Pediatric palliative care (PPC) is provided to children experiencing life-limiting diseases (LLD) or life-threatening diseases (LTD). Sixty to 90% of children with LLD/LTD undergoing PPC receive opioids at the end of life. Analgesia is often insufficient. Reasons include a lack of knowledge concerning opioid prescribing and adjustment of opioid dose to changing requirements. The choice of first-line opioid is based on scientific evidence, pain pathophysiology, and available administration modes. Doses are calculated on a body weight basis up to a maximum absolute starting dose.
Morphine remains the gold standard starting opioid in PPC. Long-term opioid choice and dose administration is determined by the pathology, analgesic effectiveness, and adverse effect profile. Slow-release oral morphine remains the dominant formulation for long-term use in PPC with hydromorphone slow-release preparations being the first rotation opioid when morphine shows severe adverse effects. The recently introduced fentanyl transdermal therapeutic system with a drug-release rate of 12.5 µg/hour matches the lower dose requirements of pediatric cancer pain control. Its use may be associated with less constipation compared with morphine use. Though oral transmucosal fentanyl citrate has reduced bioavailability (25%), it inherits potential for breakthrough pain management. However, the gold standard breakthrough opioid remains immediate-release morphine. Buprenorphine is of special clinical interest as a result of its different administration routes, long duration of action, and metabolism largely independent of renal function. Antihyperalgesic effects, induced through antagonism at the κ-receptor, may contribute to its effectiveness in neuropathic pain. Methadone also has a long elimination half-life (19 [SD 14] hours) and NMDA receptor activity although dose administration is complicated by highly variable morphine equianalgesic equivalence (1 : 2.5-20). Opioid rotation to methadone requires special protocols that take this into account. Strategies to minimize adverse effects of long-term opioid treatment include dose reduction, symptomatic therapy, opioid rotation, and administration route change. Patient- or nurse-controlled analgesia devices are useful when pain is rapidly changing, or in terminal care where analgesic requirements may escalate. In this article, we present detailed pediatric pharmacokinetic and pharmacodynamic data for opioids, their indications and contraindications, as well as dose-administration regimens that include practical strategies for opioid switching and dose reduction. Additionally, we discuss the problem of hyperalgesia and the use of adjuvant drugs to support opioid therapy.
Opioids are used increasingly for the management of pediatric palliative care (PPC); 60-90% of these children receive opioids at the end of life.[1'3] Pediatric management lags behind that of adults. Reports on chronic pain are generally from case series, and controlled trials are few in children. Almost all chronic pain interventions have been adapted from their use in adult chronic pain. Pediatric strategies are still evolving. This paper outlines current knowledge, practices, and guidelines used by the authors.
1 . Pediatric Palliative Care (PPC)
The following WHO definition of pediatric palliative care (PPC) was adopted by the International Meeting for Palliative Care in Children, Trento (IMPaCCT).[4'5] The principles apply to cancer and other pediatric chronic disorders.
*Palliative care for children is the active total care of the child's body, mind, and spirit, and also involves giving support to the patient's family.
*It begins when illness is diagnosed, and continues regardless of whether or not a child receives curative treatment directed at the disease.
* Health providers must evaluate and alleviate a child's physical, psychologic, and social distress.
* Effective palliative care requires a broad multidisciplinary approach that includes the family and makes use of available community resources. It can be successfully implemented even if resources are limited.
PPC can be provided in tertiary care facilities, in community health centers, or even in children's homes.
1 .2 Who Should Receive PPC?
Based on 'A Guide to the Development of Children's Palliative Care Services', edited by the Association for Children's Palliative Care and the Royal College of Paediatrics and Child Health, UK/61 all children with life-limiting disease (LLD) or life-threatening disease (LTD) are eligible for palliative care. Those children may be further categorized; details are presented elsewhere.161 Mortality from life-limiting and terminal illness is 1 .2/10 000 in the UK and 3.6/10000 in the Republic of Ireland; these rates are thought to be similar to those in other developed countries.171
2. Pain in PPC
Many children with LLD experience pain at their end of life.[1-3] More than 60-70% of parents feel their child received inadequate pain relief at the end of life.'891 Analgesia often is insufficient because physicians are insecure with opioid dose administration and fail to adjust the opioid dose fast enough to match changing requirements.'10-1 '1
2. 1 Core Principles of Pain Management
The hallmarks of pain management in PPC are summarized elsewhere.'51 The core principles for opioid therapy are:
* Severe and uncontrolled pain should be regarded as a medical emergency and requires timely active intervention.
* Information on pain must be elicited from all relevant sources on a regular basis. Pain-assessment tools should be used and include the FLACC scale (Face, Legs, Activity, Cry, Consolability), the Faces Pain Scale and the Paediatric Pain Profile.[12-13]
* The WHO 'analgesic ladder' approach (see figure 1 and section 3) should be used, recognizing that starting at level 2 or 3 instead of at level 1 may be appropriate. Although the use of nonopioids in individual children with LLD or LTD may be useful, there are no publications in support of regularly adding nonopioids to opioids in ppc.[4-14-15]
* Adequate doses of analgesics should be administered 'by the clock,' i.e. at regularly scheduled intervals. Additional doses should be given on an 'as needed basis' to treat breakthrough pain.
* A sufficient dose and an appropriate pharmacologic formulation (e.g. sustained-release preparation or continuous infusion) should be chosen to enable children and their families to sleep undisturbed throughout the night without waking with pain or to administer medication. The appropriate opioid dose is the dose that effectively relieves pain. Inappropriately invasive and painful routes of drug administration should be avoided whenever possible.
* Side effects of medication must be anticipated and treated proactively. Opioid pain therapy in children with LLD or LTD does not lead to addiction but may lead to physical tolerance. When dose reduction is appropriate, the dose should be reduced gradually in order to avoid physical symptoms of withdrawal.
* Never use opioids without considering nonpharmacologic therapies as well.[16-18l
2.2 Pain Causes in PPC
The cause of pain in PPC is influenced by the underlying condition. In children with cancer, pain may be cancer related (infiltration or compression of bone, soft tissue, or nerves, cerebral edema), cancer associated (paraneoplastic syndrome, acute herpetic neuralgia or postherpetic neuralgia, invasive infection, venous thrombosis, decubitus ulcer), or therapy associated (postoperative pain, minor painful intervention, side effects of radiation or chemotherapy, graft-versus-host disease). In children with noncancer LLD there are multiple pain causes. Often the underlying cause of pain such as gastroeosophageal reflux, gastritis, constipation, cystitis, muscle spasticity, hip subluxation, pathologic bone fractures, or shunt dysfunction can be diagnosed and treated. Only if causal treatment fails and pain is severe, should opioids be used. Unnecessary painful procedures should be avoided in all children with LLD or LTD. Procedural pain should be anticipated and managed proactively.
3. The WHO Recommendations
The WHO analgesic ladder advocates a three-step approach to analgesic use, illustrated in figure 1 and described in sections 3. 1-3.3. This ladder differentiates between nonopioids, weak or strong opioids, and adjuvants. The starting opioid dose is referenced to bodyweight and limited to a maximum upper dose (see table I for starting doses and table II for equianalgesic doses). However, initially more than ten times the starting dose may be necessary to control pain. Other WHO recommendations are that in children with LLD and chronic pain analgesics should be given 'by the clock' and 'by the appropriate route.' Routes of opioid administration are shown in table III. Compatibility data are regularly updated in formularies.'191
Adjuvant drugs are those that are not classic analgesics, but exhibit analgesic properties or relieve symptoms when administered concomitantly with pain treatment in specific circumstances. The mean number of comedications was 13.9 (SD 8.9) in a study by Drake et al. concerning pain during the last week of life in children. These investigators concluded that comedication plays a major role in PPC pain therapy. Important adjuvant drugs or therapies in PPC are as follows:
* neuropathic pain: anticonvulsants, antidepressants, corticosteroids, ketamine, regional anesthesia, topical lidocaine;
* malignant bone pain: radiation or radionuclide therapy, corticosteroids;
* noncancer bone pain (osteoporosis, osteogenesis imperfecta): bisphosphonates;'2 ' ]
* pancreatitis: ketamine, regional anesthesia;
* intracranial pressure, nerve compression: glucocorticosteroids;
* hepatic capsular distention: glucocorticosteroids;
* muscle spasm: benzodiazepines, baclofen.
