【Pediatric anesthesia】Opioid use in infants and young children

~Opioid use in infants and young children~

Opioids are widely used to treat moderate to severe pain in infants and young children, especially in the early postoperative period
.
Safe and effective use of opioids begins with careful patient screening for age-related metabolic differences, dose titration, and aggressive treatment of opioid-induced adverse effects
.
Over the past 30 years, prescriptions for opioids for children have experienced cyclical fluctuations
.
A series of cases in the 60s and 70s of the 20th century showed that pediatric patients, especially infants and young children, received insufficient doses of opioid analgesics after surgery or advanced cancer, partly due to a lack of understanding of the process of opioid metabolism and a limited
ability to assess pain in children.
A deeper understanding of opioid pharmacokinetics, developmental neuroanatomy, and effective pain scores has led to more appropriate doses of opioids and their widespread use
in pain management in infants and young children.
In the 80s and 90s of the 20th century, opioids were widely used in many developed countries to treat postoperative pain and cancer pain
.
Over the past 15 years, though, opioid abuse has become a major public health problem, especially in the United States
.
In addition to the problem of opioid abuse, reducing opioid use has become an important topic
in postoperative pain management due to the adverse effects of opioids in patients' postoperative recovery period.

There is increasing interest in multimodal pain management in children and ERAS programmes
.
There is good evidence that acetaminophen-NSAIDs in combination with regional anaesthesia can help reduce opioid use and enhance postoperative analgesia
.
However, studies of gabapentin and low-dose ketamine as part of a multimodal pain management programme have shown mixed results
.
Although multicomponent ERAS studies in children are limited, studies have shown that adolescents with idiopathic scoliosis who undergo posterior fusion with bundled care can achieve early postoperative mobility and shorten hospital stay
.

1.
Ontogenogenesis of opioid action

Opioid receptors are widely distributed in the forebrain, brainstem, and spinal cord
during the second trimester.
Its function gradually matures with the development and birth of the fetus
.
For example, studies have found that although juvenile rats (day 5 after birth) have a large number of opioid receptors distributed in the brainstem and forebrain, the proportion of Gi/O coupling protein in juvenile rat brain specimens is less than 5%
of adult rats, according to the determination of the proportion of guanosine triphosphate to enkephalin binding ratio in the striatum of the brain.

There has been a wide range of animal studies
on the effects of acute or chronic opioid use on growth and development.
For example, long-term exposure to opioids in rats before and early postnatal periods has been found to lead to reduced brain volume, neuronal storage density, and dendritic cell development, leading to learning
and motor dysfunction.
In addition, long-term exposure to opioids in juvenile rats can develop tolerance, withdrawal symptoms, and opioid-induced hyperalgesia, and the effects of opioids, ketamine, and other drugs on developing animals are altered
by the presence of pain, injury, and/or inflammation.
In some models, the use of opioids prior to injury or inflammation has clear long-term benefits
.
Therefore, extrapolating the benefits or harms of analgesics in newborns in intensive care should be made with great caution based on animal studies, in part because most animal models cannot fully mimic all the conditions
that arise in humans in long-term intensive care situations.

For newborns in intensive care, they undergo a large number of invasive procedures and mechanical ventilation, which in itself can cause great stress and distress
.
Several studies have investigated the analgesia, adverse effects, and potential long-term effects of opioids, both scheduled and given during specific invasive procedures
, on mechanically ventilated neonates.
In the NEOPAIN trial, infants who received morphine injections for a long time did not show longer neurological damage compared with controls, but there was basically no evidence of any benefit from taking these measures for pain, and irregular increases in morphine treatment doses in open-label trials may lead to worse outcomes
.
In addition, morphine has little
effect on indicators of pain behavior during pain in preterm infants.
Currently, there is no consensus
on the benefits and harms of opioids or sedatives in critically ill neonates.
Long-term opioid treatment in critically ill neonates and children is often prone to opioid tolerance; When opioids are interrupted or stopped, children may also experience withdrawal symptoms
.

When choosing a specific opioid, a variety of influencing factors should be considered, including tolerance to oral and enteric absorption, adverse drug reactions, pain severity, and whether pain is exacerbated
.
For example, oral administration is the treatment
of mild to moderate pain of choice for children who can tolerate oral administration and have good gastrointestinal absorption.
Intravenous administration should be given in children whose pain is severe and requires rapid control, whose pain worsens rapidly, or who cannot tolerate oral administration
.

