from - who | world health organization...from: nicky king [nicky.king@ sent: 27 august 2008 12:05...

From: Jennifer Ssengooba [jnsengoba@

Sent: 01 September 2008 18:08

To: emlsecretariat

Subject: Essential drugs for palliative care for children

Follow Up Flag: Follow up

Flag Status: Green

2008-09-08

Contribution from DR Jenny I have found long-term oral and stat dosed promethazine very useful in the controlling of vomiting in HIV positive children inwhose care i have been involved in the last 7 years at Mildmay Pediatrc Care Centre. Diazepam for anxiety Morphine (carefully titrated doses) for breathlesness and terminal agitation. Dr Jennifer Ssengooba (+256)772 447727 You could contact me on the telephone and email above for details. I have been brief because i'm trying to beat the deadline against failing internet services in Uganda today. I

From: Nicky King [Nicky.King@

Sent: 27 August 2008 12:05

To: emlsecretariat

Subject: comment on ELMc Palliative care


Flag Status: Green

2008-09-08

This document seems very comprehensive and well researched.I wonder if Levomepromazine could be included for the use of terminal agitation as well as nausea and vomiting. I am surprised Glycopyrronium has not been included for respiratory secretions as it has the benefit of not crossing the blood brain barrier and being usefully orally (or via a tube) for excessive secretions, a common problem for the non oncology life shortened children. Regards Dr Nicky King Medical Director Ellenor Lions Hospices The Ellenor Centre St Ronans View, East Hill Drive, Dartford Kent, DA1 1AE

From: Mike Miller [mikemiller

Sent: 31 August 2008 19:12

To: emlsecretariat

Subject: comments on Draft for EMLc Pallaitive Medications


Flag Status: Green

2008-09-08

Dear Sir/Madam I apologise for the last minute reply and if I am not using the correct format. I have read the Application for the EMLc prepared by Linda Brooke and others at Alder Hay Children’s Hospital and am impressed by the quality and extent of the work. It makes useful material for teaching and training. I would like to add the following comments:

1. PAIN: Is there really a need for codeine? In my practice I consider it inferior to morphine and more constipating and more sedative. I think it only has a place as it is erroneously thought by many to be not as addictive and as such allowed by some countries when morphine is discouraged or very difficult to obtain.

2. ANXIETY:I would like to add the formulation of 10mg/ml that is the preparation of choice for buccal administration. For buccal administration the medication needs to be as concentrated as possible and reasonably palatable. I have known children choke on the IV preparation of midazolam (5mg/ml) given buccally. I apologise for not being able to find which salt of midazolam this preparation is. Unfortunately the expense (due to this being a special preparation) and lack of availability will mean that this very useful medication is not suitable for the EMLc.

3. VOMITING:I would support Ondansetron not being included. It is usefully less sedating than the included anti emetics but even with this advantage is rarely used in paediatric palliative practice.

4. CONSTIPATION: I think that the inclusion of a Macrogol (such as Movicol) is essential. It is one of the few painless and non-invasive treatments for impaction, but is very messy. I assume there is a lack of standardisation of what I think is a cheap medication. Reasons for it being left out should be stated.

5. RESPIRATORY SECRETIONS: There is a spelling mistake in the first paragraph pg 10 – ANTIMUSCARUARINIC for antimuscarinic.

6. DEFINITION OF PAEDIATRIC PALLIATIVE CARE – Should support in Bereavement be included? I was pleased and surprised to find this document so useful to read and so full of easily accessible information. I will certainly publicise its existence when it is in its final draft. Yours truly, Dr Michael Miller Consultant in Paediatric Palliative Medicine Martin House Grove Road Clifford Wetherby LS23 6TX United Kingdom

From: Currow, David (RGH)


To: Subject: FW: [Fwd: RE: Consultation on the Palliative Care Section of the WHO Essential Medicines List

for Children]

2008-09-08

Dear Liliana This is a very comprehensive work and the authors are to be commended for the detail and exceleence of the work. For breathlessness and for terminal agitation, I am concerned that the most widely used benzodiazepine in paediatrics - clonazepam drops which are designed to be administered sublingually - are not included. Rather, midazolam is listed as an injectable formulation. As such, midazolam is not community friendly and is not easily administered by family memebers. By contrast, clonazepam sublingualy for which pharmacokinetic and pharmacodynamic data are available can be adminsitered with predictable benefits in a formulation that is commercailly available. It is also available at a fraction of the cost of midazolam. Happy to discuss David

From: Anne Hunt [AHunt@uclan


To: emlsecretariat

Subject: re WHO essential medicines_children's palliative care


Flag Status: Green

Attachments: transdermal fentanyl_hunt et al.pdf; Population pharmacokinetics_Hunt et al.pdf; Hunt & Burne_problems in neurodegen_1995.pdf; Anne Hunt.vcf

2008-09-08

With reference to the essential medicines list for children_palliative care, I would like to bring the following to your attention in case they are useful and escaped your search.

1. With regard to prevalence of symptoms in children with life-limiting conditions other than cancer - Hunt, A., Burne, R., 1995. Medical and nursing problems of children with neurodegenerative disease. Palliat Med 9 (1), 19-26. This paper includes a report on symptoms listed on a children's hospice database for each visit of 45 children with a neurodegnerative condition to the hospice over a 12 month period. (paper attached).

2. Though the section on Fentanyl transdermal patches cites Zernikov's review the table suggests that none of the studies is done in children's palliative care populations. note - Collins, J.J., Dunkel, I.J., Gupta, S.K., Inturrisi, C.E., Lapin, J., Palmer, L.N., Weinstein, S.M., Portenoy, R.K., 1999. Transdermal fentanyl in children with cancer pain: feasibility, tolerability, and pharmacokinetic correlates. J Pediatr 134 (3), 319-323 and Hunt, A., Goldman, A., Devine, T., Phillips, M., 2001. Transdermal fentanyl for pain relief in a paediatric palliative care population. Palliat Med 15 (5), 405-412. (paper attached).

3. Re morphine - Although you do not consider dose in your recommendations, in relation to possible greater needs for morphine in younger children I wonder if this paper may be useful Hunt, A., Joel, S., Dick, G., Goldman, A., 1999. Population pharmacokinetics of oral morphine and its glucuronides in children receiving morphine as immediate-release liquid or sustained- release tablets for cancer pain. J Pediatr 135 (1), 47-55. (paper attached).

4. Might you consider adding docusate enema by rectal route for constipation? 5. Reference 15 is omitted from the table on page 22.

With very best wishes, Anne Dr Anne Hunt RSCN PhD Senior Research Fellow in Children's Palliative Care Room 414, Brook Building Department of Nursing University of Central Lancashire Preston PR1 2HE

Transdermal fentanyl for pain relief in a paediatricpalliative care populationAnne Hunt Institute of Child Health, London; RCN Institute, Radcliffe Infirmary, Woodstock Road, Oxford,Ann Goldman Institute of Child Health, London, Tom Devine Paediatric Oncology Department, RoyalMarsden Hospital, Sutton and Marianne Phillips Department of Paediatric Haematology/Oncology,Llandough Hospital, Penarth, on behalf of FEN-GBR-14 Study Group

Abstract: This multicentre, observational study examined the efficacy of thetherapeutic transdermal fentanyl system (TTS-fentanyl) in children requiring opioids forpain in life-threatening disease. Forty-one children receiving oral morphine (median dose60 mg/day) transferred to transdermal fentanyl (median dose 25 �g/h according with themanufacturer’s dose conversion guidelines). Twenty-six children completed the 15-daytreatment phase, seven died due to disease progression and eight were withdrawnbecause of adverse events, inadequate analgesia or a change to parenteral opioids.After 15 days, the median fentanyl dose was 75 �g/h (range 25–250 ). No seriousadverse events were attributed to fentanyl. There was a trend toward improved side-effects and convenience with fentanyl. Twenty-three of 26 parents (three missing) and25 of 26 investigators considered transdermal fentanyl to be better than previoustreatment. For all records available (at 15 days or on withdrawal if earlier), 75% (27/36)reported that fentanyl treatment was ‘good’ or ‘very good’. The findings suggest thattransdermal fentanyl is both effective and acceptable for children and their families.

