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Systemic analgesics for children
Paediatrics
Systemic analgesics for children
after rectal administration.1 The time to reach maximum serum concentration following rectal administration varies between 1 and 2.5 hours. Rectal administration of drugs is contraindicated in neutropenic patients (risk of sepsis) and in those with ulcera tive or acute inflammatory conditions of the rectum or anus. An intravenous preparation of paracetamol has become available recently. Initial experience with intravenous paracetamol is that a high effect-site concentration after intravenous administration is associated with high analgesic potency. When administered intravenously, paracetamol should be given as an infusion over 15 minutes.
Mary Rose
Abstract
Neonates: the clearance of paracetamol in neonates is reduced and the volume of distribution is increased. The dose of para cetamol therefore needs to be reduced in neonates (Table 1). Bioavailability following rectal administration is higher in neonates compared with infants and children.
Pain in children can be treated safely and effectively by using combinations of simple analgesics (paracetamol and non-steroidal anti-inflammatory drugs) and opiates, the choice of analgesic being determined by the severity of the child’s pain. Safe clinical practice requires an understanding of the age-related changes in the pharmacokinetics and pharmacodynamics of analgesics in neonates, infants and children. Pain should be regularly assessed, and where appropriate local anaesthetic techniques and nonpharmacological techniques should be used in combination with systemic analgesics. Analgesia for children should be administered, assessed and/or supervised only by individuals with adequate training and experience. This article covers a spectrum of systemic analgesics, from simple to complex, used for the treatment of acute pain in children.
Dosing: there are several dosage regimens for paracetamol, indicating that the optimum regimen is still to be determined. The regimen depends on the age of the child, the route of administration and the duration of treatment. The current recommendations in the BNF for Children are shown in Tables 1 and 2. Adverse effects and toxicity: when the maximum daily dose of paracetamol is observed it is well tolerated. The maximum daily dose is limited by the potential for hepatotoxicity, which can occur when the daily dose exceeds 150 mg/kg. Multiple doses may accumulate in children who are malnourished or dehydrated.
Keywords analgesia; morphine; non-steroidal anti-inflammatory drugs; paediatrics; paracetamol
NSAIDs NSAIDs are effective for the treatment of mild or moderate pain in children. In addition to their analgesic effect they have antiinflammatory and antipyretic effects. They also have an opioidsparing effect. The combination of NSAIDs and paracetamol produces better analgesia than either drug alone. Their mechanism of action is the inhibition of COX activity, thereby blocking the synthesis of prostaglandins and thromboxane (Figure 1). Aspirin is not used in children because of the risk of Reye’s syndrome. Selective COX-2 inhibitors have been developed with the expectation that the analgesic and anti-inflammatory effects of NSAIDs would be retained whilst reducing the risk of gastric irritation and bleeding. However, in adult studies potential improvements in safety have been offset by an increase in the incidence of adverse cerebral and cardiac thrombotic events. Reports of the use of selective COX-2 inhibitors in children demonstrate equal efficacy with non-selective NSAIDs. However, the role of selective COX-2 inhibitors in paediatric practice is yet to be established.
Paracetamol Paracetamol is a mild analgesic. On its own it can be used to treat mild pain in combination with non-steroidal anti-inflammatory drugs (NSAIDs); with a weak opioid such as codeine it can be used to treat moderate pain. Studies have demonstrated an opioid-sparing effect when it is administered postoperatively. Paracetamol inhibits prostaglandin synthesis in the hypothalamus via inhibition of cyclooxygenase (COX) 3. It has antipyretic and analgesic effects. The plasma concentrations required for antipyresis are 10–20 mg/litre. The concentrations required for analgesia have not been fully elucidated, but are at least as high as those required for antipyresis. Routes of administration: paracetamol is available for oral administration in syrup, tablet and dispersible forms. After oral administration maximum serum concentrations are reached in 30–60 minutes. Because the mechanism of action is central there is a further delay before maximum analgesia is achieved. Suppositories are available; however, there is wide variation in the bioavailability of paracetamol following rectal administration. Studies have demonstrated the need for higher loading doses (40 mg/kg) to achieve target plasma concentrations of 10 mg/l
Available preparations and routes of administration: NSAIDs are available in syrup, tablet, ‘melt’ (placed on tongue or can be swallowed), suppository and intravenous formulations (Table 3). Melt preparations are particularly useful in older children who are reluctant to swallow tablet preparations but also reluctant to swallow the relatively large volume of liquid necessary to deliver their dose.
Mary Rose, FRCA, is Consultant in Paediatric Anaesthesia and Pain Management at the Royal Hospital for Sick Children, Edinburgh. She qualified from the Royal Free Hospital, London. Her areas of interest are the management of acute, chronic and cancer related pain in children.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:5
Adverse effects of NSAIDs are listed below: • hypersensitivity reactions • reduced platelet aggregation and prolonged bleeding time 184
© 2007 Elsevier Ltd. All rights reserved.
