23 - Gastrointestinal symptoms
Editors: Goldman, Ann; Hain, Richard; Liben, Stephen
Title: Oxford Textbook of Palliative Care for Children, 1st Edition
Copyright 2006 Oxford University Press, 2006 (Chapter 34: Danai Papadatou)
> Table of Contents > Section 3 - Symptom care > 21 - Pain pharmacological management
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21
Pain pharmacological management
Ross Drake
Richard Hain
Introduction
Children suffer from a wide range of malignant and non-malignant conditions that ultimately result in death in childhood or young adulthood. The disease trajectory may differ for individual illnesses, but in most, pain is both prevalent and distressing [1, 2, 3]. Control of pain, therefore, plays, a central role in maintaining a satisfactory quality of life, a primary aim of palliative care.
A multidisciplinary team of professionals, trained in paediatrics and with a family-centred care focus, should care for children. The team should be responsive to the requirements of individual children and their families, openly discuss treatment strategies, and anxieties and misconceptions (often particularly evident when opioids are being considered). Response to treatment needs to be monitored frequently and modified whenever appropriate. Pain management is not always straightforward and specialist advice should be sought if initial basic approaches are not effective.
The symptom of pain illustrates very well a number of fundamental precepts of good symptom management in palliative care. An approach to managing pain should flow from these basic principles.
The first is that pain is subjective; it is what the patient says it is . The subjective nature of pain has been acknowledged in principle for many years. It means that in order to meet the needs of the individual patient, any pain management approach should be constantly subjected to review and modification in the light of its effectiveness. A continual cycle of prescription, review, and titration is necessary.
Pain, like all symptoms, occurs simultaneously in all domains of a child's experience. It is tempting to consider pain to be a primarily physical phenomenon, but the reality is that it will have ramifications in emotional, psychosocial, and existential or spiritual domains. Furthermore, problems that occur in any of these other domains, will also influence pain. Any therapeutic approach that fails to take this into account is unlikely to succeed [4]. A combination of pharmacological and non-pharmacological approaches to pain is usually necessary.
A third guiding principle in palliative care is that its value to the patient should be carefully considered by weighing up its burden and its benefits. To do this clearly requires some knowledge of the pathophysiology of pain, and the pharmacology of drugs used to treat it. Ideally, this should be based on published evidence. This is not always available for those working in children's palliative care. Published evidence is generally rather sparse, and what there is usually comes from studies in adults who are either healthy or suffering from cancer. Extrapolation from these studies to children is often necessary, but should be undertaken with caution since children and adults differ in anatomy and physiology as well as their cognitive responses to pain and analgesia. This is particularly true in the neonatal period [5, 6, 7, 8].
A rational approach to treatment is not, however, limited to deriving practice from published studies. It is intuitively reasonable to use medications for an individual that have been effective and well tolerated in the past. Where there is no evidence, an empirical approach based on an understanding of the drugs themselves and on observation of their effectiveness in patients is rational.
This chapter will consider the pharmacological management of pain in children with life-limiting conditions and, wherever possible, will draw on the pool of knowledge gained from studies in children themselves.
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World health Organization guidelines
Overview
In the 1980s, the World Health Organization identified a global problem in managing pain in adults with cancer [9]. It was recognized that underlying this were a number of uncertainties and misconceptions regarding pain and how it should be treated. Prominent among these was a widespread concern about the use of major opioids. At that time, major opioids were often seen primarily as drugs of addiction that should usually be avoided unless there was no alternative. Children were, by common consent, considered particularly vulnerable to the adverse effects of opioids and these were often withheld. This over-cautious approach was often justified by early studies that seemed to suggest that children experienced pain less intensely than adults [10].
In attempting to address some of the confusion and misunderstanding, the WHO drew up a simple and rational stepwise approach to the management of cancer pain in adults [9]. The guidelines were subsequently republished with little modification for children [4]. The WHO approach (Figure 21.1) is based on the assumption that, for most children, pain will gradually increase as their illness progresses, and that this increase in pain intensity should be matched by the stepwise introduction of progressively stronger analgesics.
On the first step are simple analgesics, essentially limited in children to paracetamol, on the second are minor or weak opioids, and on the third major or strong opioids. One aim of this model is to avoid cycling through alternative medications of the same potency as an alternative to selecting a stronger class of drug. If step 2 is no longer effective, a major opioid on step 3 is required.
Around this basic stepwise approach to analgesia, the WHO built a simple but rational set of guidelines. They were intended to be educational rather than definitive, but their practical usefulness has been such that they remain more or less unchanged at the present time.
 |
Fig.21.1 World Health Organization Analgesic Ladder (adapted from (4)). The WHO approach has been summarized in four phrases: |
By the ladder enabling a stepwise approach to treatment commencing with non-opioids and increasing to strong opioids (Figure 21.1). The level at which a child enters the ladder is determined by the child's needs, the intensity of pain and response to previous treatments.
By the clock regular scheduling ensures a steady blood concentration, reducing the peaks and troughs of pro re nata (PRN) dosing.
By the appropriate route use the least invasive route of administration. The oral route is convenient, non-invasive and cost effective.
By the child individualize treatment according to the child's pain and response to treatment.
The extent to which these principles can be extended beyond management of cancer pain is not clear. There is little in the guidelines that is specific for a malignant cause and, in the absence of evidence to the contrary, it seems reasonable to assume that they can be usefully applied to the much wider range of conditions that characterizes palliative care in children. The following sections consider each of the steps in turn, as well as some of the more general principles of selecting a suitable drug, dose, and route as well as the use of appropriate adjuvants.
Caveats
Although the WHO approach remains the most widely accepted and standardized one, there is debate about some aspects. Perhaps the most important of these, are around the middle minor opioid step. With respect to their pharmacological effect, a minor opioid is little or no different from a small dose of a major opioid. The second step of the WHO ladder is, therefore, seen by some as effectively redundant and introducing an unnecessary complication [11].
Furthermore, some opioids traditionally classified as weak, such as tramadol, may in practice have a much higher analgesic potency through non-opioid mechanisms. These intermediate opioids have no obvious place in the WHO ladder and yet can sometimes be of value in practice.
Debate has also surrounded the categorisation of non-steroidal anti-inflammatory drugs as adjuvants. By definition, an adjuvant has always been considered to be a drug that, while it can give relief from pain in certain situations, is not itself inherently analgesic. This definition is appropriate for carbamazepine, for example, which is of proven analgesic efficacy in many forms of neuropathic pain, but has no place in managing pain outside this indication. It is not equally suitable for non-steroidal anti-inflammatory drugs, which
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have considerable inherent analgesic activity [11] and this aspect is reflected in an update of the WHO guidelines in adults [12].
Despite these reservations, the WHO guidelines provide an uncomplicated and logical framework for managing pain, based on an understanding both of the nature of the pain and of the medications available to treat it.
Simple analgesia (Step 1)
The range of non-opioid analgesics available for use in children is very narrow. Aspirin (acetylsalicylic acid) is an effective analgesic with additional antipyretic and anti-inflammatory properties. It therefore has one of the properties of an ideal medication in palliative care, namely that the one drug can do several things.
The effectiveness of aspirin, however, is limited by the unfamiliarity of most paediatricians with the drug. In most countries, it was withdrawn from use in children under 12 following concerns in the 1980s regarding a possible association with Reye syndrome. Although this is not relevant for most indications in palliative care, aspirin is rarely used in practice.
Aspirin inhibits platelet aggregation, an irreversible effect whose duration is therefore the lifespan of the platelets, that is 2 3 weeks. This makes it unsuitable for use in most children with thrombocytopenia or dysfunctional platelets.
Paracetamol (Acetaminophen)
Paracetamol provides good relief for mild pain and alongside other analgesics plays an important role in the relief of moderate to severe pain. It is widely used and well tolerated in children, both for its analgesic and anti-pyretic properties. It has a central action through inhibition of prostaglandin synthesis in the hypothalamus and by blocking spinal hyperalgesia mediated by substance P and N-methyl D-aspartate (NMDA). It has no peripheral action or anti-inflammatory effect.
Oral doses are absorbed rapidly from the duodenum, but peak analgesic effects are not seen for 1 2 h. This is due to a lag between peak plasma and effect site concentrations in the CNS. The high oral absorption rate in conjunction with similar volumes of distribution at different ages means that loading doses vary little over age groups. Individual clearance values for paracetamol can be predicted from weight and age, with most of the age-related changes in clearance being completed by 1 year of age. After this age, increasing weight results in decreased clearance, although adult clearance is reportedly higher.
The anti-pyretic activity of paracetamol occurs at a plasma concentration of 10 20 mg/L [13]. This range correlates with analgesic activity and a target concentration of 10 mg/L produces 50% of the maximum pain relief in children [14].
In many countries the rectal route is no longer considered appropriate in children, for cultural and legal reasons. It is usually contraindicated anyway if there is a risk of neutro- or thrombocytopenia. Even when permissible, tolerated and safe, absorption of rectal paracetamol is slow and erratic [15, 16]. It often fails to reach effective serum concentration and is not recommended in the palliative setting, except perhaps when short-term administration will allow analgesia to be maintained while a problem such as vomiting is controlled.
Metabolism of paracetamol occurs in the liver with around 5% excreted unchanged in the urine. The primary metabolites are a glucuronide (50 60%) and sulphate (25 35%). The majority of the remainder being metabolized by the cytochrome P450-catalyzed oxidative system forming N-acetyl-p-benzoquinone imine (NAPQI) and another catechol metabolite. NAPQI is hepatotoxic but is preferentially conjugated with intracellular tripeptide glutathione to a non-toxic metabolite. Hepatotoxicity, in the form of centrilobular necrosis of the liver, occurs when the hepatic synthesis of glutathione is overwhelmed. This is more likely to occur with doses greater than 150 mg/kg/day for 2 8 days [17], but has been reported at therapeutic doses [18, 19]. Factors that may increase the risk of toxicity include chronic administration, concurrent viral infection, hepatic or renal disease, acute malnutrition, dehydration, and enzyme induction with medications like carbamazepine, phenobarbital, isoniazid, and rifampicin.
Non-steroidal anti-inflammatory drugs
Non-steroidal anti-inflammatory drugs other than aspirin, are considered in more detail under the adjuvants section (see below). Unlike other adjuvants, NSAIDs do have inherent analgesic activity [11] and some would consider them simple analgesics. However, this categorisation is not wholly satisfactory either. The potency of non-steroidals varies considerably and while some offer analgesia comparable with paracetamol, others can compare with the potency of major opioids [20]. For the purposes of this chapter, NSAIDs are considered to be adjuvants with a particular role in managing bone pain. It should be borne in mind that in practice, their application is much wider than this would suggest.
Opioids
Opioids are the mainstay of good analgesia for most children at some point in the palliative phase of their condition. They are divided somewhat arbitrarily into weak (or minor )
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opioids and strong ( major ) opioids. The pharmacological distinction between them is unclear and indeed, at a receptor level, their actions are precisely the same. If there is a clear difference between the two groups, it is that the dose of a weak opioid cannot be escalated indefinitely if they are not adequately effective. This is not due to a true pharmacological ceiling effect (i.e. caused by full receptor occupancy so that further receptor-drug interaction is impossible). Rather, it seems to be a limit imposed in practice by the occurrence of adverse effects that make further increases simply intolerable.
There are, nevertheless, some practical advantages to distinguishing between weak and strong opioids. Many patients who could benefit from opioid therapy, particularly adolescents and young adults, are reluctant to start them. This can be for many reasons, many deriving from a culture disproportionately concerned about the risk of addiction. Other reasons for reluctance or poor compliance stem from the perception of morphine as a drug whose prescription marks the beginning of the road towards death.
Such fears and misconceptions should on the whole be explored rather than perpetuated by prescribing alternatives. For some patients, this is not enough and the choice for them is between a minor opioid and no analgesia at all. Irrespective of whether such fears are rational, they can powerfully compromise good pain control, and there is little point in prescribing the ideal drug regimen if it is clear that the child or young person will not comply. It is in this situation that the availability of effective alternatives that are perceived to be safer can be of real practical value.