Key words: child; pain; analgesics; opioid; terminal care; palliative care

Resumé: Cette étude multicentrique par observation examine l’efficacité du Fentanyltransdermique (TTS-fentanyl) chez les enfants nécessitant des opioïdes pour douleur dansle cadre de maladies incurables. Quarante et un enfants recevant de la morphine orale(dose médiane de 60 mg/jour) ont été mis sous Fentanyl transdermique (dose médianede 25 �g/h selon la table de conversion fourni par le fabricant). Vingt-six enfants ont ététraités quinze jours, sept sont décédés en raison de la progression de la pathologie ethuit ont été sevrés en Fentanyl en raison d’effets adverses, d’analgésie inadéquate oude nécessité de mise sous opioïdes par voie parentérale. Au bout de 15 jours, la dosemédiane de Fentanyl était de 75 �g/h (de 25 à 250 ). Aucun effet secondaire sérieux n’a été imputé au Fentanyl. La tendance était plutôt celle d’une amélioration au regarddes effets secondaires et de l’aspect pratique avec le Fentanyl. Vingt-trois des 26 parents(3 absents) et 25 des 26 investigateurs ont considéré que le Fentanyl transdermique étaitun meilleur traitement que le précédent. Parmi tous les résultats disponibles (à 15 joursou lors du sevrage avant cette date), 75% (27/36) ont déclaré que le Fentanyl était untraitement bon « ou très bon ». Ces résultats suggèrent que le Fentanyl transdermiqueest à la fois efficace et acceptable pour les enfants et leurs familles.

Mots-clés: enfant; douleur; analgésiques; opioïdes; soins terminaux; soins palliatifs

Palliative Medicine 2001; 15: 405–412

© Arnold 2001 0269–2163(01)PM448OA

Address for correspondence: Anne Hunt, Research Fellow, Royal College of Nursing Institute, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK. E-mail:[email protected]

07PM448.qxd 9/8/01 1:57 pm Page 405

Introduction

Over two-thirds of children with progressive malig-nant disease experience pain requiring opioid anal-gesia;1 pain relief is an important part of theirpalliative care. The standard pharmacologicaltreatment is oral morphine, which is available in avariety of short- and long-acting formulations.2However, this treatment is not ideal in all clinicalsituations. Analgesia is accompanied in some chil-dren by troublesome side-effects such as drowsiness,constipation and itching. When oral therapy is notpossible, for example due to severe nausea or whena child’s level of consciousness decreases, alterna-tive more invasive routes, i.e. subcutaneous, intra-venous or rectal must be used. The therapeutictransdermal fentanyl, system (TTS-fentanyl, Durogesic® patch, Janssen-Cilag Ltd) offers analternative potent analgesic, available by a non-invasive route.

While intravenous and epidural fentanyl arewidely used for children in acute settings and trans-dermal fentanyl is widely used in adult palliativecare, transdermal fentanyl is not yet licensed for usein children. It is, however, an attractive option forthe management of persistent pain in childrenrequiring a strong opioid, particularly pain associ-ated with life-threatening disease, where a non-invasive method of pain relief is a particular assetin allowing parents to care for their child at homein the terminal stages of their disease.

Literature relating to the use of TTS-fentanyl inchildren is sparse and mainly anecdotal. Carefullycontrolled observational studies are required toinvestigate the safety and efficacy of the route.Collins and colleagues assessed the feasibility, tol-erability and the pharmacokinetics of TTS-fentanylin children with cancer pain.3 Eleven patients, pre-viously receiving morphine, were assessed over sixtreatment days (two patch changes). Ten of the 11patients completing the treatment period continuedto use TTS-fentanyl following the study. TTS-fen-tanyl was found to be feasible and well tolerated andto yield fentanyl pharmacokinetic data similar tothose for adults. The current study assesses the useof TTS-fentanyl in a larger number of patients overa treatment period of 15 days with a follow-onperiod of 3 months. The population includes children with life-limiting disorders other than cancer.

Methods

Patients (aged 2–18 years) who required opioidtreatment for pain associated with cancer or otherlife-threatening conditions were eligible for thestudy provided they had been receiving a stable doseof oral morphine of at least 30 mg/day for 48 h orlonger. Children in the terminal phase of their dis-ease were not excluded from the study as they werefelt to be the population most likely to use and bene-fit from the transdermal route. Informed signedconsent was obtained from the child’s parents andwhere feasible the child’s assent was also obtained.The study received approval from local researchethics committees at all (n � 11) participating centres.

TreatmentAll participants were transferred from morphine to transdermal fentanyl following the manufac-turer’s guidelines for dose conversion (see Table 1).Patients receiving 4-hourly immediate-releasemorphine were advised to take one further dose ofmorphine 4 h after the first patch was applied.Those taking sustained-release oral morphine hadtheir first patch applied when the last dose of sustained-release morphine was given. All partici-pants had access to immediate-release oral morphinefor breakthrough pain and were advised to increasethe dose of rescue morphine in line with anyincrease in fentanyl dose, using a dose conversionchart. The transdermal fentanyl patches were nor-mally replaced every 72 h with increments of 25�gfentanyl/h used as required. Larger incrementscould be used for patients receiving higher doses offentanyl. Participants used the transdermal fentanylfor 15 days (i.e. five patch changes). At the end ofthe 15-day treatment phase, after discussionbetween the parents, investigator, and child if able,

406 A Hunt et al.

Table 1 Manufacturer’s recommended dose conversion,oral morphine to transdermal fentanyl

Total daily dose, oral morphine Fentanyl dose (mg) (�g/h)

�135 25135–224 50225–314 75315–404 100405–494 125495–584 150

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patients were eligible to continue in a long-term follow-up phase of 12 weeks.

AssessmentsThe children completed the assessments whereverpossible, but if they were unable to do so, their par-ents or carers made assessments. All participantscompleted diaries, which recorded use of rescuemedication, bowel function and severity of pain.Pain assessments, using the Faces Affect scale,4were made twice daily as well as before and 1 h afterany rescue medication was taken. Assessments oftreatment (pain control, sleep quality and conve-nience of the patch for parents and child) as well asside-effects (presence or absence of drowsiness,constipation, itchiness and dry mouth) were madeby the patient or parent every 3 days when patcheswere changed. Parents also reported, every 3 days,on the child’s level of activity using the Play Performance Scale.5 On day 15 of the study (or onwithdrawal from the study if earlier), global assess-ments of the child’s treatment with respect to paincontrol, side-effects, convenience and satisfactionwith the treatment, were made by parents and inves-tigators. The primary outcome measure was thepatients’ (or parents’) assessment of their satisfac-tion with the treatment, as measured on a four-point verbal rating scale, at day 15 (or on with-drawal from the study if earlier).

