Introduction

Pain management in children is a critical component of paediatric care, as untreated pain can have deleterious effects on both the physical and psychological well-being of young patients. Unfortunately, paediatric pain is often poorly recognized and undertreated, and managing it effectively can be complex. Exposure to severe pain without adequate management is associated with adverse long-term outcomes such as chronic pain, anxiety and depressive disorders later in life.

The World Health Organization (WHO) analgesic ladder provides a framework for escalating pain treatment, starting with non-opioid analgesics and progressing to stronger medications as needed. However, this traditional stepwise approach has its limitations, particularly in paediatric populations where the potential for adverse effects is a significant concern. To address this, a multimodal analgesic strategy, which involves combining multiple techniques and agents from different classes, has proven to be more effective in reducing pain transmission and perception while minimizing the adverse effects associated with any one agent.

Unfortunately, strong evidence-based recommendations in paediatric pain management remains limited due to challenges and ethical considerations in research, wide variability in drug pharmacokinetics and dynamics across age groups, and difficulty in objectively assessing pain in younger children. The aim of this review is to highlight systemic analgesic options for children based on current evidence, including important considerations for neonates. A range of drugs are discussed, focussing on pharmacokinetic and pharmacodynamic features, as well as their potential adverse side effects and risks. Dosing recommendations for the medications discussed in this review can be found in the British National Formulary for Children ( www.bnfc.nice.org.uk ).

Paracetamol

Paracetamol (acetaminophen, N-acetyl-p-aminophenol) is used as an anti-pyrectic and analgesic agent. It is available in oral (tablet, elixir), rectal and intravenous preparations. Paracetamol is an effective analgesic for mild to moderate pain, with level I evidence showing that it decreases opioid requirements after major and minor surgery in children. Furthermore, it is synergistic with other analgesic agents, increasing effectiveness and duration. ^, The recommended dose for children varies widely in literature and across institutions, with scant pharmacological and safety data to support the use in term and premature neonates. ^, A similar effect-compartment concentration of 10 mg/litre should be aimed for in all paediatric age groups. The proposed mechanisms of analgesic action include inhibition of prostaglandin synthesis, potential active metabolite influence on central cannabinoid/transient receptor potential vanilloid 1 (TRPV1) receptor and indirect serotonergic effects. ^,

Paracetamol has good oral bioavailability (>90%) and less predictable rectal bioavailability (25–98%). ^, Peak plasma concentrations are reached within 30 minutes with liquid and effervescent formulations (longer with capsules and tablets). Neonates have delayed oral absorption due to slower gastric emptying, however this reaches adult rates by 6–8 months of age. The delay between plasma and effect site equilibration (t1/2keo) is 30–50 minutes. It is predominantly metabolized by hepatic glucuronide conjugation (UGT1A6) which is immature in neonates, in whom sulphate conjugation plays a greater role. A small portion (1–10%) is metabolized by cytochrome P450 (CYP) 2E1 enzyme to produce NAPQI which is hepatotoxic. NAPQI is rapidly metabolized with glutathione and eliminated in healthy children. However, there is a risk of hepatic necrosis with NAPQI accumulation that can be seen with concomitant use of CYP2E1 inducing agents, paracetamol overdose, or with inadequate glutathione stores seen with liver disease or malnutrition. Clearance is reduced in neonates, but rapidly increases and reaches adult rates during infancy.

Paracetamol has a good safety profile in children and infants. ^, A review assessing a range of adverse effects (including abdominal, hepatic, skin, respiratory and neurological effects) suggests paracetamol has similar safety and tolerability profiles compared to placebo if prescribed and administered at recommended doses.

Due to its metabolite (NAPQI), there is a risk of hepatoxicity with paracetamol administration. However, the risk for liver toxicity appears very low if the daily paracetamol doses remain <90 mg/kg in healthy children. ^, Risk factors may include fasting/malnourished state, vomiting, dehydration, systemic sepsis, pre-existing liver disease and prior paracetamol intake. Intravenous paracetamol in haemodynamically unstable children has been associated with hypotension. Emerging evidence suggests that maternal paracetamol use may influence premature closure of the fetal ductus arteriosus and use in pregnancy should be limited to the minimum dose and duration that is clinically necessary. Overall, paracetamol is a safe and effective analgesic agent for mild to moderate pain in infants and children.