Paediatrics
Paracetamol dosing guide: oral and rectal administration Age
Route
Loading dose (mg/kg)
Maintenance dose (mg/kg)
Interval (hours)
Maximum dose (mg/kg/24 hours)
Duration at maximum dose (hours)
28–32 weeks PA
Oral Rectal Oral Rectal Oral Rectal
20 20 20 30 20 40
10–15 15 10–15 20 15 20
8–12 12 6–8 8 4 6
30
48
60
48
90
72
32–52 weeks PA > 3 months
PA, postconceptual age
Table 1
• inhibition of prostaglandin-mediated renal function • gastric irritation and bleeding • exacerbation of asthma in a predisposed subgroup of patients with asthma (possibly the result of excess production of leukotrienes) • delayed bone healing in rats, mice and rabbits. Because of their effect on platelet aggregation NSAIDs are contraindicated in children with a coagulation defect. These drugs should be used with caution in children undergoing surgical procedures that are expected to involve considerable dissection of tissues. In particular, the use of ketorolac has been associated with a high incidence of bleeding. NSAIDs and tonsillectomy – there has been much debate about whether NSAIDs increase the risk of post-tonsillectomy haemorrhage. A Cochrane Review in 2005 concluded that the use of NSAIDs did not cause an increase in bleeding that required a return to theatre. There was significantly less nausea and vomiting when NSAIDs were used compared with alternative analgesics. Renal and gastrointestinal adverse effects – renal toxi city is low in healthy children, but NSAIDs should be avoided in patients with renal disease and dehydration. NSAIDs do not produce more gastrointestinal problems than placebo when used for 1–3 days for postoperative pain. Of the NSAIDs available, ibuprofen has the lowest incidence of adverse gastro intestinal effects and the most evidence to support its safe use in children. Therefore, ibuprofen should be the drug of choice when the oral route is available. Piroxicam and naproxen have a role in long-term use, where their reduced frequency of dosing may improve compliance. NSAIDs and asthma – the incidence of asthma in children is increasing and it is important that affected children are not
unnecessarily denied access to the benefits of NSAIDs. It is important to check that there were no problems with previous exposure to NSAIDs. A recent study showed no change in lung function in a group of 70 children with asthma given a single dose of diclofenac under controlled conditions.2 Therefore, most children with asthma can safely receive NSAIDs. About 2% of asthmatic children are susceptible to aspirininduced bronchospasm; 5% of this subgroup are cross-sensitive to other NSAIDs. When there is no history of previous exposure, NSAIDs should be avoided in children with severe/brittle asthma. These drugs should be used with caution in children with severe eczema, multiple allergies or those with nasal polyps. NSAIDs and bone healing – animal studies have shown impaired bone healing in the presence of NSAIDs. However, there is very little evidence to support the view that short-term use of NSAIDs in humans impairs bone healing. For children
Activity of COX-1, COX-2 and lipoxygenase Arachidonic acid
Lipoxygenase
COX-1
COX-2
Leukotrienes
Prostaglandins (homeostatic) • Mucosal protection • Platelet aggregation • Renal blood flow
Prostaglandins (inflammatory)
Intravenous paracetamol dosing guide Body weight (kg)
Dose
Interval (hours)
Maximum dose
10–50
15 mg/kg
4–6
> 50
1g
4–6
60 mg/kg/ 24 hours 4 g/24 hours
Non-steroidal anti-inflammatory drugs inhibit cyclooxygenase activity (COX-1 and COX-2)
Table 2
ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:5
Figure 1
185
© 2007 Elsevier Ltd. All rights reserved.
Paediatrics
Tramadol is a weak mu opioid receptor agonist. It also has a stimulating effect on the descending inhibitory (gammaaminobutyric acid (GABA)ergic, noradrenergic and serotonergic) pain pathways in the spinal cord. The dose in children is 1–2 mg/kg three times a day. Tramadol does not cause respiratory depression but is associated with a high incidence of nausea and vomiting.
