REVIEW

Multimodal analgesia in children

Myron Yaster

Acute and chronic pain management in children is increasingly biofeedback, transcutaneous electrical nerve stimulation, and
characterized by either a multimodal or a preventive analgesia acupuncture. Using the neurophysiology of pain as a blueprint,
approach, in which smaller doses of opioid and nonopioid the molecular targets and strategies used in multimodal pain
analgesics, such as nonsteroidal anti-inflammatory drugs, local management are described. Finally, weight-based dosage
anaesthetics, N-methyl-D-aspartate antagonists, a2-adrenergic guidelines for commonly used opioid and nonopioid analgesics
agonists, and voltage-gated calcium channel a-2 d-proteins, are are provided to facilitate therapy.
combined alone and in combination with opioids to maximize Eur J Anaesthesiol 2010;27:851–857
pain control and minimize drug-induced adverse side effects. A Published online 7 April 2010
multimodal approach uses nonpharmacological complementary
Keywords: analgesics, anticonvulsants, clonidine, gabapentin, narcotic
and alternative medicine therapies too. These include antagonists, non-steroidal antiinflammatory drugs, opioid, pain,
distraction, guided imagery, hypnosis, relaxation techniques, pregabalin, regional anesthesia techniques

Introduction modal pain treatment, but in order to understand these

The treatment and alleviation of pain is a basic human therapeutic strategies, a basic review of pain physiology
right regardless of age.1,2 The old ‘wisdom’ that young is required.
children neither respond to, nor remember, painful
experiences to the same degree that adults do is simply Neurophysiology of pain
untrue.3 Many, if not all, of the nerve pathways essential Pain is more than simply the physiological transmission of
for the transmission and perception of pain are present nociceptive input from a site of injury to the brain, and its
and functioning by 24 weeks’ gestation.4,5 Recent subsequent modulation within the central nervous sys-
research in newborn animals has revealed that failure tem. Rather, it is a complex sensation that is integrated
to treat pain leads to ‘rewiring’ of the nerve pathways and given value at higher, conscious brain centres. Like
responsible for pain transmission in the dorsal horn of the symphonic music, no two people experience it the same
spinal cord and results in increased pain perception in the way. Despite the fact that the physiology of sound
future.6,7 This confirms human newborn research in transmission is the same in all of us, symphonic music
which failure to provide anaesthesia or analgesia for to some is simply awful and to others it is glorious. As we
newborn circumcision resulted not only in short-term integrate neural transmissions, we give them subjective
physiological perturbations but also in longer term beha- value based on our age, culture, genes, previous experi-
vioural changes, particularly during immunization.3,8–10 ence and education, values, and state of mind. The same
As pain physicians we champion the benefits of analgesia is true for pain.
and often minimize or even deny the negative effects of Many, if not all, of the nerve pathways essential for the
therapy. Indeed, some opioid-induced side effects such transmission, perception, and modulation of pain are
as nausea, vomiting, itching and constipation are so present and functioning by 24 weeks of gestation.4,5
common and severe that many patients choose to experi- Although neural transmission in peripheral nerves is
ence the pain rather than the treatment. Because of this, slower in neonates because myelination is incomplete
acute and chronic pain management in both children and at birth, the major nociceptive neurons in neonates as
adults is increasingly characterized by a multimodal or well as in adults are either unmyelinated C fibres or thinly
‘preventive analgesia’ approach in which smaller doses myelinated Ad fibres. Following an acute injury such as
of opioid and nonopioid analgesics, such nonsteroidal surgical or accidental trauma, inflammatory mediators are
anti-inflammatory drugs (NSAIDs), local anaesthetics, released which lower the pain threshold at the site of
N-methyl-D-aspartate (NMDA) antagonists, and a2-adre- injury (primary hyperalgesia) and in the surrounding
nergic agonists, are combined to maximize pain control uninjured tissue (secondary hyperalgesia). These inflam-
and minimize adverse side effects. In the next sections, matory mediators, which include hydrogen and potass-
we will review some of the drugs used in multimodal– ium ions, histamine, leukotrienes, prostaglandins, cyto-
kines, serotonin, bradykinins, and nerve growth factors,
From the Departments of Anaesthesiology, Critical Care Medicine and Pediatrics,
The Johns Hopkins University, Baltimore, Maryland, USA make a ‘sensitizing soup’, which together with repeated
Correspondence to Myron Yaster, MD, Richard J. Traystman Professor of stimuli of the nociceptive fibres cause decreased excit-
Pediatric Anesthesia, Critical Care Medicine, and Pain Management, Depart- atory thresholds and result in peripheral sensitization.
ments of Anaesthesiology, Critical Care Medicine and Pediatrics, The Johns
Hopkins University, Baltimore, MD 21287, USA
They are also targets of therapeutic intervention.
E-mail: myaster1@jhmi.edu Secondary effects of peripheral sensitization include
0265-0215 ß 2010 Copyright European Society of Anaesthesiology DOI:10.1097/EJA.0b013e328338c4af

Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.

 852 Yaster

hyperalgesia, an increased response to a noxious stimulus, operative and postoperative analgesia, targets multiple
and allodynia, whereby nonnociceptive fibres transmit sites along the pain pathway, and is referred to as
noxious stimuli resulting in the sensation of pain from ‘preventive’ or ‘multimodal’ analgesia.1,3 Indeed, acute
nonnoxious stimuli. paediatric (and adult) pain management is increasingly
characterized by a multimodal or ‘balanced’ approach in
As the primary afferent neurons enter the spinal cord they
which smaller doses of opioid and nonopioid analgesics,
segregate and occupy a lateral position in the dorsal horn.
such as NSAIDs, local anaesthetics, NMDA antagonists,
These afferent neurons release one or more excitatory
and a-2 adrenergic agonists, are combined to maximize
amino acids (glutamate and aspartate) or peptide neuro-
pain control and minimize drug-induced adverse side
transmitters (substance P, neurokinin A, calcitonin gene-
effects.15 Additionally, a multimodal approach includes
related peptide, cholecystokinin, and somatostatin).
nonpharmacological complementary and alternative
‘Second-order’ neurons that receive these chemical sig-
medicine therapies too. These include distraction,
nals integrate the afferent input with facilitatory and
guided imagery, hypnosis, relaxation techniques, bio-
inhibitory influences of interneurons and descending
feedback, transcutaneous electrical nerve stimulation,
neuronal projections. It is this convergence within the
and acupuncture.16 Taking this approach, activation of
dorsal horn that is responsible for much of the processing,
peripheral nociceptors can be attenuated by providing
amplification, and modulation of pain. Nociceptive
NSAIDs, antihistamines, serotonin antagonists, and local
activity in the spinal cord and the ascending spinotha-
anaesthetics. Within the dorsal horn, nociceptive trans-
lamic, spinoreticular, and spinomesencephalic tracts carry
mission and processing can be affected by the adminis-
messages to supraspinal centres (periaqueductal grey,
tration of local anaesthetics, neuraxial opioids, a-2 adre-
locus caeruleus, hypothalamus, thalamus and cerebral
nergic agonists (clonidine and dexmedetomidine), and
cortex) where they are modulated and integrated with
NMDA receptor antagonists (ketamine and methadone).
autonomic, homeostatic, and arousal processes. This
Within the central nervous system, pain can be amelio-
modulation, particularly by the endogenous opioids
rated by systemic opioids, a-2 adrenergic agonists,
gamma aminobutyric acid (GABA) and norepinephrine,
voltage-gated calcium channel a-2 d (Cav-a2-d) proteins
can either facilitate pain transmission or inhibit it.
(the anticonvulsants gabapentin and pregabalin), and
Modulating pain at peripheral, spinal, and supraspinal
pharmacological (benzodiazepines and a-2 agonists)
sites helps to achieve better pain management than
and nonpharmacological (hypnosis and acupuncture)
targeting only one site, and is the underlying principle
therapies that are thought to reduce anxiety and induce
of multimodal treatment.
rest and sleep.
Preemptive analgesia, preventive analgesia
and multimodal analgesia Weaker nonopioid analgesics with antipyretic
The possibility that pain after surgery might be preemp- activity
tively prevented or ameliorated by the use of opioids, The ‘weaker’ or ‘milder’ analgesics with antipyretic
local anaesthetics given preoperatively, or both has been activity constitute a heterogeneous group of nonopioid
one of the most cherished beliefs held by this generation analgesics. The most common are paracetamol, classic
of anaesthesiologists.11,12 Whether this actually occurs in NSAIDs (ibuprofen, naproxen, ketoprofen, and diclofe-
adults is not so clear.11,13,14 There is no evidence to either nac), and the selective cyclooxygenase (COX-2) inhibi-
validate or disprove this notion in children at all. Rather tors (celebrex) (Table 1).17–20 They produce various
than discarding it altogether, over the last few years the degrees of analgesia, anti-inflammatory, antiplatelet,
concept of preemptive analgesia has expanded and and antipyretic effects primarily by blocking peripheral
evolved to include the reduction of nociceptive inputs and central prostaglandin and thromboxane production
before, during, and after surgery. This expanded con- through inhibition of cyclooxygenase types 1, 2, and 3.
ceptual framework, which includes preoperative, intra- Prostaglandin and thromboxane sensitize peripheral