Safety evaluationsThe occurrence of any adverse events was notedthroughout the study. The patients’ heart and respiratory rates were recorded every 3 days. Ateach patch change, skin previously covered by thepatch was examined for signs of erythema,oedema, itching or papules/pustules. These features

were recorded as either absent, mild, moderate orsevere.

Results

Patient characteristicsParticipants were recruited from 11 centres acrossthe UK between February 1996 and August 1998.Forty-one children (median age 10.5 years: range2.6–18.8) entered the study. Thirty-six patients hada malignant disease (32 solid tumours, four haema-tological malignancies). The remaining five childrenhad a life-limiting neurological or neuromuscularcondition (Table 2). Reasons for transfer includeddifficulty with or reluctance in swallowing oral medi-cation and occurrence of unacceptable morphineside-effects.

Thirty-four children transferred to fentanyl at apatch size of 25 �g/h, five at 50 �g/h, one at 75 �g/hand one at 150 �g/h. The median daily dose of oralmorphine at entry was 60 mg (range 0–520). Twochildren who had not received morphine at30 mg/day immediately prior to entry were allowedto enter the study. One case was a 14 year old whorefused to take oral medication but had receivedintermittent doses of intramuscular morphine. Thesecond was an 18 year old about to sit examinationswho was reluctant to take morphine on account of having previously experienced unacceptabledrowsiness with it.

Treatment phaseOf the 41 patients, 26 completed the 15-day treat-ment phase. Of the 15 who did not complete, sevendied due to progression of their disease and eightwere withdrawn. Withdrawals from the study were

Transdermal fentanyl for paediatric palliative care 407

Table 2 Patient and dosage characteristics (median and range) at transfer from morphine to transdermal fentanyl

Male/ Age Morphine Morphine dose Fentanyl Fentanyl dose Days inDiagnosis n female (years) dose (mg) (mg/kg/day) dose (�g/h) (�g/kg/h) study

Haematological 4 4/0 8.6 (4.9–17.0) 65 (60–80) 2.3 (1.0–5.1) 25 (25–25) 1.0 (0.4–1.6) 24.5 (0–55)malignancy

Brain tumour 5 4/1 6.7 (2.6–12.8) 60 (30–180) 2.7 (1.1–5.2) 25 (25–50) 1.4 (0.5–2.3) 13.0 (4–92)Other solid 27 18/9 10.5 (2.6–18.8) 50 (0–520) 2.5 (0–7.9) 25 (25–150) 1.5 (0.4–2.4) 23.0 (0–213)

tumourNeuro- 5 4/1 15.7 (8.0–16.9) 60 (30–125) 2.3 (0.7–2.6) 25 (25–50) 0.8 (0.6–1.0) 22.0 (1–460)

musculardisease

Median (range) 10.5 (2.6–18.8) 60 (0–520) 2.5 (0–7.9) 25 (25–150) 1.3 (0.4–2.4) 21.5 (0–460)

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due to inadequate analgesic response (5), change toparenteral opioids with adjuvants in the terminalphase (1), and adverse effects (increase in cough (1)and disturbed night (1)).

Doses received. Nine (35%) patients required anincrease in patch size within the first 3 days. Thir-teen (50%) required an increase in the first 6 days.Five (19%) patients required two increases withinthe first 6 days. There was no obvious relationshipbetween the need for an increase in fentanyl doseand the morphine dose administered previously. At 15 days the median fentanyl dose was 75 �g/h(range 25–250). Doses received at 15 days weresimilar across diagnostic groups (Table 3).

Children who completed the 15-day treatmentphase were divided into two subsets by age (below(n � 13) and above (n � 13) 10 years of age). After15 days, titration, no statistical difference was seen in patch strength (�g/h) between the two agegroups at start or at 15 days. However, the dosereceived, when calculated according to weight(�g/h/kg), was significantly greater in youngerchildren at start (median 1.6 and 0.7 �g/h/kg in theyounger and older group, respectively) and at 15days (median 5.4 and 1.4 �g/h/kg in the younger and older group, respectively) (Mann–Whitneytest P � 0.0001 for 0 and 15 days). Children in theyounger group had significantly more doseincreases (median 3, range 1–5 in the younger groupvs median 2, range 0–5 in the older group)(Mann–Whitney test P � 0.05).

Assessment of efficacy. Every third day, childrenor their parents were asked to rate the effects of thepatch as either poor, fair, good or very good. On thethird day of treatment the assessments were six

(17%) very good, 17 (49%) good, nine (26%) fairand three (8%) poor. On the fifteenth day, treat-ment assessments were available from 25 cases andthese were seven (28%) very good, 14 (56%) goodand four (16%) fair. When the last recordedassessments for patients who withdrew before 15days are included (36/41 assessments available) 75%(27/36) regarded the patch as either good or verygood and the great majority of children and parentsfound the patch convenient (Figure 1). At 15 days23/26 (three missing) parents and 25/26 investiga-tors considered TTS-fentanyl to be better (from‘slightly better’ to ‘much better’) than previoustreatment.

Serious adverse events. Three deaths occurredwithin 24 h of transfer from morphine to fentanyl.Four further deaths occurred later in the treatmentphase. No death was considered to be due to thefentanyl. The other events reported as serious werethose requiring admission to hospital. Eleven ofthese events were recorded in eight children.Again, these events were related to the underlyingdisease rather than to fentanyl, for example spinalcord compression, intestinal obstruction fromtumour, need for blood or platelet transfusions andinvestigation of pain.

Adverse events. Most (62%) adverse events wereconsidered to be related to the underlying diseaserather than to fentanyl. Those thought definitely(13%) or possibly (25%) due to fentanyl includedsymptoms commonly associated with opioids suchas nausea, vomiting, constipation and itching. Central nervous system symptoms thought possiblyor definitely due to fentanyl occurred in a total of13 (32%) patients. These included agitation (5),

408 A Hunt et al.

Table 3 Dose of transdermal fentanyl (median and range) at 15 days and 12 weeks

Fentanyl dose Fentanyl dose Fentanyl dose Patients at Fentanyl dose (�g/kg/h) at Patients at (�g/h) at (�g/kg/h) at

Diagnosis 15 days (�g/h) at 15 days 15 days 12 weeks 12 weeks 12 weeks

Haematological 2 25 (25–25) 1.1 (0.7–1.6) – – –malignancy

Brain tumour 2 75 (50–100) 1.7 (1.4–1.9) 1 100 2.8Other solid tumours 19 75 (25–250) 2.4 (0.7–8.6) 3 150 (125–525) 3.7 (2.5–16.7)Neuro-muscular 3 75 (50–100) 1.8 (1.3–3.0) 2 88 (75–100) 2.7 (1.4–4.0)

disease

Median (range) 75 (25–250) 1.9 (0.7–8.6) 113 (75–525) 3.2 (1.4–16.7)

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convulsions (3), hallucinations (3), paranoia (2),depression (2), insomnia (2), vivid dreams (1), dysk-inesia (1), aggressive reaction (1) and anxiety (1).

From an analysis of diary comments and listing ofadverse events, three children had symptoms in thefirst few days after transfer (such as sweating,abdominal cramps, diarrhoea, blocked nose,depression) which may have been related to mor-phine withdrawal. Where recognized at the time,these symptoms responded to breakthrough dosesof morphine; where not recognized, symptomsappeared to resolve over 2–3 days.

Side-effects (patient treatment assessments). In Figures 1 and 2 the patients’ assessments of fentanylat 15 days (or on withdrawal if earlier) are com-pared with the previous treatment. Fentanylshowed some improvement in pain relief, in consti-pation and in nausea and vomiting. Particularlymarked improvements were seen in itch and in drymouth although differences did not reach statisticalsignificance.