The following section considers practical issues of prescribing opioids by addressing the following three questions:
Which drug to select?
How much, and how often?
By what route?
Which drug to select?
Minor or weak opioids (Step 2)
Once simple analgesia is no longer effective to control pain, a weak opioid should be introduced. They should be added to, rather than substituted for, a non-opioid agent, and when they do not provide adequate pain relief, should be changed to a strong opioid. There is no rationale to substitute within the group.
Weak opioid analgesics are often described as having a ceiling effect , that is that above a certain concentration, further increases in dosage do not result in better effect. There is little to support this concept in therapeutic practice. Indeed, for codeine, it would be difficult to explain such a difference from morphine, given the prominent role morphine itself plays in mediating analgesia after demethylation of codeine (see below). What is certainly true in practice, however, is that in higher doses, the analgesic effect of weak opioids is often out-weighed by adverse effects, imposing a de facto ceiling limit on the tolerability of this group of drugs. It is partly for this reason that this step of the ladder has been the subject of debate, with calls for it to be replaced by low dose morphine.
Codeine is the weak opioid agent recommended by WHO for children. There are few alternatives and, on the whole, little to separate them in terms of efficacy although tramadol has a more complex therapeutic and adverse effects profile than others in this group.
Codeine
Codeine is a derivative of morphine. It is about one tenth as potent as morphine, and 10% of it is converted to morphine by hepatic metabolism, making morphine the primary means through which codeine exerts its effect. Codeine has a similar half-life to morphine in adults, that is, 2.5 3.5 h. It has an oral bio-availability around 60% with an onset of analgesic action of 20 min, peaking at 1 2 h and lasting from 4 to 8 h. While there is some evidence that codeine itself has some direct anal-gesic capability [21], its analgesic action derives mainly from its metabolic by-products, and in particular from morphine and its active derivatives. The main metabolite is codeine-6-glucuronide, which has weak binding capacity. Other active metabolites include small amounts of norcodeine and morphine-6-glucuronide (M6G), as well as the inactive compound morphine-3-glucuronide (M3G), which has no affinity for opioid receptors.
Morphine is derived by demethylation via the cytochrome P450 system sub-type 2D6 (CYP2D6), for which over 50 different genetic variants have been identified. Some of these variations result in an enzyme which is unable to convert codeine to morphine. Individuals with enzyme variations of this type, derive limited analgesic effect from codeine and may account for, as much as, 30% of some populations [22].
Codeine has a side effect profile common to all opioids (Table 21.1). The most troublesome of these is constipation. The recommended oral dose is 0.5 1.0 mg/kg every 4 h for children 6 months of age and older, to a maximum of 60 mg/dose. It comes as a syrup, tablet and parenteral formulation. Parenteral administration confers no advantages over morphine and is associated with marked histamine release and hypotension.
Other minor opioids include dihydrocodeine and propoxyphene. Dihydrocodeine is a semi-synthetic analogue of codeine with a bioavailability of 20%. The onset of analgesic
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Table 21.1 Adverse effects of opioids | ||||||||||||||||||
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action is around 30 min and the duration of action ranges from 3 to 6 h. The low oral bioavailability means that it is equipotent to codeine when taken orally but has double the potency with parenteral administration. Propoxyphene is a congener of methadone, but only has an efficacy equivalent to that of paracetamol. It has an active metabolite, norpropoxyphene, which accumulates with repeated dosing and is toxic to the CNS.
Tramadol
Tramadol is a centrally acting synthetic derivative of codeine with weak affinity for the mu-opioid receptor, around 10 times weaker than codeine. There is also relatively weak nonopioid activity through inhibition of presynaptic serotonin and noradrenaline reuptake and stimulation of neuronal serotonin release. The active mono-O-de(s) methyl-tramadol (+) or M1 metabolite (via CYP2D6) has a mu-opioid affinity 200 times that of morphine. The combination is synergistic and gives tramadol, a potency of 1/5th to 1/10th that of morphine for oral and parenteral administration, respectively.
Oral bio-availability is around 70% but increases to 90 100% with multiple doses. Peak effect is achieved after 2 h and the duration of action is around 4 6 h. Tramadol is metabolized in the liver and around 90% excreted by the kidneys. The adverse effects are similar to those of other opioid agents and, in overdose, can result in severe respiratory depression and central nervous system symptoms such as convulsion [23].
Major or strong opioids (Step 3) Morphine
The category of major opioids offers the greatest variety to professionals working in palliative care in children [24]. The wide range of products currently available in some countries reflects not only clinical need but also commercial expediency. The result has been a plethora of medications, all with very similar therapeutic and adverse-effects profiles. Most are little different from the archetype in this category, morphine itself, and none can boast the long history of safety and effectiveness that morphine offers.
Nevertheless, some new products do offer genuine advantages, either because of the drugs themselves or because of the formulations that are available. Additionally, there may be value for some patients in switching from one major opioid to another of a different class, even when the two are similar, since the patient may be less tolerant to some of the desirable effects of the new drug (see below).
There is, therefore, a role for many of the alternatives to morphine that have become available, providing they are used discriminatingly, and as a result of clinical decision making based on an understanding of the drugs themselves. Where there is no such advantage, morphine remains the drug of first choice for most children in whom the weak opioids of step 2 are no longer enough.
Opioid drugs are defined by their capacity to interact with mu-opioid receptors, of which there are a number of sub-types. Opiates are naturally occurring opioids such as morphine and diamorphine. Many opioids interact with other opioid receptors, notably kappa (e.g. oxycodone) and delta-opioid (e.g. methadone). Some also have activity at non-opioid receptors involved in analgesia (e.g. methadone, tramadol). In the following section, morphine will be considered first and other major opioids later, in so far as they differ from it.
Morphine acts in the CNS and with regular administration has an oral to parenteral (intravenous or subcutaneous) ratio between 1 : 2 and 1 : 3. After oral administration the onset of effect is seen after 20 30 min with peak activity reached at 60 90 min. The duration of action ranges from 3 to 6 h.
Thirty-five percent of the oral dose is made available, with the principal site of metabolism being the liver. The main metabolic process is glucuronidation with M3G and M6G, the main metabolites. M3G does not have analgesic activity, M6G does, and probably contributes significantly to the anal-gesic effect. M3G is the predominant metabolite in children, but the elimination clearance of M3G is greater than M6G. M3G:M6G ratios change with maturation of the hepatic and renal systems [5, 6, 8, 25]. M6G clearance is reduced in renal failure and a reduction in morphine dose is necessary to avoid toxicity.
The pharmacokinetics of morphine in neonates have been studied [5, 8, 26]. Birth weight, gestational and postnatal age influence glucuronidation of morphine, and glucuronidation is present, albeit at a reduced level, in preterm and term neonates. The volume of distribution increases from 1.17 L/kg at birth to 1.94 L/kg in the first few months. Half-life decreases from around 10 hours in the preterm infant to 2 h in young children, while clearance increases from around 2 ml/kg/min to between 20 and 25 ml/kg/min, respectively. There is no evidence that morphine passes more easily into the cerebrospinal fluid of children than adults [26].
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The oral, subcutaneous, intravenous, epidural, or intrathecal route can be used to administer morphine. Oral morphine comes as an immediate- and sustained-release preparation. Elixir and tablets provide the immediate-release options, while sustained-release preparations include tablets and capsules. The capsule contains granules that allow a controlled release of morphine. The capsule can be opened and the granules sprinkled in soft foods such as yoghurt or jam. If the granules are chewed, then the slow delivery effect is lost. In the opioid na ve child, the starting dose of morphine is equivalent to oral morphine 1.0 2.0 mg/kg every 24 h.
The increased half-life and reduced clearance in infants under 6 months of age warrants a more cautious approach when initiating therapy and the initial dose should be reduced by 25 30% of the dose recommended for older children. Treatment should then be adjusted according to analgesic effect and incidence of side effects.
Undue emphasis is often placed on the risk of inducing respiratory depression in children with the initiation of opioid analgesia. Children older than 3 months of age are probably at no greater risk of developing significant opioid-induced respiratory depression than adults [26, 27], though vulnerability may be increased in younger infants as a result of metabolic and anatomical immaturity and consequent differences in pharmacokinetics [28, 29].
This does not, of course, mean that pain in a neonate should remain untreated but that a more cautious approach should be taken to prescribing medication for younger infants. As in all age groups, the dose of opioids should then be carefully monitored and titrated as quickly as is necessary to provide symptom relief.
Major or strong opioids (Step 3) Alternatives to morphine
Diamorphine (heroin)
Much of the important research in palliative medicine and symptom control has been in the use of diamorphine. In countries where it is available, it is usually used in effect as the parenteral form of morphine.
Diamorphine is a pro-drug that is quickly metabolized by deacetylation to an active metabolite, mono-acetylmorphine, and then more slowly to morphine through which its analgesic activity is largely mediated. In laboratory studies, however, both diamorphine and mono-acetyl morphine are also active in their own right at delta-opioid receptors [30, 31].
The characteristics of diamorphine are, as might be expected, similar to morphine except that it has increased solubility and is highly hydrophilic. This confers a significant clinical advantage that large doses can be given in small volumes. Its potency is 1.5 2 times that of morphine when the two are given by the same route. It has gained a spurious reputation as a drug of addiction and because of this, is difficult to obtain in many countries. In reality, there is no evidence of any increased potential for addiction over morphine, and it is a useful and highly effective analgesic.
Fentanyl
Fentanyl is a highly lipophilic synthetic mu-agonist with around 100 times the potency of morphine. Many of its proven advantages over morphine, relate to the formulations in which it is available. It is, however, wholly synthetic and of a different class from morphine. It is, therefore, a suitable agent for opioid rotation (see below) where adverse effects of opiates have become dose-limiting. Like morphine/diamorphine, fentanyl has been studied reasonably extensively in children [32, 33, 34, 35, 36, 38, 39, 40, 41 43 44, 45]. Perhaps for these reasons, it is usually considered the second-line major opioid in children after morphine/diamorphine.
It is not available as an oral formulation, but there are transdermal [32, 38] and intranasal [39] delivery systems. Parenteral administration of fentanyl has an onset of action of less than a minute, but rapid redistribution to inactive tissues such as fat, rather than elimination, means a short duration of action, of around 30 45 min. However, large or multiple dosing increases the analgesic action as elimination becomes the determinant of effect duration. Elimination is hepatic with glucuronidation to inactive metabolites that are then excreted by the kidney. The pharmacokinetics of fentanyl are age-dependent with wider volumes of distribution and higher clearance values in neonates and infants [40, 41], and adult values are reached around 2 months of age, when allometric scaling is used [42].
There are three fentanyl congeners. Alfentanil is about 5 10 times less potent and has an extremely short duration of action, usually less than 15 20 min. However, it can prove to be a useful alternative, especially when subcutaneous administration of fentanyl is compromised because of excess volume requirements and may cause less postoperative respiratory depression than either morphine or fentanyl. Sufentanil and Remifentanil are 10 times more potent than fentanyl. Application in palliative medicine is limited but intranasal Sufentanil can be helpful for rapid relief from incident pain. Remifentanil has unique pharmacokinetic properties characterized by small volumes, rapid clearance, and low variability compared with other intravenous anaesthetic agents.
Transdermal fentanyl
In a small, open label study in children with cancer pain [32], transdermal fentanyl was found to be well tolerated and have pharmacokinetic parameter estimates similar to those for
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adults but with less variability. Peak plasma concentrations of a 25 mcg/h fentanyl patch were reached around 24 h (18 to >66 h) followed by a slow decline from the peak concentration, consistent with 72 h dosing, in most children.
The advantage of the transdermal formulation of fentanyl is that it is easy to use, requires no needles, and needs changing only every 48 72 hours, while usually providing a relatively consistent degree of analgesia. These make it an ideal major opioid formulation in the maintenance phase (see below). It is not usually suitable, however, in the initiating or titration phases. The smallest patch size, 25 mcg per hour, is equivalent to around 40 mg in 24 h of oral morphine. This is too large for most opioid na ve children. Furthermore, the patch sizes then go up in 25 mcg increments, making titration against an individual patient's pain very difficult. Attempts to divide the patch, either by cutting it or occluding part of it, are anecdotally successful but are not recommended by the manufacturer. This is because, until recently the nature of the transdermal delivery system was such that the drug could leak from a cut surface, and the rate of drug absorption is dependent on surface area so that covering half the patch does not necessarily mean the child receives half the dose of fentanyl in a given period. The manufacturers have recognized this potential weakness in an otherwise very valuable formulation, and are developing a new transdermal system which, like transdermal buprenorphine, can be cut down to allow fractions of a patch to be administered.
