. The evidence for pharmacological treatment of
neuropathic pain. Pain. 2010 Sep;150(3):573-81.
✤
Multi-mechanism agent
Tramadol: RCTs: polyneuropathy
and post-amputation pain Hollingshead,
Cochrane Database Syst Rev 2005 , Sindrup, Pain 1999, 83:85-90;
Wilder-Smith, Anesthesiology 2005,103:616-28
✤
Strong opioids: RCTs: efficacious
for neuropathic pain (NP),
including phantom limb pain,
chronic peripheral and central
NP Huse, Pain 2001,90:47-55; Morley Palliat Med 2003,
17:576-87; Rowbotham N Eng J Med 2003, 384:1223-32; Eisenberg
E, McNicol E, Carr DB. Opioids for neuropathic pain. Cochrane
Database Syst Rev. 2006 Jul 19;3:CD006146.
Integrative, rehabilitative &
supportive therapies
✤
✤
✤
✤
Expected part of treatment
protocol; Age-appropriate
modalities include
✤
Acupressure, acupuncture,
aromatherapy
Physical (massage, TENS,
comfort positioning, allowing
family for close contact/touch)
Rehabilitation (physical
therapy, occupational therapy)
Behavioral (deep breathing,
imagery, hypnosis, smartphone/tablet “apps”)
Neuropathic Pain Mechanisms
Periaqueductal
grey
Thalamus
Central Sensitization:
Activities in C-Fibers drives
changes in 2nd neuron
on
eur
dN
2n
ng
di
en ion
sc bit
De nhi
I
Glial activation & cytokine
release
also involved?
Result: áexcitability
and synaptic efficiency
+
+
Aδ
or
C
Injury induced
accumulation of
Na-channels
=> ectopic firing
fib
Injury
er
Reduced
inhibition in
Dorsal Horn
Altered Synaptic Transmission:
Ca-channel
[α-2-δ dysfunction?)
+
+
Peripheral Sensitization:
Response to Tissue Injury
Tricyclic antidepressants (TCA)
✤
61 RCTs (20 antidepressants):
TCAs are effective; NNT of 3.6
(for the achievement of at least
moderate pain relief). Saarto T, Wiffen
✤
Loprinzi CL, Sloan JA, Novotny PJ, Soori GS, et al. Phase III
evaluation of nortriptyline for alleviation of symptoms of cisplatinum-induced peripheral neuropathy. Pain. 2002 Jul;98(1-2):
195-203. Kautio AL, Haanpaa M, Saarto T, Kalso E. Amitriptyline
in the treatment of chemotherapy-induced neuropathic symptoms.
Journal of Pain and Symptom Management. 2008 Jan;35(1):31-9.
PJ. Antidepressants for neuropathic pain. Cochrane Database Syst
Rev. 2007 Oct 17;(4):CD005454
✤
No effect of amitriptyline in HIV
neuropathy Kieburtz K, Simpson D, Yiannoutsos C,
Max MB, Hall CD, Ellis RJ, et al. A randomized trial of amitriptyline
and mexiletine for painful neuropathy in HIV infection. AIDS
Clinical Trial Group 242 Protocol Team. Neurology. 1998 Dec;51(6):
1682-8. Shlay JC, Chaloner K, Max MB, Flaws B, Reichelderfer P,
Wentworth D, et al. Acupuncture and amitriptyline for pain due to
HIV-related peripheral neuropathy: a randomized controlled trial.
Terry Beirn Community Programs for Clinical Research on AIDS.
JAMA.1998 Nov 11;280(18):1590-5.
No effect in chemotherapyinduced neuropathy (pain not
primary outcome) Hammack JE, Michalak JC,
✤
Secondary amine TCAs (e.g.
nortriptyline) better tolerated
than tertiary amine TCAs (e.g.
amitriptyline) with comparable
analgesic efficacy Max, N Eng J Med
1992,326:1250-6; Rowbotham, J Pain 2005,6:741-6; Watson,
Neurology 1998,51:1166-71
Amitriptyline
✤
Dosage: initial 0.1 mg /kg ->
titrate to 0.4 mg/kg p.o., [max.
20-25 mg] (usually not up to 1-2
mg/kg/day) once at night ✤
✤
wean: decrease gradually!