NSAIDs: preparations and routes of administration NSAID
Dose (mg/kg)
Maximum daily dose (mg/kg/day)
Routes of administration
Ibuprofen Diclofenac
10.0 1.0
40.0 3.0
Ketorolac Naproxen Piroxicam
0.5 7.5 0.4
2.0 15.0 0.4
Oral, ‘melt’ Oral, rectal, intravenous Intravenous Oral Oral, ‘melt’
Morphine continues to be the opioid of choice for the management of severe pain in children. The most common routes of administration are oral and intravenous. Table 4 shows the dosing guidelines. Children as young as 5 years can use patient-controlled analgesia (PCA) (Figure 2). For younger children or those unable to operate a PCA, continuous morphine infusion or nurse-controlled analgesia can be used. Morphine has a long half-life, so therapeutic plasma concentrations and adequate analgesia may be delayed by several hours after starting an infusion or PCA. Hence, before commencing an infusion technique, morphine should be titrated to achieve an analgesic effect so that the infusion or PCA can then serve to maintain therapeutic plasma concentrations. Similarly, a child who has been asleep may need extra boluses on wakening to achieve previous analgesic levels. If respiratory depression occurs the infusion should be discontinued for a period of time. If respiratory depression is severe it should be treated with increments of 4 μg/kg of naloxone. Other means of analgesia may need to be considered if the child is still in pain. Adverse effects of morphine – the main adverse effect of morphine is respiratory depression. This condition is usually preceded by sedation. Other adverse effects include: • nausea and vomiting • pruritus • urinary retention • constipation. Children aged less than 2 years are less susceptible to the emetic effects of morphine, although they are still susceptible to pruritus. Adverse effects of morphine should be anticipated and treated. Anti-emetics commonly used in children are
NSAIDs, non-steroidal anti-inflammatory drugs
Table 3
undergoing most orthopaedic procedures the benefits of the perioperative use of NSAIDs outweigh the potential risks. However, for major orthopaedic procedures (e.g. spinal fusion, limblengthening procedures or where bone healing has previously been difficult) some consideration should be given to NSAID use on a case-by-case basis. Neonates: ibuprofen and indomethacin are used for closure of patent ductus arteriosus in neonates. Pharmacokinetic data have been established from this practice, which show a reduced clearance and an increased volume of distribution in neonates. Ibuprofen reduces the glomerular filtration rate in neonates by 20%. There are also concerns about the potential for NSAIDs to alter cerebral perfusion in neonates. Therefore, it is recommended that NSAIDs are not used in neonates. Ibuprofen is licensed for use in children aged more than 3 months. Opioids Codeine is a mild opioid used for moderate pain. The Oxford League Table of Analgesic Efficacy ranks drugs in order of their number needed to treat (NNT) to produce 50% pain relief for 4–6 hours in adult patients with moderate to severe pain. Codeine 60 mg has a NNT of 17 (placing it at the bottom of the table). However, the combination of paracetamol and codeine dramatically improves the NNT to 1.9. After absorption, codeine undergoes extensive metabol ism with 5–15% of a given dose undergoing O-demethylation with CYP2D6 to form morphine. CYP2D6 is a cytochrome P450 enzyme, and up to 47% of children aged less than 12 years lack the enzyme maturity to convert codeine to its active metabolite. Therefore, their analgesic response will be poor, although they will still experience mu receptor-mediated side effects, namely nausea and vomiting, constipation and itch. Codeine can be administered orally, rectally and by intramuscular injection. The intramuscular route should never be used in awake children. The dose is 1 mg/kg four times daily. The intravenous route is not recommended because of dangerous hypotension related to histamine release. Following rectal or intramuscular administration, peak plasma concentration is achieved within 30 minutes. However, the concentrations achieved following rectal administration are consistently lower than those of all other routes.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:5
Morphine dosing guidelines Route
Age
Oral
0–1 1–3 >3 0–1 1–3 >3 0–1 1–3 >3
Intravenous bolus Intravenous infusion
PCA NCA
Dose month months months month months months month months months
80 μg/kg, 4 hourly 100 μg/kg, 4 hourly 200–300 μg/kg, 2–4 hourly 25 μg/kg 50 μg/kg 100–200 μg/kg Up to 4 μg/kg/h Up to 10 μg/kg/h Up to 40 μg/kg/h
Bolus
Background
Lockout
20 μg/kg 20 μg/kg
4 μg/kg/h 20 μg/kg/h
5 min 30 min
PCA, patient-controlled analgesia; NCA, nurse-controlled analgesia
Table 4
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© 2007 Elsevier Ltd. All rights reserved.
Paediatrics
mature. Because of these factors neonates are more susceptible to the respiratory depressant effects. Nevertheless neonates can safely receive morphine provided the reduced doses (Table 4) are observed, the neonate is nursed in a high-dependency setting and the mandatory monitoring is observed. If pain is not controlled by these reduced doses, the dose may be increased in a setting where ventilation can be assisted if necessary. If given as a bolus to neonates, the morphine should be diluted to 1 mg/ml and administered in a 1 ml syringe. Other opioids: oxycodone, diamorphine, and fentanyl are alternatives to morphine. Oxycodone has a potency of two, relative to morphine. Oxycodone may have some effect in neuropathic pain. Subcutaneous diamorphine is useful in situations where high doses are required because the increased solubility of diamorphine allows relatively large doses to be dissolved in small volumes of diluent, which in turn allows the infusion to be run at less than 1 ml/hour. The ability to prepare diamorphine in low volumes of diluent also makes it suitable for intranasal administration. The intranasal administration of diamorphine provides effective analgesia for children presenting with fractures. Fentanyl is available as a transdermal preparation, which is useful in the management of long-term pain. The smallest fentanyl patch, which releases 12 μg/kg/hour of fentanyl, is equivalent to an oral dose of morphine of 45 mg in 24 hours. When a patch is initially applied it takes up to 24 hours for maximal plasma concentrations to be achieved. Patches are changed every 3 days. When a change in dose is made, it takes up to 24 hours for the plasma concentrations to change. Therefore, fentanyl patches are unsuitable for acute pain management.
