Maternal, Newborn, Child and Adolescent Health and Ageing (MCA)

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GUIDELINE FOR THE MANAGEMENT OF CHRONIC PAIN IN CHILDREN

WHO Guideline for the management of chronic pain in children

Scope and key question

I. Background
Pain in children is a public health concern of major significance in most parts of the world. For many
children, this pain is chronic. Chronic pain is experienced by about a quarter to a third of children (1-
3), with about 1 in 20 experiencing debilitating pain (4). As the leading cause of morbidity in children
and adolescents in the world today, chronic pain is a major health concern.
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue
damage, or described in terms of such damage. Chronic pain is pain that persists or recurs for longer
than 3 months. The 11th revision of the International Classification of Diseases (ICD-11) categorizes
chronic pain as follows:
- Chronic primary pain
- Chronic cancer-related pain
- Chronic postsurgical or post traumatic pain
- Chronic secondary musculoskeletal pain
- Chronic secondary visceral pain
- Chronic neuropathic pain
- Chronic secondary headache or orofacial pain
Chronic primary pain is characterized by significant emotional or functional disability and is diagnosed
independent of identified biological or psychological contributors. Non-primary or “secondary” pain
diagnoses is pain caused by a clear underlying aetiology such as a disease, injury, lesion or their
treatment (5).
Initial theories behind the origin of pain included the “gate theory” that described nociceptors and
touch receptors. When painful stimuli reaches a specific intensity, a gate opens and activate pathways
leading to pain being experienced (6). This was later augmented with sensory-discriminative, affective-
motivational and cognitive-evaluative components in a biomedical model of pain (7-11).
The biomedical model, however, explained pain as a dichotomy of physiological or psychological
origin, where any pain response that did not correlate with the degree of tissue damage was
considered psychological. Anatomical, physiological and biochemical pathology seen from physical
examination and diagnostic tests, however, often do not adequately explain the persistence of chronic
pain, even in chronic secondary pain related to a medical condition.
The biopsychosocial model of pain was introduced to try to explain the complexities of chronic pain
(12). Illness results from a complex interaction between various biological, psychological and social
factors. The “neuromatrix” model of pain (13, 14) further carried this forward by introducing the stress
component into the pain equation.
Current models to explain chronic pain assumes a progression from homeostasis to dysregulated
allostatic changes and spiralling distress cycle leading to chronic pain, mediated at least in part by
changes in the central nervous system mechanisms (15-18). Recent epidemiological (19-24),
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GUIDELINE FOR THE MANAGEMENT OF CHRONIC PAIN IN CHILDREN

physiological (25-29) and neurobiological (16-18, 30-41) studies have strengthened this hypothesis of
chronic pain. Interdisciplinary care of chronic pain in children and adolescents incorporates physical
treatment with cognitive, behavioural, environmental and emotional interventions (42-50).

II. Review of latest evidence

A. Safety and efficacy of use of medicines for pain in children
A recent overview of reviews of pharmacologic management of chronic pain in children found 23
systematic reviews of randomized controlled trials investigating pharmacologic treatment of children
and adolescents with chronic pain, further categorized into chronic cancer-related pain and chronic
non-cancer pain (51). Sixteen of them did not find any studies of children with chronic cancer-related
or non-cancer pain. The 7 remaining systematic reviews, combined, included 6 relevant trials, all were
on chronic non-cancer pain in children. The characteristics of the 6 trials are shown in the table (see
annex) (52-57). None of the trials had more than 200 subjects (range was 14 to 115 subjects). No trials
were found on pharmacologic interventions for chronic cancer-related pain. The overview of reviews
assessed that the quality of evidence was very low and gave little confidence in the effect estimates.
Pain in children differs to that in adults (58-60), due to immaturity in the anatomical expression of
neurotransmitters and neuromodulators, developmental potential, plasticity of the central nervous
system and psychosocial milieu (61-63). Exposure to chronic pain in early life have implications on the
incidence, severity and duration of chronic pain, and for long term maladaptive neurologic changes
(64-69). Yet, despite these differences, pharmacologic management of adult pain is often extrapolated
downward to the paediatric population even when this management was not intended to be given to
children. In part, this is due to the obvious lack of evidence for pharmacologic management of pain in
children (70, 71).
The role of nonpharmacologic interventions for chronic pain, on the other hand, has had a longer
history of research and success (72-81), with the neurobiological processes now being more clearly
elucidated (16, 19, 20, 28, 35, 45, 46, 82, 83).