✤
✤
Effect: days - weeks; depends on
length of symptoms
Adverse effects: arrhythmia: EKG
(QTc, WPW?), anticholinergic /
antihistamine (dry mouth,
constipation, blurred vision,
sedation)
Desipramine: anecdotal evidence
of sudden death in children Amitai Y,
Frischer H: Excess fatality from desipramine in children and
adolescents. J Am Acad Child Adolesc Psychiatry 2006. 45(1):54-60
Nociceptive Pathways & Primary Sites of Action of Analgesics
Periaqueductal
grey (endorphins)
Thalamus
TCA
SSRIs
Methadone
Tramadol
on
eur
dN
2n
ng
di
en ion
sc bit
De nhi
I
+
Integrative
(non-pharmacological)
therapies
Aδ
or
C
er
fib
Opioids
Injury
Acetaminophen
(Paracetamol)
Tricyclic Antidepressants:
(+) Opioid analgesia via
serotoninergic mechanism at
brainstem
NSAIDs
Gabapentinoids: Ca-channel α2-δ ligands
Voltage-gated
Ca-channel
α2-δ subunit
G
[dysfunction?/upregulation role in neuropathic pain]
Postsynaptic
nerve
terminal
Presynaptic
nerve
terminal
Glutamate
Substance P
Gabapentinoids
✤
Gabapentin: 15 studies (1468
participants) (post-herpetic
neuralgia, diabetic
neuropathy, cancer related
neuropathic pain, phantom limb
pain, Guillain Barré syndrome,
spinal chord injury pain, various
neuropathic pains) Wiffen PJ, McQuay
✤
HJ, Edwards JE, Moore RA. Gabapentin for acute and chronic
pain. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD005452.
✤
✤
42% improved compared to 19%
on placebo
NNT for effective pain relief in
diabetic neuropathy 2.9; post
herpetic neuralgia 3.9
Pregabalin: Effective in post
herpetic neuralgia, painful
diabetic polyneuropathy,
central neuropathic pain (19
studies, 7003 participants):
effective 300 mg-600 mg daily
(at 150 mg daily was generally
ineffective). Moore RA, Straube S, Wiffen
PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic
pain in adults. Cochrane Database Syst Rev. 2009 Jul 8;
(3):CD007076.
✤
No overall evidence for
superior efficacy for either of
these drugs in neuropathic
pain, although lower cost may
favor gabapentin Finnerup NB, Sindrup SH,
Jensen TS. The evidence for pharmacological treatment of
neuropathic pain. Pain. 2010 Sep;150(3):573-81.
Gabapentin postoperatively?
✤
✤
17-day, term infant, 3kg, TGA
(post OP day #15), day 10 post
ECMO; max. fentanyl 8 mcg/
hr, episodes of severe
irritability (pain? withdrawal?)
unrelieved by opioids,
dexmedetomidine:
04/10/2012: Gabapentin 4
mg/kg Q6h
Analgesic adjunct in the immediate
postburn period
✤
Gabapentin is ineffective as an
analgesic adjunct in the immediate
postburn period. Wibbenmeyer L1, Eid A, Liao
J, Heard J, Horsfield A, Kral L, Kealey P, Rosenquist R J Burn Care
Res. 2014 Mar-Apr;35(2):136-42
✤
Pregabalin not effective .Pain. 2011 Jun;152(6):
1279-88. doi: 10.1016/j.pain.2011.01.055. Epub 2011 Mar 12.
Pregabalin in severe burn injury pain: a double-blind, randomised
placebo-controlled trial. Gray P1, Kirby J, Smith MT, Cabot PJ,
Williams B, Doecke J, Cramond T.
