SPECIAL TOPIC SERIES
From Tramadol to Methadone
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ON OPIOID THERAPEUTICS AND CONCERNS IN PEDIATRICS
Opioids in the Treatment of Pain and Dyspnea
in Pediatric Palliative Care
Stefan J. Friedrichsdorf, MD*†
Background: More than 15,000 children die annually in the United
States due to an underlying life-limiting disease and the majority of
those children experience distressing symptoms, which are not
adequately relieved, such as pain and dyspnea. Multimodal anal-
gesia, that is multiple agents, interventions, rehabilitation, psycho-
logical modalities, and integrative (nonpharmacologic) therapies,
act synergistically for more effective pediatric pain and symptom
control with fewer side effects than a single analgesic or modality.
However, opioids, such as morphine, fentanyl, hydromorphone,
oxycodone, and methadone (in the United Kingdom: diamorphine)
remain the mainstay medication to effectively treat pain and dysp-
nea in children with serious illness.
Methods: This article reviews commonly used opioids in Pediatric
Palliative Care, which a special emphasis on 2 potentially partic-
ularly effective multimechanistic opioids: tramadol and methadone.
Results: Methadone, due to its multimechanistic action profile, is
possibly among the most effective and most underutilized opioid
analgesics in children with severe unrelieved pain at end of life.
However, methadone should not be prescribed by those unfamiliar
with its use: Its effects should be closely monitored for several days,
particularly when it is first started and after any dose changes.
Conclusions: Tramadol appears to play a key role in treating epi-
sodes of inconsolability in children with progressive neurologic,
metabolic, or chromosomally based condition with impairment of
the central nervous system. However, the recent 2017 United States
Food and Drug Administration (FDA) warning against pediatric
use of tramadol does not seem to be based on clinical evidence, and
therefore puts children at risk for unrelieved pain or increased res-
piratory depression.
Key Words: pain, pediatrics, opioids, methadone, tramadol, pal-
liative care, Hospice and Palliative Medicine
(Clin J Pain 2019;35:501–508)
O ver 21 million children 0 to 19 years would benefit
annually from a palliative care approach worldwide, > 8
million needing specialized Pediatric Palliative Care (PPC).1
In the United States alone, > 42,000 children died in 2013,
55% of the infants younger than 1 year.2 The leading causes of
pediatric deaths include accidents (7645 children), suicide
Received for publication January 15, 2019; revised January 16,
2019; accepted January 17, 2019.
From the *Children’s Hospitals and Clinics of Minnesota; and
†Department of Pediatrics, University of Minnesota, Minneapolis,
MN.
The author declares no conflict of interest.
Reprints: Stefan J. Friedrichsdorf, MD, Children’s Hospitals and
Clinics of Minnesota, Minneapolis, MN 55404 (e-mail: stefan.
friedrichsdorf@childrensMN.org).
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/AJP.0000000000000704
Clin J Pain  Volume 35, Number 6, June 2019
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
(2143), and homicide (2021). Leading life-limiting conditions
include congenital malformations and chromosomal abnor-
malities (5740) followed by malignancies (1850).