Table 1 Dosage guidelines for commonly used nonopioid analgesics with antipyretic effects
Name Dose (mg kg
1) frequency Comments

Ibuprofen 4–10 q 6–8 h Available as an oral suspension

Maximum adult dose 2400 mg kg
1
Ketorolac i.v. or i.m. 0.5 q 6 h Maximum dose 30 mg kg
1 or 90–120 mg kg
1 day
1 (adult)
Paracetamol 10–15 p.o. q 4 h Lacks anti-inflammatory activity
30 p.r. q 6–8 h The daily maximum paracetamol dose in the preterm, term,
and older child is 60, 80, 90 mg kg
1, respectively
Salicylates 10–15 q 4 h Permanently inhibits platelet aggregation and adhesion
Gastrointestinal irritability
Reye syndrome precludes routine use in children

i.m., intramuscular; i.v., intravenous; p.o., orally; p.r., rectally; q, every.

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 Multimodal analgesia in children 853

nerve endings and vasodilate blood vessels causing pain, all of the desirable anti-inflammatory and analgesic pro-
erythema, and inflammation. perties without the gastrointestinal and antiplatelet side
effects. Unfortunately, the increased risk of myocardial
These analgesic agents are administered enterally via the infarction in adult patients receiving COX-2 inhibitors
oral or, on occasion, the rectal route and are particularly has dampened much of the enthusiasm for these drugs
useful for inflammatory, bony, or rheumatic pain. Par- and has led to the removal of some of them (rofecoxib)
enterally administered agents, such as ketorolac and from the marketplace.31,32
paracetamol, are available for use in children in whom
the oral or rectal routes of administration are not
possible.21 Unfortunately, regardless of dose, the non- Paracetamol
opioid analgesics are limited by a ‘ceiling effect’ above One of the most commonly used nonopioid analgesics in
which pain cannot be relieved by these drugs alone. paediatric practice remains paracetamol, although its
Because of this, the weaker analgesics are often adminis- analgesic effectiveness in the neonate is unclear.33,34
tered in oral combination with opioids such as codeine, Unlike aspirin and other NSAIDs, paracetamol produces
oxycodone, or hydrocodone. analgesia centrally as a COX-3 inhibitor and via activation
of descending serotonergic pathways.34,35 It is also thought
Only a few trials have compared their efficacy in head-to- to produce analgesia as a cannabinoid agonist and by
head competition, and, in general, these studies have antagonizing NMDA and substance P in the spinal cord.36
shown that there are no major differences in their analgesic Paracetamol is an antipyretic analgesic with minimal, if
effects when appropriate doses of each drug are used. The any, anti-inflammatory and antiplatelet activity and takes
commonly used classic NSAIDs have reversible antiplate- about 30 min to provide effective analgesia. When admi-
let adhesion and aggregation effects, which are attributable nistered orally (p.o.) in standard doses, 10–15 mg kg
1,
to the inhibition of thromboxane synthesis.22,23 As a result, paracetamol is extremely well tolerated, effective, and has
bleeding times are usually slightly increased but, in most very few serious side effects. When administered rectally,
instances, they remain within normal limits in children higher doses, 25–40 mg kg
1, are required.37,38 Because of
with normal coagulation systems. Nevertheless, this side its known association with fulminant hepatic necrosis, the
effect is of such great concern, particularly in surgical daily maximum paracetamol dose, regardless of formu-
procedures in which even a small amount of bleeding lation or route of delivery, in the preterm, term, and older
can be catastrophic (e.g. tonsillectomy and neurosurgery), child is 60, 80, 90 mg kg
1, respectively. Thus, when
that few clinicians prescribe them even though the evi- administering it rectally, it should be given every 8 h rather
dence supporting increased bleeding is equivocal at than every 4 h. Finally, an intravenous (i.v.) formulation of
best.24,25 Finally, many orthopaedic surgeons are also paracetamol is now available in Europe and can be used in
concerned about the negative influence of all NSAIDs, patients in whom the enteral route is unavailable. This
both selective and nonselective COX inhibitors, on bone formulation has been associated with better analgesia than
growth and healing,26–28 and consequently they are reluc- oral paracetamol in clinical trials in adult patients and in
tant to use them. children is equally effective and less painful than the
‘prodrug’ formulation.21
The discovery of at least three COX isoenzymes, referred
to as COX-1, COX-2, and COX-3, has enhanced our
Opioids
knowledge of NSAIDs.29,30 The COX isoenzymes share
Over the past 30 years, multiple opioid receptors and
structural and enzymatic similarities, but are specifically
subtypes have been identified and classified. There are
regulated at the molecular level and may be distin-
three primary opioid receptor types, designated mu (m)
guished by their functions. Protective prostaglandins,
(for morphine), kappa (k), and delta (d). These receptors
which preserve the integrity of the stomach lining and
are primarily located in the brain and spinal cord, but also
maintain normal renal function in a compromised kidney,
exist on peripheral nerve cells, immune cells, and some
are synthesized by COX-1.25,29,31 The COX-2 isoenzyme
other cells (e.g. oocytes).39–41 The m receptor is further
is inducible by proinflammatory cytokines and growth
subdivided into several subtypes, which determine the
factors, implying a role for COX-2 in both inflammation
different pharmacological profiles of the opioids. These
and control of cell growth; in addition, it is found in the
are the m1 (supraspinal analgesia), m2 (respiratory depres-
brain and spinal cord, where it may be involved in nerve
sion and inhibition of gastrointestinal motility), and m3
transmission, particularly for pain and fever. Prostaglan-
(anti-inflammation and leucocytes).42–44 Both endogen-
dins made by COX-2 are also important in ovulation and
ous and exogenous agonists and antagonists bind to
in the birth process.25,29,31 The discovery of COX-2 has
various opioid receptors.
made it possible to design drugs that reduce inflammation
without removing protective prostaglandins in the Opioid receptors, which are found anchored to the plasma
stomach and kidney made by COX-1. In fact, developing membrane both presynaptically and postsynaptically,
a more specific COX-2 inhibitor was a ‘holy grail’ of drug decrease the release of excitatory neurotransmitters from
research because this class of drug was postulated to have terminals carrying nociceptive stimuli. These receptors