Gabapentinoids: Ca-channel α2-δ
ligands
✤
✤
Conversion from Gabapentin
(Neurontin) -> Pregabalin (Lyrica)
Approximately 6-7:1
Gabapentin
300 mg TID
Gabapentin
900 mg / day
/6
Pregabalin
150 mg / day
Pregabalin
75 mg BID
Nociceptive Pathways & Primary Sites of Action of Analgesics
Periaqueductal
grey (endorphins)
Thalamus
TCA
SSRIs
Methadone
Tramadol
on
eur
dN
2n
ng
di
en ion
sc bit
De nhi
I
+
Integrative
(non-pharmacological)
therapies
Combination:
Amitriptyline &
Gabapentin
Aδ
or
C
er
fib
Inhibitors of excitatory
glutamate systems:
Gabapentin/Pregabalin
Carbamazepine*
Valproate
Injury
Acetaminophen
(Paracetamol)
Opioids
NSAIDs
Sodium Channel Blocker: Topical
Lidocaine
✤
Lidocaine (systemic or local):
Decrease of neuropathic pain
related to decrease of ectopic
ongoing activity in injured
afferent nerve fibers Kirillova I, Teliban
A, Gorodetskaya N, Grossmann L, Bartsch F, Rausch VH, et
al. Effect of local and intravenous lidocaine on ongoing
activity in injured afferent nerve fibers. Pain. 2011 Jul;152(7):
1562-71.
✤
Topical Lidocaine 5% patch
(Lidoderm®, generic
available). Metaanalysis: Data
is conflicting Finnerup NB, Sindrup SH, Jensen
TS. The evidence for pharmacological treatment of
neuropathic pain. Pain. 2010 Sep;150(3):573-81.
✤
Efficacy of IV lidocaine
supported by RCTs
✤
Oral mexiletine, tocainide,
flecainide are analgesic in
neuropathic pain: High side
effect liability from oral drugs;
generally considered third-line
(1) Oskarsson P et al, Diabetes Care, 1997;20:1594-1597
Challapalli et al, Cochrane Database Sys Rev. 2005;CD003345
(2) Portenoy R: The Annual Assembly of American Academy
of Hospice and Palliative Medicine, Austin, TX, 2009 (3)
Ferrante FM, Paggioli J, Cherukuri S, Arthur GR. The
analgesic response to intravenous lidocaine in the treatment
of neuropathic pain. Anesthesia and analgesia.1996 Jan;82(1):
91-7.
IV Lidocaine for Burn Pain
✤
As current clinical evidence is based
on only one RCT as well as case
series and reports, intravenous
lidocaine must be considered a
pharmacological agent under
investigation in burns care, the
effectiveness of which is yet to be
determined with further welldesigned and conducted clinical
trials. Wasiak J, Mahar PD, McGuinness SK, Spinks A, Danilla
S, Cleland H, Tan HB. Intravenous lidocaine for the treatment of
background or procedural burn pain. Cochrane Database of
Systematic Reviews 2014, Issue 10. Art. No.: CD005622. DOI:
10.1002/14651858.CD005622.pub4.
Opioid induced tolerance
and hyperalgesia
Opioid
mu-receptor
stimulation
Genes
Inhibition of Ca
channels:
âneurotransmitter
release
Alter
response
characteristics
of neuron =>
Suppress
neuronal
excitability
uncoupling
Gi/o proteins
activation
generation
Protein Kinase-C
Membrane
Hyperpolarization
(K+ channel)
Other
neuromodulators
Opioid induced tolerance
and hyperalgesia
Opioid
mu-receptor
Gi/o proteins
activation
Chen L, Nature 1992; 365:521-3
Proteine Kinase-C
activation
NMDA-receptor
NMDA-Receptor Channel Blocker
Na+
Ca2+
Glycine
recognition site
Glutamate
recognition site
Cell membrane
Mg2+
K+
1. Membrane potential at resting level
"
-> channel blocked by Magnesium
Excitatory NMDA (N-Methyl-d-Aspartat) Receptor channel complex
NMDA-Receptor Channel Blocker
Na+
Ca2+
Glycine
recognition site
Glutamate
recognition site
Cell membrane
K+
2. Membrane potential changed as a result of áexcitation
â Opioid-sensitivity
!
- Central (dorsal horn) sensitization
- radiation of pain
- spontaneous pain
- Hyperalgesia, allodynia
NMDA-Receptor Channel Blocker
Na+
Ca2+
Glycine
recognition site
Glutamate
recognition site
Cell membrane
Ketamine
K+
3. Phencyclidin (PCP) - binding sites [uncompetitive NMDA receptor
antagonists with moderate affinity]
- Ketamine
- Methadone
- Levorphanol
- (Dextrometorphane?)