Non-steroidal anti inflammatory drugs (NSAIDs)

NSAIDs are anti-inflammatory, anti-pyretic and analgesic agents that have proven efficacy in the management of post-operative pain in children. They are available in oral, rectal, intravenous and intramuscular formations, depending on the drug. They bind to the cyclo-oxygenase (COX) site on the prostaglandin H ₂ synthetase enzyme, inhibiting the metabolism of arachidonic acid and reducing prostaglandin synthesis. More specifically, NSAIDs act on the COX-1 and COX-2 isoforms. COX-1, a constitutional enzyme primarily found in gastric mucosa, renal parenchyma, platelets and osteoblasts, has traditionally been attributed to most of the adverse effects seen with NSAIDs. Whereas COX-2 is an inducible enzyme responsible for prostaglandin production in response to injury. Non-selective NSAIDs (e.g. ibuprofen, diclofenac, ketorolac, naproxen, ketoprofen, indomethacin) inhibit both COX-1 and COX-2 isoenzymes. Selective COX-2 inhibitors have subsequently been produced (celecoxib, parecoxib, rofecoxib) with the aim to decrease the incidence of unwanted adverse effects seen with non-selective NSAIDs. However, evidence has shown that the biological activity of the isoforms is more complex and both are involved in many physiological processes, as well as the production of inflammatory mediators. In addition, there is little evidence supporting the role of selective COX-2 inhibitors in the paediatric population.

The pharmacology of NSAIDs in children is similar to that in adults; however, there are a few key developmental differences in enzyme activity and organ function. Although NSAIDs are generally well absorbed orally, factors such as gastric pH and motility, which differ by age, can influence drug absorption in younger children. NSAIDs are metabolized primarily in the liver by cytochrome P450 enzymes and capacity can vary significantly with age. In neonates and infants, these enzymes are underdeveloped leading to prolonged drug half-lives and slower clearance. Enzyme activity reaches adult levels by 3 months old, resulting in more predictable metabolism and clearance. Diclofenac in particular shows age-related changes in clearance, with highest rates occurring in children between 1 and 3 years old. NSAIDs are primarily excreted through the kidneys. In neonates, immature renal function may prolong the excretion of NSAIDs and their metabolites, increasing the risk of accumulation and toxicity.

Safety and efficacy data support the use of non-selective NSAIDs in children and infants greater than 3 months of age weighing over 5–6 kg. ^, Additionally, the use of NSAIDs improves analgesia while reducing rates of nausea and vomiting. Ibuprofen and diclofenac have been shown to work synergistically with paracetamol, halving the required dose to achieve the same analgesic effect. ^, The choice of which NSAID to use depends on available formulations and convenience of administration, with specific benefits depending on the dose and route administered, perioperative timing of administration, duration and regularity of dosing, as well as the type of surgery involved.

Serious adverse effects from non-selective NSAIDs are rare in children over 6 months of age. More commonly, children experience nausea, dizziness and headache. While children are generally less prone to severe gastrointestinal (GI) complications than adults, prolonged or high-dose NSAID use can lead to gastritis, ulcers, and GI bleeding. Furthermore, NSAIDs can reduce renal blood flow and nephroprotective prostaglandin effects. ^, As such, they can increase the risk of acute kidney injury in children, particularly in neonates, infants, or those with pre-existing renal conditions. In some cases, NSAIDs can precipitate bronchospasm, especially in children with asthma and other atopic conditions. NSAIDs are contraindicated in children with previous or current gastric ulceration, severe cardiac failure, liver and renal dysfunction. Caution should be used in children with asthma and those at increased risk of bleeding.

Evidence has shown that NSAIDs can safely be used in healthy children across multiple surgical specialties without an increase in postoperative bleeding rates.

The use of COX-2 selective inhibitors (coxibs) in children remains an area of contention. Paediatric data and understanding of the pharmacokinetic-pharmacodynamic relationships and adverse effects of these agents is limited and use is largely off-license. Parecoxib use in children has been found to reduce early postoperative pain scores, postoperative nausea and vomiting (PONV) and postoperative opioid consumption. Similarly, celecoxib has been found to reduce pain and additional analgesic requirement in the acute post-tonsillectomy period in children. The safety profile of coxibs in the setting of allergy or contraindication to non-selective NSAIDs is encouraging, but safety data specific to short term perioperative use is limited. The role of coxibs in children remains unclear and advantages over commonly used non-selective NSAIDs have not been fully demonstrated.