3. 1 WHO Step 1 : Nonopioid Analgesic (± Adjuvant Drug)
Common nonopioid analgesics are paracetamol (acetaminophen), metamizol (dipyrone), Ibuprofen, and diclofenac. Selective cyclo-oxygenase (COX)-2 inhibitors such as celecoxib and etoricoxib are not currently established in pediatrics and it is seldom necessary to use these long term. The nonselective non-COX-inhibitors are generally well tolerated. The higher cost of the selective COX-2 inhibitors, their potential for adverse cardiovascular effects, and their lack of analgesic action outside of anti-inflammatory effects render the nonselective non-COX inhibitors preferred agents.
A Cochrane analysis found no evidence to support nonopioids for the treatment of tumor-related pain.1231 A retrospective analysis of data from pediatric oncology yielded similar results; children already receiving opioids gained no advantage from the addition of nonopioids, even if those drugs alone showed a positive effect.'15' These results emphasize the exceptional role of opioids for pain control in children with life-limiting conditions.
3.2 WHO Step 2: Weak Opioid (± Nonopioid Analgesic, ± Adjuvant Drug)
Whether weak opioids (such as tramadol and codeine) should be regularly used in children with LLD and pain and whether opioid therapy should be initiated with a very low dose of a strong opioid is still under debate. No clear benefit of highdose codeine over low-dose morphine has been reported in the literature. The existence of such benefits is unlikely because codeine is metabolized to morphine. Pharmacodynamic variability, pharmacokinetic influences (e.g. cytochrome P450 [CYP]2D6), and the ???-µ-opioid-receptor-mediated analgesic effects of tramadol result in a huge therapeutic dose window; its indication in severe visceral or neuropathic pain is questionable. Tramadol and codeine both exhibit an analgesic ceiling effect, i.e. a dose exceeding 10mg/kg/day may not significantly improve analgesia but nearly always exacerbates adverse effects.
3.2. 1 Tramadol
Tramadol is a u-agonist, inhibiting the reuptake of the neurotransmitters noradrenaline and serotonin. Both mechanisms are synergistic for tramadol-mediated analgesia.[24-29] The drug has been widely embraced for short-term postoperative analgesia but experience with long-term use of tramadol in children is limited to a case report'301 of two siblings with Ehlers-Danlos syndrome who received tramadol 50-1 50 mg/day for 30 months with reportedly good results. Tramadol may be preferable to other opioids in the management of pancreatitis because of its supposedly relaxant effect on the sphincter of Oddi.
Tramadol is hydrophilic and well absorbed in all parts of the gut. Tramadol shows a first-pass effect; bioavailability is 65% orally and 78% rectally. Bioavailability may increase with repeated oral administration, as a result of hepatic enzyme saturation.'321 After oral administration of the immediate release preparation, the peak analgesic effect is achieved after 2 hours, and the duration of action is 4-6 hours.
Tramadol is metabolized by CYP2D6 into the pharmacologically active metabolite O-desmethyl-tramadol (Ml metabolite) with only 15-30% unchanged renally excreted. Single nuclear polymorphisms for CYP2D6 result in four distinct groups of individuals; poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultra rapid metabolizers. Approximately 10% of Europeans are devoid of a functional active allele for CYP2D6'331 and are unable to metabolize tramadol (poor metabolizers). In contrast, 4-5% of Caucasians are ultra rapid metabolizers. Higher concentrations of the (+)M 1 metabolite and greater analgesic efficacy of tramadol are reported in extensive metabolizers, with reduced nausea, vomiting, and tiredness amongst poor metabolizers.'341 Tramadol-induced analgesia is reduced by 30% in adults who are poor metabolizers,'331 but pediatric literature is scant.'351 Analgesia mediated through neurotransmitters (noradrenaline or serotonin) is independent from CYP2D6 activity.
An elimination half-life (t^sub ½^) of 3.6 (SD 1.1) hours, a serum clearance of 5.6 (SD 2.7) mL/kg/minute, and a volume of distribution (Vd) of 4. 1 L/kg (SD 1 .2) have been reported in 5-year-old children given oral tramadol drops.'361 The (+)-enantiomer concentration was 14.2% (SD 4.9) greater than that of the (-)-enantiomer. The M 1 metabolites had a (-)-enantiomer concentration 92.3% (SD 75.1) greater than that of the (-t-)-enantiomer. The M1 t^sub ½^ was 5.8 (SD 1 .7) hours.'361 In children aged 1-12 years, similar data have been reported after intravenous administration.'371
The maturation of tramadol pharmacokinetics has been described using a two-compartment pharmacokinetic model. Clearance is reduced at birth, but undergoes rapid maturation. Clearance increased from 25 weeks postconception age (PA) [5.52 L/hour/ 70 kg] to reach 84% of the mature value (24 L/hour/70 kg) by 44 weeks PA (standardized to a 70-kg person using allometric 'quarter-power' models).'381 The central Vd decreased from 25 weeks PA (256 L/70 kg) to reach 120% of its mature value by 87 weeks PA.
The affinity of tramadol for opioid receptors is 6000 times weaker than that of morphine, but the active (+)-Ml metabolite has an affinity 200 times greater than that of tramadol,'341 likely mediating the attributed opioid effect of tramadol. Both the ureceptor effect and reduced serotonin uptake in descending spinal cord pathways may contribute to the emetic effect of tramadol. A serum tramadol concentration above 100 ng/mL is associated with satisfactory analgesia for postoperative pain in children.'361
Codeine (methylmorphine) is available both as the natural and semisynthetic drug. It is frequently used in combination with paracetamol or ibuprofen in children. Whilst the WHO recommend the use of codeine in PPC, there are no data to promote this drug in preference to other opioids.'41
Oral codeine is rapidly absorbed with approximately 50% of the dose undergoing first-pass metabolism. Glucuronidation is the major metabolic clearance pathway, but minor pathways are N-demethylation to norcodeine (10-20%) and O-demethylation (CYP2D6) to morphine (5-15%). Codeine is also excreted unchanged in the urine (5-1 5%).'391 N-demethylation in the perinatal period is comparable to that in adults, while the other metabolic pathways develop beyond the newborn period. Concomitant medications competing for the CYP2D6 enzyme pathway (e.g. amiodarone, cimetidine, celecoxib, hydroxycarbamide, metoclopramide) may reduce clearance.'39-401
An analgesic ceiling effect is apparent, with increased side effects resulting from codeine receptor occupancy but without any increased analgesic effect.'4'1
Peak plasma concentrations occur at 1 hour. The plasma elimination t^sub ½^ is 3-3.5 hours in adults after oral administration.'421 The longer t^sub ½^ in neonates (e.g. 4.5 hours) is the result of immature clearance while the shorter t^sub ½^ in infants (e.g. 2.6 hours)'431 is attributable to size factors.'381 Intramuscular absorption is faster and rectal administration is associated with slower and variable absorption. A Vd of 3.6L/kg and a clearance of 0.85 L/hour have been described in adults but there are few data detailing pediatric pharmacokinetic development changes.