Ketamine
Sedative-Hypnotic-Dissociative
Dosing: 1-2 mg/kg/dose IV
✤
✤
Analgesic (subanesthetic)
Dosing: IV: 1-5 mcg/kg/min
[=0.06-0.3 mg/kg/hr]
✤
Adverse effects: intracranial
hypertension, tachycardia,
psychotomimetic
phenomena (euphoria,
dsyphoria, vivid
hallucinations) -> at lowdose??
✤
37 RCTs (n=2240): subanesthetic
Ketamine effective in reducing
morphine requirements in first
24 hours after surgery, reduces
postoperative nausea and
vomiting; Adverse effects are
mild or absent. Bell RF, et al. Perioperative
ketamine for acute postoperative pain. Cochrane Database Syst
Rev. 2006 Jan 25;(1):CD004603
✤
Metaanalysis: NMDA
antagonists (& mexiletine) have
no consistent clinical relevant
efficacy in neuropathic pain
Finnerup NB, Sindrup SH, Jensen TS. The evidence for
pharmacological treatment of neuropathic pain. Pain. 2010 Sep;
150(3):573-81.
Ketamine
Steady-state oral/parenteral ratio unclear
Bio-availibilty 93% IM/IV; 20% PO
✤
Ketamine -> norketamine
✤ Potency ketamine: norketamine 3:1 (anesthetic); 1:1 (analgesic)
✤ Plasma half-life: ketamine 1-3 hrs; norketamine 12 hrs
✤ Maximum blood concentration of norketamine: oral > IV
✤
✤
✤
✤
Domino E, Clinical Pharm Therapeut 1984, 36:645-53; Clements JA, J Pharm Scienc 1982,71:539-42
Estimated at 1:1- 1:3 (i.e. 1mg IV = 1-3 mg PO) Benitez-Rosario MA, Salinas-Martin A,
Gonzalez-Guillermo T, Feria M. A strategy for conversion from subcutaneous to oral ketamine in cancer pain patients: effect of a 1:1 ratio. Journal
of Pain and Symptom Management. 2011 Jun;41(6):1098-105.
Other Adjuvant Analgesics / Coanalgesics
✤
α-Adrenergic Agonists
(Dexmedetomidine; clonidine)
✤
✤
Postsynaptic alpha-2adrenergic & mu-opioid
receptors activate the same
K-channel via inhibitory Gi/
0 -proteins
decrease postoperative
opioid consumption, pain
intensity, and nausea.
Recovery times are not
prolonged. Blaudszun G, Lysakowski C, Elia
N, Tramer MR. Effect of Perioperative Systemic alpha2
Agonists on Postoperative Morphine Consumption and
Pain Intensity: Systematic Review and Meta-analysis of
Randomized Controlled Trials. Anesthesiology. 2012 Jun;
116(6):1312-22.
✤
✤
Benzodiazepines: gammaaminobutyric acid (GABA)
receptors
Capsaicin: 2 Metaanalyses
Finnerup
NB, Sindrup SH, Jensen TS. The evidence for pharmacological
treatment of neuropathic pain. Pain. 2010 Sep;150(3):573-81. Mou,
J., et al., Efficacy of Qutenza(R) (capsaicin) 8% patch for
neuropathic pain: a meta-analysis of the Qutenza Clinical Trials
Database. Pain, 2013. 154(9): p. 1632-9.
SensorySelective (NociceptiveSelective) Nerve Blockade
✤
Schumacher MA, Eilers H. TRPV1 splice variants: structure and
function. Front Biosci. 2010;15:872-882. Binshtok AM, Bean BP,
Woolf CJ. Inhibition of nociceptors by TRPV1-mediated entry of
impermeant sodium channel blockers. Nature. 2007 Oct
4;449(7162):607-10.
Nociceptive Pathways & Primary Sites of Action of Analgesics
Periaqueductal
grey (endorphins)
Thalamus
TCA
SSRIs
Methadone
Tramadol
dN
2n
Stimulation of inhibiting GABA
system
Baclofen
Benzodiazepines
Valproate
on
eur
ng
di
en ion
sc b i t
De nhi
I
+
Integrative
(non-pharmacological)
therapies
o
Aδ
rC
fib
er
Inhibitors of excitatory
glutamate systems:
Gabapentin/Pregabalin
Carbamazepine*
Valproate
NMDA-Channel Blockers
Ketamine
Methadone
Acetaminophen
(Paracetamol)
Opioids
Role of Cannabis?