Skin site. Adhesion was usually good though in 24% of patch changes a dressing such as Opsite orTegaderm was used on top of the patch to ensure

adhesion. Mild to moderate erythema on removalof the patch was reported in 30% of patch changes.Itch was rarely reported. Some children had diffi-culties with patch removal (the patch stuck too well)and occasionally children declined entry to the studybecause of a reported dislike of ‘plasters’.

Long-term follow-upOf 26 children completing the treatment phase, 24 entered the follow-on period. Of the two notentered, one died on day 15 and the other 2 dayslater. One child continued to use the patch, but theparents chose not to complete the diary and norecords were available for follow-up. Of the 23 forwhom records were available, 13 continued to usethe patch until their death, one changed back to oralopioids and two were weaned from their opioids asintervening adjuvant therapy brought about painrelief. Seven children transferred to parenteral opi-oids (with or without adjuvants) before death, andat the close of the study, one child continued to usethe patch (after more than 100 days).

Analgesic requirements. The median number of days of patch use overall was 21 days (range 0–460).Six children used fentanyl patches for more than


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Figure 1 Patient assessments of transdermal fentanyl at 15 days after transfer or on withdrawal if earlier – positive effects

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12 weeks: the median dose at 12 weeks was 125 �g/h(range 75–525 m). Three children had exceptionalanalgesic needs (400, 650 and 1400 �g/h) requiringdoses well above the advised maximum of 300 �g/h.One further child was transferred to another routeat TTS-fentanyl 300 �g/h. The child’s surface areaand the time and difficulty in removing patches werelimiting factors.

Discussion

Children who entered the study required opioidanalgesia for pain from life-threatening disease.Children with cancer formed the largest group. Alarge proportion of children with terminal cancerwill ultimately require opioid analgesia for effectivepain relief. Advice on the use of transdermal fen-tanyl has suggested that it is most appropriate forstable pain, however, contrary to the disease characteristics of adults, the terminal phase for child-ren with cancer can often be relatively short withrapidly increasing pain.6,7 Frequent adjustments toanalgesic dose and the use of adjuvants are oftennecessary. In this study too, fairly frequent adjust-ments to dose were required. Nevertheless it was

possible in most cases to manage pain well, so thatthe majority (75%) of families felt that the fentanylpatch was ‘good’ or ‘very good’.

For the group with neurological disease, palliativecare is often required over a longer period of timebut many of the pains experienced (for example musculo-skeletal pain, pain from reflux oesophagitis)may be more amenable to treatments other than opioids.8 When opioid analgesia is required somechildren may already have a nasogastric tube or gas-trostomy for feeding and ‘oral’ morphine can begiven by that route even in the very terminal stages.However, the burden of care of these children canoften be very high and fentanyl patches deliveringpain relief at a steady rate could ease the strain onparents and possibly minimize side-effects. For chil-dren without feeding tubes, but difficulty in swal-lowing, the fentanyl patch can be a particularly usefuloption. The child receiving fentanyl for the longestperiod in this study (460 days) was a 15 year old withDuchenne muscular dystrophy with heart failure,musculo-skeletal and neuropathic pain, who even-tually achieved good pain relief with transdermalfentanyl (75 �g/h) and oral ketamine.

One of the issues often raised by investigators in this study was whether or not to transfer in the

410 A Hunt et al.

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Figure 2 Patient assessments of transdermal fentanyl at 15 days after transfer or on withdrawal if earlier – side-effects

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terminal phase to an opioid by a parenteral route.In most cases described, children continued toreceive their pain relief via the patch. However, ina smaller number, particularly where a parenteraladjuvant was required, for example midazolam orcyclizine, the child was transferred to diamorphineusually by the subcutaneous route. These transferswere carried out without difficulty using the manu-facturer’s guidelines on conversion rates in reverse(fentanyl dose to centre of the range of daily mor-phine dose equivalents, divided by three to givediamorphine dose required over 24 h). An alterna-tive could have been to leave the patch on and runboth routes in tandem. As well as a need for par-enteral adjuvants, a change to the parenteral routewas necessary in some cases where the opioid doserequired to manage pain could not feasibly be metby fentanyl patches. Some difficulty was encoun-tered when a parent had previously promised thechild that they would not require any ‘needles’.

Three children were weaned off their fentanylwhen they became pain free as a result of adjuvanttherapy (for example chemotherapy or radiother-apy). Whilst withdrawal symptoms were noted inone patient when the patch size was reduced every3 days, none were noted in another when the dose was reduced at a rate of one patch size everysixth day.

This study suggests that younger children (�10years) require similar doses to the older child (�10years) and that their requirements are higher whenthe dose is calculated by weight. This may in part bea result of the starting dose at which children weretransferred and the limited fentanyl doses available,but it is in keeping with other studies in childrenrelating both to intravenous fentanyl9 and to mor-phine10,11 where differences are found with age inchildren and between children and adults. Collins et al. demonstrated a higher plasma clearance anda larger volume of distribution for children thanreported for adults in their pharmacokinetic studyof transdermal fentanyl.3

The results suggest that side-effects of transder-mal fentanyl, whilst similar to morphine, are lesstroublesome. These results are supported by manyof the studies in adults.12,13 Side-effects related tothe central nervous system were reported fairly fre-quently in our study. In the absence of quality dataon the side-effects of morphine in children, and on the prevalence of disease-related symptoms, it is

difficult to determine whether these effects wererelated to fentanyl.

A proportion of children (10%) had analgesicrequirements difficult to meet with fentanylpatches. Other studies of opioids in children alsosuggest that in the region of 10% of children willhave exceptional requirements.10,14 In an extremecase an adolescent with pancreatic cancer took control of his own drug titration and, rather thantake oral breakthrough medication, increased hispatch dose. Ultimately he was receiving 1400 �g/h(44.6 �g/kg/h) of fentanyl. His dose was stable at this level for the final 2 weeks of his life and hisquality of life was reported by his parents and nursesas good. He remained mobile until his death having used the patches for nearly 6 months.

Conclusions

Palliative care in children needs to be flexible inorder to achieve as good a quality of life and deathas is possible and it is within this context that thestudy was carried out. The data suggest that trans-dermal fentanyl is an effective drug for the man-agement of pain in children already receiving oralmorphine at a dose of 30 mg or more daily. Safetyis more difficult to assess in this population wheremany were in the terminal stage of their disease.There appears to be some improvement in the side-effect profile over morphine and the great majorityof children and parents found the patch to be a con-venient route. Occasionally children had analgesicneeds difficult to meet with fentanyl patches. A significant proportion of children transferring tofentanyl according to manufacturer’s guidelinesneeded one to two increases in their patch sizewithin the first few days after transfer. Others whowithdrew early in the study may have benefited froman increase in dose. Success of the preparation will,despite the convenience of the patch, depend onclose supervision, ongoing pain assessment, appro-priate use of breakthrough medication and ade-quate titration of fentanyl dose.

AcknowledgementsWe wish to thank the patients, their parents andstaff of the paediatric oncology centres at the RoyalMarsden Hospital, Surrey; Llandough Hospital,Penarth; Great Ormond Street Hospital, London;


07PM448.qxd 9/8/01 1:57 pm Page 411

The Children’s Hospital, Birmingham; The OxfordRadcliffe Hospital; Royal Victoria Infirmary, Newcastle; Southampton General Hospital; Uni-versity Hospital, Queen’s Medical Centre, Notting-ham, and at the Children’s Hospices: Martin House,Boston Spa; Helen House, Oxford and LittleBridge House, Fremington for their support andparticipation. The study was supported by Janssen-Cilag Ltd and we thank Julia Baird and Mark Travers for their contribution to design and co-ordination of the study.