Codeine is less potent than morphine (potency ratio 1:10), but has a high oral parenteral potency ratio (2 : 3); hepatic conversion to morphine (O-demethylation by CYP2D6) is necessary for the analgesic activity of codeine.'391 Around 10% of codeine is metabolized to morphine. The antitussive effect of codeine is not mediated via the opioid receptors.'441
Poor metabolizers (see section 3.2.1) have a poor analgesic effect,'39'451 yet still experience adverse effects, for example, sedation, pruritus, or nausea.'461 Gastrointestinal motility is affected only in extensive metabolizers, suggesting a morphinedependent mechanism of action for reduced motility.'471
3.2.3 Dlhydrocodelne, Tilidine, Dextropropoxyphene
The analgesics dihydrocodeine, tilidine, and dextropropoxiphene are seldom used in PPC; possibly because only oral preparations are available. Information on the use of combination therapy with tilidine and naloxone is confined to case reports of children with multiple severe disabilities experiencing bone or muscular pains.'481
3.3 WHO Step 3: Strong Opioid (± Nonopioid Analgesic. ± Adjuvant Drug)
Morphine is the most frequently used opioid in PPC and has a solid scientific database.'11-15'491 It can be administered through oral, rectal, intravenous, subcutaneous, peridural, or spinal routes. Important for PPC, it is available as slow- and immediate-release oral formulations. Morphine is cheap and widely available, and may be considered as the gold standard for opioid treatment in PPC.
Other strong opioids in PPC are hydromorphone (first-rotation opioid in children experiencing morphine-related side effects other than constipation), levomethadone/methadone (rotation opioid in patients with severe neuropathic pain under high-dose therapy with other opioids), buprenorphine (first choice in patients with severe renal failure and pain due to pancreatitis or as a transdermal therapeutic system [TTS] if the oral route is not possible or desired), and fentanyl (in stable pain situations as a TTS especially when oral opioids caused severe constipation, or as a fast-acting transmucosal system for breakthrough pain).
There are six publications concerning the use of slow-release morphine tablets in children; the studies involved 242 children (aged from 3 months to 19 years) of whom 215 had cancer.[50-55] In general, treatment was well tolerated and there were no severe side effects reported. The duration of administration was from 1 to 760 days with a mean duration of 7-14 days.[50,51,54] Tolerance or unexplained dose escalation were not reported. The median dosage varied between 1.4 and 2.1 mg/kg/day.'541 Children <7 years of age received the highest average morphine dosage (2.6 mg/kg/day, SD 2.8), while patients >12 years of age received the lowest dosage (1.4 mg/kg/day, SD l.l).'541 The maximum dosage administered was 84 mg/kg/day.
Future slow-release liquid preparations of morphine may enhance individual dose tailoring.[14-48]
The oral bioavailability of morphine is approximately 35% due to the first-pass effect. After oral administration of a morphine solution, the peak plasma concentration (C^sub max^) is reached within 30 minutes. The mean time to peak concentration (t^sub max^) is 1 hour with morphine tablets and 3 hours with sustained-release preparations. Intramuscular opioid administration is uncomfortable and not recommended.
Morphine is mainly metabolized by the hepatic enzyme uridine 5'-diphosphate glucuronosyl transferase-2B7 (UGT2B7) into morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G).[57,58] Metabolites are cleared renally and partly by biliary excretion. Some recirculation of morphine occurs as a result of gastrointestinal β-glucuronidase activity.'591 The fetal liver is capable of metabolizing morphine from 15 weeks' gestation.[60,61]
A concentration-response relationship for morphine in children has not been established. Target analgesic plasma concentrations are believed to be 15-20ng/mL after major surgery, but plasma concentrations in children receiving PPC are anticipated to be much higher.[62,63]
Morphine clearance matures with age reaching adult rates at 6-12 months. The increased clearance observed in children, when expressed per kilogram of bodyweight, is a size artifact and is not attributable to the increased liver size of this age group. M3G is the predominant metabolite of morphine in young children and total body morphine clearance is 80% that of 'adult' values (approximately 70 L/hour/70 kg) by 6 months. The Vd increases with a maturation half-life of 26 days from 83 L/70kg at birth to a mature value of 136 L/70 kg.'651 Elimination of the active metabolites M3G and M6G is reduced in patients with renal insufficiency, which may lead to metabolite accumulation and toxicity.'661 M3G may cause myoclonus,[58,67] and M6G-delayed respiratory depression.
Morphine pharmacokinetic parameters show large interindividual variability contributing to the range of morphine serum concentrations observed during constant infusion. Clinical circumstances, such as the type of surgery and concurrent illness,[63,69-71] contribute to this variability. Protein binding of morphine is low (from 20% in premature neonates[70,72] to 35% in adults) but has minimal impact on disposition changes with age.
M3G and M6G have pharmacologic activity. M6G has greater analgesic potency than morphine[75,76] and also has respiratory depressive effects.[77,78] M3G does not bind to opioid receptors but exhibits excitatory effects. It has been suggested that M3G antagonizes the analgesic effects of morphine and that M6G has antinociceptive and respiratory depressive effects[78,79] and contributes to the development of tolerance. M6G : morphine ratios increase with age (table IV). These ratio changes are attributed to the differential maturation of hepatic and renal clearances with age, but the clinical significance of these ratio changes remains unclear.
Hydromorphone, a semisynthetic ketone congener of morphine (dihydromorphinone), has 5-7.5 times the potency of morphine. Similar to morphine, hydromorphone is a μ-receptor agonist. Its affinity to κ- or δ-receptors is low. Hydromorphone can be administered by intravenous, subcutaneous, oral, peridural, or intraventricular routes. Highly concentrated solutions up to 100mg/mL can be prepared for intravenous and subcutaneous use, although subcutaneous administration of highly concentrated solutions may cause pain. Once- or twice-daily slow-release tablets or capsules are available. Some of these preparations may be administered through a feeding tube if necessary.
There are two pediatric case reports reporting slow-release hydromorphone to have similar analgesic success to that of morphine. In a small randomized study, hydromorphone worked as well as morphine in children with mucositis pain using a patient-controlled analgesia (PCA) pump. When children with morphine-associated side effects were switched to hydromorphone, very often these side effects resolved.
In adults, the bioavailability of oral hydromorphone is 50-60%. Hydromorphone is metabolized by the liver to the analgesically inactive hydromorphone-3-glucuronide (H3G) [>90%], dihydromorphone (<1%), or dihydroisomorphone (1%).[85-87] The onset and duration of action of the immediate- or slow-release preparations are in the same range as those of morphine.
C^sub max^ is reached after 1 hour with unretarded preparations and after 3-4 hours with slow-release preparations (adult data; see Lindena et al.'881 for a review). Slow-release hydromorphone administered to two 7-year-old children resulted in C^sub max^ values at 4-6 hours, and the hydromorphone : H3G ratio was 1 : 20-40,'831 proportions similar to those observed in adults.
A hydromorphone clearance of 51.7 (range: 28.6-98.2) mL/minute/kg is reported in children. The volume of distribution at steady state is 4 L/kg in adults but there are no pediatric data available.[81,83]
PCA with hydromorphone results in similar analgesia and side effects compared with morphine in children when administered for the management of mucositis pain after bone marrow transplantation. Plasma concentrations of around 4.7ng/mL (range: 1. 9-8.9 ng/mL) relieve mucositis in children.
3.3.3 Methadone/ Levomethadone
Methadone is a racemic mixture, containing in equal amounts the analgesic active L-isomer (levomethadone) and the poorly investigated R-isomer. The analgesic effect is mediated via the opioid μ-receptor and an antagonism at the NMDA receptor. Levomethadone referenced to dose has twice the analgesic effect of methadone.'891 The t^sub ½^ of both levomethadone and methadone have high between-subject variability. This is the reason why a switch to methadone/levomethadone is often done in an in-patient setting in children (see section 5).