PPC is about matching treatment to patient goals and is
considered specialized medical care for children with serious
illness. It is focused on relieving pain, distressing symptoms, and
stress of a serious illness and appropriate at any age and at any
stage, together with curative treatment. The primary goal is to
improve quality of life for the child and his or her family.3
Pediatric patients enrolled into PPC programs experience an
average of 9 distressing symptoms,4 and unfortunately in chil-
dren with advanced serious illness, the majority of those
symptoms (such as pain, dyspnea, and nausea/vomiting) are not
treated during the end-of-life period, and when treated, the
therapy is commonly ineffective.5–10 Evidence obtained through
randomized controlled trials (RCTs) that the integration of
palliative care improves the quality of life and prolongs life in
adults11,12 has been described in pediatric case reports as
well.13–15 Parents of children with cancer who received PPC
reported less distress from pain, dyspnea, and anxiety during the
end-of-life period.8 Children who received pediatric palliative
home care were more likely to have fun (70% vs. 45%) and to
experience events that added meaning to life (89% vs. 63%).9 In
addition, families who received PPC services report improved
communication16 and children receiving PPC experience shorter
hospitalizations and fewer emergency department visits.17
OPIOIDS IN PPC
Opioids, including morphine, fentanyl, hydromorphone,
and oxycodone as well as methadone, play a key role in the
effective treatment of pain and dyspnea in children with serious
advanced illness. An individual child differs in his or her
response to any given opioid analgesics. Even in well designed,
successful clinical trials, as much as 40% of patients do not
respond well to analgesic being studied.18 Not surprisingly,
children may require trials of several different opioids to find
effective analgesia with acceptable tolerability. Individual chil-
dren display a variety of combinations of different μ-opioid
receptor (MOR) subtypes generated through alternative splic-
ing, known to enhance protein diversity. The binding profiles
and resulting pharmacologic effects of opioid receptor subtypes
vary among μ-opioids and contribute to individual variance in
therapeutic response and incomplete cross-tolerance.19
OPIOIDS FOR TREATMENT OF DYSPNEA
Many children with serious illnesses develop dyspnea
during their end-of-life period. It is among the most common
and most distressing symptoms in PPC.7 The pathophysiology
of dyspnea is multifactorial and often not based on an
underlying lung disease, rendering oxygen administration
often ineffective.20,21 Following a clinical examination and
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Friedrichsdorf
thorough assessment of a child with dyspnea, and addressing
potentially treatable conditions such as anemia, broncho-
spasms, psycho-social-spiritual concerns, airway obstruction,
rales, increased secretions caused by artificial hydration or
nutrition, and/or anxiety, may prove helpful.22–24 Integrative
(nonpharmacological) modalities should include a fan,25 and
in addition might include repositioning, improving air circu-
lation, teaching breathing techniques, and guided imagery,
hypnosis, acupuncture and/or deep breathing, depending on
the age of the child.22,26
Opioids such as morphine, fentanyl, hydromorphone (in
the United Kingdom: diamorphine) and oxycodone remain
the gold standard and first-line pharmacology for unrelieved
dyspnea in children with serious illness.22,23 Opioids’ effects
are on µ-receptors including at the brainstem, and thereby
decrease the perception of dyspnea, the respiratory drive, the
hyper-responsiveness to hypercapnia and hypoxia, and as a
result decrease the child’s oxygen consumption.21,27–31
The starting dose for opioid-naive children for mor-
phine or other opioids for dyspnea is around 50% of the
recommended starting dose for treatment of pain. The dose
might then be titrated to effect in the same manner as for the
treatment of pain, for instance in 50% titration steps,
depending on clinical situation. If the pediatric patient is
already on scheduled opioids, likewise in can be recom-
mended to titrate to effect, for instance by increasing in 50%
escalation steps.22,23 The use of inhaled morphine for
dyspnea remains controversial and the current body of
evidence does NOT support the effectiveness of nebulized
opioids for dyspnea management.21,32 Intranasal fentanyl
on the other hand has been effectively used for infants with
breathlessness receiving palliative care.33
An enduring misconception is the belief that in the man-
agement of pain and especially dyspnea, opioids will hasten