Oral transmucosal fentanyl citrate
OTFC is a flavoured, fentanyl impregnated sugar matrix presented as a lozenge. It has been found to be a safe and reliable pre-anaesthetic medication in healthy children prior to surgery [33, 34, 35, 43] and for analgesia during inpatient and outpatient burn-wound management [44, 45]. It has a bio-availability of 33% in children [43], lower than the 50% quoted for adults probably because of either a higher first-pass extraction or increased swallowing in children. In adults, 25% is rapidly absorbed through the oral mucosa and 25% (i.e. one-third of 75%) is made available more slowly following gastrointestinal absorption and hepatic metabolism.
The lozenge is typically consumed within 20 min and analgesia first noted after 5 10 min with maximum effects at 25 45 min. The steady-state volume of distribution and clearance rates for children aged 2 10 years were comparable to adult's [43]. Effects can persist for several hours and, in adults, the plasma half-life is in the region of 7 hours. A randomized, placebo-controlled, double blind study in children [35] confirmed higher rates of pruritus and nausea compared with placebo. The incidence of nausea increases with higher OTFC doses.
The rescue dose for breakthrough pain is, as always, based on the regularly scheduled pain medication and can be given as fentanyl itself or as the equivalent dose of some other opioid such as morphine.
Hydromorphone
Hydromorphone is a hydrogenated ketone of morphine with very similar pharmacokinetic and pharmacodynamic properties to morphine [46]. It has an oral bioavailability of 40 60% with a rapid onset of action and duration of action of 4 6 h and is also effective when given by the subcutaneous, intravenous, epidural and intrathecal routes. The elimination half-life is 3 to 4 hours and, like morphine, shows wide intra-subject pharmacokinetic variability. It is between 5 and 7.5 times more potent [47], and 2 10 times more lipid soluble. Like morphine, it is metabolized in children to the 3- and the 6-glucuronide [46].
It is unclear whether hydromorphone has advantages over morphine in children [36, 47]. In countries where diamorphine is not yet available, however, its greater potency than morphine can provide an alternative practical solution to the problem of dissolving high opioid doses for parenteral administration.
Methadone
Methadone has a very different chemical structure from morphine and is a racemic mixture. The analgesic efficacy is not only mediated through the mu-opioid receptor (L-enantiomer) but by desensitization of the d-opioid receptor and antagonism of the NMDA receptor (L- and D-enantiomers). This often makes it a useful agent in neuropathic pain syndromes. Activity of the d-receptor is critical for the development of morphine-induced tolerance and dependence and concomitant exposure to morphine and methadone suppresses the mechanisms leading to opioid tolerance.
Methadone is a basic and lipophilic drug that is known for its high oral bio-availability (80 90%), and very long duration of action (4 24 h). It is very slowly metabolized in the liver, does not rely on renal excretion and the elimination half-life averages 19 h in children aged 1 18 years, range 4 62 h [48]. There is also wide individual variation in plasma and elimination half-life in neonates [49, 39]. Enzyme inducers such as carbamazepine, phenobarbitone (Phenobarbital), phenytoin, and rifampicin increase the metabolism of methadone while amitriptyline and cimetidine reduce metabolism. Methadone leads to higher plasma levels of zidovudine.
Outside some case reports [50, 51, 52], there is relatively little research on the use of methadone in children [24]. One direct comparison with morphine [53] showed that it was more effective for postoperative analgesia. A second study [54] suggests that methadone had a greater impact than morphine on
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respiratory depression, although this was of no clinical significance for either drug.
It is important that the safety and effectiveness of methadone should be established in children. Methadone potentially has a unique place among major opioids. It is of a very different chemical structure from morphine, making it a suitable opioid where opioid switching (see below) is considered. But the unique advantage of methadone is that in addition to analgesic efficacy mediated through the mu-opioid receptor, methadone also acts through antagonism of the N-methyl D-aspartate (NMDA) receptor [55]. The NMDA receptor is important in the pathophysiology of neuropathic pain. Methadone, therefore, combines in principle the pharmacological effects of both a major opioid such as morphine and those of an NMDA antagonist such as ketamine.
With this in mind, it is perhaps surprising that methadone is not more widely used in the management of pain in children. Certainly, in adults it has found a valuable role in the management of cancer pain [37, 56, 57]. Dextromethorphan, another combined opioid/NMDA antagonist [58] seems nevertheless to be a relatively poor analgesic [59].
Oxycodone
Oxycodone has similar properties to morphine but has additional kappa-receptor agonist activity and has been effective in providing analgesia for neuropathic pain syndromes in adults. Oral bio-availability is around 50 60% and potency equivalent to morphine. Parenteral potency is 75% of morphine. Onset of action is 20 30 min after oral administration, with duration of action of 4 h. The plasma half-life is around 3.5 h but increases during renal failure.
The pharmacokinetic profile was studied in 40 children, aged 6 93 months, undergoing surgery [60] . Patients received a single 0. 1 mg/kg dose of oxycodone under anaesthesia either by the intravenous, intramuscular, buccal, or nasogastric route with blood samples being evaluated over the next 12 h.
Peak drug concentrations were approximately twice as high after intravenous administration than after intramuscular dosing (mean 82 versus 34 mcg/L) and were considerably higher than buccal or gastric administration (9.8 and 0.2 mcg/L, respectively). Terminal elimination half-life was approximately 150 minutes in all groups. These parameters are similar to those observed in adults. On the other hand, the elimination half-life and clearance values have been found to be higher in adults and have been associated with greater ventila-tory depression in children when given intravenously after surgery, at comparable analgesic doses of other opioids [61]. Anecdotally, vomiting, pruritus, and delirium appear to be less common in children than in adults.
Oxycodone is metabolized in the liver mediated by the CYP2D6 enzyme system. Metabolites are, generally, inactive except for oxymorphone. Oxymorphone has similar characteristics to morphine but has 10 times the potency and is manufactured in its own right as a parenteral formulation.
Buprenorphine
Buprenorphine also offers some potential advantages over morphine, related mainly to its formulation. It is available as, both a sublingual and a transdermal formulation, both of which have obvious advantages in paediatric practice.
Buprenorphine is a partial mu-agonist and has mixed agonist and antagonist properties at other receptors. In practice, its effects seem to be similar to those of morphine. Its onset of action is approximately 30 min and the peak around 3 h. Its half life is three hours, but the duration of action can be as long as 9 [62].
The sublingual formulation avoids first past metabolism without the need for an injection. 400 mcg of the sublingual preparation is approximately equivalent to 300 mcg parenterally.
Perhaps the biggest advantage of buprenorphine, however, is its availability in a transdermal patch that, unlike that of fentanyl, can be divided without apparently jeopardising its delivery. In the United Kingdom, there are three patch sizes releasing 35 mcg/h, 52.5 mcg/h, and 70 mcg/h, each for 72 h. The drug is held in a matrix [63]. It appears that this can be divided without compromising the drug delivery, although there remain few studies in children.
One theoretical problem with buprenorphine has been the fact that it is a partial agonist. This has two implications. The first is that there is a genuine pharmacological ceiling dose as receptor occupancy approaches 100%. However, it appears that this does not occur until 3 5 mg of buprenorphine daily in adults [62, 64]. The potency of buprenorphine is 60 times that of morphine, so this ceiling dose occurs at an oral morphine equivalent of 180 300 mg in 24 h. There are certainly some children who require these doses and this should be borne in mind when changing to buprenorphine.
The second consequence of the partial agonist nature of buprenorphine is, that it can block opioid receptors to the effect of morphine or other major opioids. Again, however, in practice this is probably only a problem in high doses when receptor occupancy becomes close to complete. Furthermore, since buprenorphine can be used for breakthrough pain, the solution is simply to avoid using other major opioids alongside buprenorphine at high doses [62].
Because buprenorphine has a very high affinity for opioid receptors, it is not easily displaced by the pure opioid antagonist naloxone, and considerable amounts of naloxone may be needed. Inadvertent overdoses, or idiosyncratic exaggerated
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responses to normal doses, should be treated additionally with respiratory stimulants such as doxapram.
Other opioids
Opioids such as pentazocine and butorphanol are less likely to cause respiratory depression than morphine but have an increased tendency toward sedation and other central nervous system toxicity including dysphoria, at therapeutic doses.
Pethidine (Meperidine) is a short half-life opioid which in the past was used for moderate to severe pain in children. It has little to recommend it, being both less potent, and more toxic than morphine. The enteral absorption of pethidine is erratic [54, 65]. Furthermore, accumulation of its long-acting neurotoxic metabolite norpethidine causes convulsions [66, 67, 68, 69]. They can also cause irritability, insomnia, myclonus and seizures. Toxicity is possible at any dose, but is more likely at high doses, with renal or hepatic insufficiency or with accumulation after repeated dosing for more than 2 3 days. With increasing evidence of the safety and efficacy of alternatives, pethidine now has little place in the management of pain in children.
Initiation phase
How much and how often?
The concept of a starting dose is central to good pain management, and is rather different from the way in which many other drugs are used. In most drug prescriptions, the expectation is that one standard dose per kilogram will be enough to achieve the desired effect. By contrast, the initial prescription for analgesics is a starting point from which it is expected that titration will occur until pain is under control. It is often helpful to make this clear to the child and the family, in order that they do not feel discouraged if the initial prescription is not quite enough to control the pain. In effect, there are three phases in the prescription of major opioids. The first is initiation. This is followed by a period of titration in which, the aim is to match the degree of pain with enough drug to provide analgesia but without exceeding this and incurring unnecessary adverse effects. The third phase is a maintenance phase in which a reasonably stable dose of medication has been reached. In reality, of course, this maintenance phase may simply represent a period of slower titration. A combination of disease progression and perhaps opioid tolerance means that a process of continual review is necessary even during the maintenance phase to ensure that adequate analgesia is achieved.
It may also be necessary to telescope the titration phase into a few hours or minutes by slow and careful infusion of parenteral opioid in cases where there is very severe pain that needs urgent intervention (see below). This is a relatively rare procedure in children, but has been described more often in adults [70, 71, 72].
The three phases (initiation, titration and maintenance) are characterized by specific approaches both to dosing and formulation.
Starting dose and frequency
Anxiety often surrounds the initial prescription of major opioids, particularly for those who are relatively inexperienced in their use in children. In practice, there are two ways to arrive at a safe and appropriate initial dose. If the child is not already receiving opioids, it should be calculated on the basis of the child's weight. For children who are already receiving opioids (minor or major), there is likely to be some tolerance and a dose-per-kilo approach will often underestimate the child's true requirements. Instead, the dose of opioids already required by the child should be used as a guide to the appropriate initial dose of the new drug. Typically, this occurs as a child moves from step 2 (minor opioids) to step 3 (major opioids). It is often useful to calculate the dose using both methods. The need to move to step 3 implies that the child's pain is not yet adequately controlled, so when the two calculations arrive at different doses, the higher figure is usually the more appropriate.
Calculating an initial dose using a dose per kilogram
In countries where major opioids are available to children, most formularies will offer a suitable dose-per-kilogram of the child's weight. This is based on the assumption that the volume of distribution per kilogram is the same in children as for adults. In other words, that if 10 mg of morphine given to a 70 kilo adult results in a suitable and effective serum concentration, then half that dose given to a 35 kilo child will have the same result. Although this assumption may only be approximately correct [25, 26], in practice dosing guidelines based on it seem to work reasonably well.
Most formularies recommend as a starting dose an equivalent to oral morphine 1 2 mg/kg/24 h. There is relatively little direct evidence from paediatric studies, but one study [25] seems to suggest that this will usually result in adequate anal-gesia with little toxicity.