European Journal of Anaesthesiology 2010, Vol 27 No 10

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 854 Yaster

belong to the steroid superfamily of G protein-coupled neuropathic and chronic pain, but are now increasingly
receptors. Their protein structure contains seven trans- being used to treat acute pain as part of a multimodal
membrane regions with extracellular loops that confer therapeutic regimen.
subtype specificity and intracellular loops that mediate
subreceptor phenomena.41 These receptors are coupled Antidepressants
to guanine nucleotide (GTP)-binding regulatory proteins Because serotonin and norepinephrine mediate descend-
(G proteins) and control transmembrane signalling by ing inhibition of ascending pain pathways in the brain and
regulating adenylate cyclase [cyclic AMP (cAMP)], var- spinal cord, antidepressant medications, which inhibit
ious ion (Kþ, Ca2þ, and Naþ) channels and transport their reuptake, may have efficacy in relieving pain.50
proteins, neuronal nitric oxide synthetase, and phospho- Antidepressants that enhance norepinephrine action
lipase C and A2.42,45,46 Signal transduction from opioid are more effective analgesics than those, such as many
receptors occurs via bonding to inhibitory G proteins (Gi of the newer antidepressants, that predominantly
and Go). Analgesic effects are mediated by decreased enhance serotonin action.50 Older antidepressants,
neuronal excitability from an inwardly rectifying Kþ particularly the tricyclics, amitriptyline, doxepin, and
current, which hyperpolarizes the neuronal membrane, nortriptyline, have been the most thoroughly studied
decreases cAMP production, increases nitric oxide syn- and are thought to cause analgesia by norepinephrine
thesis, and increases the production of 12-lipoxygenase and serotonin reuptake inhibition.51 They also have other
metabolites. Indeed, synergism between opioids and pharmacological properties that may contribute to analge-
NSAIDs occurs as a result of the greater availability of sia such as reducing sympathetic activity, NMDA recep-
arachidonic acid for metabolism by the 12-lipoxygenase tor antagonism, anticholinergic activity, and sodium
pathway, after blockade of prostaglandin production by channel blockade. Newer, nontricyclic antidepressants
NSAIDs.47 Some of the unwanted side effects of opioids, seem to be less efficacious analgesics but have not been
such as pruritus, may be the result of opioid binding to studied for this use in children.
stimulatory G proteins (Gs) and may be antagonized by
low-dose infusions of naloxone.46,48,49 The most com- Antiepileptic agents
monly used opioids in paediatric practice are listed in Like the tricyclic antidepressants, antiepileptic adjuvant
Table 2. analgesics are burdened with an unfortunate name. Most
families and physicians who are unaware of their analgesic
Analgesic adjuvants properties question the use of an antiepileptic drug in a
Adjuvant pain medications are drugs whose primary child who does not have seizures. Gabapentin and prega-
indication is not to treat pain, but they may have analgesic balin have been most widely studied and used for the
properties in specific circumstances. Many of the drugs treatment of chronic pain conditions such as postherpetic
which will be discussed below were initially used to treat neuralgia, diabetic neuropathy, and complex regional pain

