SPECIAL COMMUNICATION

Current Status of Pain Management

in Children
Richard F. Howard, MB, FRCA

ORE THAN 25 YEARS HAVE

passed since the first

reports were published of
the inadequate treatment of childrens pain.1,2 Since then,
even the youngest and most immature
infant has been shown to be potentially in need of analgesia, improvements in the quality of pain treatment
have been documented, and pain treatment services for children have been
established.3-5 Researchers in many
countries have also discovered much
about the causes, mechanisms, and
treatment of pain; much more is now
known about the safe and effective
management of pain in infants and
children. However, bridging the gap
between this knowledge and everyday
clinical practice remains a major difficulty.6-8 Implementation of pain measurement for all children who are potentially in pain, application of effective
up-to-date treatments, and improved
research and education on the causes,
prevention, and short-term and longterm effects of pain and analgesia remain
important priorities.
Early research and teaching in pediatric pain management were largely directed toward identifying and allaying
the undertreatment of acute pain in hospital settings. Particular emphasis was
placed on pain in infancy, postoperative pain, and the pain of diagnostic and
therapeutic procedures, often in ill patients in intensive care and in children
with cancer. In recent years, there has
been increasing awareness that children who are otherwise healthy at home
may needlessly experience pain during minor illness or after surgery.9,10
2464

Many changes have taken place in pediatric pain management since the
undertreatment of childrens pain was first reported. Notable advances include an increase in understanding pain during development and improvements in the management of acute pain. Although much more about the safe
and effective management of pain in children is now known, this knowledge has not been widely or effectively translated into routine clinical practice. Lack of suitable research on which to firmly establish evidence-based
care is likely to have contributed to this situation. A subject of considerable
interest recently is the discovery that the experience of pain in early life may
lead to long-term consequences. New research findings from laboratory and
clinical studies have clearly identified possible mechanisms and provided
evidence that long-term behavioral changes can extend far beyond what would
be considered the normal period of postinjury recovery. Timing, degree of
injury, and administered analgesia and its nature may be important determinants of the long-term outcome of infant pain. Chronic pain, including
neuropathic pain, is far more common in children than was thought. The assessment and treatment of this pain and its functional consequences present a considerable unmet challenge. There is a pressing need for further
research and clinical development in the management of pain in children.
www.jama.com

JAMA. 2003;290:2464-2469

Pain and its treatment may have consequences beyond the normal period of
recovery, and there is a substantial
population of children who endure
long-term pain and would benefit from
access to better pain management.11
This article describes the elements of
contemporary pain-management practice in children, with particular emphasis on some of the areas in which there
have been recent improvements in understanding or that remain particularly problematic. Future research studies and areas of practice in need of
further development are suggested.
Certain related fields, such as pediatric palliative care and symptom management, have not been specifically considered here.

JAMA, November 12, 2003Vol 290, No. 18 (Reprinted)

Original research studies and

reviews were obtained by searching
MEDLINE, EMBASE, and Cochrane
Library databases for articles from
1966 to 2003; additional material was
obtained by using the Google Web
search engine. Key words and phrases
included pediatric, neonatal, infant
pain, acute, chronic, procedural, treatment, nociception, hyperalgesia, and
development.
Author Affiliations: Anaesthesia and Pain Management, Children Nationwide Pain Research Centre, and
Department of Anaesthesia, Great Ormond Street Hospital for Children NHS Trust, London, England.
Corresponding Author and Reprints: Richard F.
Howard, MB, FRCA, Department of Anaesthesia, Great
Ormond Street Hospital for Children NHS Trust, Great
Ormond Street, London WC1N 2JH, England (e-mail:
r.howard@ich.ucl.ac.uk).