San Diego, CA
✤
AAP Handout for parents
"Despite relaxed
regulations, marijuana
harms developing brain":
http://aapnews.aappublications.org/content/
36/3/4.full.pdf+html
✤
Updated AAP policy
opposes marijuana use,
citing potential harms,
lack of research http://
aapnews.aappublications.org/content/early/
2015/01/26/aapnews.20150126-1
Injury
NSAIDs
Sodium-channel
blockade
carbamazepine*
lidocaine
Case Example: Multimodal (Opioid-sparing) Analgesia
Opioids
Non-Opioids
• Tramadol? („weak“)
• Acetaminophen /
Paracetamol
• NSAIDs
WHO-Principles
• “By the clock”
• “By the child”
• “By the appropriate
route”
• “By the WHO ladder”
• Morphine („strong“)
Integrative
Therapies
• Massage
• Heat/cold
• Deep Breathing
• Biofeedback
• Hypnosis
• etc.
Adjuvants
• Alpha-Agonist
• Anticonvulsants
• TCA/Antidepressants
• NMDA-receptor-channel blockers
• Na-receptor-channel blockers
• Antispasmodics
• Benzodiazepines
• Corticosteroids
• Muscle relaxants
• Radiopharmaceuticals
• Bisphosphonates
• etc.
Invasive Approaches
• Regional anesthesia
• Neuraxial anesthesia
- Epidural or intrathecal
- Nerve blocks
- Neurolytic blocks
• [Intraventricular opioids?]
• [Percutaneous cervical
cordotomy?]
Interventional management of
neuropathic pain in adults
✤
NeuPSIG recommendations 2013:
Due to the paucity of high-quality
clinical trials, no strong
recommendations can be made.
Dworkin, R.H., et al., Interventional management of neuropathic
pain: NeuPSIG recommendations. Pain, 2013. 154(11): p. 2249-61.
✤
✤
4 weak recommendations based on
the amount and consistency of
evidence, including degree of efficacy
and safety, are:
(1) epidural injections for herpes
zoster
✤
✤
✤
✤
(2) steroid injections for
radiculopathy
(3) spinal cord stimulation (SCS) for
failed back surgery syndrome
(4) SCS for CRPS type 1 (who do not
respond adequately to noninvasive
treatments and sympathetic nerve blocks)
Based on the available data, we
recommend not to use sympathetic
blocks for PHN nor radiofrequency
lesions for radiculopathy
Regional anesthesia approaches to
pain management in PPC
✤
Review of current knowledge limited
to case reports and case series: Rork, J.F.,
C.B. Berde, and R.D. Goldstein, Regional anesthesia approaches to
pain management in pediatric palliative care: a review of current
knowledge. J Pain Symptom Manage, 2013. 46(6): p. 859-73.
✤
✤
✤
✤
central neuraxial infusions
peripheral nerve and plexus
blocks or infusions
neurolytic blocks
implanted intrathecal ports &
pumps for baclofen, opioids, local
anesthetics, and other adjuvants
Adult Evidence Based
Recommendations Neuropathic Pain
✤
First Line
Tricyclic antidepressants &
other dual reuptake inhibitors
of both serotonin and
norepinephrine
✤
✤
Ca-channel α2-δ ligands
✤
✤
Select clinical circumstances:
Opioids including tramadol
✤
✤
Some circumstances: certain
antiepileptic and
antidepressants, mexiletine,
NMDA-receptor antagonists,
topical capsaicin
✤
Second Line
✤
Third Line
Certain antiepileptic and
antidepressants, mexiletine,
NMDA-receptor antagonists,
topical capsaicin
Dwokin et al. Pain 2007, 132:237-51
Opioids including tramadol
✤
Management of Neuropathic Pain
in Pediatrics:
Suggested “Non-Evidence-based” Step-by-Step Approach
(8) Regional anesthesia
(7) NMDA-receptor-channel blocker [benzodiazepine? α- agonist? IV lidocaine?]
(6) Lidocain patch (if localized pain)
(5) Tricyclic Antidepressant and Ca-channel α2-δ ligand
(4) Tricyclic Antidepressant (or Ca-channel α2-δ ligand) ± ketamine
(3) Opioid (plus non-opioid) analgesics [consider Tramadol or Methadone]
(2) Integrative therapies; manage comorbidities (anxiety, sleep disturbances)
(1) Identify and treat underlying disease process (radiation?) (corticosteroids?)