Figure 2
ndansetron, cyclizine and dexamethasone. Pruritus can be o treated with chlorpheniramine. Second-line treatment for pruritus is low-dose naloxone 0.1–1.0 μg/kg/hour. Occasionally morphine-induced nausea and vomiting or pruritus may be sufficiently severe to necessitate an opioid switch. Suitable alternatives to morphine in this situation are fentanyl, oxycodone or hydromorphone. It is important to be aware of the equi-analgesic doses of these drugs when considering an opioid switch.3 Monitoring of patients receiving intravenous morphine – mandatory monitoring for children receiving intravenous morphine should include: • respiratory rate • sedation score • oxygen saturation on air • pain assessment (see page 180). If an infusion or PCA technique is used monitoring should include checks of the pump to ensure correct functioning. The rate of infusion of a continuous infusion should always be titrated to assessed pain. Measures should be taken to prevent gravity free-flow of the morphine infusion with an antisyphon valve. If the infusion or PCA is run concurrently with intravenous fluids an antireflux valve should also be incorporated into the giving sets. The nurseto-patient ratio should be one nurse to two patients, and the patient should be positioned where they can be readily observed. Patient-controlled analgesia in children – the PCA regimen in Table 4 has been shown to be the optimum regimen, balancing the improvement in pain scores seen with the addition of a background infusion with the increase incidence of adverse effects seen with high background infusions. Nevertheless the technique should be individualized to the patient. Where high levels of pain are anticipated following major surgery or in cancer-related pain different regimens may be required. Neonates – the clearance of opioids is diminished in neonates and reaches mature values during the first 2–6 months of life. The elimination half-life of morphine in preterm neonates is 9 hours. In term neonates the elimination half-life is 6.5 hours compared with 2 hours in infants in children.4 The active meta bolites of morphine are excreted by the kidneys, and can therefore accumulate in neonates because the renal function is not fully
ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:5
Clonidine is a α2 adrenoceptor agonist with analgesic, sedative and cardiovascular effects. It is used as an opioid-sparing agent and for the treatment of opioid withdrawal. The oral dose is 1–5 μg/kg, 8 hourly; the intravenous dose is 0.1–0.5 μg/kg/hour. Patients receiving clonidine are at risk of increased sedation and hypotension. When commencing clonidine therapy, regular blood-pressure monitoring is required. Ketamine is a potent analgesic that acts as an antagonist at the N-methyl-D-aspartic acid receptor. It is a useful adjunct to opioids in the management of severe postoperative pain and cancer-related pain. It also is effective in reducing neuropathic pain. The principal side effects of ketamine are hallucinations and dysphoria. However, these adverse effects are not seen at the low doses used for analgesia. A suitable dose for the oral administration of ketamine is 0.5 mg/kg, 8 hourly, although there is a wide variation in the doses reported in published materials. The optimum dose for children is not clearly defined. Intravenous ketamine is administered at 0.1–0.2 mg/kg/hour. Gabapentin has analgesic and opioid-sparing effects in acute postoperative pain management in adults.5 Whether or not this effect can be translated to children has yet to be clarified. ◆
references 1 Anderson BJ, Holford NH, Woollard GA, et al. Perioperative pharmacodynamics of acetaminophen analgesia in children. Anesthesiology 1999; 90: 411–21.
187
© 2007 Elsevier Ltd. All rights reserved.
Paediatrics
Further reading Anderson BJ, Palmer GM. Recent developments in the pharmacological man agement of pain in children. Curr Opin Anaesthesiol 2006; 19: 285–92. Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Acute pain management: scientific evidence, 2nd edn. Melbourne: Australian and New Zealand College of Anaesthetists, 1999. Lonnqvist PA, Morton NS. Postoperative analgesia in infants and children. Br J Anaesth 2005; 95: 59–68.