2003 American Medical Association. All rights reserved.

PAIN MANAGEMENT IN CHILDREN

The Study of Pain in Children

If clinical practice is not guided by

sound evidence, it is likely to become
entrenched and empirical and is unlikely to progress and improve. The
study of pain in children requires considerable ingenuity and innovation. The
diversity and developmental range of
the pediatric population have enormous implications for the design and
conduct of clinical research and the interpretation of research findings.
There is a lack of comparable randomized controlled trials of childrens
pain management, and consequently
there are relatively few published metaanalyses or systematic reviews. Because
of this low availability of data, recommendations are frequently not based
on the highest possible levels of evidence.12-14 There are many reasons: difficulties in the measurement of pain,
developmental differences that can confound comparisons between ages,
important ethical and methodologic
considerations in the conduct of clinical trials, and economic factors. There
have been calls to improve this situation, and initiatives by the US Food and
Drug Administration and other agencies have been helpful in encouraging
the pharmaceutical industry to invest
in the proper determination of efficacy, safety testing, and licensing of
analgesics and other drugs for children.15,16 This is good news for newer
treatments, but despite these efforts
many analgesics that are most commonly used for infants and children
remain unlikely to undergo this process and still need investigation.
Pain Measurement

Commonly used definitions of pain emphasize its personal sensory, emotional, and contextual nature, placing
much reliance on an individuals ability to express what he or she feels when
in pain.17 Children, particularly those
who are preverbal or with limited cognitive capability, are clearly disadvantaged by this approach. In a sustained
effort to overcome this problem, an extensive body of literature about the measurement of pain in children has arisen.

Quantification is central to the investigation of pain and analgesia, and pain

measurement is essential in clinical
practice.
Self-report, usually by using a linear
visual analog scale, is regarded as the
most reliable estimate of pain, but only
children who have attained a certain degree of cognitive ability are able to provide information this way.18 Many selfreport scales specifically designed to be
easy for young children to understand
and use have been developed; facial expression (either drawings or photographs representing increasing degrees
of pain), color analog scales (a variant
of the visual analog scale), and ordinal
rating scales, eg, the Poker Chip Tool,
are popular and have been used by children as young as 4 years.19-22 These scales
are useful, but there are concerns about
the sensitivity and specificity of such
tools, particularly for younger children
who may not report accurately or reproducibly and who may be influenced
by how a scale is presented.23,24
When a self-report cannot be obtained or its validity is questionable,
other more indirect measures must be
used. Infants, preverbal children, and
individuals with communication difficulties may be among the most vulnerable to unrecognized pain, and yet they
are unable to describe or rate it. Behavioral observations, changes in physiologic characteristics, or combinations of these indirect measures are
used, depending on the child, context
of pain, and setting. A number of painrelated behaviors have been identified, facial expression being one of the
most reproducible; however, this behavior is age related.25 Some physiologic measures, such as heart rate, are
convenient and respond rapidly to brief
nociceptive stimuli, but they are nonspecific. Generally, the utility of physiologic measures is diminished by homeostatic mechanisms, which tend to
oppose such changes and reduce their
value over time.
Scales may incorporate any of these
types of measures, and many have been
described, each with its own advantages and limitations; there are more

2003 American Medical Association. All rights reserved.

than 20 validated for use in infancy

alone, and to date, no individual tool
has emerged as superior.26 The lack of
a gold standard or universally reliable
indicator by which to assess the accuracy of indirect pain measurement is an
important limitation. Novel approaches
may be required to obtain more specific information about the effects of
injury and analgesia on the central nervous system (CNS). Quantitative sensory testing has been used in children
able to cooperate and may be able to
provide much-needed information.27
Sensory reflexes, such as the flexion
withdrawal reflex or the abdominal skin
reflex, have properties reflecting the sensory modulation of external stimuli in
different pain states. The withdrawal
reflex is sensitized (eg, the threshold for
response is reduced) in neonates with
local inflammation caused by repeated
heel lance.28 The abdominal skin reflex
has been shown to reflect CNS hypersensitivity after surgery and that caused
by the visceral distention of chronic
hydronephrosis in infants.29,30
Children with neurodevelopmental
delay are a particularly important group
at risk of experiencing undiagnosed or
untreated acute and chronic pain.31,32
Many of these children have extreme
impairment of communication and present enormous diagnostic and therapeutic problems.33 Pain assessment tools
specifically designed for use in this
group have recently been developed and
are under investigation.34,35
Mechanisms of Pain
in Development