death and should only be administered as a last resort. This
was contradicted in the adult literature34,35 and our PPC teams
commonly observe that administering opioids, together with
comfort care to relieve dyspnea and pain, not only improves the
child’s quality of life, but also prolongs life.36 The erroneous
assumption is that opioids, titrated to effected, for dyspnea (or
pain) at end-of-life causes respiratory depression and potential
death and should therefore not be used.37 Evidence, including
systematic reviews, demonstrates that opioids are effective in
relieving breathlessness in palliative care patients and do not
compromise respiration.20,21,29–31,38–40 In fact, opioid studies
for dyspnea showed that oxygenation and CO2-levels do not
change with introduction of opioids.41 As a result, clinical
guidelines recommend the use of opioids for unrelieved dyspnea
in palliative care.42,43 Clinical experience has shown that
opioids prescribed appropriately in pediatric palliative care,
that is administered for acute pain or dyspnea, titrated to effect,
and properly monitored by prescribing clinician will over-
whelmingly not result in respiratory depression and affected
children live longer with improved quality of life.14
OPIOIDS FOR PAIN TREATMENT IN PPC
Unfortunately, even in resource-rich countries the major-
ity of children with serious advanced illnesses are suffering from
unrelieved pain.7,10 Advanced pain treatment and prevention
for children with serious illness requires multimodal analgesia,
that is employing multiple pharmacological agents, anesthetic
interventions, rehabilitation, psychological and integrative
therapies, which act synergistically for more effective pediatric
pain and symptom control with fewer side effects than single
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Clin J Pain  Volume 35, Number 6, June 2019
medication or modality.36,44–49 But opioids remain the primary
pillar of advanced pain management in PPC.50 Unfortunately,
in many countries worldwide, due to opiophobia, lack of
clinician education and/or barriers to opioid access, children
suffer severe unrelieved pain and die in agony.3,51,52 In fact,
according to a recent Lancet report, treating all children
worldwide for severe pain would cost only US$ 1 million per
year.51
The principles of opioid therapy in PPC usually mirror
those of acute pediatric pain management,46,47,50,53–58 as
described in more detail in this Clinical Journal of Pain
special issue on opioids in pediatrics. This includes sched-
uling of opioids, titrate medication to effect, and employ
opioid-rotation, if tolerance develops or dose-limiting opioid
toxicity occurs.50,59,60 Commonly used opioid analgesics
that appear safe and effective in PPC include morphine,
fentanyl, hydromorphone, oxycodone, and methadone (in
the United Kingdom only: diamorphine), and for an
important subgroup of children, tramadol.36,45–47,53,54,61–66
For usual starting doses, see Tables 1–3. In end-of-life care,
especially in children with metastatic solid tumors, opioid
doses, when titrated to effect, in our daily practice can easily
reach a range of 10 to 100 times the normal starting doses
without causing over sedation.67–70
The 2016 Guidelines for Prescribing Opioids for Chronic
Pain by the Center for Disease Control and Prevention71 do not
apply to children and teenagers.72 Its scope encompasses only
“patients aged 18 years and above with chronic pain outside of
palliative and end-of-life care.” The guidelines state further, that
the “recommendations do not address the use of opioid pain
medication in children or adolescents aged below 18 years.”
Opioids should not be administered to pediatric palliative care
patients to primarily treat primary pain disorders,73 that is
chronic pain defined that extends beyond the expected time of
healing and hence lacks the acute warning function of physio-
logical nociception. Opioids may be more likely to cause more
harm than benefit in the treatment of “primary pain disorders,”
which include conditions such as tension headaches/migraines,
widespread musculoskeletal pain/fibromyalgia, “chronic sickle
cell pain” (pain that extends beyond the expected time of acute
vaso-occlusive crisis) and, functional abdominal pain/centrally
mediated abdominal pain syndrome. Opioids administered for
primary pain disorders have low long-term efficacy, a poor safety
profile, and commonly a worse clinical outcome.74–80
MULTIMECHANISTIC OPIOIDS
Two very different multimechanistic opioids appear to
be particularly useful in pediatric palliative care, tramadol,
and methadone, and will be reviewed in more detail in the
section below.
Methadone
Methadone is an excellent opioid choice in advanced