2 Short JA, Barr CA, Palmer CD, et al. Use of diclofenac in children with asthma. Anaesthesia 2000; 55: 334–7. 3 British National Formulary for Children, 2nd edn. London: BMJ Publishing Group, 2006. 4 Berde CB, Sethna NF. Analgesics for the treatment of pain in children. New Engl J Med 2002; 347: 1094–103. 5 Ho KY, Gan TJ, Habib AS. Gabapentin and postoperative pain: a systemic review of randomized controlled trials. Pain 2006; 126: 91–101.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:5
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Systemic analgesics for children
after rectal administration.1 The time to reach maximum serum concentration following rectal administration varies between 1 and 2.5 hours. Rectal administration of drugs is contraindicated in neutropenic patients (risk of sepsis) and in those with ulcera tive or acute inflammatory conditions of the rectum or anus. An intravenous preparation of paracetamol has become available recently. Initial experience with intravenous paracetamol is that a high effect-site concentration after intravenous administration is associated with high analgesic potency. When administered intravenously, paracetamol should be given as an infusion over 15 minutes.
Mary Rose
Abstract
Neonates: the clearance of paracetamol in neonates is reduced and the volume of distribution is increased. The dose of para cetamol therefore needs to be reduced in neonates (Table 1). Bioavailability following rectal administration is higher in neonates compared with infants and children.
Pain in children can be treated safely and effectively by using combinations of simple analgesics (paracetamol and non-steroidal anti-inflammatory drugs) and opiates, the choice of analgesic being determined by the severity of the child’s pain. Safe clinical practice requires an understanding of the age-related changes in the pharmacokinetics and pharmacodynamics of analgesics in neonates, infants and children. Pain should be regularly assessed, and where appropriate local anaesthetic techniques and nonpharmacological techniques should be used in combination with systemic analgesics. Analgesia for children should be administered, assessed and/or supervised only by individuals with adequate training and experience. This article covers a spectrum of systemic analgesics, from simple to complex, used for the treatment of acute pain in children.
Dosing: there are several dosage regimens for paracetamol, indicating that the optimum regimen is still to be determined. The regimen depends on the age of the child, the route of administration and the duration of treatment. The current recommendations in the BNF for Children are shown in Tables 1 and 2. Adverse effects and toxicity: when the maximum daily dose of paracetamol is observed it is well tolerated. The maximum daily dose is limited by the potential for hepatotoxicity, which can occur when the daily dose exceeds 150 mg/kg. Multiple doses may accumulate in children who are malnourished or dehydrated.
Keywords analgesia; morphine; non-steroidal anti-inflammatory drugs; paediatrics; paracetamol
NSAIDs NSAIDs are effective for the treatment of mild or moderate pain in children. In addition to their analgesic effect they have antiinflammatory and antipyretic effects. They also have an opioidsparing effect. The combination of NSAIDs and paracetamol produces better analgesia than either drug alone. Their mechanism of action is the inhibition of COX activity, thereby blocking the synthesis of prostaglandins and thromboxane (Figure 1). Aspirin is not used in children because of the risk of Reye’s syndrome. Selective COX-2 inhibitors have been developed with the expectation that the analgesic and anti-inflammatory effects of NSAIDs would be retained whilst reducing the risk of gastric irritation and bleeding. However, in adult studies potential improvements in safety have been offset by an increase in the incidence of adverse cerebral and cardiac thrombotic events. Reports of the use of selective COX-2 inhibitors in children demonstrate equal efficacy with non-selective NSAIDs. However, the role of selective COX-2 inhibitors in paediatric practice is yet to be established.
Paracetamol Paracetamol is a mild analgesic. On its own it can be used to treat mild pain in combination with non-steroidal anti-inflammatory drugs (NSAIDs); with a weak opioid such as codeine it can be used to treat moderate pain. Studies have demonstrated an opioid-sparing effect when it is administered postoperatively. Paracetamol inhibits prostaglandin synthesis in the hypothalamus via inhibition of cyclooxygenase (COX) 3. It has antipyretic and analgesic effects. The plasma concentrations required for antipyresis are 10–20 mg/litre. The concentrations required for analgesia have not been fully elucidated, but are at least as high as those required for antipyresis. Routes of administration: paracetamol is available for oral administration in syrup, tablet and dispersible forms. After oral administration maximum serum concentrations are reached in 30–60 minutes. Because the mechanism of action is central there is a further delay before maximum analgesia is achieved. Suppositories are available; however, there is wide variation in the bioavailability of paracetamol following rectal administration. Studies have demonstrated the need for higher loading doses (40 mg/kg) to achieve target plasma concentrations of 10 mg/l
Available preparations and routes of administration: NSAIDs are available in syrup, tablet, ‘melt’ (placed on tongue or can be swallowed), suppository and intravenous formulations (Table 3). Melt preparations are particularly useful in older children who are reluctant to swallow tablet preparations but also reluctant to swallow the relatively large volume of liquid necessary to deliver their dose.
Mary Rose, FRCA, is Consultant in Paediatric Anaesthesia and Pain Management at the Royal Hospital for Sick Children, Edinburgh. She qualified from the Royal Free Hospital, London. Her areas of interest are the management of acute, chronic and cancer related pain in children.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:5
Adverse effects of NSAIDs are listed below: • hypersensitivity reactions • reduced platelet aggregation and prolonged bleeding time 184
© 2007 Elsevier Ltd. All rights reserved.