The extent to which a newborn is able

to detect and respond to a painful
stimulus was once a critical question in
pediatric medicine and the subject of
considerable debate. The study of developmental neurobiology has clarified how sensory information is processed in early life and has begun to
fully elucidate the mechanisms of the
short-, medium-, and long-term effects of pain. Clear, measurable responses to noxious stimulation, which
are suppressed by local anesthetics, opioids, and other drugs with known an-

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PAIN MANAGEMENT IN CHILDREN

algesic activity, can be observed from

the earliest age. The stress response to
pain is considerable at all ages, and the
effects of pain on the immune system
may also be important.36,37
The nervous system at birth displays
a remarkable hypersensitivity to sensory stimuli in comparison with that of
the adult. Thresholds of response to mechanical and thermal stimulation are reduced, and further sensitization can occur with sustained or repetitive inputs
in the noxious and nonnoxious range,
which is a manifestation of profound differences in pain processing between the
immature and mature nervous system.38 Primary sensory neuron function, modulation of inputs by spinal and
descending mechanisms, and the processes of central and peripheral sensitization undergo extensive postnatal reorganization and change to reach
maturity. Such structural and functional changes in the peripheral nervous system and CNS involve alterations in expression, distribution, and
function of receptors, ion channels, and
neurotransmitters, of regulatory factors such as neurotrophins, and of intracellular regulatory proteins, all of
which profoundly affect the character of
nociceptive responses at different stages
of development.39
The postnatal appearance of allodynia and hyperalgesia associated with
tissue injury is superficially similar to
that of the adult but differs in onset, pattern, and sensitivity to treatment; eg,
inflammatory hypersensitivity in the
early postnatal period is more sensitive
to epidurally administered local anesthetic than later in development, and
differences in opioid receptor distribution and function lead to altered, agedependent, opioid analgesic effects.40,41
Central nervous system plasticity, including novel gene induction and altered synaptic excitability, is now well
recognized as an important component of physiologic and pathologic pain
states at all ages, and the effects of this
plasticity on a developing nervous system that is already undergoing reorganization is considerable.42 Study of the
underlying mechanisms and conse2466

quences of pain and analgesia in development is currently a particularly

exciting and important field of neurobiology. An understanding of these
events is essential for effective analgesic intervention and the discovery of new
targets for therapies.
Prolonged Effects
of Early Pain Experience

Pain and its management, especially in

infancy, may have consequences for later
pain-related behavior and perception.43-45 Studies in infants having repeated heel lancing have shown behavioral and other effects that outlast the
painful stimulus by hours or days28,46;
local anesthesia modified the development of sensitivity in 1 study.28 More
long-term differences (months) in subsequent pain behavior between infants
who had circumcision as neonates with
and without analgesia have also been reported.47 A recent study found that major surgery in the neonatal period, in this
case with effective postoperative analgesia, had little effect on subsequent pain
response in infancy.48
Laboratory studies in animal models have shown that it is quite possible
to induce long-term behavioral and
CNS effects from early injury, which
persist into adulthood. In the rat,
wounding of the skin at birth leads to
a number of changes in the skin and
CNS that do not occur with similar
wounds in adults, including local hyperinnervation and prolonged mechanical sensitivity for some time after healing.49 In humans, repeated needle prick
in the neonatal period causes complex
and persistent behavioral effects later,
including reduced pain thresholds.
More severe injury in the form of inflammation is capable of permanent alterations in sensory processing; some,
but not all, of these effects appear to be
modified by analgesia.50-52 The clinical
significance of such findings remains
unclear, so further study is required.
Acute Pain