B. Dependence and misuse potential

Studies have shown an increasing prevalence of prescription opioid use and misuse among American
adolescents and young adults (84, 85). Reported prescription opioid misuse is common among
adolescents and young adults and often associated with additional substance abuse.
Using data from the US National Longitudinal Study of Adolescent to Adult Health (with almost 15,000
participants), Groenewald and colleagues (86) showed adults with a history of adolescent chronic pain
were more likely to misuse opioids than those without history of chronic pain, even after controlling
for other known risk factors. Among those who experienced adolescent chronic pain, race (White),
exposure to trauma, and other substance use were associated with subsequent opioid misuse.
Conversely, nonmedical prescription opioid use was prospectively associated with subsequent heroin
use in adolescence (87).
More lifetime prescriptions of opioids among young adults lowers their perceived risk of occasional
misuse (88). In turn, higher frequency of opioid misuse is associated with opioid use disorder and
withdrawal symptoms (89). Among American adolescents, any use, prescription drug misuse, medical
misuse, nonmedical misuse and presence of substance use disorder symptoms were more likely
among children with poos school adjustment or those not in school (90).
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GUIDELINE FOR THE MANAGEMENT OF CHRONIC PAIN IN CHILDREN

Recently, neuroscience research has provided some mechanistic understanding of the effects of
opioids and addiction-related processes, and may in the future suggest avenues for management of
chronic pain, both pharmacologic and nonpharmacologic (91-94).

C. Public health benefits and risks of different strategies for ensuring appropriate access
The UN Office of Drugs and Crime World Drug Report 2019 (95) highlight the “global paradox of too
much and not enough” in describing the difficulty of ensuring the availability of controlled substances
for medical and scientific purposes while preventing their diversion and misuse. International drug
control conventions aim to remove barriers that limit the availability of accessibility of controlled
drugs for medical use, based on legal and regulatory frameworks and clinical guideline on rational
prescription practices.
Many low-income countries face difficulties in balancing necessary access for medical purposes while
curbing abuse with limited resources and health care systems that are already struggling to provide
universal health coverage. The management of pain requires a broad and multidisciplinary approach
that addresses its physical and psychosocial dimensions. Human rights norms require that pain
management be incorporated as part of the basic health package under their universal health
coverage schemes (96). Chronic pain in children should be a high priority for public health research
and policy.

III. Analytical framework or logic model

A possible analytic framework for the effect of the intervention to modulate pain is presented in the
following figure:

a Ascending afferent nociceptive pathways for pain perception (simplified from Price (17))
b Descending pain modulatory pathways (simplified from Schweinhardt and Bushnell (97) and Fields (98))

IV. Key question

Based on the analytical framework (above), the questions were drafted in population, intervention,
control, outcomes (PICO) format, and summarized in the table below.
 Maternal, Newborn, Child and Adolescent Health and Ageing (MCA)
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GUIDELINE FOR THE MANAGEMENT OF CHRONIC PAIN IN CHILDREN

Among children with chronic pain associated with a medical illness or condition, would giving
nonpharmacologic, pharmacologic or a combination of management interventions compared to
placebo produce significant pain reduction and other critical outcomes?
Population

• Children and adolescents (0-19 years) in chronic pain (pain that persists or recurs for longer
than 3 months)
This population will include children with any medical illness or condition where pain is a
symptom or where pain is related to an illness or the treatment of an illness, i.e., chronic
secondary pain.
This population will exclude children with chronic primary pain.
Subgroups

• By severity: Mild or moderate pain vs. severe pain

• By age: Less than 10 years of age vs. 10 years of age or older

Interventions

• Nonpharmacologic and pharmacologic interventions

o Cognitive and behaviour interventions such as pain neuroscience education, activity
pacing, relaxation, distraction, mindfulness, sleep hygiene
o Psychological interventions such as cognitive-behavioural therapy, acceptance and
commitment therapy
o Physical treatments such as physiotherapy, occupational therapy, interventional
procedures (e.g. nerve blocks)
o Pharmacologic: acetaminophen (paracetamol), non-steroidal anti-inflammatory drugs,
opioids, antidepressants, anti-epileptic drugs
Comparator