Paediatrics
Paracetamol dosing guide: oral and rectal administration Age
Route
Loading dose (mg/kg)
Maintenance dose (mg/kg)
Interval (hours)
Maximum dose (mg/kg/24 hours)
Duration at maximum dose (hours)
28–32 weeks PA
Oral Rectal Oral Rectal Oral Rectal
20 20 20 30 20 40
10–15 15 10–15 20 15 20
8–12 12 6–8 8 4 6
30
48
60
48
90
72
32–52 weeks PA > 3 months
PA, postconceptual age
Table 1
• inhibition of prostaglandin-mediated renal function • gastric irritation and bleeding • exacerbation of asthma in a predisposed subgroup of patients with asthma (possibly the result of excess production of leukotrienes) • delayed bone healing in rats, mice and rabbits. Because of their effect on platelet aggregation NSAIDs are contraindicated in children with a coagulation defect. These drugs should be used with caution in children undergoing surgical procedures that are expected to involve considerable dissection of tissues. In particular, the use of ketorolac has been associated with a high incidence of bleeding. NSAIDs and tonsillectomy – there has been much debate about whether NSAIDs increase the risk of post-tonsillectomy haemorrhage. A Cochrane Review in 2005 concluded that the use of NSAIDs did not cause an increase in bleeding that required a return to theatre. There was significantly less nausea and vomiting when NSAIDs were used compared with alternative analgesics. Renal and gastrointestinal adverse effects – renal toxi city is low in healthy children, but NSAIDs should be avoided in patients with renal disease and dehydration. NSAIDs do not produce more gastrointestinal problems than placebo when used for 1–3 days for postoperative pain. Of the NSAIDs available, ibuprofen has the lowest incidence of adverse gastro intestinal effects and the most evidence to support its safe use in children. Therefore, ibuprofen should be the drug of choice when the oral route is available. Piroxicam and naproxen have a role in long-term use, where their reduced frequency of dosing may improve compliance. NSAIDs and asthma – the incidence of asthma in children is increasing and it is important that affected children are not
unnecessarily denied access to the benefits of NSAIDs. It is important to check that there were no problems with previous exposure to NSAIDs. A recent study showed no change in lung function in a group of 70 children with asthma given a single dose of diclofenac under controlled conditions.2 Therefore, most children with asthma can safely receive NSAIDs. About 2% of asthmatic children are susceptible to aspirininduced bronchospasm; 5% of this subgroup are cross-sensitive to other NSAIDs. When there is no history of previous exposure, NSAIDs should be avoided in children with severe/brittle asthma. These drugs should be used with caution in children with severe eczema, multiple allergies or those with nasal polyps. NSAIDs and bone healing – animal studies have shown impaired bone healing in the presence of NSAIDs. However, there is very little evidence to support the view that short-term use of NSAIDs in humans impairs bone healing. For children
Activity of COX-1, COX-2 and lipoxygenase Arachidonic acid
Lipoxygenase
COX-1
COX-2
Leukotrienes
Prostaglandins (homeostatic) • Mucosal protection • Platelet aggregation • Renal blood flow
Prostaglandins (inflammatory)
Intravenous paracetamol dosing guide Body weight (kg)
Dose
Interval (hours)
Maximum dose
10–50
15 mg/kg
4–6
> 50
1g
4–6
60 mg/kg/ 24 hours 4 g/24 hours
Non-steroidal anti-inflammatory drugs inhibit cyclooxygenase activity (COX-1 and COX-2)
Table 2
ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:5
Figure 1
185
© 2007 Elsevier Ltd. All rights reserved.
Paediatrics
Tramadol is a weak mu opioid receptor agonist. It also has a stimulating effect on the descending inhibitory (gammaaminobutyric acid (GABA)ergic, noradrenergic and serotonergic) pain pathways in the spinal cord. The dose in children is 1–2 mg/kg three times a day. Tramadol does not cause respiratory depression but is associated with a high incidence of nausea and vomiting.