Multimodal therapy is the mainstay of

acute pain treatment. It may involve
pharmacologic and nonpharmacologic

JAMA, November 12, 2003Vol 290, No. 18 (Reprinted)

methods and should take place in a

child-friendly environment. Severe pain
should never go untreated. Safe protocols have been devised for the use of potent opioid analgesia, and experience
with analgesic use in children is now
extensive.53 Pharmacotherapy for pediatric pain has been well reviewed recently.54,55 Techniques such as patientcontrolled analgesia can be used for
children older than 5 years, and nursecontrolled morphine infusions that allow more flexibility in administering analgesia are common for those too young
to use patient-controlled analgesia.5,56
Local anesthesia in many forms has also
become routine; topical preparations (lidocaine-prilocaine or amethocaine) are
the mainstay of procedural pain management, and local nerve blocks and epidural analgesia are used extensively for
perioperative pain.57,58 Early studies of
epidural analgesia have confirmed the
cardiovascular safety and efficacy of the
technique for postoperative pain and reduction of the stress response to surgery, but its place in the practice of pediatric pain management is still not
clearly established.59,60
Although newer local anesthetic
drugs are now available, bupivacaine remains frequently used; however, either L-bupivacaine or ropivacaine may
be a more sensible choice when toxicity is a particular concern.61 Agents new
to acute pain treatment and with novel
mechanisms of action, such as ketamine and clonidine, are being used
systemically and epidurally.62-64 The appropriate use of many, more established agents such as acetaminophen
and codeine is being updated and refined.65,66 The management of acute procedural pain often includes the use of
cognitive-behavioral strategies: distraction, guided imagery, and hypnosis by
trained practitioners. Intuitively, these
approaches are helpful and are generally liked by children, many of whom
respond positively.67 For infants and
younger children, comfort measures
such as cuddling, swaddling, auditory
and tactile stimulation, and suckling
may reduce behavioral and physiologic responses to acute pain.68-70 They

2003 American Medical Association. All rights reserved.

PAIN MANAGEMENT IN CHILDREN

are not regarded as a substitute for analgesia but are generally easy to implement and can be particularly effective
at reducing the unpleasantness and distress of painful events.
Parents are increasingly recognized as
important participants in pain management in hospital settings and as primary caregivers at home.71 Parents may
underestimate and undertreat pain, a
particular concern because outpatient
surgery is prevalent.10,72,73 Pain assessment tools for use by parents have been
designed to help parents recognize pain
and guide pain management. Better communication with parents can improve
subsequent pain management.74,75
Chronic Pain

Chronic or recurrent pain affects a large

number of children, girls more often
than boys. Epidemiologic studies suggest that many children do not receive
appropriate help or treatment.11,76-78 The
underlying causes of childhood chronic
pain and the emotional, social, health,
and economic impact on an individual and on society have been insufficiently studied.79 Recurrent abdominal pain, for example, can lead to
physical and emotional disability in
later life. Little is known of its mechanisms or the effects of treatments on
long-term outcomes. 80-83 Recurrent
headache is common among adolescents; chronic musculoskeletal pain is
also increasingly diagnosed, as are other
so-called idiopathic pain syndromes.
Some patients respond to reassurance
and treatment with simple analgesics,
but a significant proportion go on to develop various degrees of chronicity and
disability that are difficult to treat.84,85
Neuropathic pain, ie, pain caused by
abnormal functioning of the nervous system, may also have been underrecognized; reflex sympathetic dystrophy or
chronic regional pain syndrome was
thought to be rare in children until reports started to appear in the 1980s, and
it is now much more frequently diagnosed.86,87 Unintentional injuries, surgery including amputation, tumor, metabolic disorders, toxic neuropathies, and
neurodegenerative disorders leading to

nerve damage or disordered function are

some of the recognized sources of neuropathic pain in children.88 Treatment
of neuropathic pain is often unsatisfactory, and in common with other childhood chronic pain syndromes, there is
evidence that the best results are obtained by combining psychologic, physical, and pharmacologic treatments.89-91
Chronic pain management services,
some with inpatient treatment and rehabilitation programs, have been developed in several pediatric centers around
the world. Such programs typically involve clinicians who have pain management skills and are from a number of disciplines; they provide direct patient
treatment and serve as practical and educational resources to others. Examples
of patients with underlying disease who
may also benefit from this multispecialist approach to pain management include some cancer patients and those
with juvenile rheumatoid arthritis, sickle
cell disease, or epidermolysis bullosa.78,92-94 The assessment and treatment of such patients should place particular emphasis on restoration of
function and improvements in the quality of life, in addition to control of pain
intensity.95
Future Research and
Developments