The importance of prescribing regular and breakthrough medication has already been emphasized (see above). Immediate release oral morphine is the preferred first line major opioid and a sixth of the total daily dose should be prescribed regularly 4 hourly. It is often undesirable and unnecessary to wake the child to receive the night time dose, and some clinicians will double the dose before bed-time to make up for this missing dose.
The breakthrough dose should be the same as the regular four hourly dose, that is one-sixth of the total daily dose. It is important to explain to families that although the breakthrough dose and the regular dose are the same, they perform
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two different functions. The regular dose is to try to keep the pain away and the breakthrough dose is to treat pain if it happens despite that . This is important because, without that understanding, parents may withhold a breakthrough dose if it is needed just before or just after a regular one, rather than giving the extra dose in addition.
The breakthrough dose achieves two things. It ensures that analgesia is available to the child should the regular analgesia be inadequate. It also provides some measure of the child's requirement for such additional analgesia, which allows a process of rational and safe titration (see below).
The frequency with which breakthrough medication should be made available is unclear, and practice varies from centre to centre. Traditional practice was to offer the breakthrough dose as needed four-hourly, but increasingly among adults, it is being offered as often as is necessary, even up to hourly. Once an oral breakthrough dose has been given, there is, perhaps, little to be gained by giving a further dose within an hour of a previous one, since it can take thirty to sixty minutes for the effect of an oral dose to become apparent.
Opioids should usually be started enterally unless there is no alternative. Where it is thought necessary to commence them using a parenteral formulation, standard dosing protocols are usually available, or again, a dose can be calculated by conversion from any existing opioid requirements. Rarely, it may be necessary to intervene more urgently, and the appropriate dose can be established on the basis of rapid titration to the child's requirements (see below).
Calculation of an initial dose by conversion from existing opioid requirements
An important and fundamental concept in the pharmacology of analgesia in palliative care is that of analgesic equivalence among opioids. Most major opioids work in the same way on the same receptors, but with differing potency. This means that the analgesic effectiveness of any opioid can be expressed in terms of how it compares with other opioids. Fentanyl, for example, is 75 times as potent as morphine when both are given parenterally.
The route should also be taken into consideration: morphine is twice as potent given by the parenteral route as it is when given orally, so that parenteral fentanyl is 150 times the potency of oral morphine.
The concept of analgesic equivalence can also be extended to minor opioids. For example, codeine is approximately one-tenth as potent as morphine, while pethidine is about one-sixth as potent. Equivalency can be made more complex if an opioid has more than one analgesic action. For example, oral tramadol is approximately one-fifth the opioid potency of morphine, but has additional non-opioid analgesic properties that make its effects less predictable.
By convention, the potency of all opioids is expressed in terms of their equivalence to oral morphine (Table 21.2). This enables appropriate conversions to be made, not only between morphine and other opioids, but also among different non-morphine opioids. For example, since hydromorphone is approximately five oral morphine equivalents (OME), and oxycodone is approximately two OME, it is clear that hydro-morphone must be two and half times as potent as oxycodone. A patient on oxycodone wishing to convert to hydromorphone would therefore be expected to have the same pain relief if the dose were divided by two and a half (see Example 1).
In deciding on a starting dose of an opioid, it is important to consider what opioids, if any, a child is already receiving. A child whose pain is barely controlled on step 2 of the WHO ladder despite 30 mg of codeine six times a day, will need something in excess of 18 mg of oral morphine as an initial dose. Many standard texts in palliative care [62, 73] include tables of opioid equivalence, and practitioners in palliative medicine in children should become familiar with these.
Table 21.2 Some oral morphine equivalents | |||||||||||||||||||||||||||||||||||||||||||||
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Example 1
Patient receiving 15 mg oral oxycodone in 24 h, needing to change to hydromorphone. Published tables suggest that relative potency of oral oxycodone is two OME (i.e. twice the potency of oral morphine) and relative potency of hydromor-phone is 5 OME (i.e.five times the potency of oral morphine).
Oral morphine equivalent of oxycodone 15 2=30 mg oral morphine
Oral hydromorphone equivalent 30/5=6 mg oral hydromorphone.
So, 15 mg oral oxycodone is equivalent to 6 mg oral hydromorphone. Total daily dose of hydromorphone should in principle, therefore, be 6 mg. In practice, the dose should be further reduced to take account of incomplete cross-tolerance, see below.
A further situation in which it may become necessary to select an initial dose, occurs in children already on strong opioids who need to change to a new one. This is termed opioid substitution' or, if repeated, rotation . Although it is unusual for this to become necessary, in some children tolerance to strong analgesia probably occurs even in a therapeutic setting. The solution usually is simply to increase the dose of major opioid, but rarely such increases are constrained by dose-limiting toxicity, often by neuroexcitability. In this situation, it may be necessary to change to an alternative strong opioid of a different class [38, 74]. A child who has become partially tolerant to the analgesic effects of morphine, may well be less tolerant to those of fentanyl, a phenomenon termed incomplete cross-tolerance .
The effectiveness of opioid rotation or substitution in this way depends in part on the different adverse effects profiles of different opioids. It is mainly, however, because changing to a new opioid allows a reduction in the total opioid dose without any loss of analgesia. The dose reduction is conventionally twenty five per cent. In converting from one major opioid to another, therefore, there are two stages in the calculation (example 2). The first is calculation of an equianalgesic dose of the new opioid, based on oral morphine equivalency (see above). The second is a 25% reduction in that dosage to effect a reduction in toxicity.
Methadone, another potent opioid in a different class from morphine, would seem a useful alternative to fentanyl when considering substitution, particularly if there is an element of neuropathic pain. Its use is complicated by its unusual pharmacokinetics that mean the conversion factor is dependent on the dose of the previous opioid [75, 76, 77]. Furthermore, again because of its unpredictable pharmacokinetics, it is usually recommended that methadone should be commenced in a hospital setting. This makes it unsuitable for use in children needing palliative care, in whom facilitating early discharge home is always a priority. The need for this caution is not, however, entirely clear in practice, as outpatient prescription has been reported to be safe [78] with careful monitoring.
Example2 Opioid substitution
After titration, a child receiving a subcutaneous infusion of morphine receives 500 mg in 24 h but is becoming toxic, with neuroexcitability, sweating and myoclonus. The decision is made to switch to an alternative opioid. Parenteral fentanyl (150 times analgesic potency of oral morphine) is selected because it is a synthetic opioid with a structure very different from morphine.
Step 1:Calculating Theoretical Equianalgesic Dose Of Fentanyl
Oral morphine equivalent of sc morphine= 500 2=1000 mg oral morphine
Parenteral fentanyl equivalent of 1000 mg oral morphine 1000 mg 150 6.67 mg parenteral fentanyl in 24 h.
Step 2:Reducing Dose By 25% To Account For Incomplete Cross-Tolerance
25% parenteral fentanyl dose=0.25 6.67=1.67 mg parenteral fentanyl
Final dose of parenteral fentanyl, taking into account both equianalgesic potency in theory and incomplete cross-tolerance in practice, is:
6.67-1.67=5 mg in 24 h
(cross check: 5 150=750 mg oral morphine equivalent i.e. 75% of original 24 hrly opioid requirements).
Rarely, it is necessary to titrate rapidly against pain in order to establish an appropriate starting dose. The indication is for very severe pain for which, a more measured approach would condemn the child to prolonged suffering. In this situation, the parenteral route is the most appropriate. The opioid should be infused slowly over half and hour or so until analgesia is achieved. There are a number of methods used to calculate the total daily dose required, once this has been achieved; perhaps the simplest [72] is to assume that it represents the equivalent of a single four hourly dose, and accordingly give six times this dose in 24 h (Example 3). This can be given by any appropriate route, and as any opioid, providing appropriate conversions in doses are made.
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Example3 Rapid titration
A child with severe pain related to a sarcoma requires 6 mg intravenous morphine to achieve analgesia.
Oral morphine equivalent=2 6=12 mg
Assume this represents four-hourly breakthrough requirement.
Total 24 hourly requirement=6 6=36 mg oral morphine equivalent
Can give in several ways: 6 mg immediate release morphine 4 hrly 18 mg morphine via continuous sc infusion over 24 h 12 mg diamorphine via continuous sc infusion etc. over 24 h
Dose interval how often should opioids be given?
Another of the fundamental principles of the WHO pain ladder for children is that opioid medication should always be given by the clock rather than simply being available when it is needed. There are numerous reasons for this.
It is comparatively unusual for pain that, at its worst, is intense enough to need a major opioid, to disappear completely at other times. There are exceptions to this, particularly in managing episodic pain (see below), but in general, if pain is severe enough to warrant major opioids, it is likely to require them to be given on a regular basis.
Perhaps more importantly, the aim of analgesia is to keep the patient free from pain. Any prescription that relies on the occurrence of pain to trigger an analgesic intervention is inherently unsatisfactory. To allow access to analgesia to be contingent on reporting the need for it, ensures that a child must inevitably experience pain and can never be free from it.
There are also sound theoretical reasons for always giving major opioids regularly. In the case of morphine, there is evidence [79, 80] that single doses are considerably less effective than repeated doses. In other words, the effectiveness of the first dose of morphine is less than that of the fifth or sixth regular dose. The explanation for this is thought to be accumulation of the active metabolite M6G, which has a longer-half life and therefore accumulates after repeated dosing. Regular repeated doses are, therefore, usually mandatory in the prescription of major opioids.
The exact dosage interval is governed largely by the half-life of the medication and its duration of action. The half-life of morphine in children is probably somewhat shorter than in adults [24, 25, 26]. But perhaps this difference is insignificant compared with the wide variability observed between individual patients [81, 82]. Certainly, in practice a four-hourly dosing schedule for immediate-release oral morphine seems to work well in children as in adults.
It follows that where the half-life of a drug is increased, the dosage interval should also be lengthened to accommodate it. For children in the neonatal period, for example, renal clearance of morphine and its active metabolite M6G are less than in older children or adults. Dosage intervals of six, eight, or even twelve hours are therefore often suggested [83]. For children with poor renal function from other causes, such as those dying from renal failure, clearance of morphine may also be reduced and adjustments should be made to the dosing interval. One approach is to reduce the dosing interval of the immediate release morphine to 8 or 12 hourly. Where renal dysfunction is particularly severe, however, it may be preferable to give morphine one milligram per kilo as needed, with no regular dose at all. Although this appears to break one of the golden rules of the WHO Pain Ladder, reduced clearance of morphine and M6G means that the child will maintain an acceptable serum level even with intermittent dosing.
In summary, when considering the appropriate frequency with which analgesia should be prescribed, the most important characteristics are those of the drug itself. However, it is also important to consider the characteristics of the patient, in particular as a result of coexistent disease, which may impact on clearance of the drug.
Management of episodic pain is considered elsewhere (see below).
Titration phase
The purpose of the titration phase is to match the dose of analgesia prescribed with the degree of pain experienced by the patient. If pain is counteracted by adequate analgesia, it is also true that some of the effects of analgesia are countered by pain. The risk of clinically significant respiratory depression, for example, is very small if the dose of opioid prescribed is not excessive in relation to the degree of pain experienced by the patient. Titration is the means by which the correct dose of analgesia is determined to keep the child comfortable without unnecessary toxicity.
The opioid of choice in the titration phase is oral morphine. Other oral medications with relatively short half-lives, such as hydromorphone, methadone or oxycodone could also be used. Formulations with long half-lives or slow release delivery systems, such as fentanyl patches or slow release preparations of morphine or oxycodone, would not be appropriate for titration.
The essence of titration is the ongoing review of the regular opioid dosage, based on the amount of breakthrough
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 |
Fig.21.2 Prescribe-review cycle in titration phase of opioid prescription. |
medication the child has required (Figure 21.2). Once appropriate initial doses of regular and breakthrough opioid have been selected, the prescription should, if possible, be left for 48 h and then reviewed. If the child has needed only one or two breakthroughs in each 24-h period, then the dose of regular analgesia is probably about right and no alteration needs to be made. If, on the other hand, the child has needed more than this, the total daily dose of the regular opioid prescription should be increased by the amount of breakthrough that has been required (Example 4). It is imperative that each time the total daily dose of regular opioid is reviewed, the breakthrough dose should also be increased so that it remains approximately a sixth of the total daily dose. This is because, as tolerance develops, the breakthrough dose will become progressively less effective unless it is increased in proportion to the regular dose.