Competing interestsAnne Hunt and Ann Goldman have been reim-bursed by Janssen-Cilag Ltd for attendance at sci-entific meetings to present data from the study.Anne Hunt has been reimbursed by Janssen-CilagLtd for consultancy work.

References

1 Goldman A, Bowman A. The role of oralcontrolled-release morphine in pain relief inchildren with cancer. Palliat Med 1990; 4: 279–85.

2 World Health Organisation. Cancer pain relief andpalliative care in children. Geneva: WHO, 1998.

3 Collins JJ, Dunkel IJ, Gupta SK et al. Transdermalfentanyl in children with cancer pain: feasibility,tolerability, and pharmacokinetic correlates. JPediatr 1999; 134: 319–23.

4 McGrath PA, deVeber LL, Hearn MT.Multidimensional pain assessment in children. In:Fields HL, Dubner R, Cervero F eds. Advances inpain research and therapy. New York: Raven Press,1985: 387–93.

5 Lansky SB, List MA, Lansky LL, Ritter-Sterr C,Miller DR. The measurement of performance inchildhood cancer patients. Cancer 1987; 60:1651–56.

6 Chambers EJ, Oakhill A, Cornish JM, Curnick S.Terminal care at home for children with cancer. Br Med J 1989; 298: 937–40.

7 Goldman A, Beardsmore S, Hunt J. Palliative carefor children with cancer-home, hospital, or hospice?Arch Dis Child 1990; 65: 641–43.

8 Brady M. Treatment of common symptoms inpaediatric palliative care. CME Bulletin Palliat Med1999; 1: 63–68.

9 Singleton MA, Rosen JI, Fisher DM. Plasmaconcentrations of fentanyl in infants, children andadults. Can J Anaesth 1987; 34: 152–55.

10 Hunt A, Joel S, Dick G, Goldman A. Populationpharmacokinetics of oral morphine and itsglucuronides in children receiving morphine asimmediate-release liquid or sustained-release tabletsfor cancer pain. J Pediatr 1999; 135: 47–55.

11 Robieux IC, Kellner JD, Coppes MJ et al. Analgesiain children with sickle cell crisis: comparison ofintermittent opioids vs. continuous intravenousinfusion of morphine and placebo-controlled studyof oxygen inhalation. Pediatr Hematol Oncol 1992; 9:317–26.

12 Ahmedzai S, Brooks D. Transdermal fentanyl versussustained-release oral morphine in cancer pain:preference, efficacy, and quality of life. The TTS-Fentanyl Comparative Trial Group. J PainSymptom Manage 1997; 13: 254–61.

13 Donner B, Zenz M, Strumpf M, Raber M. Long-term treatment of cancer pain with transdermalfentanyl. J Pain Symptom Manage 1998; 15: 168–75.

14 Collins JJ, Grier HE, Kinney HC, Berde CB.Control of severe pain in children with terminalmalignancy. J Pediatr 1995; 126: 653–57.

412 A Hunt et al.

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47

Oral morphine is the drug of choice formoderate to severe cancer pain both inadults and in children. However, themanagement of cancer pain with mor-phine in children can be complicatedby several factors. Varying misconcep-tions may deter both professionals and

parents from providing adequate painrelief for children.1 They may fear thedevelopment of physical dependence,psychologic addiction, tolerance, andside effects, particularly respiratorydepression. In addition, few pharma-cokinetic or pharmacodynamic dataare available for children, althoughmost literature suggests that after the

neonatal period children handle mor-phine in the same way as adults. Al-though a number of studies examineoral morphine pharmacokinetics inadults, evidence that relates to childrenof different ages is very limited. Conse-quently, wide variations exist (from 0.4to 2.4 mg/kg/d) in recommended dos-

PPopulation pharmacokinetics of oral morphine andits glucuronides in children receiving morphine asimmediate-release liquid or sustained-release tabletsfor cancer painAnne Hunt, RSCN, BSc, MPhil, Simon Joel, BSc, Gina Dick, RSCN, and Ann Goldman, MB, FRCPCH

From the Institute of Child Health and Great Ormond Street Hospital Trust; ICRF Medical Oncology Department,St. Bartholomew’s Hospital, London, England; and the Royal Marsden Hospital, Sutton, England.Funded by CLIC UK (Cancer and Leukaemia in Childhood Trust), Elizabeth Clark CharitableTrust, and REACT (Research, Education and Aid for Children with potentially terminal illness).

Submitted for publication July 1, 1998; revision received Dec 9, 1998; accepted Feb 23, 1999.

Reprint requests: Anne M. Hunt c/o RCN Institute, Radcliffe Infirmary, Woodstock Rd, Ox-ford OX2 6HE, United Kingdom.

Copyright © 1999 by Mosby, Inc.

0022-3476/99/$8.00 + 0 9/21/98205

AUC Area under the plasma concentrationtime curve

Cav Average plasma morphine concentra-tion (AUC/t)

Cl Plasma clearanceF BioavailabilityGFR Glomerular filtration rateIRMS Immediate-release morphine sulfate

liquidka Absorption rate constantM3G Morphine-3-glucuronideM6G Morphine-6-glucuronideMST Sustained-release morphine tabletsVD Volume of distribution

Objectives: (1) To determine the pharmacokinetics of morphine, mor-phine-6-glucuronide (M6G), and morphine-3-glucuronide (M3G) in chil-dren with cancer receiving morphine as immediate-release morphine liquidor sustained-release tablets. (2) To determine differences with age withinthe group and from adults. (3) To explore relationships between plasmaconcentration and pain measurements.

Study design: Blood samples were collected and plasma analyzed by high-performance liquid chromatography with electrochemical and fluorescencedetection. Population pharmacokinetic parameters were derived with theprogram P-PHARM.

Results: Forty children with a median age of 11.4 years (range 1.7 to 18.7years) received a median dose of 1.4 mg/kg/d (range 0.4 to 24.6 mg/kg/d). Amedian of 4 blood samples per child was collected. Plasma clearance ofmorphine was 23.1 mL/min per kg body weight. The volume of distributionwas 5.2 L/kg. Molar ratios of M3G/morphine, M6G/morphine, andM3G/M6G were 21.1, 4.7, and 4.2, respectively. Children <11 years hadsignificantly higher clearance and larger volume of distribution for mor-phine and its glucuronides than older children and adults. Regression analy-sis indicated average plasma morphine concentration equal to dose(mg/kg/d) × 8.6 (95% confidence interval 7.4 to 9.9). Significant pain waspresent in 30% of the children. Higher pain scores were recorded in chil-dren with average morphine concentrations <12 ng/mL (P < .01 MW).

Conclusion: Age differences in morphine pharmacokinetics exist withinchildren and compared with adults. The study supports a starting dose of1.5 to 2.0 mg/kg/d to provide plasma morphine concentrations >12 ng/mL inchildren with cancer pain unrelieved by mild to moderate strength analge-sia. (J Pediatr 1999;135:47-55)

See editorial, p. 12.