2.
Adverse reactions of opioids and their treatment

Opioid use may cause a range of adverse effects, including nausea, vomiting, constipation, urinary retention, pruritus, sedation, and respiratory depression
.
Although some children may have different adverse effects depending on the opioid used, there are few data to suggest that the adverse effects of commonly used opioids vary widely
.
For most children, serious adverse effects of opioids, such as persistent nausea or itching, can be as distressing
as pain.
Postoperative analgesia should consider reducing opioid dosing, including NSAIDs, to avoid adverse effects
of opioids during postoperative recovery.

Adverse effects of opioids can occur
by acting on both peripheral and central sites.
For example, opioid-induced nausea and vomiting involve the activity
of chemical receptor trigger zones and receptor agonists in the gastrointestinal tract.
Some opioids produce pruritus through peripheral histamine release, however, intrathecal low-dose morphine injections can cause severe pruritus, suggesting that signaling and nerve transmission in the spinal horn and caudate nucleus are an important cause
.

Adverse opioid reactions should be aggressively prevented and treated
.
Developing a proactive program, including an adverse effects management programme, facilitates rapid delivery
of treatment.
The evaluation of patients with adverse effects following opioid use should include the severity of the adverse effects, the degree of discomfort of the patient, the expected duration of opioid therapy, and careful identification of other factors
that may be mistaken for an adverse opioid reaction.
For example, severe itching may be due to opioid use, but it can also be an allergic reaction
to other medications.

Constipation is almost universal in patients treated with opioids, even for short-term use
.
Therefore, stimulant laxatives
should be routinely used for patients who are expected to need more than 1~2 doses of opioids.
Methylnaltrexone does not easily penetrate the blood-brain barrier and can be used as a peripheral opioid receptor antagonist
.
The drug has been used to treat opioid-induced refractory constipation
.
The dose of methylnaltrexone given to children is extrapolated from adult studies
.

For some patients, the itching caused by opioids is just as painful as
the pain.
In patients receiving parenteral opioid treatment, the incidence of itching is about 13%, while in patients receiving intrathecal or epidural opioid treatment, the incidence of itching can reach 20%~80%.

Opioid-induced itching may occur by activating opioid receptors
in the brain and colloid.
Although people are accustomed to using antihistamines to treat itching, research evidence shows that the use of μ receptor antagonists, such as naloxone injections, can treat both opioid-induced itching and nausea
caused by them.
In addition, antihistamines can worsen opioid-induced sedation, constipation, and urinary retention
.
In a prospective randomized trial of 46 children receiving low-dose naloxone [0.
25 microgramkg·hour] infusions with morphine-controlled analgesia after surgery, the incidence and severity of opioid-induced pruritus and nausea were significantly reduced
.
And patients did not increase
pain scores and morphine use after oral small doses of naloxone.
Ultra-low doses of naloxone infusions have shown differences in the binding of opioid receptors to G-stimulating and G-inhibitory proteins, and therefore do not lead to reversal
of analgesia.
Nalbuphine is a widely used lip-type receptor antagonist used to treat opioid-induced nausea and vomiting, but results have been inconsistent
in its efficacy in pediatric patients.

Nausea and vomiting are major sources of patient discomfort, especially during the postoperative period
.
Studies have confirmed that the occurrence of postoperative nausea and vomiting is closely related to postoperative opioid dosing, but other causes
such as electrolyte abnormalities or renal impairment should also be considered.
Ondansetron is a selective 5-HT3 receptor antagonist commonly used to treat nausea and vomiting
.
Phenothiazines, butyrylovenes, and metoclopramide are also commonly used for antiemetics, but these agents carry risks
associated with extrapyramidal reactions.
Currently, there is good evidence to support the use of low-dose naloxone for opioid-induced nausea and vomiting
.
Among them, the standard dose of low-dose naloxone for the treatment of opioid-induced itching and nausea is 0.
25 μg/(kg·h).

Children with advanced cancer often feel tired and sleepy, and opioid use tends to exacerbate these symptoms
.
In addition to this, other treatable causes of fatigue, such as anemia, sleep disturbances, and depression
, should be considered.
A cross-sectional study of parents of 141 children who died of cancer suggested that nearly 96% of children felt fatigued and nearly 50% felt very tired16
.
But only 13% of these children received direct treatment
.
Using opioids too aggressively to treat pain may further exacerbate fatigue and drowsiness
.
Methylphenidate is an adrenergic receptor agonist, which indirectly increases the release
of dopamine and norepinephrine.
Studies in adults support the use of methylphenidate against opioid-induced sedation and fatigue
.
In addition, methylphenidate can also provide partial analgesia and has an antidepressant effect, which is especially beneficial
in children with advanced cancer.

Article from: Gregory's Pediatric Anesthesia

Contributed by Wu Yajun

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