NSAIDs: preparations and routes of administration NSAID
Dose (mg/kg)
Maximum daily dose (mg/kg/day)
Routes of administration
Ibuprofen Diclofenac
10.0 1.0
40.0 3.0
Ketorolac Naproxen Piroxicam
0.5 7.5 0.4
2.0 15.0 0.4
Oral, ‘melt’ Oral, rectal, intravenous Intravenous Oral Oral, ‘melt’
Morphine continues to be the opioid of choice for the management of severe pain in children. The most common routes of administration are oral and intravenous. Table 4 shows the dosing guidelines. Children as young as 5 years can use patient-controlled analgesia (PCA) (Figure 2). For younger children or those unable to operate a PCA, continuous morphine infusion or nurse-controlled analgesia can be used. Morphine has a long half-life, so therapeutic plasma concentrations and adequate analgesia may be delayed by several hours after starting an infusion or PCA. Hence, before commencing an infusion technique, morphine should be titrated to achieve an analgesic effect so that the infusion or PCA can then serve to maintain therapeutic plasma concentrations. Similarly, a child who has been asleep may need extra boluses on wakening to achieve previous analgesic levels. If respiratory depression occurs the infusion should be discontinued for a period of time. If respiratory depression is severe it should be treated with increments of 4 μg/kg of naloxone. Other means of analgesia may need to be considered if the child is still in pain. Adverse effects of morphine – the main adverse effect of morphine is respiratory depression. This condition is usually preceded by sedation. Other adverse effects include: • nausea and vomiting • pruritus • urinary retention • constipation. Children aged less than 2 years are less susceptible to the emetic effects of morphine, although they are still susceptible to pruritus. Adverse effects of morphine should be anticipated and treated. Anti-emetics commonly used in children are
NSAIDs, non-steroidal anti-inflammatory drugs
Table 3
undergoing most orthopaedic procedures the benefits of the perioperative use of NSAIDs outweigh the potential risks. However, for major orthopaedic procedures (e.g. spinal fusion, limblengthening procedures or where bone healing has previously been difficult) some consideration should be given to NSAID use on a case-by-case basis. Neonates: ibuprofen and indomethacin are used for closure of patent ductus arteriosus in neonates. Pharmacokinetic data have been established from this practice, which show a reduced clearance and an increased volume of distribution in neonates. Ibuprofen reduces the glomerular filtration rate in neonates by 20%. There are also concerns about the potential for NSAIDs to alter cerebral perfusion in neonates. Therefore, it is recommended that NSAIDs are not used in neonates. Ibuprofen is licensed for use in children aged more than 3 months. Opioids Codeine is a mild opioid used for moderate pain. The Oxford League Table of Analgesic Efficacy ranks drugs in order of their number needed to treat (NNT) to produce 50% pain relief for 4–6 hours in adult patients with moderate to severe pain. Codeine 60 mg has a NNT of 17 (placing it at the bottom of the table). However, the combination of paracetamol and codeine dramatically improves the NNT to 1.9. After absorption, codeine undergoes extensive metabol ism with 5–15% of a given dose undergoing O-demethylation with CYP2D6 to form morphine. CYP2D6 is a cytochrome P450 enzyme, and up to 47% of children aged less than 12 years lack the enzyme maturity to convert codeine to its active metabolite. Therefore, their analgesic response will be poor, although they will still experience mu receptor-mediated side effects, namely nausea and vomiting, constipation and itch. Codeine can be administered orally, rectally and by intramuscular injection. The intramuscular route should never be used in awake children. The dose is 1 mg/kg four times daily. The intravenous route is not recommended because of dangerous hypotension related to histamine release. Following rectal or intramuscular administration, peak plasma concentration is achieved within 30 minutes. However, the concentrations achieved following rectal administration are consistently lower than those of all other routes.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:5
Morphine dosing guidelines Route
Age
Oral
0–1 1–3 >3 0–1 1–3 >3 0–1 1–3 >3
Intravenous bolus Intravenous infusion
PCA NCA
Dose month months months month months months month months months
80 μg/kg, 4 hourly 100 μg/kg, 4 hourly 200–300 μg/kg, 2–4 hourly 25 μg/kg 50 μg/kg 100–200 μg/kg Up to 4 μg/kg/h Up to 10 μg/kg/h Up to 40 μg/kg/h
Bolus
Background
Lockout
20 μg/kg 20 μg/kg
4 μg/kg/h 20 μg/kg/h
5 min 30 min
PCA, patient-controlled analgesia; NCA, nurse-controlled analgesia
Table 4
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mature. Because of these factors neonates are more susceptible to the respiratory depressant effects. Nevertheless neonates can safely receive morphine provided the reduced doses (Table 4) are observed, the neonate is nursed in a high-dependency setting and the mandatory monitoring is observed. If pain is not controlled by these reduced doses, the dose may be increased in a setting where ventilation can be assisted if necessary. If given as a bolus to neonates, the morphine should be diluted to 1 mg/ml and administered in a 1 ml syringe. Other opioids: oxycodone, diamorphine, and fentanyl are alternatives to morphine. Oxycodone has a potency of two, relative to morphine. Oxycodone may have some effect in neuropathic pain. Subcutaneous diamorphine is useful in situations where high doses are required because the increased solubility of diamorphine allows relatively large doses to be dissolved in small volumes of diluent, which in turn allows the infusion to be run at less than 1 ml/hour. The ability to prepare diamorphine in low volumes of diluent also makes it suitable for intranasal administration. The intranasal administration of diamorphine provides effective analgesia for children presenting with fractures. Fentanyl is available as a transdermal preparation, which is useful in the management of long-term pain. The smallest fentanyl patch, which releases 12 μg/kg/hour of fentanyl, is equivalent to an oral dose of morphine of 45 mg in 24 hours. When a patch is initially applied it takes up to 24 hours for maximal plasma concentrations to be achieved. Patches are changed every 3 days. When a change in dose is made, it takes up to 24 hours for the plasma concentrations to change. Therefore, fentanyl patches are unsuitable for acute pain management.