HUNT ET AL THE JOURNAL OF PEDIATRICS

JULY 1999

ing schedules for the administration oforal morphine to children. The findingthat the morphine metabolite mor-phine-6-glucuronide has potent anal-gesic properties2,3 makes it importantthat investigation of this metabolite beincluded in pharmacokinetic studies.Because of the relatively small popula-tion, evaluation of opioid pharmacoki-netics, pharmacodynamics, and dosageguidelines in children with cancer re-quires multicenter and even multina-tional studies. A further difficulty isthat for this population, conventionalpharmacokinetic analysis would not bepossible, because in most cases onlysparse blood sampling could be consid-ered appropriate or ethical.

Therefore this study, with the use ofpopulation methods, aims to determinethe pharmacokinetics of morphine andits glucuronides in children receivingregular oral administration of eitherimmediate-release morphine sulfateliquid (Oramorph–Boehringer Ingle-heim) or sustained-release tablets (MSTContinus–Napp) for cancer pain and toinvestigate the effect of age on these pa-rameters and the relationship of plasmamorphine and glucuronide concentra-tions with pain relief.

METHODS

PatientsChildren entering the study received

IRMS liquid at the same dose for atleast 2 days or MST for at least 3 days.Each child attended 1 of 7 participat-ing centers and could have been re-ceiving care either in hospital or athome. Ethical approval was obtainedfrom committees responsible for eachcenter. Informed signed consent wasobtained from the child’s parents and,when the child was mature enough tounderstand,4 his or her assent was alsoobtained. If a child was not matureenough to give assent, he or she was in-cluded only if blood was already beingtaken for another purpose or if he orshe had a central line in situ. The chil-dren continued to receive their medica-

tion in the dose and form that was cus-tomary for them. No dietary or behav-ioral restrictions were made. Samplingwas discontinued if the child requiredany additional opioid for breakthroughpain. Samples taken up to that timewere included in the analysis.

Blood SamplingA median of 4 (range 1 to 11) 2-mL

blood samples was collected from eachchild. Samples were collected intoplastic lithium heparin tubes and cen-trifuged at 3500 rpm (1200g) for 10minutes, and the plasma was stored at–20°C until analysis was performed.An additional 1 mL blood was drawnfor assessment of liver and renal func-tion. The glomerular filtration rate(mL/min/1.73m2) was estimated ac-cording to the method of Counahan etal5: height (cm)/plasma creatinine(µmol/L) × 38. A ratio of height (cm)to plasma creatinine (µmol/L) of <1.5was taken as an indicator of clinicallysignificant renal impairment.6

Morphine and GlucuronideAssays

Plasma samples were analyzed formorphine, morphine-3-glucuronide,and M6G by high-performance liquidchromatography with electrochemicaland fluorescence detection after solid-phase extraction was performed.7

Pain AssessmentPain was assessed during the dosing

interval with 1 of 3 pain assessmenttools depending on the developmentalstage of the child. For older children anumeric scale marked 0 to 10 or theFaces Affect Scale8 was used. Foryounger children the Douleur EnfantGustave Roussy behavioral scale wasprovided.9 The timing of pain assess-ments within the dosing interval variedwith each child.

Pharmacokinetic AnalysisPharmacokinetic analysis was per-

formed with P-PHARM (Simed SA,Creteil, France), a population pharma-

cokinetic analysis program that alsoprovides parameter estimates for indi-vidual subjects. To model the plasmaconcentration-time data in children,previous estimates of clearance, vol-ume of distribution, absorption rateconstant, and lag time were first deter-mined by modeling data from a previ-ously published study in adults.10 Anabsolute morphine bioavailability of34% after IRMS and 24% after MSTwas assumed, as reported in the origi-nal study, as a measure of the delivereddose reaching the systemic circulationas morphine. The “apparent bioavail-ability” estimates for M6G and M3Gwere again a measure of the proportionof the oral dose reaching the systemiccirculation as each of these glu-curonides. This proportion was deter-mined from the area under the plasmaconcentration-time curve for M6G orM3G relative to the total molarAUC12h (morphine + M6G + M3G)after IRMS or MST in adults, whichwas 12.5% for M6G and 85% forM3G. With these “bioavailability” val-ues, estimates of Cl, VD, ka, and lagtime in adults were derived with P-PHARM. The resulting parameter es-timates were then used as the startingparameter estimates for analysis of thechild data.

Although it was possible to model kaand lag time in the adult data, whichhad full concentration-time profiles,the more sparse child data could not bemodeled for ka without markedly af-fecting VD. Consequently ka and lagtime were fixed. For morphine the me-dian ka calculated in adults afterIRMS was 6 hour-1; after MST it was0.8 hour-1. Lag time for IRMS was 0hours, and for MST it was 0.25 hours.For the glucuronides ka after IRMSwas 0.7 hour-1, and after MST it was0.16 hour-1. Lag time was 0.3 hours forglucuronides after IRMS and 0.35hours after MST. Bioavailability wasfixed for both morphine preparationsat 0.125 for M6G and 0.85 for M3G.

To obtain individual parameter esti-mates of Cl and VD for the adult and

48

THE JOURNAL OF PEDIATRICS HUNT ET AL

VOLUME 135, NUMBER 1

child data, Cl and VD were modeledwith an expectation maximization al-gorithm based on an iterative fittingprocedure.11 Subsequently, 12 sepa-rate P-PHARM analyses were under-taken for morphine, M6G, and M3Gin adults receiving IRMS or MST andin children receiving IRMS or MST.In each case a 1-compartment linearmodel with homoscedastic (equal erroracross the concentration range) mea-surement of error variance was used.Performance of the model was as-sessed from the distribution of residu-als between measured and fitted dataand by performance of a Student t teston the residuals. Residuals were exam-ined for relationship with covariablesage, weight, and glomerular filtrationrate.

After the initial fitting procedure wasperformed, parameter estimates for indi-vidual subjects were calculated, compris-ing VD, Cl, and time to maximum con-centration. The following parameterswere then calculated from VD and Cl.

• Elimination half-life (T1⁄2) (0.693/[Cl/VD]).

• The AUC4h for IRMS andAUC12h for MST (F[Dose]/Cl[L/hr]).

• AUC4h for IRMS was then mul-tiplied by 3 to provide AUC12h

• Average plasma concentration foreach individual was AUC/t witht = dosing interval.

Fluctuation (Cmax/Cmin) was as-sessed from raw data of patients pro-viding at least 5 plasma samples in theinterval.

Statistical AnalysisStatistical tests were performed with

the statistical package SPSS/PC. Sev-eral parameters were not normally dis-tributed (Ryan-Joiner test). Theskewness was particularly obvious forglucuronide clearance and AUC. Con-sequently, nonparametric statisticaltests have been used. Comparison be-tween 2 groups was made with aMann-Whitney U test. Two-tailed testswere used, and a 2-tailed P value of

<.05 was required to reject the null hy-pothesis. The average plasma mor-phine concentration was plottedagainst the actual dose (milligrams perkilogram per day), and a linear regres-sion analysis was performed to deter-mine the relationship between plasmaconcentration and dose. Stepwise re-gression analysis was undertaken onCav of morphine, M6G, and M3G,each corrected for dose and weight toassess the impact of the covariablesage, sex, GFR, and drug preparation(IRMS or MST).

RESULTS

Patients and DosesChildren (n = 43) were recruited to

the study at an average rate of 1 childper month over a period of 31⁄2 years.One, receiving morphine at 0.6mg/kg/d, did not have measurable plas-ma concentrations of morphine orM3G. A further 2 were excluded fromthe final pharmacokinetic analysis. Inthe first, serum creatinine was 575µmol/L, and in the second, serum albu-min was only 23 g/L, both markedlydifferent from the rest of the group. Al-though it would be useful to determinethe effects of such parameters on thepharmacokinetics of morphine and itsglucuronides in this population, toofew subjects had such markedly im-paired renal or hepatic function tomake such an analysis meaningful. In

addition, inclusion of data from these 2patients may have biased the popula-tion estimates.