Methadone has high oral bioavailability (80-90%)'901 and appears in plasma within 30 minutes after oral administration. The t^sub max^ is 4 hours, although the analgesic effect starts earlier (1-2 hours after administration). Protein binding is high in adults (85%). Methadone lacks active metabolites. Enzyme inducers such as carbamazepine, phenobarbital, phenytoin, or rifampicin increase the metabolism of methadone while amitriptyline or cimetidine reduce its metabolism.'19'911
The mean t^sub ½^ after a single application of methadone was 19 hours (SD 14 hours, range: 4-62 hours) in children (aged 1-18 years).[92,93] Adult data describe a clearance of 178 mL/minute, a volume of distribution at steady-state (Vd^sub ss^) of 410L, and a t^sub ½^ of 25 hours (SD 22 hours); there are few pediatrie pharmacokinetic data. Yang et al. have used an age-dependent physiologically-based pharmacokinetic model to study methadone metabolism and pharmacokinetics in children; these estimates require confirmation. Neonatal data report a slower t^sub ½^ of 44 hours (SD 22 hours) with a large range (3.8-62 hours).
There is not much experience with methadone use in children with LLD.[96-97] Adult experience suggests that methadone or levomethadone exhibit analgesia even if morphine, fentanyl, or hydromorphone have failed; this is attributable to effects at the NMDA receptor. Methadone is 2.5-20 times more analgesic than morphine. Consequently, it is difficult to define an equianalgesic dose for an individual patient. Methadone is not superior to morphine when used in adults as the first-line opioid. Data on pediatric equianalgesic doses to other opioids are missing. Sabatowski et al. achieved good analgesia using a morphine conversion ratio of 20 : 1 (morphine : methadone) when high morphine doses were used prior to opioid rotation.
Fentanyl, a pure μ-opioid-receptor agonist, is commonly used as either a transdermal preparation to manage chronic pain or as a transbuccal preparation for breakthrough pain (oral transmucosal fentanyl citrate [OTFC]).
Intranasal fentanyl can also be used to manage acute pain episodes and is as effective as intravenous morphine.'991 Intranasal fentanyl preparations for use in adult breakthrough pain are in the pipeline. Fentanyl patient-controlled iontophoretic transdermal systems are likely to have an increasing role in PPC.
Fentanyl Transdermal Therapeutic System (TTS)
The use of fentanyl TTS should be restricted to patients with a stable analgesia requirement. It should never be used at the start of pain therapy. Because of its slow absorption and long apparent t^sub ½^, the drug is unsuitable for rapid titration of dose to effect. It is not recommended for use in opioid-naive children because of the increased risk of respiratory depression. Details of opioid rotation to fentanyl TTS are given in section 5. The practice of cutting fentanyl matrix-based TTS patches with the intention of reducing the dose should be frowned upon because delivery characteristics may be altered.
Most studies have used a reservoir-based transdermal delivery system, exhibiting a proported minimal drug release rate of 25 µg/ hour. Refinements of delivery system technology by dispersing fentanyl-containing dipropylene glycol droplets in a silicon matrix system has resulted in a new fentanyl TTS that can deliver the lower drug release rate of 12.5 µg/hour, allowing children as young as 2 years to gain benefit from this preparation.
A total of 1 1 observational clinical or pharmacokinetic studies on pediatric fentanyl TTS have been conducted involving a total of 311 children aged from 3 months to 18 years. There are no pediatric randomized or controlled cohort studies.[102-112] Eight reports on the use of fentanyl TTS included children with cancer or other LLD.[105-111] The total duration of fentanyl TTS therapy ranged from 1 day to 15 months, with a median treatment duration of 21-58 days. Tolerance or opioidinduced hyperalgesia was not reported. A maximal dosage of 16.7 µg/kg/hour (1400 µg/hour) was used. Children <10 years of age need a higher dose per kilogram than children >10 years of age, an observation similar to that observed for morphine consumption and consistent with increased clearance in younger children when expressed per kilogram. In the study by Hunt et al. therapy in 15 of 41 children had to be stopped prematurely as a result of adverse events, inadequate analgesia, a change to parenteral opioids, or death attributable to disease progression. Both parents and medical professionals judged fentanyl TTS therapy as 'satisfactory' in all published studies.
Fentanyl is released at a constant rate from the adhesive patch into a skin depot. Release from the skin to the systemic circulation has been described using a first order rate constant. An observed pediatric mean time-concentration profile suggests that delivery to the skin does not occur at a constant rate over a 72-hour period and that delivery is reduced prematurely, possibly because of suboptimal patch-to-skin adhesion difficulties. The fentanyl TTS is best changed every 48 hours. Drug resorption per time unit is increased with fever. Excessive sweating may lead to patch detachment.
Fentanyl is metabolized by oxidative N-dealkylation (CYP3A4) into norfentanyl, and hydroxylized. Pharmacogenetic influences and concomitant drug influences (e.g. induction of CYP3A4 with alcohol; inhibition with fluconazole, omeprazole, Cimetidine) impact on clearance. In adults, the traditional reservoir-based and modern matrix-based fentanyl TTS proved bioequivalent.[115,116]
Pharmacokinetic data for fentanyl TTS are limited to C^sub max^, t^sub max^, t^sub ½^, and clearance estimates derived from calculation of the area under the plasma concentration-time curve. Children 7-16 years of age take longer to reach steady-state concentrations than adults.[102,105] In some patients, peak serum concentrations were not reached before 66 hours. Most pediatric pharmacokinetic data are derived from low-quality studies comprising only a small number of patients in each study (see reviews by Zernikow et al.). Fentanyl clearance reaches adult values (approximately 50 L/hour/70 kg) within the first 2 weeks of life. The Vd^sub ss^ for fentanyl is 5.9 L/kg in term neonates and decreases with age to 4.5 L/kg during infancy, 3.1 L/kg during childhood, and 1.6 L/kg in adults. There is high betweenindividual parameter variability in the pediatric population and, consequently, the time-concentration profile variability is also huge. Drug clearance in children is higher than in adults when referenced to bodyweight. After removing the patch, fentanyl plasma concentrations decrease slowly because the residual epidermal depot continues to release drug into the body.
Oral Transmucosal Fentanyl Citrate (OTFC) ('fentanyl lozenge')
Fentanyl citrate is rapidly absorbed through the oral mucosa because it is highly lipophilic. Patients are advised to rub the berry-tasting OTFC gently on the inside of the cheek for 15 minutes rather than to chew; absorption is best achieved by positioning the 'lozenge' in the buccal pouches. Attempts should be made to swallow as little of the resulting salivary juices as possible. The OTFC may be used in children from 2 years of age.
There are no studies on the use of OTFC for pediatric breakthrough pain. Only one case report is available, which describes effective therapy in a child with brain metastases and rapid-onset, short-lasting headache.'481
OTFC is effective in the treatment of breakthrough pain in adult oncology; although there seems to be no firm relation between the scheduled daily opioid dose and the required dose of OTFC.[119) Treatment is initiated using the smallest available (200 µg) OTFC.
Only 25% of a fentanyl dose is transmucosally absorbed. Two-thirds of the remaining swallowed fentanyl will undergo degradation as a result of the hepatic first-pass effect. In adults, fentanyl plasma concentration is proportional to the OFTC dose. Bioavailability in children is less than that in adults (33-36% vs 52%), and C^sub max^ is reached later (53 minutes).[121-123] These data suggest that children swallow a greater proportion of the substance during transmucosal fentanyl administration than adults; this contributes to the low incidence of overadministration in children.