After a further 48 h, the process should be repeated and once again the total daily dose of regular opioid amended in line with the child's requirements for breakthrough opioid. In this way, it is usually possible to find a 24-h regular dose that allows the child to need only a small number of breakthrough doses.
This approach has a number of advantages. It allows the 24-h regular opioid dose to be very precisely titrated against the child's experience of pain. Furthermore, increases in regular opioid dose can be made with confidence since they only reflect what the child has already received over the previous 48 h, with no ill effect. This can be reassuring for parent and professional alike.
The reason for delaying changes to the regular opioid dosage for 48 h, is to allow the opioid to reach steady state at the new dose. Too frequent changes in dosage can result in increases being made disproportionately to the degree of pain, so that the child, in effect, receives too high a dose of opioids and is therefore at risk of some of the adverse effects. There are clearly situations however, in which more rapid titration is necessary, for example, where the pain is severe, or where there
Example 4 Prescription, titration and maintenance of opioids
Day 0: A child of 30 kg commences 1 mg/kg/24 h oral morphine that is 30 mg/24 h. This is prescribed as an immediate-release oral preparation of morphine. This regular dose is given as 5 mg every four hours. The additional breakthrough dose is one sixth of the total daily dose, that is 5mg, prescribed as needed (prn) orally 1 4 hourly.
Day 1:The child requires four breakthrough doses, each of 5 mg.
Day 2: The child requires two breakthrough doses, each of 5 mg.
Review after 48 h. Child has needed average of three breakthrough doses each day, implying that regular dose is not yet enough and needs to be increased.
Regular dose: Increase in 24 hourly regular dose should be 3 5=15 mg, so new regular total daily dose is 30+15=45 mg/24 h.
Breakthrough dose: New breakthrough dose remains one sixth of total daily dose 45-i- 6 7.5 mg prescribed as needed (prn) 1 4 hourly.
Day 3: The child requires two breakthrough doses, each of 7.5 mg.
Day 4: The child requires one breakthrough dose of 7.5 mg.
Review after 48 h. Child has needed average of 1.5 breakthrough doses each day, implying that regular dose is still not enough and needs to be increased further.
Regular dose: Increase in 24 hourly regular dose should be 1.5 7.5=10 mg, so new regular total daily dose is 45+10=55 mg/24 h.
Breakthrough dose: New breakthrough dose remains one sixth of total daily dose 55/6=9 mg prescribed as needed (prn) 1 4 hourly.
Days 5 8. Child requires only occasional additional breakthrough doses.
Review every 48 h. Few additional breakthrough doses have been necessary, implying opioid prescription is now well matched against child's pain. This marks the end of the titration phase and the beginning of the maintenance phase:
Regular dose: Change to more convenient formulation. Total daily morphine dose is 55 mg, approx=30 mg twice daily of 12 hourly slow release morphine formulation.
Breakthrough dose: Breakthrough dose remains one-sixth of total daily dose 60/6=10 mg prescribed as needed (prn) 1 4 hourly. Remains as immediate release preparation.
Continue regular review process, including changing needs for breakthrough, tolerability of the drug and formulation, and possibility of narcotisation.
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is rapid disease progression such that the severity of pain is increasing faster than 48 hour titration would allow.
If titrating opioids in this way fails to impact adequately on the pain, it may be because the pain is inherently, wholly or partially, insensitive to opioids. The first of these is extremely unusual but the second is seen, not infrequently. Neuropathic pain (see below) is one cause; although opioids remain the most effective analgesic agent for neuropathic pain, additional approaches such as adjuvants or neurolytic procedures may improve the situation.
There are many other reasons for pain to be relatively resistant that are outside the scope of this chapter, but are considered elsewhere in the book. Among these, perhaps the most important to consider is that pharmacological management of pain tends to address mainly its physical aspects. Pain in which these physical elements are only a small contribution (often referred to, perhaps misleadingly, as total pain ) will typically respond only poorly to the approaches to prescription and titration described above. Attempting to relieve pain without addressing the patient's non-physical concerns is likely to lead to frustration' [4].
Maintenance phase
For most children, the titration phase will come to an end when it is no longer necessary to keep adjusting the total daily dose of regular opioid. At this point, it is usually helpful to change to a long acting formulation if this has not already been done. In paediatric palliative medicine, slow release morphine preparations that can be given 12 or 24 hourly are first line, and in most countries fentanyl patch is second line. The relative potency of fentanyl means that the patches should really only be prescribed to a child receiving more than 30 40 mg of oral morphine equivalent in 24 h. In practice, however, fentanyl patches seem to be well tolerated even when they represent an increase in the dose of opioid.
It is not necessary for the breakthrough opioid to be the same as the regular one. There is, indeed, a theoretical advantage in combining some; for example, oral morphine (primarily a mu-1 receptor agonist) with fentanyl (primarily a mu-2 receptor agonist) may, in theory, give better overall blockade of receptors than either one alone.
The pharmacokinetics of some slow release preparations of morphine are not the same in children as in adults [25]. It appears that the absorption of slow release morphine formulations is erratic and their slow release nature may be less reliable. For this reason, slow-release-preparations of morphine in children are sometimes given 8 rather than 12 h. This rather reduces their usefulness and for children requiring 8-hourly slow release morphine; it may be better to consider an alternative.
Clinical experience is that some children find they need to change fentanyl patches every 48 rather than 72 h, in order to avoid increasing requirements for breakthrough towards the time of the next patch change.
Of course, even during the maintenance phase, the dose should be subject to review (Example 4). For most children, the maintenance phase is not a true plateau but a much more gradual gradient in the increase of their pain. Further increases will be needed as a result mainly of disease progression, but perhaps also due to the development of tolerance.
Sometimes, the dose may need to be revised downwards and reduced rather than increased. The need for such a decrease can be inferred from the sudden development of toxicity. A child, who is receiving an appropriate dose of opioid for the degree of pain, will typically experience very few of the side effects that are countered by pain, particularly drowsiness and respiratory depression.
Should adverse effects from opioids develop unexpectedly despite careful titration, the cause may be narcotisation . There are three common reasons for narcotisation to occur.
The pain has become suddenly less severe. This is usually because some other therapeutic intervention has been effective. For example, radiotherapy to a malignant metastasis may reduce or even abolish pain at that point completely. Similarly, a nerve block or epidural anaesthetic may provide very effective analgesia, such that a previously appropriate dose of opioid is now too high. Less commonly progression of the disease itself can paradoxically provide symptom relief. For example, nerve damage that initially causes pain may, when it progresses, instead cause regional anaesthesia.
Clearance of the opioid may be acutely impaired. The commonest cause is a sudden deterioration in renal function, resulting in accumulation of morphine and its metabolites. The cause may not be immediately obvious; renal function may be impaired both by the underlying disease and by some of the interventions, palliative or otherwise, introduced in its management.
Interactions with other drugs. Polypharmacy is common in the palliative phase, even in the paediatric specialty. It is not always possible to predict how a certain combination of drugs will impact on a child's conscious level. The introduction of psychoactive drugs such as midazolam or phenothiazines may induce drowsiness that can masquerade as opioid toxicity.
Management of adverse effects
Opioids are the main pharmacological tools available and the majority of children will have a favourable outcome. However,
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excessive adverse effects will be suffered by a significant minority and when they occur, can jeopardize optimal management of pain. Children are likely to refuse medication that causes distressing side effects, even if it is effective. Adverse effects should be anticipated, specifically addressed with the patient and the family, and relieved as rapidly as possible.
Most evidence-based practice is derived from work in adults [74]. There is little evidence in children and it seems reasonable to apply these principles to paediatric patients, but, as always, extrapolating with caution.
The adverse effects (Table 21.1) can be dealt with in one of two ways:
Substitution of a different opioid in order to reduce the total opioid dose
Symptomatic management of the adverse effect
Dose reduction of systemic opioids
Unless there has been a reduction in pain, it is unlikely that a simple reduction in the dose of opioid will be possible without jeopardising good pain relief. Tolerance to the analgesic effects of one opioid does not necessarily mean it will have occurred equally to all of them, however. This gives the opportunity to reduce the total opioid dose (measured in oral morphine equivalents) by switching to an alternative opioid. This is more likely to be effective if the opioid is of a different class, since incomplete cross-tolerance is more probable. The technique of opioid substitution or rotating has been considered above.
Symptomatic management of the adverse effect
This involves the use of drugs to prevent or control adverse effects and adds to the child's medication burden. All children commencing a major opioid should, for example, also be prescribed stimulant and softening laxatives (see Chapter 23, Gastrointestinal symptoms). Generally speaking, additional medications should be avoided if possible, as children may be reluctant to take yet another medication and polypharmacy often increases the risk of further adverse effects or drug interactions.
The effects of underlying disease and of other drugs can mimic opioid toxicity, particularly in neuropsychiatric problems such as drowsiness, cognitive dysfunction, and myclonus [74]. As an initial step, it is important to ensure that opioids are indeed the cause. Substitution of a different opioid or (very rarely) replacement with an alternative, non-opioid approach may be required.
If these fail, it may be necessary to begin specific therapy. The agents recommended for symptomatic management of the adverse effects of opioids are often based on anecdotal experience and clinical observation. They lack support from prospective studies on efficacy or toxicity over the long-term or systematic evaluation of retrospective data.
Nausea and vomiting
This is relatively rare in children and antiemetics are not normally prescribed prophylactically. Alternative explanations should usually be sought if nausea or vomiting occurs on established treatment. Haloperidol is often recommended in adults for opioid induced symptoms [see Chapter 23, Gastrointestinal symptoms] but in children, other dopamine anatagonists such as domperidone, ametoclopramide or broader-spectrum antiemetics such as levomepromazine may be more acceptable.
Constipation
Constipation is extremely common among children receiving opioids and should be anticipated and prophylactic laxatives prescribed as soon as the prescription is made. A combination stimulant and softener should be used. Lactulose, favoured by paediatricians in many countries for constipation in children, is not appropriate for opioid induced constipation.
Oral opioid antagonist naloxone may help reverse opioid induced constipation (see Chapter 23, Gastrointestinal symptoms). Transdermal fentanyl probably causes less constipation than morphine in adults [84, 85 86].
Pruritus
The management of pruritus due to opioids is considered in more detail in Chapter 28, Skin symptoms. It is not uncommon in infants and young children [87], and seems to occur particularly around the nose and face. Substitution of an alternative opioid is usually effective.
Sedation
The patient and/or the family should be informed that there might be an initial period of drowsiness when opioid therapy is commenced or increased, but that this will generally subside within a few days. Unfortunately, on occasion, the sedative effect persists and contributing factors such as hepatic, renal or central nervous system disease should be considered. Reduced renal function can result in accumulation of morphine's centrally acting metabolite, M6G, and an opioid not reliant on renal excretion, may be better tolerated. Opioid rotation has had a positive effect on the prevalence and severity of drowsiness, as has a change from oral to subcutaneous morphine.
Psychostimulants such as methylphenidate (familiar to most paediatricians for its role in managing hyperactivity disorders) have had a demonstrable effect in a number of adult studies. They have also been effective in adolescents with
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cancer [88]. In all of the studies, however, the use of psychostimulants has been associated with adverse effects such as hallucinations, delirium, psychosis, decreased appetite and tremor. Psychostimulants are contraindicated when there is a history of psychiatric disorders, and relatively contraindicated in patients with substance abuse problems or paroxysmal tachyarrhythmia. There is little information about their use for this indication in younger children.
Cognitive impairment
Some patients, especially young children, receiving opioids become agitated rather than sedated. It may be appropriate to check their renal and/or hepatic function and adjust the dose of opioid accordingly. The adequacy of pain control dictates the approach taken. Good control allows a trial reduction in the dose of opioid or lengthening of the dosing interval but poor control indicates opioid rotation.