Of the remaining 40 children, 18 re-ceived IRMS and 22 received MST.Children taking IRMS received a me-dian dose of 5 mg (range 2 to 20 mg),with the dose repeated every 4 hours.Children taking MST received a medi-an dose of 30 mg (range 5 to 460 mg),repeated every 12 hours. Patient char-acteristics are summarized in Table I.The group comprised 31 male patientsand 9 female patients, with 14 patientshaving hematologic malignancies andthe other 26, solid tumors. No signifi-cant difference was seen between thegroups receiving IRMS and MST inage, weight, GFR, or number of daysreceiving morphine. Four children hada height to creatinine ratio of <1.5, indi-cating a clinically significant degree ofrenal impairment. These 4 had GFRbetween 33 and 65 mL/min/1.73m2.Two patients had hepatic enzymes (ala-nine transaminase) more than twice theupper limit of normal for their age. Twoother children had raised serum biliru-bin. Most children were receiving mul-tiple other medications.

The adult study comprised data from10 patients with cancer who were re-ported to have normal liver and renalfunction and who had undergonepharmacokinetic investigation after re-ceiving IRMS and MST on separateoccasions as part of a bioavailability

49

Characteristic Median Range

Age (y) 11.4 1.7-18.7Weight (kg) 34 12-70Serum creatinine (µmol/L) 52 25-167GFR (mL/min) (*) 58 22-118GFR (mL/min/1.73m2) 95 33-144Dose in 24 h (mg) 35 10-1380Dose (mg/kg/d) 1.4 0.3-25Days receiving morphine 7 2->365Days at dose 3 2->150

*Glomerular filtration rate estimated from formula (height [cm]/plasma creatinine (µmol/L) ×38).5

Table I. Sample characteristics (n = 40)


JULY 1999

study.10 However, 1 adult was exclud-ed from the population analysis be-cause of exceptionally high metabolitelevels suggestive of renal impairment.

Population PharmacokineticAnalysis

Mean parameter values and covari-ance for Cl and VD were estimated forboth IRMS and MST. In each case theresiduals fitted to a normal distributiondid not show significant bias andshowed no relationship with the co-variables age, weight, or GFR.

The only significant difference inpharmacokinetic parameters betweenIRMS and MST in the children was fortime to maximum concentration, whichwas 1 hour after IRMS and 3 hoursafter MST. These values were the samefor morphine, M6G, and M3G (P <.001 for each). Children receiving MSThad a lower morphine AUC (median 77

ng/mL/h) than did those receivingIRMS (median 105 ng/mL/h), althoughthe difference was not statistically sig-nificant. The pharmacokinetic datahave therefore been pooled. Examina-tion of the values of clearance correctedfor weight found the values to beskewed, the skewness being particular-ly marked for glucuronide clearanceand AUC. The medians (and lowerquartile and upper quartiles) of the in-dividual pharmacokinetic parametersare therefore presented in Table II, withdata presented both for all subjects andin subsets divided by age based on me-dian age (11 years) and previous stud-ies that have suggested higher clearancein prepubertal children.12,13 No signifi-cant difference was found in dose(mg/kg/d) or in GFR (mL/min/1.73m2)between these 2 age groups.

With regard to the adult data, a sig-nificant difference was seen in mor-

phine AUC between IRMS and MST(187 vs 112 ng/mL/h, respectively, P <.01), but not for M6G or M3G AUC.Results were available for the same 9adults who each had received IRMSand MST. The average results forthese 2 preparations in each adult weretaken to allow statistical comparisonwith the pooled children’s data. The re-sults demonstrate significant differ-ences between younger and older chil-dren and between children and adultswith regard to morphine but especiallywith regard to the glucuronides.

Effect of Covariates onPharmacokinetic Parameters ofMorphine

With all children included, the Cav =6.6 × dose (milligrams per kilogramper day) with a 95% confidence inter-val for the slope of 5.9 to 7.3 (R2 =0.86; P < .001). All but 3 children re-

50

<11 y >11 y Adults** All children(n = 18) (n = 22) (n = 9) (n = 40)

Age (range) 6.3 (1.7-9.0) 13.8 (11.0-18.7) (44-79) 11.4 (1.7-18.7)Morphine

Cl (mL/min/kg) 37.4 (20.1, 48.5)* 21.9 (16.9, 26.7) 15.2 (12.2. 17.3)� 23.1 (17.0, 38.1)Apparent VD (L/kg) 7.1 (4.0, 8.8)* 4.7 (2.9, 5.7) 2.9 (2.4, 3.2)� 5.2 (3.2, 7.3)T1/2 (h) 2.1 (1.7, 3.1) 2.4 (1.9, 2.7) 3.2 (2.9, 3.9)� 2.3 (1.7, 2.7)AUC12h

# 57 (42, 113) 98 (78, 118) 147 (124, 179)¶ 86 (58, 113)M6G

Cl (mL/min/kg) 3.0 (2.1, 4.1)‡ 1.1 (0.9, 1.8) 0.8 (0.6, 1.9)§ 1.9 (1.0, 2.9)Apparent VD (L/kg) 0.42 (0.28, 0.54)‡ 0.19 (0.09, 0.28) 0.15 (0.08, 0.18)� 0.26 (0.16, 0.41) AUC12h

# 294 (231, 453)‡ 853 (517, 1073) 1167 (585, 1463)§ 497 (302, 992)M3G

Cl (mL/min/kg) 4.9 (2.9, 6.3)‡ 2.0 (1.6, 2.9) 0.8 (0.8, 1.3)¶ 2.8 (1.7, 4.8) Apparent VD (L/kg) 0.76 (0.52, 1.16)‡ 0.33 (0.20, 0.44) 0.14 (0.10, 0.27)¶ 0.42 (0.31, 0.77)AUC12h

# 1312 (1014, 1866)‡ 3206 (2191, 4064) 7724 (5359, 8317)¶ 2186 (1424, 3773) Molar ratios

M3G:M 19.1 (10.5, 22.6)* 24.4 (18.1, 31.56) 32.0 (24.7, 49.9)� 21.1 (15.7, 30.0) M6G:M 3.9 (2.4, 5.6)* 6.5 (4.3, 7.8) 4.8 (3.3, 7.9) 4.7 (3.7, 7.3)M3G:M6G 4.4 (4.1, 4.9) 4.1 (3.5, 4.7) 5.8 (5.0, 10.9)¶ 4.2 (3.6, 4.7)

Median (lower quartile, upper quartile).Statistical comparisons have been made in children <11 years and >11 years of age (*P < .05, †P < .01, ‡P < .001) and between all children and adults

(§P < .05, �P < .01, ¶P < .001).#AUC12h: normalized in children to a dose of 0.45 mg/kg in 12 hours; in adults to a dose of 30 mg in 12 hours (weight of 67 kg assumed).**Nine adults received both IRMS and MST in turn. The mean of values for both preparations has been used. Children are 40 patients (18 receiving

IRMS and 22 receiving MST).

Table II. Individual pharmacokinetic parameters of oral morphine and its glucuronides, M6G and M3G, in children with cancer(age < and >11 years) and in adults with cancer



ceived a dose of <4 mg/kg/d. The re-maining 3 subjects received 5.7, 12.5,and 24.6 mg/kg/d. Therefore thisanalysis was repeated excluding these3 subjects, such that within the typicaldose range of 0.3 to 4 mg/kg/d, the Cav= 8.6 × dose (milligrams per kilogramper day) with a 95% confidence inter-val for the slope of 7.4 to 9.9 (R2 = 0.5;P < .001) (Figure).