• Active or placebo comparators

Comparison may include comparisons between different combinations of management
options, pharmacologic vs. non-pharmacologic management, or within drug class comparisons
and between drug comparisons.
Outcomes

• Reduction in pain intensity (30% reduction; 50% reduction; etc.); continuous pain intensity
• Global judgement of satisfaction with treatment

• Health-related quality of life; functional disability; role functioning

• Depression
• Sleep
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GUIDELINE FOR THE MANAGEMENT OF CHRONIC PAIN IN CHILDREN

• Cost
• Disorders due to use of psychoactive substances

• Other adverse events (such as misuse of prescription medicines and non-medical use of
related psychoactive substances)
 Maternal, Newborn, Child and Adolescent Health and Ageing (MCA)
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GUIDELINE FOR THE MANAGEMENT OF CHRONIC PAIN IN CHILDREN

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Annex:
Table: Characteristics of individual randomized controlled trials
First author, Drug class (drug Pain condition Sample Outcomes reported Adverse events (AE) reported
year name) size; age
Arnold, 2016 Antiepileptic Fibromyalgia n = 107; No significant difference in mean pain score 38 (70.4%) children in the pregabalin arm
(52) (pregabalin) 12-17 compared to placebo experience 1 or more AE
years old
Better patient global impression of change Common AEs: dizziness, nausea, headache,
compared to placebo (53% vs. 30%) increased weight, fatigue, somnolence,
oropharyngeal pain, pain in extremity,
pyrexia, back pain, upper respiratory tract
infection, vomiting
1 child from pregabalin arm had serious AEs
(cholelithiasis, major depression)
3 children from pregabalin arm had severe
AE (migraine, cholelithiasis, major
depression, pain, ligament sprain)
Bahar, 2008 Antidepressant Recurrent abdominal pain n = 33; No difference in reduction in abdominal pain Weight gain was see in both amitriptyline
(53) (amitriptyline) (irritable bowel syndrome) 12-18 intensity or frequency compared to placebo and placebo groups
years old
No difference in overall quality of life scores No other adverse events were reported
compared to placebo
No difference in interference with
schoolwork, sports or friends compared to
placebo
Brown, 2016 Antidepressant Complex regional pain n = 34; Decrease in pain intensity on a coloured Three children discontinued the trial due to
(54) (amitriptyline) vs. syndrome 7-18 analogue scale (above minimally important adverse events: one child on amitriptyline
antiepileptic years old difference of 1/10) from both drugs (no developed secondary pain; one child on
(gabapentin) difference between groups): gabapentin developed secondary pain; and
[no placebo arm] Amitriptyline decrease of 1.16 + 2.26 one child on gabapentin had an unexpected
 Maternal, Newborn, Child and Adolescent Health and Ageing (MCA) Department
GUIDELINE FOR THE MANAGEMENT OF CHRONIC PAIN IN CHILDREN

Gabapentin: decrease of 1.56 + 2.27 foreign body at the pain site requiring
surgery.
Better sleep score for both drugs (no
difference between groups) No serious AE reported
Roohafza, 2014 Antidepressant Recurrent abdominal pain n = 115; No difference in reduction in pain intensity, Children from the citalopram group
(55) (citalopram) 6-18 depression, anxiety, somatization score experienced more drowsiness and dry
years old compared to placebo mouth. Other side effects included
insomnia, nausea, fatigue, headache,
dizziness, allergic reaction and loss of
appetite.
No serious AE reported
Saps, 2009 (56) Antidepressant Recurrent abdominal pain n = 90; No difference in overall sense of 3 children from the amitriptyline arm
(amitriptyline) (irritable bowel syndrome, 8-17 improvement from treatment compared to withdrew from the study from AE (fatigue,
functional abdominal pain or years old placebo rash, headaches)
functional dyspepsia)
No difference in pain relief compared to
placebo
Symon, 1995 Serotonin Recurrent abdominal pain n = 14; 8 fewer days of abdominal pain noted 2 children had adverse events (drowsiness,
(57) antagonist (functional abdominal pain) 5-13 compared to placebo (unclear total duration increased appetite)
(pizotifen) years old of observation)
Children given pizotifen gained more weight
Significantly lower index of pain severity and compared to placebo (1.25 kg vs. 0.38 kg)
lower index of misery (tools were not
validated) compared to placebo