Codeine

Codeine is an opioid analgesic used for the treatment of mild to moderate pain and as a cough suppressant. It is a prodrug that exerts its effects after being metabolized into its active form, primarily morphine. It is available in oral, rectal and intramuscular formulations. The intravenous preparation should be avoided due to marked histamine release resulting in severe hypotension. ^, Codeine’s pain-relieving properties primarily result from its conversion to morphine, which binds to mu-opioid (MOP) receptors in the central nervous system and inhibits pain signalling pathways. Codeine itself has weak analgesic activity and relies on its conversion to morphine to produce the majority of its therapeutic effects.

Codeine is moderately well absorbed from the gastrointestinal tract, with a bioavailability of approximately 40–60%. Oral codeine has a similar time to peak effect but decreased total absorption versus PR and IM delivery, reaching peak plasma concentrations about 1–2 hours after oral administration. ^, It is hepatically metabolized primarily via the CYD2D6 enzyme with approximately 10% being converted to morphine. It is also metabolized by CYP3A4 to inactive metabolites. Codeine has a variable elimination half-life that differs with age. In adults, the terminal elimination half-life is approximately 3–3.5 hours, while in neonates, due to immature metabolic clearance, the half-life extends to about 4.5 hours, and in infants, it decreases to around 2.6 hours.

The CYP2D6 enzyme is subject to genetic polymorphisms and interindividual variability in function. As such, codeine metabolism varies significantly depending on the CYP2D6 enzyme phenotype present. The most common phenotype, present in 70% of Caucasians and 92% of Asians, is termed extensive metabolism and displays 1–2 times CYP2D6 activity. Intermittent or poor metabolizers with reduced or no CYP2D6 activity are found in approximately 46% of children in the UK and will show little or no analgesic effect from codeine. Conversely, ultrarapid metabolisers have more than two times CYP2D6 activity and are at increased risk of sedation and respiratory depression, especially in breastfeeding neonates, infants and those with underlying sleep apnoea.

Paediatric use of codeine, especially following adenotonsillectomy, has been associated with mortality, particularly in ultrarapid metabolizers of the CYP2D6 enzyme. Codeine has also been shown to be less effective than ibuprofen for acute musculoskeletal pain in children, and although it is as effective as ibuprofen for fracture pain, ibuprofen results in fewer adverse effects and better functional outcomes. As a result, multiple regulatory authorities worldwide, including those in the US, UK, Europe and Australia no longer support its use in children. ^,

Tramadol

Tramadol is an atypical opioid with antinociceptive and antineuropathic effects. It is useful as part of a multimodal analgesic strategy for acute and neuropathic pain in children. It acts synergistically as a weak opioid agonist and monoaminergically as a serotonin and norepinephrine reuptake inhibitor. Tramadol is available as a racemic mixture of two enantiomers in various formulations including intravenous, rectal and oral. The oral immediate release (IR) preparation has 70% bioavailability with its effects peaking at 3 hours, and a half-life of 6 hours. Some formulations combine IR and modified release (MR) preparations which allows biphasic release of the drug, with peak plasma levels at 9 hours.

Tramadol is converted by CYP3A4 and CYP2D6 enzymes into the active metabolite O-desmethyl-tramadol (or M1) which has 200 times greater affinity for the MOP receptor than the parent compound. Due to CYP genetic polymorphisms, there can be inter-individual variability of analgesic effect, with extensive metabolisers experiencing greater efficacy. Evidence of harm from toxicity via this mechanism is lacking; however, the US Food and Drug Administration (FDA) has issued warnings with tramadol following cases of children with serious breathing problems (including three deaths) associated with its use. In these cases, patients were prescribed high concentration (100 mg/ml) drops which is more likely to have contributed to overdose and toxicity. This formulation has since been replaced by a lower concentration of 10 mg/ml in many countries. Nevertheless, a contraindication of use has been issued by the FDA in children less than 12 years, and those less than 18 years for pain following adenotonsillectomy. Additionally, a warning has been issued for patients between 12 and 18 years who are obese or are at increased risk of serious breathing problems (for example, those with obstructive sleep apnoea or severe lung disease). Other possible adverse side effects include nausea and vomiting, lowered seizure threshold, agitation and serotonin syndrome (when used in combination with SSRIs).