Conclusions Pain
✤
Use multimodal (opioid-sparing)
analgesia
✤
✤
✤
✤
✤
incl. combination of integrative methods,
rehabilitation and analgesic medications
Patients/Parents do NOT have to
choose between poor pain control
or over sedation
Opioids should NOT be
administered long-term
Opioids NOT indicated for chronic
pain
Treatment protocol for painful
procedures is expected standard of
care in 21st century:
✤
positioning, topical anesthesia,
integrative therapies, sucrose
✤
✤
✤
plus/minus sedation; systemic
anesthesia
Neuropathic pain often underassessed and under-treated
Careful step-by-step approach
(combining integrative,
rehabilitative, pharmacological
and interventional therapies)
warranted
First Line medications: Opioids (?),
Amitriptyline, Gabapentin
✤
Low-dose Ketamine may represent a potent
adjuvant analgesia
✤
ADDENDUM
Non-Opioids (“Simple” Analgesia)
✤
Acetaminophen (Paracetamol)
✤
10-15 mg/kg PO/PR Q4-6h;
dose limit: <2 years: 60mg/
kg/day, >2 years: 90mg/kg/
day, max. 4g
✤
✤
Has to be watched for rare
hepatotoxic side effects
(0-6 months of age) was
associated with allergic
sensitization/history of asthma
in girls at 10 years of age
Bakkeheim E,
✤
✤
✤
FDA 2013: max. 650mg/dose;
max. OTC (!) 2.6-3 mg/day
Mowinckel P, Carlsen KH, Haland G, Carlsen KC. Paracetamol in early infancy: the risk of
childhood allergy and asthma. Acta paediatrica. 2011 Jan;100(1):90-6.
✤
Generally well tolerated
Lacks gastrointestinal and
hematological side-effects
Meta-analysis (30 studies, 2364
patients): IV acetaminophen
reduces postoperative nausea
and vomiting
Apfel, C. C., A. Turan, et al. (2013). "Intravenous
acetaminophen reduces postoperative nausea and vomiting: A systematic review and metaanalysis." Pain 154(5): 677-689.
Ibuprofen
✤
Ibuprofen: 5-10mg/kg PO TDSQID; dose limit 2400mg/day
✤
✤
✤
✤
Least gastrointestinal side
effects among the NSAIDs
Caution with hepatic or
renal impairment, history of
GI bleeding or ulcers
May inhibit platelet
aggregation
✤
Acetaminophen (Paracetamol)
& Ibuprofen can usually be
used in combination, e.g.
scheduled Q6h administered at
the same time!
Ketorolac (Toradol®): < 2 years:
0.25 mg/kg i.v.; > 2 years: 0.5
mg/kg i.v., max. 30mg, max. 5
days
Opioid Sparing
✤
RCT Postsurgical pediatric
patients: NSAID vs placebo,
with parenteral opioids as
rescue analgesics, the NSAID
groups typically show lower
pain scores and a 30% to 40%
reduction in opioid use
Vetter T, Heiner E.
Intravenous ketorolac as an adjuvant to pediatric patient-controlled analgesia with morphine.
J Clin Anesth 1994;6:110– 3.
Case Example 1: Andrea
✤
✤
10-year-old girl in severe acute
(!) pain (e.g. metastasized
osteosarcoma, sickle cell crisis);
weight: 20 kg
PCA pump currently not
available
✤
Choice of opioid?
✤
Immediate release morphine
✤
...unless...
Case Example Morphine
✤
Route of administration?
✤
Per kg dosing: Maximum 50 kg
✤
Lean weight for obese children
✤
Please write the order (small
group work
Case Example Morphine
(Immediate Release)
✤
✤
✤
Scheduled (round-the-clock) dose
✤
IV: !0.1 mg x 20 kg = 2 mg Q4h ! (= 12 mg/day)
✤
PO: !
0.3 mg x 20 kg = 6 mg Q4h ! (= 36 mg/day
Breakthrough (rescue) dose = 1/10 - 1/6 of daily dose (Q1-2h)
✤
IV:! !