Table 2 Commonly used m-opioid agonists

Agonist Equipotent i.v. dose (mg kg
1) Comments

Morphine 0.1 ‘Gold standard’, very inexpensive, seizures in newborns

Histamine release (? use in asthma and hypotension)
Oral bioavailability 20–30% (give three times the i.v. dose p.o. or 0.3 mg kg
1)
Extended duration tablet and sprinkles available
Liquid preparation formulated in concentrations of 2–20 mg ml
1
Hydromorphone 0.02 Less itching and nausea than morphine
Useful i.v., p.o., and epidural
Fentanyl 0.001 Ideal for short painful procedures; may be administered i.v., epidural, intranasal,
transmucosal, and transdermal
Bradycardia; minimal haemodynamic effects
Chest wall rigidity
Oral transmucosal dose of 10–15 mg kg
1, transdermal for chronic pain only,
intranasal dose (1–3 mg kg
1) useful when no i.v. access is available
Methadone 0.02–0.1 Liquid preparation available (70þ% bioavailability) (useful when i.v. access unavailable)
Long duration of action makes it ideal for cancer pain, prolonged pain (limb trauma),
and weaning dependent patients; morphine equivalence is reduced in dependent patients
NMDA antagonist, suggesting role in neuropathic pain
Codeine 1.2 ‘Prodrug’ must be metabolized (10% of administered dose) into morphine by cytochrome
P450 2D6 isoenzyme in liver; poor metabolizers get no analgesia, rapid metabolizers may
produce toxic amounts of morphine
Liquid preparation available (70þ% bioavailability)
Oxycodone and hydrocodone 0.1 p.o. only (60% bioavailability)
Less nausea than codeine
Sustained release oxycodone tablet cannot be crushed or given via a gastric tube and has
high diversion and abuse potential

i.v., intravenous; NMDA, N-methyl-D-aspartate; p.o., orally.

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 Multimodal analgesia in children 855