Myoclonus
Myoclonus is an involuntary muscle contraction while conscious and can occur with high opioid doses or in-patients on long-term opioid therapy due to the accumulation of neurotoxic metabolites such as morphine 3-glucuronide. It is an idiosyncratic reaction. Empirical approaches that have been used [74] are based on benzodiazepines, particularly midazolam or clonazepam, or muscle relaxants such as baclofen or dantrolene. Valproic acid has also been used with effect. Opioid rotation accompanied as always by a reduction in total opioid dose can also be helpful.
Urinary retention
Urinary retention can be caused by any opioid given by any route but, anecdotally, is more frequent when given epidurally or spinally, often after rapid dose escalation. Interventions to counter the effect include the application of external bladder pressure, starting a low dose infusion, or using intermittent catheterisation. Other options include substitution to an alternative opioid such as fentanyl, or trying a cholinomimetic agent, such as bethanecol, to stimulate effective bladder contractions.
Respiratory depression
Respiratory depression due to opioid administration in children is much feared but grossly overestimated. Pain is a very effective stimulant to respiratory drive and apnoea is highly unlikely if titration is carried out appropriately as above. An exception is if narcotisation occurs (see above), usually as a result of a sudden reduction in pain stimulus or in capacity to clear opioids. It is rarely necessary to administer opioid antagonist naloxone, and since doing so carries the certainty of simultaneously reversing analgesia, it should not be undertaken lightly.
Physiologic dependence, tolerance, and addiction
Many of the misconceptions around opioid use surround the issues of dependence, tolerance, and addiction. Such misconceptions are so common that they must be pro-actively addressed and reviewed with all health professionals, patients, and families. Dependence and tolerance are physiologic events and are not indicative of addiction, which is a psychological phenomenon.
Physiologic dependence may occur. Dependence is the occurrence of physical symptoms attributable to withdrawal, when the dose of opioids is reduced too quickly. If the dose of opioid needs to be reduced (for example, if there has been another analgesic intervention, and narcotisation is anticipated), it should be done slowly. One practical approach is to reduce the dose by 25% every two days, aiming to reduce the dose to zero over the course of one or two weeks.
Tolerance is defined as a requirement for increasing opioid doses to maintain the same degree of pain relief. There are many mechanisms underlying this phenomenon, including alterations in G-protein expression and opioid receptor regulation. The solution to increasing needs for opioids in the terminal phase is usually simply to increase the dose. The most common cause of increased opioid requirements is advancing disease; the contribution of tolerance, if any, is usually trivial.
Addiction, that is, an individual's craving for opioids for their psychological impact rather than for pain relief, is probably no more likely to occur in patients receiving opioids for pain than in the general population [89]. It is important that irrational fear of addiction does not interfere with proper prescribing as part of good palliative care, and similarly that useful therapeutic medications, such as diamorphine, do not remain unavailable to these vulnerable patients because of misunderstanding among lawmakers.
Which route?
Oral or other enteral
An enteral route usually oral but often gastrostomy is always to be preferred if it is available. Oral medications can be administered without advanced skill and are relatively easy to titrate. They must be acceptable to children, so important considerations are palatability, tablet size, solution volume, and frequency of administration.
Palatability has been improved by the manufacture of better tasting flavoured vehicles; and a variety of syrups, ice creams, jam, and sauces can be used. Manufacturers have
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moved away from only providing medications in tablet form, which made it difficult for children who were unwilling or unable to swallow tablets, and have developed concentrated solutions for children requiring high doses of a medication. The frequency of administering a medication can be prohibitive to children. In general, analgesics that need to be taken every 4 h are impractical for anything but short-term administration. However, many analgesics are now available in sustained-release preparations. The preparation of some products means that even the contents of an opened capsule can be mixed with soft foods without losing their slow-release formulation. If they are actually chewed, however, these granules will, in effect, become immediate-release preparations, so this often remains an unpredictable approach.
The oral route is not appropriate when children:
prefer a different route of administration;
are actively vomiting;
are unable to comply (e.g. if drowsy or unconscious);
have a significant gastrointestinal or swallowing dysfunction with risk of aspirating, as might be seen in neurological impairment;
are experiencing a severe pain crisis, when parenteral administration may become necessary for rapid titration.
Subcutaneous
Parenteral routes should be used when rapid titration is required or when a child is unable to tolerate the oral route. Several types of device are available to provide parenteral delivery of analgesics by continuous infusion, intermittent boluses or both. Opioids can be used alone or administered in combination with other medications such as anti-emetics, benzodiazepines and corticosteroids.
Patient controlled analgesia [PCA] permits even very young children to self-administer small doses of opioid analgesics parenterally at frequent intervals. Delivery systems have the versatility of being able to provide a continuous infusion, also known as a background infusion or basal rate, at the same time. A variation on the theme of PCA is parent/nurse controlled analgesia (PNCA), which has been successfully and safely adopted for use in younger children or neurologically impaired children [90].
The pharmacokinetics and efficacy of subcutaneous delivery are equivalent to intravenous delivery (see below). The usual volume limit for a subcutaneous infusion is 3 ml/h. This does not normally pose a problem because of the availability of many highly potent and/or soluble opioid preparations, particularly diamorphine but also hydromorphone and oxymorphone.
A short gauge indwelling non-metallic needle system, most often placed over the upper arm or abdominal wall, provides intermittent and/or continuous delivery of medication. The chest can also be used as a site for needle placement but care must be taken, as a small risk of causing a pneumothorax exists. If irritation, erythema or induration occurs at the insertion site then the needle site should be changed. There are no firm rules on how long a needle should remain in situ. Anecdotally, non-metallic needles have been successfully used for periods up to 21 days. However, the site should be checked on a regular basis and carefully examined in the event of poor pain control, as inflammation of the area may be uncomfortable as well as impairing drug delivery.
Intravenous
The need for repeated and usually increasingly difficult re-siting of a peripheral cannula, combined with the challenge of safely maintaining it outside a hospital environment, means that this route is usually impractical for a child at home. A long-term percutaneous catheter or other central venous device is often used in children with difficult venous access or who need long-term therapy such as blood products or parenteral nutrition. It may also be available for palliative interventions, though this should be balanced against the risk of infections and their treatment.
Fortunately, the much simpler subcutaneous route is equally suitable for most medications in the palliative phase (see below). The intravenous route, whether central or peripheral, is rarely necessary.
Novel routes
One of the keys to delivering effective medication to children, is to find a route that they will find acceptable. The transdermal route has provided a valuable alternative to injections when oral dosing is not possible (see above).
A number of other routes have also been used in paediatric palliative medicine. The transmucosal route has been used, particularly for diamorphine and midazolam. It avoids first pass metabolism, and can provide rapid intervention for breakthrough pain, anxiety or dyspnoea. Buccal (transmucosal) midazolam can be of particular value in breaking the cycle of acute shortness of breath and anxiety.
A variation on the buccal transmucosal route is the nasal approach. The nasal approach has been used for many years to deliver some hormones and again has found a place in delivering midazolam either through a spray [91] or simply through a small dose in a syringe with no needle.
Opioids delivered through a nebulizer have been the subject of considerable study in the management of dyspnoea [92]. Although a consensus seems to be emerging that they are
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not generally effective, individual patients do seem to derive some benefit [93]. The effects of nebulised local anaesthetics on cough have been examined in adults [94].
Any facemask or nebulizer should be used with some caution. Many children find it claustrophobic and intolerable, and bronchospasm may, albeit rarely, complicate administration of any nebulized route.
Other routes
In many cultures, children dislike rectal administration, particularly on a chronic basis. The rectal route can, however, be useful as a means of avoiding parenteral administration over the short term, if children are unable to tolerate oral anal-gesics. The strength of analgesic suppositories is limited but oral sustained-release or immediate-release preparations can be given via the rectum at the usual intervals. The rectal route is usually contraindicated during episodes of neutropenia and thrombocytopenia because of the risk of infection and bleeding, respectively.
Intramuscular administration can rarely be justified in children, given the number of alternatives that are now available. Although the absorption profile of analgesia given by this route means that a single bolus can deliver sustained serum levels for longer than other parenteral routes, it is inevitably painful to administer. This forces the child in pain to have to consider whether the pain he/she is already in is severe enough to out-weigh the discomfort of the remedy. This is an invidious choice that a child should not have to make, and ensures that he/she will remain in pain.
Adjuvants
Identifying a patient's pain syndrome is important for both diagnosis and treatment. There are some general principles for adjuvant use [95].
Choose each medication based on the balance of intended effects and side effects. For example, the analgesic and sedating properties of amitriptyline can benefit a child with dysaesthesia who is also experiencing insomnia.
Be sure the child and/or family have a good understanding of what to expect, especially the slow onset of action, need for long-term use, and likely development of side effects and tolerance to these over time.
Start at low doses and increase the dose slowly to aid tolerance to side effects.
Increase the dose of each medication until analgesia is achieved, side effects are unmanageable, or high therapeutic drug levels are obtained.
Make sure that each drug is tried for long enough as many require several weeks to reach maximum efficacy.
For neuropathic pain
Neuropathic pain (Chapter 26, Neurological and neuromuscular symptoms) is characterized by altered sensation occurring in a recognisable nerve distribution which is usually dermatomal, but can also follow a vascular distribution in the case of sympathetic-mediated pain.
Alterations in sensation can range from simple hypoaesthesia or numbness to abnormal non-painful sensations such as tingling (paraesthesia) and abnormal noxious sensations such as burning (dysaesthesia). Clinically, simple touch becomes a painful stimulus (allodynia), painful responses become magnified (hyperalgesia), and responses to relatively innocuous stimuli are prolonged and exaggerated (hyper-pathia). The patient's description, therefore, provides the best indication that the pain is neuropathic in origin. Historically, descriptions of two types of pain have been used to initiate treatment despite poor consistency in their predictive value. Epicritic pain is sharp, lancinating, and pricking pain that is likely to be associated with A- fibres and reported to respond to anti-convulsant therapy. Protopathic pain is dull, burning and poorly localized and postulated to be transmitted by the polymodal C-fibres and treated with an anti-depressant. Motor dysfunction is a late finding in neuropathic pain, implying considerable nerve damage.
The amino acid, glutamate, is a major neuroexcitatory transmitter in the CNS and plays a key role in the generation of neuropathic pain. The acute response to pain is mediated through glutamate activation of a-amino-3-hydroxy-5-methylisoxazole-4-proprioninc acid (AMPA) receptors. If the right conditions exist, including prolonged stimulation of the AMPA receptor, then released peptides and glutamate lead to activation of the N-methyl d-aspartate (NMDA) receptor and prolonged pain states are generated. This phenomenon is known as wind-up and results in dramatic increases in the duration and magnitude of cell responses while the input into the spinal cord is unchanged.
The cause of neuropathic pain is very dependent on the disease process and is often related to compression, direct invasion, or infection of the peripheral nerves or spinal cord. Opioid therapy remains the central plank of pain management, [24] even where there is a neuropathic element. Although neuropathic pain is more likely than other types of pain to be partially opioid resistant [96], opioids are nevertheless more likely to be effective than other therapies. In other words, adjuvant therapies are more specific, but less potent.
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Treatment of neuropathic pain involves the use of opioids and adjuvant analgesics. In adults with cancer, opioid responsiveness cannot be reliably predicted in individual patients solely on the basis of the type of pain [97]. In view of this, a trial of opioid therapy should not be withheld or limited, solely on the basis of inferred pathophysiology.
Once a diagnosis of neuropathic pain is made, an adjuvant should be added; this should not wait until other analgesic approaches have failed. Most adjuvants for neuropathic pain tend to be neuroactive; their primary site of action includes the central or peripheral nervous system. They are drawn from a wide range of medications that enhance pain relief and/or allow a reduction in the amount of opioid used. The dose of an adjuvant therapy required for analgesia is often less than that required for its primary indication.