(1.2 - 2 mg)!
✤
PO:!
!
1.2 mg Q1h PRN
(3.6 - 6 mg) ! 3.6 mg Q1h PRN
if pain score > ...?..../10 and no signs of over sedation
Case Example: Sean
✤
✤
✤
10-year-old boy in severe acute
(!) pain (e.g. metastasized
osteosarcoma, sickle cell crisis);
weight: 20 kg
PCA pump now available
Question: PCA bolus only or
continuous infusion plus PCA
bolus?
✤
Meta-Analysis: Addition of
continuous (or background)
infusion to the demand (or PCA
bolus) dose for IV-PCA is NOT
associated with a higher
incidence of respiratory events
than PCA bolus alone in
pediatric patients (in contrast to
adults).
George JA, Lin EE, Hanna MN, Murphy JD, Kumar K, Ko PS, et al.
The effect of intravenous opioid patient-controlled analgesia with and without background
infusion on respiratory depression: a meta-analysis. J Opioid Manag. 2010 Jan-Feb;6(1):47-54.
Opioid Dose Escalation for
Acute (!) Pain
✤
How to increase the dose?
✤
50 per cent rule !
Please write PCA Order
✤
Morphine (and Plan B: Fentanyl and Plan C: Hydromorphone)
✤
Patient (or nurse-) controlled analgesia: PCA
✤
(1) Continuous Infusion
✤
(2) PCA- Dose
✤
(3) Lock-Out Time
✤
(4) Maximum number of boluses per hour
Continuous Infusion / PCA Dose
✤
✤
(1) Background (continuous) infusion i.v./s.c.:
✤
Morphine: 15-20 mcg x 20 kg = 0.3-0.4 mg/hr
✤
Fentanyl: 0.5-1 mcg x 20 kg = 10 -20 mcg/hr
✤
Hydromorphone: 2-5 mcg x 20 kg = 40 - 100 mcg
(2) PCA- Dose
✤
Same as above / hourly dose (e.g 0.4 mg morphine)
✤
Unless there is a good reason not to...
PCA Order Set
✤
(3) Lockout time:
✤
✤
(5) - 10 minutes
(4) Maximum number of boluses per hour:
✤
4 (-6) ....however, depends on the clinical scenario
✤
Loading dose? ...depends... (hourly dose x 1-4...)
✤
Lower starting dose? ...depends...age... if multimodal analgesia...
✤
How to increase the dose?
✤
50 per cent rule
Example for 50% titration orders:
✤
Patient (or nurse-) controlled analgesia: PCA
✤
Background infusion i.v./s.c.: !!
✤
Bolus i.v./s.c.: 0.4 mg (max 6 per hour); Lockout time: 5 (-10) minutes
0.4 mg/hr
Example for 50% titration orders:
ÆIf receiving > __ boluses/hour for > __ consecutive hours AND
if unrelieved pain AND no over sedation or dose limiting side
effects, increase PCA by 50% as follows:
Æ Step 1: Continuous infusion 0.6 mg/hr, PCA dose 0.6 mg, max.
6 boluses/hr
Æ Step 2: (if á again) Continuous infusion 0.9 mg/hr, PCA dose
0.9 mg, max. 6 boluses/hr
Æ Step 3: (if á again) Continuous infusion 1.35 mg/hr, PCA dose
1.35 mg, max. 6 boluses/hr
Further Training
Education in Palliative & End-of-life Care [EPEC]: Become an EPECPediatrics Trainer | Phoenix, AZ | May 4-5, 2015
http://www.cvent.com/d/q4qy0y
8th Annual Pediatric Pain Master Class | Minneapolis, MN | June 20-26,
2015 http://www.cvent.com/d/24q69s
Twitter: @NoNeedlessPain
Stefan J. Friedrichsdorf, MD, FAAP
Associate Professor of Pediatrics, University of Minnesota
Medical Director, Department of Pain Medicine, Palliative Care &
Integrative Medicine
Children's Hospitals and Clinics of Minnesota
2525 Chicago Ave S | Minneapolis, MN 55404 | USA
612.813.6450 phone | 612.813.6361 fax
[email protected]
Blog: http://noneedlesspain.org
http://www.childrensmn.org/services/
painpalliativeintegrativemed