syndromes. Interestingly, despite their names, gabapentin dexmedetomidine have evaluated its use in the immedi-
and pregabalin are not GABAergic and produce analgesia ate perioperative period; therefore, any long-term
by binding to Cav-a2-d proteins in the spinal cord and benefits are not yet clear.
central nervous system.52 Increasingly, they are being used
in the perioperative period as a component of multimodal N-Methyl-D-aspartate receptor antagonists
pain therapy.53–55 Adult studies have demonstrated their NMDA receptor antagonists, such as ketamine and
effectiveness (1200 mg gabapentin and 300 mg pregabalin methadone, are important modulators of chronic pain
p.o.) at enhancing postoperative analgesia and preopera- and some studies show them to be useful in preventive
tive anxiolysis, preventing chronic postsurgical pain, analgesia. They reduce acute postoperative pain, analge-
attenuating the haemodynamic responses to laryngoscopy sic consumption, or both, when they are added to more
and intubation, and reducing postoperative delirium.56 conventional means of providing analgesia, such as
The main side effect of both drugs is somnolence. opioids and NSAIDs, in the perioperative period.59
Paediatric studies are lacking at this time. NMDA receptor antagonists may reduce pain by two
nonmutually exclusive mechanisms; a reduction in cen-
tral hypersensitivity and a reduction of opioid tolerance.
Alpha-2 adrenergic agonists: clonidine, tizanidine, and
Nevertheless, the effectiveness of NMDA antagonists in
dexmedetomidine
preventive analgesia has been equivocal at best.59,60
Norepinephrine is involved in the control of pain by
Ketamine is well known as a dissociative general anaes-
modulating pain-related responses through various path-
thetic and may be an effective adjuvant in pain manage-
ways. Alpha-2 adrenergic agonists, such as clonidine,
ment when used in low doses (0.05–0.2 mg kg
1 h
1).61
tizanidine, and dexmedetomidine, have well established
I cannot, however, recommend it in paediatric practice in
analgesic and sedative profiles and wide application in
general, and in newborn patients in particular, until more
perioperative multimodal pain management. Clonidine is
evidence to support its use emerges.62
the prototype and most widely studied of this class of
drugs. It can be administered via the epidural, i.v.,
Regional anaesthesia and analgesia
subcutaneous, p.o., and transdermal routes. It is tradition-
Over the past 30 years, the use of local anaesthetics and
ally used as an antihypertensive and to minimize the
regional anaesthetic techniques in paediatric practice has
symptoms of opioid withdrawal.57 However, when admi-
increased dramatically. Unlike most drugs used in
nistered p.o., i.v., or transdermally, clonidine may reduce
medical practice, local anaesthetics must be physically
opioid requirements and improve analgesia. Similarly,
deposited at their site of action by direct application,
the addition of clonidine to local anaesthetic solutions
requiring specialized needles and patient cooperation.
for neuraxial or peripheral nerve blocks may enhance and
Because of this, for decades, children were considered
prolong analgesia. Clonidine can be a useful antineuro-
poor candidates for regional anaesthetic techniques.
pathic agent, especially in children who cannot tolerate
However, once it was recognized that regional anaesthe-
oral medications or who have coexisting problems such as
sia could be used as an adjunct, and not a replacement for
steroid-induced hypertension.58 However, the analgesic
general anaesthesia, its use increased dramatically.
benefits remain controversial and its use is limited by side
Regional anaesthesia offers the anaesthesiologist and
effects, which include bradycardia, hypotension, and
pain specialist many benefits. It modifies the neuroendo-
excessive sedation.54,55
crine stress response, provides profound postoperative
Compared with clonidine, dexmedetomidine is a more pain relief, ensures a more rapid recovery, and may
selective a-2 antagonist, has a shorter duration of action, shorten hospital stay with fewer opioid-induced side
and is noted in the perioperative period for its opioid- effects. Furthermore, as catheters placed in the epidural,
sparing and analgesic effects. Because dexmedetomidine pleural, femoral, sciatic, brachial plexus, and other spaces
does not cause respiratory depression, despite its potent can be used for days or months, local anaesthetics are
sedative effects, it is increasingly being used in patients increasingly being used not only for postoperative pain
for deep procedural sedation, as a general anaesthetic relief but also for medical, neuropathic, and terminal
adjuvant in the operating room, and for sedation of pain.63–69 Peripheral nerve blocks provide significant
intubated patients in the ICU. As a sedative with analge- pain relief after many common paediatric procedures.
sic properties, it may be particularly useful in patients at Techniques range from simple infiltration of local anaes-
high risk of opioid-induced airway obstruction and respir- thetics to neuraxial blocks such as spinal and epidural
atory depression (e.g. patients with obstructive sleep analgesia. To be used safely, a working knowledge of the
apnoea and morbid obesity). Initial studies recom- differences in local anaesthetic metabolism in infants and
mended a loading dose of dexmedetomidine, 1 mg kg
1, children is necessary.65,70,71
followed by an infusion of 0.4 mg kg
1 h
1. However,
this regimen may cause cardiovascular side effects Conclusion
(bradycardia and hypotension). Therefore, avoidance of Using the neurophysiology of pain as a blueprint, I have
a loading dose is preferred. Of note, most studies of highlighted some of the drugs and drug families used in

European Journal of Anaesthesiology 2010, Vol 27 No 10

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 856 Yaster

multimodal pain management. The underlying principle 27 Einhorn TA. Cox-2: where are we in 2003? The role of cyclooxygenase-2 in
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