Much of the data concerning management of neuropathic pain has been derived from studies on adults with painful diabetic neuropathy (PDN), post herpetic neuralgia (PHN), or trigeminal neuralgia (TN). There is discrepancy between the research findings and clinical experience in neuropathic pain syndromes other than TN [98]. There are many other medications in use, but information on efficacy is either very limited or contradictory. Agents in this group include systemic or topical administration of anaesthetic agents such as mexiletine and lidocaine, systemic administration of -2 adrenergic receptor agonists like clonidine and the topical agent, capsaicin. This does not mean that such agents should be discarded as an option, but their application considered after failure of other options or for specific situations. For example, systemic lidocaine, either as a bolus or infusion, in anti-arrhythmic doses can be useful in gaining control of severe neuropathic pain exacerbation as an emergency measure.
The use of any benzodiazepine as an adjuvant agent for neuropathic pain should be actively discouraged, as a careful review of the literature reveals insufficient evidence to support any meaningful analgesic properties in most clinical circumstances [99].
Anticonvulsants
Many anti-convulsants have found a use in treating neuropathic pain. This may relate to the similar mechanisms that exist between seizures and pain propagation. The potential mechanisms of action include:
Prolonged inactivation of the sodium channel carbamazepine, phenytoin, lamotrigine, topirimate, valproic acid.
Prolonged activation of the chloride channel through the -aminobutyric acid (GABA) receptor vigabatrin, topiri-mate, valproate.
Prolonged activation of the chloride channel as a direct effect on the channel barbiturates, benzodiazepines.
Calcium channel modulation gabapentin.
Only carbamazepine, phenytoin, gabapentin, and lamotrigine have been studied in randomized clinical trials for relief of pain in neuropathic pain syndromes and of these agents, only carbamazepine and gabapentin have been shown to have a positive effect in all studies [98]. A systematic review of anti-convulsant drug management for neuropathic pain showed carbamazepine and phenytoin to be efficacious but there was not enough evidence for valproic acid [100].
Carbamazepine and its derivative oxcarbazepine [101] are effective in the treatment of neuropathic pain for patients with trigeminal neuralgia (TN). This class of drug has peripheral and central actions and has the ability to suppress spontaneous A and C-fibre activity without affecting normal nerve conduction. The most common adverse effects are dizziness and light-headedness. Nystagmus, nausea and vomiting, gum hypertrophy and megaloblastic anaemia are other side effects.
Gabapentin seems to be well tolerated for this indication in children [102, 103]. Other anti-convulsants have been associated with a variety of idiosyncratic adverse effects that include Stevens-Johnson syndrome, aplastic anaemia, hepatotoxicity, and systemic lupus-like syndromes. These are rare, but can be fatal.
Antidepressants
There is good evidence that tricyclic anti-depressants (TCA) have a beneficial effect in neuropathic pain [104, 105]. The mechanism is not fully elucidated but is likely to be due to their multi-modal activity, inhibition of presynaptic reuptake of norepinephrine and serotonin, NMDA receptor antagonism, and an inhibitory action on sodium channel activity. The more selective serotonin reuptake inhibitors do not seem to have as significant an effect on neuropathic pain independent of their anti-depressant activity.
The numbers needed to treat to get at least a 50% reduction in pain compared with placebo (NNT) for TCA, across different neuropathic pain conditions, is between 2 and 3. That is, every second or third patient will derive more than 50% pain relief. In a meta-analysis study of anti-depressants compared with placebo [104] of 100 patients treated for neuropathic pain, 30 would obtain more than 50% pain relief, 30 would have minor adverse reactions, and 4 would need to stop therapy because of a major adverse effect.
The most commonly used and most studied agent is the tertiary amine TCA, amitriptyline. Other tertiary agents in use include imipramine and doxepine while secondary amines
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include desipramine and nortryptiline. They are generally well absorbed from the gastrointestinal tract, peak in the plasma after 2 8 h, and have long half-lives ranging from 20 h for amitriptyline to 80 hours for protryptiline. This makes them ideal for once daily dosing, which is best given at night to either reduce or make use of their sedative side effect. They are lipophilic and strongly protein bound and widely distributed to the brain and other organs.
Adverse effects are common and may be dose-limiting although clinical experience suggests they may be better tolerated in children than in adults. Adverse effects are more likely with TCAs that include a tertiary amine group and include:
Sedation
Sympathomimetic tremor, insomnia (use as morning dose)
Anti-muscarinic dry mouth, blurred vision, constipation, urinary hesitancy, confusion
Cardiovascular orthostatic hypotension, conduction defects (prolongation of QT interval), arrhythmia
Neurologic seizures
Metabolic/endocrine weight gain
Psychiatric withdrawal syndrome (avoid abrupt discontinuation of therapy).
Fortunately, the dose required for effectiveness against neuropathic pain is usually much less than that required for anti-depression and it is often possible to find a well-tolerated dose. Common practice for amitriptyline is to commence one tenth of the usual total daily dose for depression, given as a single nighttime dose. The dose is then escalated gradually until there is analgesia. If the total daily dose for depression is reached without analgesic effect, tricyclics should be considered ineffective and be discontinued.
NMDA antagonists
NMDA receptor antagonists have a potential use for any pain syndrome with the sensory abnormalities of neuropathic pain, inflammatory pain, phantom limb pain or peripheral vascular disease. Some opioids, particularly methadone (see above) combine opioid and NMDA antagonist properties, and are a good choice in principle for this indication.
Ketamine binds non-competitively with the NMDA receptor. It has been used most frequently as a dissociative anaesthetic agent by activating the limbic system, and depressing the cerebral cortex. The result is profound analgesia, slight respiratory depression, cardiovascular stimulation, and maintenance of protective reflexes and amnesia. At sub-anaesthetic doses, the analgesic effect continues but without impairment of consciousness. There are two enantiomers for ketamine and the (+) isomer is 3 more potent as an analgesic, 1.5 more potent as an anaesthetic, and causes less excitation than the (-) isomer. Commercially available preparations contain equal concentrations of both enantiomers.
Parenteral bioavailability is around 93%, but a high hepatic first pass metabolism that means around 16%, is available after oral administration. Analgesic effects following oral administration are seen after 30 min and the half-life is around 1 3 h.
Ketamine is a homologue of phencyclidine (PCP, angel dust) and similarly has psychomimetic effects, such as vivid dreams, hallucinations, confusion, delirium and feelings of detachment from the body. This potential drawback typically occurs when emerging from an anaesthetic. They are less likely to be associated with the lower doses used for analgesia, in children under the age of 16 years and with slow administration, and can be managed in the same way as delirium using haloperidol and benzodiazepines. Additional adverse reactions involve skin reactions at the site of sub-cutaneous administration, cardiovascular excitability, excess salivation, and enhanced gastrointestinal transit. Ketamine is also a potent cerebral vasodilator and increases cerebral blood flow by about 60% and therefore, is not recommended for patients with increased intracranial pressure.
In the palliative setting, ketamine can improve analgesia in morphine tolerant patients with neuropathic pain [106] but 40% of patients had central adverse effects. In children receiving parenteral administration, a loading dose of 0.1 to 0.2 mg/kg, can be followed by an infusion rate of 0.1 to 0.3 mg/kg/h, and this can be increased to effect, intolerable side effects or a maximum infusion of 1.5 mg/kg/h.
For bone pain
In contrast with the nature of distribution of neuropathic pain, bone pain is typically well localized and may be indicated by a patient by pointing to a specific spot. It can be intense and very severe and is sometimes described as boring or like a drill . The timing of the pain depends on the underlying cause which can include marrow expansion from leukaemia or solid tumours, or metastatic spread to bone cortex (for example, with osteosarcoma or Ewing's sarcoma).
Non-malignant causes of bone pain can include:
Primary defects and structural bone proteins (osteogenesis imperfecta)
Bone abnormalities in the context of systemic disease (mucopolysaccharidosis)
The effects of systemic treatment (especially steroids)
The effects of immobilisation in neurodegenerative conditions and cerebral palsy.
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Where it is due to a fracture, bone pain may be intermittently very severe or episodic in nature (see below) which can complicate its management since analgesia sufficient for pain, at its worst, may be too toxic for pain, at its least.
Procedures that immobilize the bone may be effective in reducing bone pain, particularly if associated with a fracture. Opioids are, as always, the most reliably effective analgesics. However, useful adjuvants include non-steroidal anti-inflammatory drugs, bisphosphonates, and radiotherapy.
Non-steroidal anti-inflammatory drugs
The NSAIDs are a heterogenous group of powerful anti-inflammatory agents that inhibit the activity of the cyclooxygenase (COX) enzyme, and thus the production of prostaglandin and thromboxane. The specific mechanism of analgesic action is not known, but blockade of prostaglandin production does not account for the total analgesic effect.
There is a wide array of essentially equi-analgesic agents [107]. The oldest NSAID (acetyl-salicylic acid or aspirin) is often considered an inferior analgesic and possesses two other undesirable features that make it less suitable for use as a primary analgesic in children. It has non-linear elimination kinetics (slower elimination at higher concentrations) that increases the risk of toxicity in the form of salicylate poisoning. Its use in children with febrile illness has been associated with the development of Reye's syndrome [108], though this is debated [109]. Depending on the stage of the child's disease, the latter concern may not be as relevant to children with palliative care needs.
NSAIDs are, broadly, grouped according to selectivity for the two isoforms of COX; constitutive COX-1 and inducible COX-2. COX-1 is present in all tissues and is involved in physiological functions, such as gastrointestinal mucosal protection, platelet function, and regulation of renal haemodynamics and electrolyte balance. COX-2, normally undetectable in tissue, is involved in inflammation, mitogenesis, and specialized signal transduction. There is considerable increase in COX-2 activity with inflammation. The non-selective NSAIDs inhibit both isoforms to varying degrees making them effective anti-inflammatory and analgesic agents, while the selective COX-2 inhibitors have poor analgesic activity outside of their anti-inflammatory action.
The mechanism of action in blocking the COX-1 pathway may not completely explain the analgesic efficacy, but does seem to account for their adverse effects. These are either predictable and dose-dependent or unpredictable and dose-independent.
Predictable Effects Include:
Haematological decreased platelet adhesion. Decreased platelet aggregation and prolongation of bleeding time results from inhibition of platelet thromboxane A2 activity. Aspirin is the only agent to inhibit platelet aggregation irreversibly, and inhibition by other preparations depends on blood concentration and has not been a practical concern for children having surgery or dental extractions. It is generally held that children with pre-existing reduced platelet counts or bleeding disorders (such as those with relapsed leukaemias) should avoid NSAID where possible, though there is little published evidence to support this caution.
Gastrointestinal dyspepsia, haemorrhage, peptic ulceration, perforation. Clinically significant gastropathies are unusual during chronic use in children with juvenile rheumatoid arthritis [110]. Taking these agents with food can minimize the gastrointestinal effects. Avoidance is advised in children with a history of peptic ulceration.
Renal salt and water retention, interstitial nephritis. Renal toxicity is low in normal healthy children [111], but risk increases in those with pre-existing renal problems or hypovolaemia [112].
Pulmonary bronchospasm. NSAID-induced broncho-spasm occurs in 8 20% of asthmatic adults but seems to be uncommon in children [113, 114]. However, they should be avoided in children with previous reactions to NSAIDs and practitioners should remain alert to the possibility of idiosyncratic reactions.
Unpredictable events can include effects on the following systems:
Central nervous system (CNS) tinnitus, dizziness, headache, anxiety, aseptic meningitis, psychiatric-type reactions
Gastrointestinal diarrhoea
Haematological thrombocytopaenia, haemolytic anaemia, agranulocytosis, aplastic anaemia
Immunological anaphylaxis
Hepatic hepatitis, Reye's syndrome
Skin rash, pruritis, angioedema, severe skin reactions
COX-2 selectivity appears to correlate with a reduction in, but not elimination of, gastrointestinal adverse events and platelet aggregation problems. However, this has to be weighed against their relatively poor analgesic cover outside of their anti-inflammatory action and other potential adverse effects. This was highlighted in 2004 by the worldwide withdrawal of rofecoxib (Vioxx) after clinical trial data indicated an increased incidence of serious thrombotic events, myocardial infarction, and stroke among adult patients receiving long term rofecoxib compared with placebo.