OTFC 200 µg is about equivalent to morphine 2 mg given intravenously, or oral morphine 6 mg. The concomitant administration of two OTFC 400 µg each was found to be bioequivalent to the administration of one OTFC 800 µg.
There was no difference observed in postoperative pain control between transmucosal fentanyl and intravenous morphine (mean time to reach significant pain reduction: 4.2 minutes with transmucosal fentanyl 200 µg vs 5.4 minutes with intravenous morphine 2 mg); this is attributable to the slow effect site equilibration half-time (17 minutes) of morphine. The duration of drug-induced analgesia also did not differ between the drugs (145 minutes with transmucosal fentanyl vs 130 minutes with intravenous morphine).
Buprenorphine is a morphine derivative of the alkaloid thebaine, and a semisynthetic partial μ-agonist and κ- and δ-receptor antagonist.[126,127] It has been available worldwide for parenteral, sublingual, and epidural/caudal application for 25 years.[128-135] Buprenorphine use for heroin-addicted adults has increased the exposure to children through accidental ingestion.[136,137] A transdermal therapeutic system containing buprenorphine has been approved for use in adults and has been available in Germany since 200 1.[139-141] Current TTS delivery systems release buprenorphine at a rate of 35, 52.5, or 70 µg/hour over a 72-hour period or at a rate of 5, 10, or 20 µg/hour over a 7-day period. The smallest available buprenorphine TTS (5 µg/hour) is approximately equivalent to oral morphine 10 mg/day. The transdermal patch design is based on matrix technology, and the delivery rate is proportional to the application surface area. The lower dose delivery systems (5, 10, or 20 µg/hour) are more suitable for children. Buprenorphine TTS is not currently licensed for pediatric use.
A small retrospective study in children reported 12 of 13 pediatric oncology patients given sublingual buprenorphine 2.5-10 µg/kg every 12 hours (dose escalation) became free of pain while experiencing only minimal adverse effects. No patient required drug discontinuation. The optimal sublingual dosage proved to be 5 µg/kg every 12 hours. A case report has described the transdermal use of buprenorphine in PPC: a 10-year-old girl with neuroblastoma received 70 µg/hour for a period of 5 weeks with good analgesia and no severe side effects. Since buprenorphine appears to have minimal effect on the tone of the sphincter of Oddi, this drug may have an advantage in the treatment of pancreatitis-related pain.[31,143]
Buprenorphine undergoes extensive first-pass metabolism. The relative bioavailability of an oral formulation is only 10-16%. Attempts to bypass this first-pass effect have resulted in intranasal, sublingual, and buccal administration; appropriate formulations show relative bioavailabilities of 30-55%.[126,144] The t^sub max^ was 30-60 minutes after sublingual droplet application and 90-360 minutes after sublingual tablets. C^sub max^ values were reached within 30 minutes of intranasal administration in adults and the analgesic effect lasted 6-8 hours after sublingual administration.  The relative bioavailability of transdermal buprenorphine is 50%, and effective plasma drug concentrations are reached within 12-24 hours with a C^sub max^ of 0.3 µg/L achieved 60 hours after application of buprenorphine TTS 35 µg/hour for 72 hours in adults - pediatric data are not available. 
The metabolic pathways of buprenorphine are not fully understood. Buprenorphine is metabolized by N-dealkylation to the active metabolite norbuprenorphine. CYP3A4 accounts for about 65% of norbuprenorphine production, and CYP2C8 for about 30%. Glucuronidation (UGTB27) is a major elimination pathway for both buprenorphine and norbuprenorphine. Glucuronidated products can undergo biliary excretion followed by some enterohepatic recirculation. About 10-30% of the drug is eliminated via urine. The presence of mildly to moderately impaired liver function does not require any buprenorphine dose adjustment. There was no significant change of buprenorphine metabolism in patients experiencing renal failure, but metabolites excreted by the renal system (e.g. norbuprenorphine and buprenorphine-3-glucuronide) accumulate.
Buprenorphine is highly lipophilic and bound to a- and β-globulin plasma proteins (96%).  The pharmacokinetics of this agent have usually been described using two- or threecompartment models. In children, pharmacokinetic parameter estimates are poorly described. Clearance is reduced in premature neonates, consistent with immaturity of UGTB27. The only pediatric pharmacokinetic study available suggests that clearance (3.6 [SD 1.1] L/hour/kg) in children (aged 4-7 years) is three times higher than that in adults but values for Vd^sub ss^ are similar. This high clearance estimate, however, was estimated using truncated data and may be unreliable.
Antihyperalgesic effects are induced through antagonism at the κ-receptor. This action may contribute to the effectiveness of buprenorphine in patients with neuropathic pain that is poorly controlled with opioids that possess predominantly μ-receptor activity (e.g. morphine). Buprenorphine shows slow receptor association (30 minutes) but exhibits high affinity to multiple sites from which dissociation is slow and incomplete (50% binding after 1 hour).
Confusion exists because animal data suggest that the antinociceptive dose-response curve for buprenorphine is bell shaped. The agonist effect is reduced at high doses (1 mg/kg), but such a high single dose is unlikely to be used for pain treatment in PPC. The mechanism for the observed bellshaped response curve has not been elucidated. Non-competitive autoinhibition where μ- or κ-receptor mediated analgesia is potentiated by interaction of buprenorphine with the δ-receptor has been proposed as a possible contributor.
Clinical doubt exists about a ceiling dose (maximal effect) with buprenorphine.  The dose-effect response for ventilation has been described in healthy human volunteers using a sigmoid maximum effect (E^sub max^) equation. With increasing dose, minute ventilation decreased from 20 L/minute to a plateau of 9.1 L/minute. There was no decrease in minute ventilation at doses >3 µg/kg.
An understanding of concentration-response relationships is muddied by the active demethylated metabolite norbuprenorphine. Norbuprenorphine provides antinociceptive efficacy similar to buprenorphine with analgesic activity shown to be dose dependent in rodent models. In the rat, respiratory depression with norbuprenorphine is ten times more pronounced than with buprenorphine despite the greater polarity of norbuprenorphine reducing blood-brain barrier permeability.
Oxycodone (dihydrohydroxycodeinone) is a semisynthetic μ-agonist that has high bioavailability, a short duration of action, and a high analgesic potency (about double that of morphine). Oxycodone is well suited for postoperative analgesia. There are no data on the use of this agent in PPC. In many countries, oxycodone formulation was initially limited to an oral retarded drug preparation, but fast-acting buccal and intravenous preparations are now available.
Oxycodone is derived from the naturally occurring opioid, thebaine. The relative bioavailability of intranasal, oral, and rectal formulations is approximately 50% that of intravenous administration in adults.[159-161] Oxycodone is metabolized to noroxycodone and oxymorphone.
Mean values of drug clearance and Vd^sub ss^ were 15.2 (SD 4.2) mL/minute/kg and 2.1 (SD 0.8) L/kg, respectively, in children after ophthalmic surgery. Pharmacokinetic parameter estimates show large interindividual variability.[163,164] The median (range) values for clearance were 9.9 (2.3-17.2) mL/min/kg in neonates <1 week of age, 20.1 (3.7-40.4) mL/min/kg in infants 1 week to 2 months of age, and 15.4 (14.8-80.2) mL/min/kg in those aged 2-6 months. The values for volume of distribution at steady state were 3.3 (1.9-4.7) L/kg, 5.6 (1.3-8.5) L/kg, and 3.2 (1.8-6.0) L/kg, and for t^sub ½^ were 4.4 (2.4-14. 1) hours, 3.6 (1.6-11.6) hours, and 2.0 (0.8-3.9) hours, respectively.
