Morphine is a very versatile molecule, dispensable through various routes, of which PO and IV are the most used in hospitalized patients. The hydrophilic properties of morphine allow longer duration of analgesia compared to more lipophilic opioids.

The total body clearance of morphine represents 80 % of the adult range 6 months after birth and 96 % by 1 year of age [29]. Morphine undergoes hepatic metabolism and then renal excretion. Infants and premature neonates may display a large range of elimination half-life due to immaturity of the glucuronidation mechanism. Half-life may vary from 9 ± 3 h in premature neonates, 6.5 ± 2.8 h in term neonates, to 2.0 ± 1.8 h in infants and children [26, 27, 30].

Fentanyl is frequently used for acute pain prevention and management during surgery. It also offers benefits in patients with renal failure or in those at risk of histamine release. Its high lipid solubility promotes fast IV or IN onset with peak of action of less than 5 min or 15 min, respectively. New dispersion formulation like oral transmucosal fentanyl citrate (OTFC) may be interesting for moderately painful procedures of short duration, when IV access is not in place or not desirable [31].

Fentanyl is commonly used as continuous infusion in PICU and NICU. Premature babies and infants are at risk of accumulation due to a reduced plasmatic clearance [32].

Sufentanil is eight to ten times more potent than fentanyl. The clearance of sufentanil in normal children is twice that in adolescents; thus a greater maintenance regimen is necessary. In opposition to fentanyl, sufentanil presents less accumulation over time during continuous infusion, thus offering stable plasmatic levels with shorter half-life and less postoperative respiratory depression. Its lipophilic properties promote residual analgesia and diminished postoperative agitation in PACU.

Another advantage is its versatility of use through different routes, like intranasal. A single IN dose as premedication may cover analgesia for short and moderately painful procedures, for example, myringotomies, dressing changes, or tubes removal [33], with the combined advantage of providing preprocedural anxiolysis and sedation.

Remifentanil is rapidly metabolized in the plasma by nonspecific esterases and does not accumulate with prolonged infusions [34]. Those properties allow high titratability and make remifentanil a useful molecule for short procedures with minimal post-procedural pain, like cardiac catheterization or biopsies. One drawback is the potential induction of acute opioid tolerance (AOI) and opioid-induced hyperalgesia (OIH) [35] precluding its use during a prolonged time and/or at high dose. Infusion rates between 0.1 and 0.3 mcg/kg/min seem not to induce AOI or OIH [35].

Oxycodone is 1.5–2 times more potent than oral morphine and is provided in short-acting and long-lasting PO formulation. The metabolism in patients older than 6 months shows stable values and clearance 50 % higher than adults [36, 37]. Onset, peak, and duration of action are similar to those of oral morphine, thus rendering oxycodone a valid option for opioid rotation in the context of opioid-induced hyperalgesia or due to adverse effects.

Hydromorphone is commonly used in the paediatric population due to its renal elimination as an inactive metabolite and lack of histamine release [38, 39]. It is five to seven times more potent than morphine with similar onset and duration of action. Common routes of administration are IV, PO, or epidural. Hydromorphone is also a popular second-choice molecule when opioid rotation is needed. PCA mode is convenient; however one should be careful with conversion calculation and the risk of errors with small boluses.

Methadone has been safely used for postoperative pain in children [40], burns [41], or trauma [42], by IV or PO routes. It is also frequently used for opioid rotation and treatment of opioid withdrawal syndrome due to its NMDA receptor antagonist properties [43]. The longer duration of action could represent a double-edged sword, as side effects related to over dosage would last longer. The administration of methadone in opioid-naive patient should only be initiated in a hospital setting, paying close attention to side effects and various drug interactions.

Methadone is considered a second-line opioid for acute pain management; however it could be used as a single bolus co-analgesic for procedures that are relatively painful in the first 24 h [44] like orchidopexy, as weaning from regional anaesthesia or in the context of surgery with high nociceptive impact like spinal surgery.

Nalbuphine is an agonist-antagonist semi-synthetic opioid with pharmacological potency comparable to morphine, usually indicated in procedures with minimal to moderate pain intensity. Because of its κ-receptor agonist and μ-receptor antagonist properties, the risk of respiratory depression associated with μ-receptor is prevented. The effect on the κ-receptor reduced the incidence of emergence agitation in PACU [45]. Nalbuphine has minimal effect on bowel or bladder function, characteristics of interest in ambulatory surgery. On the other hand, nalbuphine has a ceiling effect above 0.4 mg/kg, and the induced sedation may trigger upper airway obstruction.