Tapentadol

Tapentadol is a centrally acting analgesic that exhibits two synergistic mechanisms of action. It acts as a MOP receptor agonist and noradrenaline reuptake inhibitor resulting in analgesia comparable to pure MOP receptor agonists with a significant reduction in opioid-related side effects. There is growing evidence for use of tapentadol in acute paediatric pain across all age-groups. ^, However, it remains limited by a low number of studies and small sample sizes.

Tapendatol has a poor oral bioavailability (32%) due to extensive first-pass metabolism. The available evidence suggests plasma concentrations in children are similar to those seen in adults with peak plasma concentrations at 60–90 minutes following 1 mg/kg oral dosing. It is extensively metabolized in the liver via glucuronidation and oxidation into largely inactive metabolites that are renally excreted. It has a relatively short elimination half-life of approximately 4 hours, necessitating dosing at regular intervals for sustained analgesic effect.

The side effect profile of tapentadol in children is comparable to adults and commonly includes nausea, vomiting, dizziness, somnolence and constipation. Due to its dual mechanism of action, there is a significantly reduced risk of respiratory depression with tapentadol use compared to pure opioid agonists. Though limited by sufficient data, there is no indication of higher susceptibility of neonates/infants to severe adverse reactions from tapentadol compared to older children and adults. ^{, ,}

Morphine

Morphine is a widely used potent analgesic that is efficacious against moderate to severe nociceptive pain. It is available in oral, rectal, intravenous, subcutaneous, intrathecal and epidural formulations. The analgesic action of morphine is mainly through the agonism of central and peripheral opioid receptors, namely the MOP receptor, with less effect on kappa and delta opioid receptors.

The oral bioavailability of morphine is poor (30–50%) due to high first-pass metabolism. Following oral administration, peak plasma concentrations are reached after 60 minutes and maximum analgesic effect in 90 minutes. It is metabolized in the liver predominantly (75%) into the inactive metabolite morphine-3-glucuronide (M3G), as well as in much smaller rates into active metabolites including morphine-6-glucuronide (10%), normorphone (5%) and codeine. Morphine-6-glucuronide (M6G) is more active at MOP receptors than morphine and can accumulate in hepatic and renal failure leading to respiratory depression. Morphine clearance is notably influenced by age and weight, with a significant reduction in clearance and prolonged half-life observed in neonates and infants, making age the primary determinant of dosing in children under 3 years. Furthermore, obesity with a comorbid diagnosis of severe obstructive sleep apnoea (OSA) has a pronounced effect on morphine pharmacokinetics. Research has suggested that obese children with severe OSA have higher plasma morphine concentrations compared to normal weight children, with evidence of more rapid metabolism and metabolite accumulation.

Dosing varies between formulations due to the poor bioavailability of morphine. The intravenous dose is equivalent to 2–3 times the oral dose, (for example 3–5 mg of IV morphine is equivalent to 10 mg of oral morphine). Despite variability in response, morphine remains safe when used in a controlled and well-monitored paediatric ward environment for severe pain. Morphine infusions are widely used via paediatric pain service prescribed patient-controlled analgesia (PCA) pumps. Infusions use a baseline rate and/or bolus doses administered via push button pressed by the patient or nursing staff. Lock-out times of 6–20 minutes in between boluses are based on age and dosing requirements. The risk of respiratory depression is reduced with infusions targeted to plasma concentrations <20 micrograms/litre. However, due to individual variability and difficulties with study designs, no clear relationship between plasma concentration and analgesia has been identified and rates should be titrated cautiously to response.

Commonly occurring mild to moderate morphine-related adverse effects include nausea, vomiting, constipation, dizziness, sedation, dysphoria, nightmares, itch or skin rash and urinary retention. These side effects are not life-threatening but can markedly upset children and their family or carers. More severe adverse events include dependence, respiratory depression, coma and death. ^, The risk of these major adverse events is higher in younger (less than 1 year, particularly ex-premature), children with hepatic or renal impairment, neurodevelopmental disabilities and obese children with a history of OSA or sleep disordered breathing. ^, These issues underscore the necessity for cautious opioid management in paediatric patients and emphasize the need for multimodal analgesic regimes and personalized dosing strategies to mitigate risks associated with opioid therapy.