Figure 2
ndansetron, cyclizine and dexamethasone. Pruritus can be o treated with chlorpheniramine. Second-line treatment for pruritus is low-dose naloxone 0.1–1.0 μg/kg/hour. Occasionally morphine-induced nausea and vomiting or pruritus may be sufficiently severe to necessitate an opioid switch. Suitable alternatives to morphine in this situation are fentanyl, oxycodone or hydromorphone. It is important to be aware of the equi-analgesic doses of these drugs when considering an opioid switch.3 Monitoring of patients receiving intravenous morphine – mandatory monitoring for children receiving intravenous morphine should include: • respiratory rate • sedation score • oxygen saturation on air • pain assessment (see page 180). If an infusion or PCA technique is used monitoring should include checks of the pump to ensure correct functioning. The rate of infusion of a continuous infusion should always be titrated to assessed pain. Measures should be taken to prevent gravity free-flow of the morphine infusion with an antisyphon valve. If the infusion or PCA is run concurrently with intravenous fluids an antireflux valve should also be incorporated into the giving sets. The nurseto-patient ratio should be one nurse to two patients, and the patient should be positioned where they can be readily observed. Patient-controlled analgesia in children – the PCA regimen in Table 4 has been shown to be the optimum regimen, balancing the improvement in pain scores seen with the addition of a background infusion with the increase incidence of adverse effects seen with high background infusions. Nevertheless the technique should be individualized to the patient. Where high levels of pain are anticipated following major surgery or in cancer-related pain different regimens may be required. Neonates – the clearance of opioids is diminished in neonates and reaches mature values during the first 2–6 months of life. The elimination half-life of morphine in preterm neonates is 9 hours. In term neonates the elimination half-life is 6.5 hours compared with 2 hours in infants in children.4 The active meta bolites of morphine are excreted by the kidneys, and can therefore accumulate in neonates because the renal function is not fully
ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:5
Clonidine is a α2 adrenoceptor agonist with analgesic, sedative and cardiovascular effects. It is used as an opioid-sparing agent and for the treatment of opioid withdrawal. The oral dose is 1–5 μg/kg, 8 hourly; the intravenous dose is 0.1–0.5 μg/kg/hour. Patients receiving clonidine are at risk of increased sedation and hypotension. When commencing clonidine therapy, regular blood-pressure monitoring is required. Ketamine is a potent analgesic that acts as an antagonist at the N-methyl-D-aspartic acid receptor. It is a useful adjunct to opioids in the management of severe postoperative pain and cancer-related pain. It also is effective in reducing neuropathic pain. The principal side effects of ketamine are hallucinations and dysphoria. However, these adverse effects are not seen at the low doses used for analgesia. A suitable dose for the oral administration of ketamine is 0.5 mg/kg, 8 hourly, although there is a wide variation in the doses reported in published materials. The optimum dose for children is not clearly defined. Intravenous ketamine is administered at 0.1–0.2 mg/kg/hour. Gabapentin has analgesic and opioid-sparing effects in acute postoperative pain management in adults.5 Whether or not this effect can be translated to children has yet to be clarified. ◆
references 1 Anderson BJ, Holford NH, Woollard GA, et al. Perioperative pharmacodynamics of acetaminophen analgesia in children. Anesthesiology 1999; 90: 411–21.
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Further reading Anderson BJ, Palmer GM. Recent developments in the pharmacological man agement of pain in children. Curr Opin Anaesthesiol 2006; 19: 285–92. Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Acute pain management: scientific evidence, 2nd edn. Melbourne: Australian and New Zealand College of Anaesthetists, 1999. Lonnqvist PA, Morton NS. Postoperative analgesia in infants and children. Br J Anaesth 2005; 95: 59–68.
2 Short JA, Barr CA, Palmer CD, et al. Use of diclofenac in children with asthma. Anaesthesia 2000; 55: 334–7. 3 British National Formulary for Children, 2nd edn. London: BMJ Publishing Group, 2006. 4 Berde CB, Sethna NF. Analgesics for the treatment of pain in children. New Engl J Med 2002; 347: 1094–103. 5 Ho KY, Gan TJ, Habib AS. Gabapentin and postoperative pain: a systemic review of randomized controlled trials. Pain 2006; 126: 91–101.
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