pediatric analgesia and pediatric palliative care, but it
remains underutilized.61,65,81–85 It is a µ (δ, κ)-opioid
receptor agonist, an N-methyl-D-aspartate (NMDA)-chan-
nel blocker, and a presynaptic blocker of serotonin and
norepinephrine re-uptake. Advantages include methadone’s
long half-life (allowing every 8 to 12 h dosing), high effec-
tiveness in complex pain conditions, decreased incidence of
constipation, lack of active metabolites, and safe usage in
renal failure and in stable liver disease. Cross-tolerance is
believed to be avoided secondary to its activity at NMDA
receptors.86,87 There are several disadvantages, however,
Clin J Pain  Volume 35, Number 6, June 2019 Opioids in Pediatric Palliative Care

TABLE 1. Opioid Analgesics: Usual Starting Doses

Equianalgesic Starting Dose:
Drug (Route of Dose Starting Dose: IV:PO Starting Dose: Controlled
Administration) (Parenteral) IV Ratio PO (Transdermal) Release
Morphine (PO, SL, IV, 10 mg Bolus dose: 50-100 mcg/kg 1:3 0.15-0.3 mg/kg every 4 h 0.45-0.9 mg every
SC, PR) every 2-4 h 12 h
Continuous infusion:
10-30 mcg/kg/h
Fentanyl (IV, SC, SL, 100-250 mcg Bolus dose: 1-3 mcg/kg 1:1 (IV to 12 mcg/h patch (must be on NA
transdermal, buccal) (slowly over 3-5 min— transdermal) the equivalent of at least
fast bolus may cause 30 mg oral morphine/24 h,
thorax rigidity) before switched to patch)
Continuous infusion:
1-2 mcg/kg/h
Hydromorphone (PO, 1.5 mg Bolus dose: 15-20 mcg/kg 1:5 60 mcg/kg every 3-4 h 180 mcg/kg every
SL, IV, SC, PR) every 4 h 12 h—currently
Continuous infusion: not available in
5 mcg/kg/h the United
States
Oxycodone (PO, SL, 5-10 mg NA NA 0.1-0.2 mg/kg every 4-6 h 0.3-0.9 mg/kg
PR) every 12 h
Tramadol (PO, PR) 100 mg IV not available in the 1:1 1-2 mg/kg every 3-4 h, max. 2-4 mg/kg every
United States Bolus of 8 mg/kg/d ( > 50 kg: 12 h
dose: 1 mg/kg every max. of 400 mg/d)
3-4 h
Continuous infusion:
0.25 mg/kg/h
Doses for children > 6 mo of age and are capped at 50 kg body weight.47
Calculated rescue (breakthrough) dose: 10% of 24-hour opioid dose to be given every 1 to 2 hours as needed (with a maximum number of doses in 24 hours
depending on clinical scenario).
IV indicates intravenous; NA, not applicable; PO, by mouth; PR, rectal; SC, subcutaneous; SL, sublingual.

including wide dosing variation, a long half-life (which may longer and closer patient observation than with other
lead to accumulation, making quick titration difficult), and opioids. Methadone displays typical opioid-induced side
a more complex equianalgesic conversion, which requires effects such as sedation, nausea, constipation, and at higher
doses opioid-induced neurotoxicity (including myoclonus,
hallucinations, nightmares), respiratory depression have
TABLE 2. Opioid Analgesia for Neonates and Infants 0 to 6
been described, with some case reports of hypoglycemia.88,89
Months of Age50 Usual starting doses for opioid naive children at the Pain &
Palliative Care service at Children’s Minnesota are 0.05 to
Dosing 0.1 mg/kg/dose (max, 2.5 to 5 mg PO Q8 to 12 h). For
Opioid Dose Route Interval (h) conversion rates from other opioids (via oral morphine
Morphine 0.075-0.15 mg PO/ 6 equivalent) see Table 4.
(neonates 0-30 d) PR/SL Despite its advantages, conversion to methadone
0.08-0.2 mg (infants 1-12 mo) 4-6 remains complicated in pediatric patients. There are sig-
Morphine* 0.025-0.05 mg/kg IV/SC 6 nificant problems with adult-based conversion tables used in
(neonates 0-30 d) pediatrics,59,61,84 including tremendous interindividual var-
0.1 mg/kg (infants 1-6 mo) 6
iability in relative potency estimates; tolerance development
Infusion (with PCA bolus
of same dose)
with repetitive dosing (dose reduction 25% to 75% or more
0.005-0.01 mg/kg/h for incomplete cross-tolerance often inadequately por-
(neonates 0-30 d) trayed); erroneous assumption that relative potency ratios
0.01-0.03 mg/kg/h remain irrespective of level of opioid; and no accounting for
(infants 1-6 mo) unidirectional cross-tolerance nor for possibility of active
Fentanyl* 1-2 mcg/kg (neonates & IV/SC 2-4 metabolite accumulation. As a result, methadone should not
infants 0-12 mo) be prescribed by those unfamiliar with its use. Safe use
Infusion (with PCA bolus requires that the effects of methadone should be closely
of same dose) monitored for several days, particularly when it is first
0.5-1 mcg/kg/h (neonates &
infants 0-6 mo) started and after any dosing change.

*The intravenous doses for neonates are based on acute pain manage-
ment and sedation dosing information. Lower doses are required for non-
ventilated neonates.
IV indicates intravenous; PCA, patient-controlled analgesia; PO, by
mouth; PR, rectal; SC, subcutaneous; SL, sublingual.