Clearly, there is enormous potential for

future research and a pressing need for
further clinical development in the field
of pediatric pain. The neurophysiology
of infant pain has been little studied in
the human, and many important questions about basic functions remain
unanswered. The mechanisms of nociceptive and neuropathic pain in development are far less well understood than
in the adult, and considerable research
effort will be required to redress this imbalance. The circumstances in which injury can lead to long-term consequences, which is likely to be different
from those of the adult and to depend
on the stage of development at which it
occurs, the nature of those consequences, and whether they can be prevented or modified by treatment are important clinical issues yet to be resolved.

2003 American Medical Association. All rights reserved.

Treatment itself may also have positive or negative long-term effects on the
developing nervous system; again, further study is needed. Only close collaborations between clinicians and scientists are likely to be able to provide
the means to answer these questions.
The design of clinical trials in infants and children needs more careful
consideration. Many studies have not
paid sufficient attention to developmental influences, eg, infants and teenagers are often included in the same
study group. Strategies for the assessment of efficacy in research studies
should be more standardized, and the
adoption of a common scale of values
for pain assessment tools would be
helpful.96 More attention should also be
paid to assessment of the sensitivity of
an individual tool to detect the desired outcome within each trial. More
easily comparable and appropriate outcome measures, such as restoration of
function, are needed to assess the clinical efficacy and value of many treatments currently in use and with which
to make comparisons with new treatments. Novel approaches to pain management and assessment, particularly
for children with long-term pain, should
be carefully evaluated, and the use of
more established but less conventional pain management techniques,
such as massage or acupuncture, also
needs further exploration.
In the clinical arena, regulatory
changes by authorities such as the Joint
Commission on Accreditation of
Healthcare Organizations, by leading to
the widespread adoption of minimum
care standards, are likely also to lead to
evidence of positive changes in routine practice.97 Such initiatives may also
encourage more exploration of the best
methods to achieve the basic but often
elusive objective of more effective pain
control. The implementation of good
pain management practices would also
be improved by further and better demonstration of the value of frequent pain
assessments and of the benefit of better and more appropriate prescribing in
reducing pain. The role and structure
of pain treatment services should be

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PAIN MANAGEMENT IN CHILDREN

more carefully examined and modified to help provide the highest possible standard of pain care for all patients.
Many children have benefited from
the recent substantial improvements in
the understanding and treatment of
pain; however, there may be many more
children whose pain goes unnoticed or
is poorly understood and therefore inadequately treated. All such children
must have access to appropriate and
contemporary pain management based
on the best possible evidence.
Acknowledgment: I thank M. Fitzgerald, PhD, and L.
Franck, PhD, for reviewing the manuscript.
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LETTERS