There are few pediatrie pharmacodynamic data. Much of the analgesic effect of oxycodone is exerted by its metabolite oxymorphone, which has an analgesic potency similar to morphine.'148'1621
Pethidine use in PPC is not encouraged because of concern that the metabolite norpethidine may trigger seizure activity. The t^sub ½^ of norpethidine is 20-85 hours. Use in conjunction with a monoamine oxidase inhibitor (e.g. moclobemide or tranylcypromine) may cause hyperpyrexia, arterial hypo- or hypertension, delirium, or cerebral seizures.'1651
4. Prescribing Strong Opioids in Children
Strong opioid therapy in children comprises three steps: initiation of the therapy, dose titration, and maintenance.[4,166] The opioid dose often has to be escalated in the last week of life, although occasionally a dose reduction might be necessary.
In the event of oral morphine or intravenous morphine therapy being warranted, initiation of therapy as depicted in figures 2 and 3, respectively, is recommended. In children weighing <10kg or those with cerebral damage, the starting dose should be one-third of the nominal starting dose. Children >30 kg can be given the 30-kg child dose.
4.2 Dose Titration and Maintenance
Children with LLD or LTD, like adults, experience breakthrough pain.[15,167,168] Poor general status correlates with greater breakthrough pain episodes.'1681 These episodes may be alleviated by increasing the daily regular morphine dose by 25-30% if more than three daily rescue doses are needed. The breakthrough pain opioid dose should be adjusted regularly to an increasing basal opioid need.
4.3 Dose Reduction
Situations where opioid dose reductions are necessary are the following: (i) positive effects of an antineoplastic therapy (radiation, chemotherapy, operation); (ii) initiation of a regional anesthesia; (iii) administration of potent adjuvant drugs (glucocorticosteroids, ketamine); or (iv) severe renal failure with accumulation of the opioid and other drugs. Failure to reduce an opioid dose might lead to severe toxicity. If opioid therapy lasts for no more than 5 days, the opioid dose should be tapered over a period of 3-4 days. With longer duration opioid therapy, the dose should be reduced by 20-40% over 24 hours.
Subsequent reductions of 5-10% or 10-20% per day are then made until symptoms of drug withdrawal are observed when dose reduction should be suspended. Withdrawal symptoms are best treated with extra opioid doses and not with benzodiazepines. Sometimes the concomitant administration of clonidine facilitates opioid dose reduction; the daily adult oral clonidine dose is 75-1 50 µg divided into two to three single doses. In children, there are data on preoperative Clonidine use: a 4 µg/kg dose orally reduced postoperative agitation.'1691 Opioid weaning may take several weeks.
5. Opioid Rotation
When it is intended to switch opioids, the new opioid should be started at half its equianalgesic dose because of incomplete cross tolerance. An order for adequate on-demand medication should be written. Equianalgesic doses are given in table II.
The main reasons for opioid rotation are the following:
* Weak opioids no longer effective at the ceiling dose (change from tramadol, tilidine, or codeine to morphine).
* Side effects other than constipation or hyperexcitability in patients with controlled pain (change from morphine to hydromorphone).
* Side effects (constipation) in patients with controlled pain (change from morphine to transdermal fentanyl or buprenorphine or sublingual buprenorphine).
* Side effects (hyperexcitability) in patients with controlled pain (change from morphine to buprenorphine, methadone).
* Uncontrolled pain (change from morphine to methadone).
* Inconvenience or noncompliance with oral opioid therapy (change from morphine to transdermal fentanyl).
There are several protocols for opioid rotation to methadone/ levomethadone'170'1741 that use two fundamentally different approaches, which are not evidence based in pediatrics. In one approach, previous opioid therapy is completely stopped and restarted with a fixed dose of methadone at variable dose intervals.'170'1731 In adults, the daily oral methadone dose rarely exceeds 180 mg independent of the former opioid dose.'1731 The other approach incorporates a transition period where the dose of the former opioid is reduced and partially replaced by methadone. Two common switch protocols are reported by Nauck et al.'1731 and Ripamonti et al.'1741 (see also the supplementary material ['ArticlePlus'] at http://pediatricdrugs.adisonline.com). There are two common adult protocols that have been adapted for children. These protocols are commonly used despite a lack of clinical trials to support them. This figure shows regimens commonly used in Germany.
An adult protocol for the switch from transdermal fentanyl to methadone has been published.'1751 The equivalence dose for every 25 µg/hour transdermal fentanyl patch was oral methadone 1 2 mg/ day or intravenous methadone 9.6 mg/day. The total daily dose was divided into three single doses to be administered every 8 hours. The first methadone dose is administered at the time the fentanyl patch is removed. The breakthrough methadone dose is one-sixteenth of the daily basic methadone dose. The pain score (visual analogue scale, 0-10) decreased significantly from 5.9 to 1.8 and there were fewer adverse effects with methadone. The median oral methadone dosage was 84 mg/day (range: 52-115).
As soon as children are managed with a regularly scheduled daily oral morphine or morphine equivalent dosage of >30 mg/ day, they may be switched to the smallest available fentanyl TTS (12.5 µg/hour). When higher opioid doses are administered before switching to fentanyl TTS, the initial fentanyl TTS dose has to be adjusted (see online supplementary material).'191 This recommended dose equivalence is highly conservative and does not lead to fentanyl overdosage or related adverse effects such as respiratory depression. Quite often there is the need to increase the fentanyl dose, emphasizing the need to supplement fentanyl therapy during the phase of drug adjustment (about the first 15 days of receiving fentanyl TTS) with sufficient amounts of other opioids in order to avoid undertreatment or the development of opioid withdrawal. The breakthrough pain bolus opioid dose is about one-sixth of the daily opioid dose and has to be regularly adapted to an increasing basal opioid need. A decrease in the frequency of adverse effects, particularly constipation, has been noted after switching from enteral morphine to fentanyl TTS.[108,109]
6. Opioid Doses at the End of Life
Individual dose requirements at the end of life are highly variable.[3,136] Drake et al. looked at symptoms and therapy in 30 children who died in hospital. At the end of their lives 83% of them were receiving opioids, mostly via the intravenous route, but only 44% received their medication on a regular basis as well as on demand. The mean intravenous morphine equivalent dose (MED) in the last week of life was 1.88 mg/kg/day (range: 0.25-24.5 mg/kg/day). Drake et al. observed an increase in intravenous MED by about 30% during the last week of life. Siden and Nalewajek reported that 42 of 44 children in his hospice received opioids. The median intravenous MED was 2.04 mg/kg/day (range: 0.024-1 773.6 mg/kg/day). The maximal opioid dose was reached most often on the day prior to death. Sirkiä et alJ1 1] included 70 dying pediatric cancer patients in their study, 40 of whom had been receiving opioids, mostly by continuous intravenous infusion. The authors reported an increase in parenteral mean MED from 0.8 mg/kg/day at initiation of opioid therapy to a final MED of 4.9 mg/kg/day (range: 0.2-55). In two studies, Miser et al.[177,178] reported a median subcutaneous or intravenous MED of 0.96 or 1.68 mg/kg/day, respectively. The highest parenteral MED in the treatment of dying pediatric cancer patients has been reported by Collins et al. They administered a maximum intravenous MED of 1 1 832 mg/kg/day to an infant with a localized metastasis to the mid-brain periaqueductal gray. Studies reporting pediatric end-of-life opioid therapy are consistent in showing highly fluctuating opioid need that increases in the last days of life.
7. Opioid Tolerance and Hyperalgesia
Animal and adult studies suggest that opioids may increase rather than decrease sensitivity to noxious stimuli in certain circumstances.[150,180,181] Analgesic tolerance is characterized by a decreasing analgesic effect during long-term opioid use, necessitating a dose increase. A dose increase typically leads to adequate pain control.