Tramadol
Tramadol is a multimechanistic analgesic commonly
used worldwide for pediatric pain management and palliative
care.92–95 Studies examining efficacy and safety of this medi-
cation have been conducted worldwide, and results support its

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Friedrichsdorf Clin J Pain  Volume 35, Number 6, June 2019

TABLE 3. Usual Starting Doses for Patient (or Nurse)-Controlled Analgesia (PCA) Pumps
Continuous Infusion (mcg/kg/h) PCA Bolus (mcg) Lock-out Time (min) Maximum Number of Boluses/Hour
Morphine 20 (max. 1000) 20 (max. 1000) 5-10 4-6
Hydromorphone 3-5 (max. 250) 3-5 (max. 250) 5-10 4-6
Fentanyl 1 (max. 50) 1 (max. 50) 5 4-6
Dose escalation usually in 50% increments both for continuous and PCA bolus dose (Department of Pain Medicine, Palliative Care & Integrative Medicine,
Children’s Hospitals and Clinics of Minnesota, USA).
Doses for children above 6 months of age and are capped at 50 kg body weight.47

use in children.96–107 The analgesic potency of tramadol falls
somewhere between ibuprofen and morphine.108 Although
only commercially available in tablet form in the United
States, an oral suspension may be compounded into a stable
and inexpensive liquid.109 Although tramadol is metabolized
into the more potent O-desmethyltramadol, tramadol (unlike
codeine) itself appears to be a potent analgesic.
For poor CYP2D6 metabolizers, the parent compound
tramadol remains active; hence, those individuals experience
no decrease or only a slightly diminished analgesic effect.108
Data suggests that tramadol administration may result in
fewer side effects than with opioid agonists,110 and tramadol
appears far safer than codeine when it comes to risk of
respiratory depression. One study examining statewide
poison control center data in the United States111 reported
no respiratory depression in children under 6 years of age
who ingested 10/mg/kg or less (up to 5 to 10 times the rec-
ommended dose), however 2 of 87 (2%) adults in the sample
did experience respiratory depression.
At Children’s Hospitals and Clinics of Minnesota alone
> 6000 pediatric tramadol scripts have been filled in 2016, mostly
for outpatient postoperative analgesia such as tonsillectomy.
However, it has been shown to be particularly helpful in treating
neuropathic pain and visceral hyperalgesia10 presenting as epi-
sodes of inconsolability in children with neurologic, metabolic, or
chromosomally based conditions with impairment of the central
nervous system, such as mitochondropathies.
Case Example
Charlotte, after multiple hospitalizations, presents again
as a 14-month old girl, 9 kg, with a congenital progressive
neuromuscular disorder, probably mitochondropathy (years
later diagnosed as Brown-Vialetto-Van-Laere syndrome). She
was airlifted to our hospital due to increased frequency and
duration of central apnea, severe episodes of inconsolability,
and vomiting. An extensive work-up, including blood work,
imagery, and esophagogastroduodenoscopy did not reveal an
TABLE 4. Methadone Conversion Table*
Gazelle Toombs
Total Daily Oral and Roxane
Morphine Dose (mg) Fine90 Laboratories Inc.91 Kral87
< 100 3:1 20%-30%
101-300 5:1 10%-20%
301-600 10:1 8%-12%
601-800 12:1 5%-10%
801-1000 15:1 5%-10%
> 100 20:1 < 5%
*Usual initial maximum dose following conversion from high dose
opioids: 30 mg PO/d (60 mg as in above table, reduced by 50% for incomplete
cross-tolerance).
underlying pathology. Simple analgesia (acetaminophen,
ibuprofen) appeared only moderately helpful for frequent
episodes of pain, and the primary and specialist teams had been
apprehensive about the use of opioids in a child with enigmatic
frequent apnea episodes at home requiring bagging. She was
started by the pain and palliative care team on 1 mg/kg tramadol
q6h by mouth with a dramatic improvement of her distressing
symptoms within the next hours. Her several month-long fre-
quent vomiting episodes resolved completly, her episodes of
inconsolability changed from several hour-long daily episodes to
<1 per week, and her severe apnea attacks requiring bagging at
home stopped. Over the next years Charlotte continues to present
to the palliative care clinic as a complex patient with global
motor-neurodevelopmental delay, visual loss, neurogenic bowel
and bladder, feeding intolerance with visceral hyperalgesia,
dysautonomia and required additional adjuvant analgesia
(such as gabapentin, amitriptyline, clonidine) for good
symptom control. Repeated trials of slowly decreasing
tramadol (or switching to morphine or oxycodone) resulted
in increased pain episodes, vomiting, and increased apnea.