tivity. On the other hand, glucocorticoids have a direct inhibitory effect on adiponectin secretion and expression.6 Similarly, resistin concentration is known to increase in response
to glucocorticoids and to decrease in response to TNF-.7 The
complex nature of these various mechanisms could be clarified by studying patients with RA who had not been treated
with glucorticoids.
The authors also reported that adiponectin levels in synovial fluid were positively, although not quite significantly, related to body mass index (BMI). If synovial concentrations of
adiponectins reflect plasma concentrations, then this is a surprising finding, as there appears to be a strong negative correlation between plasma adiponectin concentrations and measures of obesity.3 Moreover, plasma adiponectin concentrations
are substantially lower in men than in women, necessitating
further adjustment for sex. The lower degree of adiposity among
patients with RA may therefore represent an alternative explanation for the higher synovial adiponectin concentrations in
these individuals.
Norbert Stefan, MD
norbert.stefan@med.uni-tuebingen.de
Hans-Ulrich Haring, MD
Michael Stumvoll, MD
Department of Internal Medicine
University of Tubingen
Tubingen, Germany
1. Schaffler A, Ehling A, Neumann E, et al. Adipocytokines in synovial fluid. JAMA.
2003;290:1709-1710.
2. Krakoff J, Funahashi T, Stehouwer CD, et al. Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian. Diabetes Care. 2003;26:17451751.
3. Chandran M, Phillips SA, Ciaraldi T, Henry RR. Adiponectin: more than just another fat cell hormone? Diabetes Care. 2003;26:2442-2450.
4. Ouchi N, Kihara S, Arita Y, et al. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway. Circulation. 2000;102:1296-1301.
5. Maeda N, Takahashi M, Funahashi T, et al. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein.
Diabetes. 2001;50:2094-2099.
6. Halleux CM, Takahashi M, Delporte ML, et al. Secretion of adiponectin and
regulation of apM1 gene expression in human visceral adipose tissue. Biochem
Biophys Res Commun. 2001;288:1102-1107.
7. Shojima N, Sakoda H, Ogihara T, et al. Humoral regulation of resistin expression in 3T3-L1 and mouse adipose cells. Diabetes. 2002;51:1737-1744.

In Reply: Dr Stefan and colleagues suggest that corticosteroids might influence the levels of adipocytokines. Although
this is a possibility, none of our patients with OA were receiving corticosteroids or other immunosuppressive therapy. Furthermore, in the subgroup of patients with RA, partial corre-

2004 American Medical Association. All rights reserved.

lation analysis did not show any correlation between

adipocytokines and concomitant medication. In addition, none
of the patients with RA were receiving TNF- inhibitors.
We disagree with the suggestion of Stefan et al that our study
found a nonnegative association between BMI and either adiponectin or resistin. As expected, patients with OA had significantly higher BMI than patients with RA. However, as mentioned in our article, partial correlation analysis revealed
nonsignificant correlations between BMI and concentrations
of adiponectin (r=0.246, P=.08) and resistin (r=0.245, P=.07).
We also doubt their speculation that serum levels reflect synovial fluid levels of inflammatory arthritides such as RA. There
is no evidence in the literature for an overspill phenomenon
between serum and synovial adipocytokines. In contrast, among
patients with RA, synovial concentrations of numerous cytokines are clearly elevated compared with serum.1 Our ongoing studies2 have found that both adiponectin mRNA and protein are strongly expressed not only in synovial adipocytes but
also in activated synovial fibroblasts. Therefore, the absence
of any correlation between synovial fluid adipocytokines and
BMI is not unexpected, as synovial adipocytokines are probably produced locally, perhaps from activated synovial cells,
rather than systemically from body fat stores. Our data suggest that the increased levels of adipocytokines in synovial fluid
in patients with active RA are largely derived from activated
resident synovial cells.
Andreas Schaffler, MD
Ulf Muller-Ladner, MD
Department of Internal Medicine I
University of Regensburg
Regensburg, Germany
1. di Giovine FS, Poole S, Situnayake RD, Wadhwa M, Duff GW. Absence of correlations between indices of systemic inflammation and synovial fluid interleukin-1 (alpha and beta) in rheumatic diseases. Rheumatol Int. 1990;9:259-264.
2. Ehling A, Schaffler A, Grifka J, et al. Modulation of cytokine and MMP synthesis of synovial fibroblasts by adipocytokine adiponectin and adipocytes. Arthritis Rheum. 2003;46(suppl 1):1197.

CORRECTION
Incorrect Insertion: In the Special Communication entitled Current Status of Pain
Management in Children published in the November 12, 2003, issue of THE JOURNAL (2003;290:2464-2469), incorrect wording was inserted during the editing stage.
On page 2466 in the second paragraph under Prolonged Effects of Early Pain
Experience, the third sentence should not begin with the words In humans
because the paragraph is discussing laboratory studies in animal models.

(Reprinted) JAMA, February 11, 2004Vol 291, No. 6 695