Pain can also increase above the pre-existing level of hyperalgesia with further dose escalation leading to even more pain and to allodynia. Dose reduction or opioid rotation typically results in decreasing pain level.  This pain hypersensitivity has been attributed to a relative predominance of pronociceptive mechanisms. Acute receptor desensitization via uncoupling of the receptor from G-proteins, upregulation of the cyclic adenosine monophosphate pathway, activation of the NMDAreceptor system, release of peptides with opioid-antagonistic properties (antiopioids), as well as descending facilitation all have been proposed as potential mechanisms. Other pronociceptive properties depend on the metabolites of individual opioids. During long-term morphine therapy, M3G may accumulate, cross the blood-brain barrier, and inhibit morphine and M6G. One case report has proposed the latter mechanism in a child'1821 although this has been questioned J1831 Studies on alternative mechanisms of opioid-induced hyperalgesia and their clinical significance in children are lacking. Successful strategies that may decrease or prevent opioid-induced hyperalgesia include the concomitant administration of drugs such as NMDA antagonists, ot2-agonists, or NSAIDs, opioid rotation, or the combination of opioids with different receptor selectivity. 
8. Adverse Effects of Opioid Analgesia
The adverse effects profile of the strong opioids may differ widely within individuals. The frequency of adverse effects experienced with sustained-release morphine in children is shown in figure 4. The general profile and extent of adverse effects are shown in table V. There are four strategies to minimize the adverse effects of opioid therapy:[14,184-186] (i) dose reduction in a stable pain situation; (ii) symptomatic therapy; (iii) opioid rotation; and (iv) change of the administration route. The majority (90%) of opioid adverse effects (predominantly pruritus with morphine) in children have been shown to be successfully eliminated by opioid rotation.
8.1 General Side Effects
Constipation is the most frequent and clinically most significant adverse effect of opioid therapy.[54,86] Laxatives should be given prophylactically with initiation of opioid therapy. Manifest constipation should be treated initially with a rectal laxative, then with oral laxatives on a regular basis.
8.1.2 Nausea and Vomiting
It is appropriate to start antiemetics prophylactically with initiation of opioid therapy in children >12 years of age. Children <12 years of age may also benefit from this strategy although antiemetics are usually started reactively in younger children. Typically, children develop tolerance to the emetic effect of opioids quickly. During the first week of opioid treatment some patients will benefit from dimenhydrinate chewinggum (10 mg, 20 mg). It is common to administer 5-HT^sub 3^ receptor antagonists (ondansetron, tropisetron ) as prophylactic agents although data supporting the effectiveness of this practice are lacking. Low-dose naloxone infusion has also been used to reduce opioid-induced adverse effects.'1871 Alternative antiemetics are dopamine D^sub 2^ antagonists (domperidone) and histamine H^sub 1^ receptor antagonists (cyclizine, levomepromazine).
Pruritus is the most frequent side effect of opioid therapy in children with cancer, affecting more than 25% of patients.[54,186] It is also the main reason for opioid rotation in children.'84' As long as the pain situation is stable, one should try some dose reduction. Alternatively, one could try an antihistamine comedication. However, if these measures are unsuccessful, opioid rotation is indicated.'84' In children and adolescents with postoperative pain, intravenous naloxone (0.00025 mg/kg/hour [0.25 µg/kg/hour] constant infusion) reduced the opioid-associated side effects pruritus and nausea.'1871 Other authors have reported conflicting data in pediatric or adult intensive care.'188190' Administration of naloxone and morphine sulfate concomitantly (same syringe, same intravenous line) has been used. Because it is still debatable if 5-HT^sub 3^-receptor antagonists such as ondansetron, tropisetron, or granisetron indeed reduce opioid-related pruritus, an individual trial is warranted.
8.1.4 Urinary Retention
In children, especially in the newborn, urinary retention is a common adverse effect of opioid therapy. However, if present, it may cause panic in children. Often, urinary retention may be resolved by calming measures, the local application of a wet towel, or the sound of a running water tap. If unsuccessful, cholinomimetics such as distigmine bromide are indicated. The last resort is intermittent urinary catheterization.
8.1.5 Respiratory Depression
Provided the dose is adequate, slow-release opioids should not induce significant respiratory depression. Respiratory depression is seen, however, if an intravenous opioid is rapidly administered for painful procedures or with centrally active comedication such as benzodiazepines. During the initiation phase of parenteral opioid therapy, peripheral oxygen saturation of hemoglobin monitoring and regular assessment of the grade of sedation is mandatory. Severe respiratory depression should be antagonized with naloxone. The effective t^sub ½^ of naloxone is less than that of many of the opioids. A high-dose constant intravenous infusion of naloxone should be administered for buprenorphine-induced respiratory depression. In adults, the recommendation is an intravenous loading dose of naloxone 2 mg, administered within 90 seconds, followed by a constant rate intravenous infusion of 4 mg/hour until respiratory depression is antagonized. Pediatric data are lacking.
Opioid rotation is indicated for rare adverse effects such as hallucinations or confusion. Buprenorphine is the therapy of choice because of its κ-antagonistic effect (psychomimetic opioid effects are mediated via the κ-receptor).
Opioid-induced sedation is observed at the beginning of continuous opioid therapy in nearly every patient, and frequently with ongoing opioid therapy or when the dose is adjusted. Serum M6G accumulation as a result of renal insufficiency, progressive liver function impairment, or concomitant medication with centrally depressing drugs may exacerbate sedation. Rotation to buprenorphine is an option in children with renal compromise. If organ insufficiency is improbable, some adolescents or young adults may, at least temporarily, benefit from psychostimulants (i.e. methylphenidate; beginning with 2.5 mg in the morning).
High-opioid doses, especially of morphine or hydromorphone, may provoke myoclonus.'67,1841 Although these adverse effects are responsive to benzodiazepines, opioid-induced myoclonus is an indication for opioid rotation.
8.2 Side Effects of Individual Opioids or Administration Modes
Tramadol exhibits only minor respiratory depression, although a 10-fold overdose can cause respiratory depression and cerebral seizures.'1951 Fast intravenous injection of tramadol frequently induces nausea or vomiting.1271 Acute pediatric cancer patients given tramadol have been shown to exhibit less somnolence, constipation, pruritus, nausea, urinary retention, or sweating than patients given morphine,'14,151 although the mean intravenous MED in patients receiving tramadol was slightly lower than that in children receiving morphine.'151 Severely disabled children with epilepsy may have increased seizure frequency when administered long-term therapy with tramadol; this effect is attributable to competition for clearance pathways with anticonvulsant drugs.
The safety and quality of codeine analgesia are unpredictable in the newborn and in early infancy.'196' Twelve of 26 spontaneously breathing newborns exhibited respiratory depression and apnea after intramuscular codeine 1 mg/kg.'1971 Codeine is not recommended in the presence of hepatic failure.'1461 Renal compromise causes reduced elimination of M6G.'1981 Children who are ultra rapid metabolizers may experience life-threatening side effects after administration of small doses of codeine as a result of excessive metabolism of codeine into morphine and M6G.'199,2001 Morphine poisoning has even been described in a breast-fed neonate of a codeineprescribed mother who was an ultra rapid metabolizer.'2011
8.2.3 Morphine and Hydromorphone
Neuroexcitatory opioid-related side effects (myoclonic jerks, seizures) as a result of accumulation of M3G or H3G are well documented in adult patients receiving long-term morphine therapy especially in those with renal impairment.[86,184,202,203] In adults the frequency of neuroexcitation adverse effects correlates positively with the length of treatment and daily hydromorphone dose.[202,204] Data from children are lacking.
8.2.4 Methadone/ Levomethadone
In adults and in the pediatric intensive care setting methadone has been shown to provoke clinically significant bradycardia. Drug interactions are common and patients receiving methadone should be monitored closely for toxicity or therapeutic failure.