Diamorphine

Diamorphine has a wide range of uses and available routes of administration. It is a prodrug, rapidly metabolized by plasma esterases into the active metabolite 6-mono-acetylmorphine. This results in onset of analgesia within five minutes. Subsequent metabolism to morphine exerts a maximum analgesic effect in one hour. It is highly lipophilic and rapidly crosses the blood brain–barrier if given intravenously. It is well absorbed via subcutaneous, intranasal (IN) and intramuscular routes, and is also effective when given epidurally or intrathecally.

IN diamorphine is an attractive option as it is rapidly absorbed systemically avoiding first pass metabolism. It has an estimated bioavailability of 50% via this route with peak morphine plasma concentrations occurring at 10 minutes. For this reason, it is used in emergency medicine for trauma pain management, in combination with nitrous oxide for fracture reduction, and for the management of patients with sickle cell crises. ^, When considering opioid conversion, a conversion ratio of 1:1 intravenous morphine:IN diamorphine and 1:3 oral morphine:IN diamorphine should be used.

Fentanyl

Fentanyl is a highly lipophilic and potent MOP agonist used for the acute management of severe pain. It is estimated to be 100 times more potent than morphine. Its lipophilicity allows for effective administration via transmucosal (buccal, IN and transdermal (TD)) routes, which is particularly advantageous when intravenous access is not feasible. The high bioavailability of TD fentanyl provides sustained release which is useful for children with palliative care needs; however, the time to reach steady state serum drug concentrations following application is longer in children, and clearance is enhanced resulting in a shorter elimination half-life. IN fentanyl is increasingly being recognized as an effective treatment for acute paediatric pain management with an acceptable safety profile and ease of delivery. ^,

Fentanyl has a rapid onset and rapid redistribution to body tissues resulting in a short half-life and potential to accumulate in the tissues. This is demonstrated in its variable context sensitive half-times seen in adults (for example, 20 minutes after a 1 hour infusion and 270 minutes after an 8 hour infusion). Fentanyl is primarily metabolized by CYP3A4 into inactive metabolite norfentanyl and achieves 70–80% of adult clearance levels within the first two weeks of life. ^,

Fentanyl is predominantly used intravenously as boluses of 0.5–1 micrograms/kg, infusions of 0.5–3 micrograms/kg/hour or via a PCA pump. ^, Intranasal doses of 1–2 micrograms/kg can be used for rapid analgesia where no intravenous route is immediately available. ^,

Common adverse effects of fentanyl are similar to other opioids and are as listed above for morphine. Advantageously, rates of itch and bronchospasm are reduced with fentanyl as it does not cause histamine release, nor does it have any direct myocardial depressive effects. High doses can induce laryngeal and chest wall rigidity, which can impair ventilation.

Remifentanil

Remifentanil, a synthetic phenylpiperidine derivative of fentanyl, is a pure MOP receptor agonist. It has a quick onset (T _1/2 keo 1.16 minutes) and offset time as it is rapidly metabolized by abundant, non-specific tissue and plasma esterases. Its context-insensitive half time confers several advantages, particularly in providing intraoperative analgesia for long duration surgery, while also allowing rapid wake up and recovery, and suppression of sympathetic response during periods of stimulation (for example, laryngoscopy and surgical stimulation). It is administered intravenously either as a bolus (for example 1 microgram/kg, to provide intubation conditions) or most commonly as an infusion (0.1–1 microgram/kg/minute). Different plasma concentrations of the drug can be targeted based on the desired clinical effect; for example, analgesic effect is seen at 0.2–0.4 micrograms/litre, 2–3 micrograms/litre for laryngoscopy, 6–8 micrograms/litre for laparotomy and 10–12 micrograms/litre to obtund the stress response from cardiac surgery. It has an inactive metabolite which is excreted in the urine. Compared to other opiates, remifentanil exhibits more rapid clearance and a greater volume of distribution in infants less than 2 months of age, necessitating faster initial infusion rates for the same plasma target levels compared to older children.