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Bisphosphonates
Bisphosphonates are analogues of pyrophosphate, a natural inhibitor for the formation of calcium phosphate crystals. Their effect is to decrease bone resorption by:
Decreasing recruitment and function of osteoclasts the mevalonate enzyme pathway is inhibited.
Stimulating osteoblasts to produce an inhibitor of osteoclast formation.
Direct binding to hydroxyapatite crystals in bone, making it inherently more resistant to resorption.
These actions do not impair bone architecture or mechanical strength and lead to an increased vertebral bone mass and bone density. They are available in intravenous and oral forms and biological action is dependent on the chemical side chain. First generation bisphosphonates such as etidronate and clodronate are the least potent; second generation aminobisphosponates like alendronate and pamidronate are 10 100 times as potent as first generation drugs, while third generation agents, such as risedronate and zoledronic acid, are 10,000 times more potent.
Bisphosphonates have been used in children for 25 years. The conditions for which they are used are very diverse. In contrast with adults, in whom there is considerable experience of their use for painful metastatic malignant disease [115], in children, most experience has been in congenital and acquired forms of osteoporosis [116]. There are only limited case reports of use for bone pain in children and none is related to malignancy.
Bisphosphonate therapy appears not only to be effective but also safe, even with prolonged use. The adverse effects described with pamidronate can be divided into short and long-term.
Immediate side effects include:
Acute phase reaction common influenza-like reaction that is fever, chills, myalgia, that occurs 24 48 h after the first treatment but usually not in subsequent infusions. The symptoms may be improved by prophylactic use of paracetamol or ibuprofen.
Hypocalcaemia uncommon problem that occurs within 72 h of infusion but can be prevented by a daily intake of 1 to 1.5 g calcium.
Bone pain only reported in adults with cystic fibrosis but diminishes with subsequent infusions.
Iritis and/or uveitis uncommon.
Occasional long-term adverse effects have been reported. They include impaired bone mineralization, nephrocalcinosis and osteopetrosis [117]. There is a theoretical risk of altered bone re-modelling during periods of rapid growth, and in particular during adolescence, but this has not been demonstrated in practice [118].
Radiotherapy
Radiotherapy can be very effective if the cause of bone pain is localised metastatic malignant disease. This is true even for relatively radio-resistant tumours such as osteosarcoma, since a small reduction in the size of the lesion can have a significant effect on pain management. Some radiotherapy centres will offer a single fraction of palliative radiotherapy to sites of metastasis. This is well tolerated by children and young people, although they are often reluctant to undergo diagnostic interventions beforehand, such as plain x-ray or bone scan, that require attendance at hospital. Many radiotherapy centres will offer targeted radiation on clinical history alone in the palliative phase.
The effectiveness of radiotherapy is such that a degree of narcotisation (see above) should be anticipated among children on major opioids for metastatic bone pain.
Muscle spasm
Muscle spasm is a potent source of pain for many children with neurodegenerative conditions and particularly cerebral palsy. Benzodiazepines have been prescribed to patients in this group with good effect [119]. Baclofen and dantrolene may also be of benefit and should be offered alongside analgesic therapy.
More recently, botulinum toxin has been shown to have good efficacy in relieving the pain of muscle spasm in cerebral palsy [120, 121, 122]. The administration of botulinum toxin is a specialist skill requiring input from the local paediatric neurology or orthopaedic team. For children whose pain is significantly improved by botulinum toxin, it can often be inferred that an orthopaedic intervention to relieve muscle spasm will also be effective on a more permanent basis. The management of painful muscle spasm in cerebral palsy, therefore, requires a collaborative approach between paediatric palliative medicine, orthopaedics, and the paediatric teams mainly involved in the care of the child.
Opioids should not be withheld from children with non-malignant conditions. Given the expectation that they will survive for decades, however, it is often prudent to optimise management with non-opioid means first and proceed to opioids if these initial measures fail.
Cerebral irritation
The experience of pain is powerfully amplified by anxiety and incomprehension. Cerebral irritation, usually arising from acute hypoxic ischaemia or septic brain injury, can cause pain that is very difficult to treat using opioids and other analgesics alone. Benzodiazepines such as midazolam or lorazapam can be of benefit in reducing anxiety, but should be continued for
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only a few weeks, if possible. Phenobarbitone (Phenobarbital) is an effective sedative that has the additional advantage of being familiar to many neonatal paediatricians as an anticonvulsant. Again, it should be continued only for a few months in order to avoid the risk of unacceptable long-term side effects in these children who are likely to survive for some years. Once the acute brain injury has resolved, it is often possible to withdraw anxiolytic therapy over a period of some weeks.
Steroids
The use of corticosteroids as an analgesic adjuvant agent can be helpful in managing inflammatory-mediated pain or pain syndromes mediated by peri-tumour oedema, for example, headaches resulting from raised intracranial pressure [123], neuropathic pain secondary to spinal cord, nerve root or peripheral nerve compression, and pain resulting from capsular distension.
There are a variety of corticosteroids available, but those that have minimal or no salt-retaining properties, such as prednisolone, betamethasone and dexamethasone, are recommended. Dexamethasone is the most often used in most countries. It has a relative potency 25 times that of cortisone, and a biological half-life between 36 54 h despite a plasma half-life of 3.6 h. Betamethasone has similar characteristics to dexamethasone, while methyl-prednisone possesses 5 times the potency of cortisone, but a similar half-life.
The pharmacological actions of steroids are Protean, and this is equally true of therapeutic and adverse effects. Administration of any corticosteroid can result in a plethora of adverse events. All are more likely to occur with high doses and/or prolonged duration of treatment. They include:
Cushingoid habitus moon face, central adiposity
Skin striae, acne, skin fragility, increased bruising, poor wound healing
Muscle proximal myopathy, peripheral oedema
Gastrointestinal gastritis, bleeding, gastric ulceration and perforation
Immunological increased risk of infection, oral candidiasis
Metabolic osteoporosis, insatiable appetite, hyperglycaemia/glucosuria
Psychological restlessness, agitation, sleep disturbance, anxiety, depression, frank psychosis. In children, behaviour and mood changes are common.
The progressive distortion of a child's physical appearance should not be underestimated for the effect it has on both the child and family, especially the body image conscious adolescent. As a result, the temporal relationship of steroid use to projected life expectancy must be carefully considered and the lowest effective dose used. Options to prolonged use include maximizing opioids and other symptom-specific agents, prescribing corticosteroids as pulses. This is a brief, intense 3 5 day course repeated at set intervals or when symptoms dictate. Effective control of symptoms has been reported for up to 4 weeks [124]. In some situations, a large one-off dose can be helpful in a severe pain crisis.
A typical dose of corticosteroids for a child is 1 2 mg/kg/day of prednisolone, (maximum 60 mg/day) or 0.5 mg/kg/day (maximum 16 mg/day) of dexamethasone. The biological half-life data would suggest that once or, at most, twice daily dosing is required.
Palliative chemotherapy
The term palliative chemotherapy has been used in many different ways [123]. In its most precise sense, chemotherapy can have a role in reducing symptoms due to advanced cancer. It should only be prescribed after carefully weighing up its potential benefit against the likely burden it will impose on the patient. This would include, for example, increased need for attendances to hospital for haemoglobin, platelet and white cell counts, the possibility of nausea and vomiting and also of hair loss. Oral etoposide [126, 127, 128] can relieve symptoms caused by tumour bulk, particularly in haematopoietic malignancies and brain tumours. Vincristine and steroids can be effective in managing the pain of medullary expansion due to leukaemic transformation of the marrow. The side effects of steroids have been considered (see above) and it should be remembered that vincristine needs to be given intravenously, requiring a cannula to be sited, and can cause painful neurotoxicity for some children. For most, however, it can offer a well-tolerated tumour reducing effect.
Not all chemotherapy given to children with cancer for whom there is no longer a chance of cure can be considered truly palliative. Chemotherapy given on phase I or II clinical trials, for example, is experimental and is not, therefore, prescribed with any likelihood that symptoms will be relieved. Nevertheless, trial chemotherapy can be very valuable for some children and particularly young people who will value the opportunity of taking part in a trial that may contribute to human understanding. Many will retain the hope that trial chemotherapy will work a miracle and it is important that patients and families realise that neither long term cure, nor even palliation of symptoms, is the expectation. Any impact on symptoms is incidental to the stated goal of the trial.
Many families request chemotherapy even when it is clear that it is futile. Again, this should not be confused with palliative chemotherapy, since the intention is not to palliate symptoms.
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There may, occasionally, be a place for such futile chemotherapy but it is important to ensure that the needs of the family are carefully weighed against those of the child and that the child does not suffer simply in order to perpetuate false hope in the family.
Regional and neurolytic approaches
Neurolytic approaches include epidural, spinal and intrathecal anaesthesia as well as regional nerve blocks, or ablative therapy. They are the domain of specialist anaesthetic and neurosurgical services. Most require hospital attendance or even admission for invasive procedure, and are, therefore, relatively rarely used in children. They can be difficult for a family to manage at home.
Nevertheless, they should be considered in children for whom adequate pain relief cannot be obtained using the methods outlined elsewhere in this chapter [129]. Consultation with an appropriate colleague should be considered early when there is evidence of coeliac plexus pain or for the child with pelvic or lower limb pain, and particularly for the child who is in any case immobile.
Breakthrough and incident pain
The terms episodic' and breakthrough are not precisely the same. Pain may be episodic for three rather distinct reasons. The dose of regular medication may simply be too small, resulting in intermittent breakthrough pain. Breakthrough pain itself has been defined as a transitory exacerbation of pain superimposed on a background of persistent, usually well controlled pain' [130]. The solution is to review the regular medication and adjust the dose as outlined above.
The cause of the pain may itself be episodic. For example, movement can provoke pain from a pathological fracture or from some bone metastases. This is often referred to as incident pain . Identifying, anticipating, and where possible avoiding the provoking factors are the mainstays of treatment. Local radiation, chemotherapy or surgery can help, but even simple measures such as a sling to immobilise the affected part can be of value. Regional neurolytic approaches may also have a role.
Finally, the pain itself may simply be of an episodic nature, for example, intestinal colic or muscle spasm. This is a situation in which adjuvant therapy such as anticholinergics or muscle relaxants may be particularly helpful.
Because these causes for episodic or breakthrough pain are closely related, the definitions are often confused and the therefore incidence difficult to estimate [129]. Adult patients report a wide variety of types of pain that can break through their regular analgesia and similarly variable events that can precipitate it [132].
An ideal pharmacological intervention for breakthrough pain would be immediately accessible to the patient at the time the pain began, have a very rapid on- and off-set of action [133], and be highly potent. There is currently no such paragon. The peak effect of oral morphine, for example, may be up to an hour after its ingestion, meaning that it will often occur well after the episode of pain has subsided.
Though none is perfect, agents that approach the ideal include ketamine, inhaled nitrous oxide, parenteral opioids and oral fentanyl lozenges. More novel methods of administration include buccal diamorphine and intranasal sufentanyl. Irrespective of what is chosen to treat the breakthrough pain itself, it is important to maintain the usual regular opioid schedule [133].
Summary
Managing analgesia is, of course, only one of the aspects of caring for a dying child. Palliative care means giving attention to physical, psychosocial, and spiritual issues simultaneously. It may seem that disproportionate emphasis has been placed on what is, after all, only one symptom among many.
The reality is that pain is the commonest symptom experienced by dying children, and that it overlaps with all dimensions of a child's existence. A child who is in severe pain cannot engage with carers in a way that allows meaningful exploration of other fears or concerns. Good pain management is, therefore, a necessary, though not sufficient, first step in addressing these wider issues.
Furthermore, pain itself is a symptom that is experienced in every existential dimension. Even where the primary painful stimulus is a physical one, its perception and experience by a child will be dictated by the spiritual and psychosocial context in which it occurs. The meaning of a painful ankle caused by a football injury is very different from that caused by recurrent cancer, even where the physical elements are identical. If we are to manage what has been described as total pain effectively, we must recognise the need to address it in as broad a way as possible.
This chapter has dealt with pharmacological approaches and has focused largely on its physical aspects, but the reader is encouraged to refer to other chapters in the book that examine the wider experience of pain.
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