At age of 12 years, with 35 kg, she is currently on 35 mg
tramadol 3 times per day plus an as needed dose of 30 mg,
which she requires about once per week.
Safety of Tramadol in Pediatrics
The author applauds the United States Food and Drug
Administration’s (FDA) attempt to improve pediatric analgesic
safety. In fact we have published 3 case reports about children in
the Minneapolis/St. Paul region who died after appropriate doses
of Codeine.112 However, there appears to be a fundamental
misunderstanding about tramadol’s pharmacogenetics, pharma-
codynamics, and pharmacokinetics, which may have triggered
that the recent FDA labeling of tramadol as contraindication for
children. Both codeine and tramadol are metabolized by cyto-
chrome P450 2D6 into an active (or more active) metabolite. But
the similarities largely end there and it is not clear, why the FDA
combined the codeine warning with tramadol.113 Codeine as a
pro-drug (unlike tramadol) is ineffective as an analgesic, and
needs to be metabolized into morphine to display an analgesic
effect. Pharmacogenetic CYP2D6 enzyme activity of ultrarapid
metabolizers pose a possible a danger of metabolizing into too
and much morphine with increased risk of respiratory depression and
even death.112,114–118 Of note, ultrarapid metabolizer for
CYP2D6 increase the risk for respiratory depression not only for
33%
20%
codeine (metabolized into morphine), but also for hydrocodone
10% (metabolized into hydromorphone), and oxycodone (meta-
8% bolized into oxymorphone).
7% The FDA cites the following evidence on their website:113
5% “A search of the FAERS database from January 1969 to
March 2016 identified nine cases worldwide of respiratory
depression in children younger than 18 years of age, including
three deaths. With the exception of a 15-year-old treated for
multiple days with tramadol, respiratory depression occurred

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Clin J Pain  Volume 35, Number 6, June 2019
within the first 24 hours of drug administration. The three
fatalities occurred outside the U.S. in children younger than
6 years. Elevated serum tramadol concentrations were noted in
all three. The reasons for tramadol treatment in these children
were to treat pain after tonsillectomy, pain after clubfoot sur-
gery, and to manage fever. The one case in which CYP2D6
ultrarapid metabolizer status was reported occurred in a 5-year-
old child from France who was prescribed a single tramadol
dose in the evening post-adenotonsillectomy and returned to
the healthcare facility the next morning with opioid intox-
ication; he was resuscitated. One non-fatal U.S. case involved a
6-year-old who was prescribed tramadol for neuropathy of the
hands and feet. After the third dose, the patient experienced
respiratory depression and was unresponsive. The patient fully
recovered after receiving two doses of naloxone. Four other
non-fatal cases reported in teenagers using tramadol for
musculoskeletal pain or sciatica described unresponsiveness or
somnolence after one or a few doses of tramadol; all required
medical intervention. Two of these were U.S. cases.”
In short, the FDA classification of tramadol as a “con-
traindication” in children is solely based on case reports of 3
children in the last 48 years who died following receiving high-
concentrations drops (100 mg/mL, ie, a teaspoonful represents
500 mg or ×10 standard adult dose), a concentration not avail-
able in the United States. As alternative orally available opioids,
such as morphine and oxycodone, have a significant higher risk
of respiratory depression (especially for outpatient surgical
patients) and (with the exception methadone) fail to play an
effective role in the large number of children with progressive
neurodegenerative diseases in palliative care, the FDA warning
puts these 2 groups of children at risk. As such, after review of
the scant evidence presented by the FDA the pain service and
P&T committee, Children’s Minnesota has decided to continue
prescribing tramadol for appropriate patients.
CONCLUSIONS
Opioids remain the single most important group of
medications to effectively treat pain and dyspnea in children
with serious advanced illness. The starting dose for opioid-naive
children for morphine or other opioids for dyspnea is around
50% of the recommended starting dose for treatment of pain.
Commonly used opioids for advanced analgesia include mor-
phine, fentanyl, hydromorphone, and oxycodone. Especially
the multimechanistic opioids tramadol and methadone are
commonly and effectively used in pediatric palliative care
worldwide. The recent FDA classification of tramadol as a
“contraindication” in children is not based on evidence, but
solely based on case reports of 3 children in the last 48 years
who died following receiving high-concentrations drops, a
concentration not available in the United States.
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