Adverse effects associated with remifentanil use include bradycardia, hypotension and chest wall rigidity, as well as other common opiate-related side effects (for example, nausea and vomiting). Rebound hyperalgesia is also a concern necessitating loading with alternative analgesia prior to stopping the infusion. Respiratory depression and apnoea is usually seen with infusion rates greater than 0.184 micrograms/kg/minute, which has been useful in obtaining adequate imaging during cardiac MRI. Other useful applications include conscious sedation and analgesia during stimulating, short-duration procedures such as burn dressing changes.

Oxycodone

Oxycodone, a semisynthetic opioid, is gaining popularity in paediatrics, and can be used in the treatment of acute, chronic and neuropathic pain. Approximately 10% is metabolized via cytochrome P450 enzymes (CYP3A4 and CYP2D6) to the active metabolite oxymorphone which has a much higher binding affinity to the MOP receptor, although the parent drug exerts the majority of the analgesic effect. Genetic polymorphisms of CYP450 can affect drug metabolism, but this is yet to be correlated clinically. A proposed target plasma concentration of 35 mcg/L for effective post-operative analgesia has been proposed, far lower than concentrations associated with fatal consequences (200 micrograms/litre).

Oxycodone is available via a variety of routes including orally, rectally, intravenously and via the epidural route. The oral bioavailability of oxycodone is much higher (60%) compared to morphine (33%) accounting for its higher potency, and is available as immediate-release and modified-release preparations. It is eliminated by the kidneys, with 10% of the drug excreted unchanged. Clearance of the drug matures throughout infancy with 8% of typical adult values at 24 weeks post-menstrual age reaching 90% at 1 year of age. There are several proposed mechanisms described for the abuse potential of oxycodone. Concerns remain regarding the addictive nature and likeability of the drug, and its increased availability in the community.

Methadone

Methadone is a synthetic opioid use in children with persistent pain, in opioid weaning, or as part of a multi-modal approach to complex surgeries. ^, It acts as a mu-opioid receptor agonist, N-methyl-D-aspartate (NMDA) receptor antagonist and inhibits the reuptake of noradrenaline and serotonin. It has a similar potency to morphine, but more rapid uptake and the longest reported half-life of all commonly used opioids. ^,

While research in the paediatric population is limited, studies have shown that the pharmacokinetic profile of methadone is similar in neonates, infants and children to those reported in the adult population. ^, It has a good oral bioavailability of 70–80% but can decrease to 30% in critically ill patients due to a markedly reduced absorption rate. It has a variable onset time of 30–60 minutes orally and 10–20 minutes intravenously. It undergoes hepatic metabolism via multiple cytochrome P450 enzymes into inactive metabolites. ^{, ,}

Similar to other opioids, methadone can cause respiratory depression, constipation and biliary tract spasm. There is less sedation and euphoria seen with methadone than with other opioids. It has been shown to cause QT _c prolongation in children, however, there are no published reports of severe dysrhythmias following methadone administration.

Ketamine

Ketamine is a phencyclidine derivative with potent analgesic and dissociative anaesthetic properties. It has continued to gain popularity due to its ability to produce sedative, analgesic and amnesic properties relatively quickly with some beneficial secondary effects (including bronchodilation, maintenance of airway reflexes and preservation of sympathetic nervous tone).

Ketamine has numerous effects across a range of receptors. It is a non-competitive antagonist at the NMDA receptor. It prevents glutamate binding which reduces sodium and calcium influx and potassium efflux, decreasing excitatory neurotransmission in acute pain states. It is useful in the treatment of chronic pain when NMDA receptors are upregulated, reducing the risk of central sensitization and hyperalgesia. It has an agonist effect at the opioid receptor reducing opioid requirement and making it a useful adjunct for patients with severe surgical pain and cancer-related pain.

It is available either as a racemic mixture of the two enantiomers S (+)-ketamine and R (−)-ketamine or as the S (+)-ketamine isomer alone. The S isomer confers a two-fold analgesic potency compared to the racemic mixture; therefore, it can be used at lower doses with less side effects and a quicker recovery time. It is highly lipid soluble leading to rapid onset, and undergoes N-dealkylation via cytochrome P450 enzymes. Norketamine, the only active metabolite, has one-third to one-fifth the potency of its parent drug.