8.2.5 Fentanyl TTS
Fentanyl TTS has occasionally proved less than ideal, for example, the delivery of an increased dose may be hindered by the available body surface area of the patient, extra fixation may be required to prevent patch detachment, and this preparation is not suitable if rapid pain control is required.[106-109] Local skin irritation can be troublesome.[105,107,109] In a study by Hunt et al., in contrast to other reports, a high rate (32%) of adverse effects affecting the CNS was observed in children. The same study also reported signs of drug withdrawal in 3 of 41 patients when switched from another opioid to fentanyl TTS in the way recommended by the manufacturer. Fentanyl TTS replacement occasionally caused pain due to the excessive adhesiveness of the patch.
Respiratory depression is a possible side effect of OTFC, particularly in opioid-naive children.[208,209] Some authors have reported a high rate of nausea or vomiting[210-213] while others rarely observed those symptoms.[122,164,208,214,215] OTFC is approved for the treatment of breakthrough pain in adult oncology patients but not for sedation or premedication because of adverse effects in opioid-naive patients.
Buprenorphine is assumed to be one of the opioids that cause the least constipation, but this may be because it is commonly administered by the sublingual route, a route associated with reduced bioavailability.
The ceiling effect of respiratory depression has only been observed in healthy adult volunteers. Healthy children who have ingested high doses of buprenorphine have experienced minimal toxicity,[136,137] but this may, in part, be attributable to high first-pass clearance after oral administration. Intravenous buprenorphine seems to be more sedating than intravenous morphine in children with an increased propensity to respiratory depression.'130,148,2171 The maximal ventilatory effect of intravenous buprenorphine occurs later than with intravenous morphine. In children given intravenous buprenorphine, the respiratory rate after thoracotomy was shown to fall constantly over 2 hours, and for the following 7 hours was significantly below that seen with comparable doses of intravenous morphine despite minimal differences in partial pressure of carbon dioxide (PaCO2).'1481 Although buprenorphine reverses fentanyl-induced postoperative respiratory depression, it may contribute to respiratory depression after fentanyl anesthesia.'2181 An 11 -year-old girl given intravenous buprenorphine for postoperative analgesia after fentanyl anesthesia experienced severe respiratory depression requiring artificial ventilation in intensive care. The cause of this life-threatening complication remains uncertain.'2181 Clinically significant respiratory depression reflected by an increase in PaCO^sub 2^ to twice the basal value was observed in two children who were given intravenous buprenorphine 9.2 µg/kg postoperatively within 4 hours or 6.0 µg/kg within 2 hours.'1301 The µ-receptor affinity of buprenorphine exceeds that of naloxone.'219,2201 Reversal of buprenorphine-induced respiratory depression using naloxone is possible but requires higher doses than anticipated from use of this agent with morphine and in some cases a continuous naloxone infusion is required. In adult healthy volunteers reversal of respiratory depression induced by intravenous buprenorphine 0.2 mg was achieved (ED^sub 80^; concentration of drug producing 80% of maximum effect) with naloxone 2.5 mg infused over 30 minutes.'1541
Intravenous oxycodone was associated with more respiratory depression than comparable analgesic doses of other opioids when administered to 18 children after ophthalmic surgery.
9. Patient-Controlled Analgesia
PCA is used to treat children in pain related to surgery, burns, mucositis, bone marrow transplantation, or sickle-cell disease.[81,221-227] The self-managed delivery of analgesic boluses makes it especially suitable for treating fluctuating pain. In children younger than 7 years of age, in patients with neuromuscular limitation and limited capacity or ability for selfactivation, or in terminal care where self-activation is impossible,'2281 PCA may be activated by someone else ('PCA by proxy'), i.e. the nurse or parents.'2281 Since individual opioid need is highly variable at the end of life, PCA therapy should ideally suit the needs of dying children. In their meta-analysis, Walder et al.'229' showed that PCA provides better analgesia than conventional opioid treatment, and that it is preferred by postoperative pediatric patients. With respect to end-of-life analgesia, there is one case report on successful PCA application using methadone in an 8-year-old child with neuroblastoma.'91' A recent report'230' on eight children at their end of life showed a highly fluctuating opioid need during this period; a requirement that could be successfully met by PCA. Some of our own pediatric patients have triggered more than 20 boluses per day.
Pain should be managed using titrated opioids before PCA is started; PCA must not be started before good pain control is achieved. PCA parameters should be adjusted every 3-4 hours initially. Figure 5 details practical issues surrounding PCA for PPC.
Parents should be warned not to press the PCA control button for their sleeping child, despite good intentions. With correct monitoring, there are no objections against 'nursecontrolled analgesia.' Subcutaneous PCA is equivalent to intravenous PCA.'231' Pain from the injection site mostly subsides within a few hours after initiation.
Pulse oximetry is mandatory at the start of PCA therapy in the hospital setting. Recommended monitoring comprises PCA-system data, respiration rate, heart rate, blood pressure, pain score, sedation score, and nausea score every 2 hours. This monitoring should be done by nursing staff. In domestic palliative care, the indication for specific monitoring should be guided on clinical grounds. Regular pulse oximetry or blood pressure monitoring is not warranted. Another prerequisite for PCA is having a specialist accustomed to PCA on call (24 hours a day, 7 days a week). PCA has to be formally prescribed (filling volume, type of drug, concentration, rate, lock-out time) by a physician.
PPC management has improved dramatically over the past decade. Experience with adult therapy still guides pediatric management but the idiosyncrasies and needs of this population are now better delineated. Advances in knowledge about pediatric opioid pharmacokinetics and pharmacodynamics have been rapidly incorporated into care. New opioid formulations suitable for children (e.g. fentanyl TTS, slow-release liquid morphine preparations) are already in clinical practice. Opioids such as buprenorphine are seeing a resurgence of use because of purported reduced respiratory depression and analgesia mediated through NMDA receptors. Protocols for the initiation and maintenance of opioid therapy add consistency and safety to treatments. Estimation of daily equianalgesic doses has allowed opioid rotations that improve side effect profiles, provide better control of pain, and improve medication compliance or lessen inconvenience. While level 1 drugs of the WHO analgesic ladder have minimal impact on pain in children already receiving opioids, adjuvant medications are invaluable in patients with specific pathologies.
No sources of funding were used to assist in the preparation of this review. B. Zernikow has received consultancies from Mundipharma, JanssenCilag, Reckitt-Benckieser, and Bristol-Myers Squibb; speaking honoraria from AstraZeneca, Aventis, Boots Healthcare, Bristol-Myers Squibb, Cephalon, Grünenthal, JanssenCilag, Mundipharma, and Pfizer; and grants from AstraZeneca. E. Michel, F. Craig, and B. Anderson have no conflicts of interest that are directly relevant to the content of this review.
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Boris Zernikow,1,2 Erik Michel,3 Finella Craig4 and Brian J. Anderson5
1 Children's Hospital, Witten/Herdecke University, Vodafone Foundation Institute for Children's Pain Therapy and Paediatric Palliative Care, Datteln, Germany
2 Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, Münster, Germany
3 Children's Hospital, Ortenau Klinikum, Offenburg, Germany
4 Great Ormond Street Hospital for Children NHS Trust, Paediatric Palliative Care Team, London, England
5 Department of Anesthesiology, University of Auckland, Auckland, New Zealand
Correspondence: Dr Boris Zernikow, Vodafone Foundation Institute for Children's Pain Therapy and Paediatric Palliative Care, Children's Hospital Datteln, Witten/Herdecke University, Dr.-Friedrich-Sreiner-Srr. 5, D 45711 Datteln, Germany.