Tramadol is a weak μ-opioid receptor agonist and a monoaminergic (MAO) reuptake inhibitor [46, 47]. It is derived from codeine and metabolized in the liver through the CYP2D pathway [48]. Its MAO properties may play a role in minimizing the μ side effects like constipation and especially respiratory depression [49]. This makes tramadol an alternative option in children with known risk factor for OIRD, like obstructive sleep apnoea [50]. It was associated with a similar incidence of postoperative nausea and vomiting as morphine. It has a similar safety profile either in patients with neuropathic pain and with nociceptive pain [51].

The recommended IV dose is 1 mg/kg and 100 mg is approximately equivalent to 10 mg of morphine [52, 53]. It has been effectively used by mouth, IV, IM, caudal/epidural, or local infiltration [54] as well as topical application during tonsillectomy [55]. Tramadol/acetaminophen combination is a convenient analgesic post-tonsillectomy pain control, especially at home. One consideration to rise is the theoretical risk of hypoglycemia in predisposed patients and serotoninergic syndrome with the concomitant use of selective serotonin re-uptake inhibitors.

The patient-controlled analgesia (PCA) gives autonomy to patients over their pain control and positively influences the latter through patient’s empowerment [56]. It is a safe alternative for pain management in children of 6 years old and older. PCA implies the understanding of the concept, the ability to self-evaluate pain, and the capacity of activate the dosing device. It is also useful in hospital “frequent flyer” children younger than 6 years of age with closer monitoring from the acute pain team.

Younger children or those unable to manipulate the machine (with special needs or physical restraint) benefit from proxy-controlled analgesia, usually the nurse in charge of the patient or a parent. A recent survey of 252 American centres [57] showed that the vast majority of centres (96 %) would provide PCA but has proxy-controlled analgesia (nurse or parent) in only 38 %. Indeed, this latter technique provides excellent pain relief for children unable to use it by themselves but may create some safety challenges given the subjectivity of the proxy, bypassing the inherent safety features of analgesics dispensed by the patient itself. The main concern is a slightly augmented incidence of respiratory depression [58], easily detected by proper monitoring and treatment without major consequences. Parent-/nurse-controlled analgesia for children with developmental delay is efficient and safe but implies a reinforced monitoring, strict education of the proxy, and clear, written, instruction [59].

The standard monitoring includes oxygen saturation and respiratory rate. More advanced measurements like continuous capnography or breathing sounds through a microphone placed on the neck may further augment safety and prevent oversedation.

The use of a background continuous infusion is controversial. The aim is to improve analgesia through an increase of the plasmatic levels of opioids, especially during night-time, when patient uses PCA less. The increased risk of respiratory adverse events may not justify the potential analgesic advantages.

An acute pain team, informed proxy or nursing staff, and an adequate monitoring increase the safety independently of the modality (PCA, NCA, or PARCA) or the risk of the patient (opioid tolerant, neonates, OSA, etc.)

Acetaminophen is a common co-analgesic medication in children. The multiple routes of administration allow an easy adaptation to the patient’s needs. The intravenous route gives more reliable plasmatic levels, bioavailability, and a slightly faster onset time over rectal or oral routes [63].

Acetaminophen exerts its analgesic effects through the inhibition or prostaglandin release, as a cannabinoid ligand, enhancing inhibitory descending pathways by serotoninergic interactions [64]. The administration of acetaminophen is safe in neonates as far as doses are lowered by 50 % taking in account the longer half-life (up to 7 h).

NSAIDs analgesic effects are mediated by the inhibition of COX-1 and COX-2 activity. As a group, they inhibit the biosynthesis of prostaglandins with the subsequent reduction of excitatory amino acids [65]. Due to its opioid-sparing effects, NSAIDS are effective for the reduction of opioid-induced adverse effects [61, 66]. NSAIDS are useful for the prevention of pain rebound during weaning from regional analgesia. Parents should be taught to give NSAIDS (and acetaminophen) before wearing off a regional block [67].

Inadequate pain relief has been associated with the fear of opioids’ adverse effects at home. The association of oral ibuprofen 10 mg/kg every 8 h and oral acetaminophen 10–15 mg/kg every 6 h provided similar analgesia than PO morphine, with less respiratory adverse effects in children undergoing tonsillectomy [68]. It is possible that with adequate information, parents would have a better adherence to the postoperative pain programmes with non-opioid-based analgesic plan.

Ketorolac is commonly used intravenously, and more recently, the intranasal route has also been described [69]. Even if it has been safely used in infants, the lower age limit is still under debate. The administration of ketorolac 0.5 mg/kg every 6–8 h was associated with a 17 % incidence of bleeding events (fresh blood in tubes, surgical wound or intra-abdominal bleeding, blood-positive stools) in small infants (average 21 days) [70].