Ketamine is available via almost every route, but is most routinely given IV or IM. The bioavailability is 90% by IM, 50% by IN and 20% by oral. The IN route confers a particular advantage due to its ease of administration and rapid onset of action, which is useful where IV access is unavailable. The topical route has even been used at the site of surgery for tonsillectomy patients, with evidence of reduced pain and analgesic requirements postoperatively. The use of ketamine in neonates is yet to be determined, with concerns of enhanced neuronal apoptosis in the developing brain necessitating further research in this area.

α-2 adrenoceptor agonists

α-2 agonists have a range of uses in paediatrics including analgesia, anxiolysis, sedation and anti-emesis, without causing respiratory depression. They act on α-2 G-protein coupled receptors, and their action on α-2A and -2C subtypes (found in the central nervous system) are thought to be responsible for sedation, analgesia and sympatholytic effects. Stimulation of these receptors, specifically in the dorsal horn of the spinal column inhibits nociceptive neurons and the release of substance P. Additional effects on supraspinal areas including the midbrain, locus ceruleus and medulla results in widespread analgesia.

Adverse effects include bradycardia and atrioventricular nodal block and should be used with caution in children with cardiac conduction abnormalities. At low doses they can cause hypotension (via a central effect) and conversely higher doses can precipitate an increase in blood pressure mediated by a direct effect on smooth muscle. Care should be taken when used in patients with chronic hypertension and slow bolus administration is advised.

Clonidine is an imidazoline derivative. It has many routes of administration including oral, intravenous, intranasal and transdermal. It can also be used as an adjunct to local anaesthetic in central or peripheral regional anaesthesia to prolong the duration of block. It is well absorbed orally with minimal first-pass metabolism and a bioavailability of 70–80%. Approximately 30% is metabolized in the liver and the remainder is excreted renally. It has additional uses to those mentioned previously including control of postoperative shivering, reduced emergence delirium and reduction of the stress response to intubation and surgery. It can also reduce symptoms in neonatal opioid withdrawal syndrome.

Dexmedetomidine has greater affinity for α-2 receptors than clonidine which can explain the more pronounced cardiovascular effects observed. It is highly lipophilic with a large volume of distribution and readily crosses the blood brain barrier. It is broken down by hepatic enzymes uridine 5′-diphospho-glucuronosyl-transferase and cytochrome P450 to inactive metabolites. It can be given via nasal, buccal, rectal and oral routes. The intranasal route is a convenient, minimally invasive way of providing sedation and analgesia in children, with a bioavailability of 40.7%. This technique has proved popular for providing sedation for diagnostic radiology procedures. As an intravenous infusion, its use has been described for spontaneous ventilation in rigid bronchoscopy, in cardiac surgery, and even to facilitate awake craniotomy in children. Clearance in neonates and infants is reduced due to immature elimination pathways and therefore requires a dose reduction. It has a dose-dependent effect on MAP and heart rate, with an expected bradycardia of up to 30% from baseline when used in children. Off-licence use as an adjunct to local anaesthetic in peripheral nerve blockade has demonstrated prolonged and enhanced analgesic effect; however, the safety profile of perineural dexmedetomidine is yet to be determined.

Gabapentinoids

Gabapentinoids have traditionally been used to treat epilepsy and chronic neuropathic pain. Recently, their use has extended to the perioperative setting as part of a multimodal analgesic regimen, reducing opioid use and the incidence of chronic post-surgical pain.

The mechanism of action of gabapentinoids is not fully understood. Their primary action is through direct inhibition of voltage-gated calcium channels, reducing calcium influx and subsequent release of excitatory neurotransmitters such as glutamate. This suppresses neuronal excitability following nerve or tissue injury. Additionally, they enhance descending inhibition, prevent descending serotonergic facilitation and inhibit inflammatory mediators.

They are currently only available in oral preparations. Time to peak effect of pregabalin is quicker at 1 hour compared to 3 hours for gabapentin as it exhibits zero-order kinetics. They undergo almost no metabolism and are excreted unchanged in the urine, requiring dose adjustments in renal impairment.

Their use as part of enhanced recovery protocols for major surgery is most common in adolescent idiopathic scoliosis patients undergoing posterior spinal fusion surgery. They are also used to reduce the incidence of chronic post-surgical pain and phantom limb pain after amputation. Adverse effects are common resulting in a discontinuation rate of 11%. These include dizziness, gait disturbance, moderate weight gain and abdominal symptoms including nausea.