With Cav corrected for dose andweight, no variables significantly af-fected the dose/concentration relation-ship. Stepwise regression of morphineclearance (milliliters per minute perkilogram) and VD found age (P = .03and P = .009, respectively) to be a sig-nificant predictor of each. Morphineplasma clearance (milliliters perminute per kilogram) = 38.74 – (1.05 ×age [years]). Morphine VD = 8.17 -(0.27 × age [years]).

Effect of Covariates onPharmacokinetic Parameters ofM6G

Stepwise regression analysis of aver-age M6G plasma concentration (cor-rected for dose and weight) foundGFR (P = .001) and age (P = .009) to

be significant predictors, whereaspreparation (IRMS or MST) and sexwere not significantly predictive. With4 children with GFR from 33 to 65mL/min/1.73m2 excluded, GFR wasno longer predictive (P = .568), butpreparation received became a signifi-cant covariate (P = .02).

Effect of Covariates onPharmacokinetic Parameters ofM3G

Stepwise regression analysis of aver-age M3G plasma concentration (cor-rected for dose and weight) also foundGFR (P = .0003) and age (P = .006) tobe significant predictors but not prepa-ration (IRMS or MST) or sex. Again,when 4 children with GFR from 33 to65 mL/min/1.73m2 were excluded,GFR (P = .367) was no longer predic-tive, but preparation became a signifi-cant covariate (P = .01)

AUC Ratio of Metabolites toMorphine

Molar ratios for metabolite to mor-phine AUCs in children and adults areshown in Table II. Younger childrenhad significantly lower metabolite to

morphine ratios than the older group(P < .05).

FluctuationData from children providing 5 or

more plasma samples demonstrated amedian Cmax/Cmin ratio for morphineof 3.0 (range 1.8 to 5.2) after IRMS (n= 7) and 8.4 (range 7.2 to 21.0) afterMST (n = 5) (Mann-Whitney P < .01).The comparative figures for the adults(based on full data sets) was aCmax/Cmin ratio for morphine of 2.7(range 2.4 to 4.6) after IRMS (n = 9)and 4.8 (range 3.5 to 20.6) after MST(n = 9).

Pain: Relationship with PlasmaConcentration

Pain was assessed with 1 of 3 differ-ent measures according to the child’sage and developmental stage. No scorewas available for 9 (23%) of the chil-dren, who were mainly in the youngerage group and unable to use a self-re-port measure. Children with painscores were divided into 2 groups: (1)below and (2) at or above a thresholdof 5 on the 0 to 10 numeric scale (a di-vision commonly used in adult studies)

51

Figure. Average plasma morphine concentration (Cav) (ng/mL) calculated from AUC divided by interval versus dose (mg/kg/d) in 37 children receivingeither immediate-release morphine liquid or sustained-release tablets in range of 0.3 to 4 mg/kg/d. (Three children receiving doses in range of 5.7 to 24.6mg/kg/d excluded). Scattergram and least squares regression line through origin (y = 8.6x; 95% confidence interval, 7.4 to 9.9; R2 = 0.5; P < .001).


JULY 1999

or 0.75 (Face F) on the Faces Scale,this being the first face clearly demon-strating discomfort. Two children withbehavioral signs of pain but no scorewere included in the “above threshold”group. The behavioral scale (DouleurEnfant Gustave Roussy) was used inonly 1 child. No pain was evident inthis child, who was included in thebelow threshold group.

For IRMS no score was available for3 children. Of the remaining 15 chil-dren, 8 (44%) had scores belowthreshold (median morphine Cav 20.4,range 8.2 to 31.1), and 7 (39%) hadscores above threshold (median mor-phine Cav 5.5, range 3.7 to 10.8) (P <.01). The difference in M6G levels wasnot significant (below pain threshold,median M6G Cav 71.7, range 43.9 to295.9 vs above pain threshold, M6GCav 41.1, range 17.7 to 91.6).

For MST no score was available for4 children. Of the remaining 18 chil-dren, 13 (59%) had scores belowthreshold (median morphine Cav 8.9ng/mL, range 3.8 to 138.5), and 5(23%) had scores above threshold(median morphine Cav 16.2 ng/mL,range 10.5 to 124.2) (not significant).Four children had breakthrough painrequiring a dose of immediate-releasemorphine or for their next dose ofMST to be given early. Although painscores were seen to increase towardsthe end of the interval in some chil-dren, no overall relationship with plas-ma morphine or metabolite levels wasobserved.

DISCUSSION

There are limited data on the phar-macokinetics of morphine and its glu-curonides in children. Consequentlypractice in the administration of oralmorphine to children has been devel-oped empirically or through extrapola-tion from adults. Results reported heredemonstrate significant pharmacoki-netic differences between child andadult cancer populations. The median

morphine clearance (assuming abioavailability of 34% for IRMS and24% for MST) was 23.1 mL/min/kg,which is in keeping with studies inchildren receiving morphine intra-venously14,15 and a recent meta-analy-sis.16 Children <11 years had signifi-cantly higher morphine clearance thanolder children (37.4 vs 21.9, P < .05).This tendency for decreasing morphineclearance with age has also been ob-served in children with sickle cell dis-ease after intravenous morphine ad-ministration.12,13

The median morphine VD for chil-dren was 5.2 L/kg, again in keepingwith some other published studies.17-19

VD was greatest in the younger chil-dren (VD 7.1 vs 4.7 L/kg) (P < .05) andin both groups was greater than inadults (VD 2.9 L/kg) (P < .01). Thesedifferences in Cl and VD resulted in sig-nificantly lower AUC12h in theyounger children (57 vs 98 ng/mL/h)(P < .05). As a group, median mor-phine AUC12h in children was 59%that of the adults (86 vs 145 ng/mL/h)(Mann-Whitney P < .001). The ratio ofliver mass to body mass is increased inchildren, especially in younger chil-dren, compared with that in adults, asis hepatic blood flow. Thus drugs withhigh hepatic extraction such as mor-phine may be metabolized more rapid-ly in infants and children who wouldconsequently be expected to show de-creased AUC compared with adults.20

Higher clearance for M3G (2.8mL/min/kg) over M6G (1.9 mL/min/kg)suggests that bioavailability estimatesderived here from adults may not bewholly appropriate for children. Fromthe molar ratios proportions of dosemay be estimated at M3G 85%, M6G12.5%, and morphine 2.5% for adultsand M3G 79%, M6G 18%, and mor-phine 3% for children. Therefore theremay be some preferential metabolismto M6G or increased clearance ofM3G in children.

Children <11 years of age had signif-icantly greater VD than older childrenand adults. The glucuronides, being

hydrophilic molecules, are largely con-fined to extracellular fluid, so the dif-ference in metabolite VD between the 2groups may be explained by a greaterproportion of extracellular fluid inyounger children.21 This relativelyhigh VD in the younger children con-tributed to their substantially lowerglucuronide AUC levels. There areanecdotal reports of increased anal-gesic needs in young children.22 Al-though in this study we did not find arelationship between pain measure-ments and M6G plasma concentration,it is possible that lower M6G AUC inyounger children (294 ng/mL/h vs 853ng/mL/h) (P < .001) could contributeto these increased analgesic require-ments.

The regression analyses of averageplasma M6G and M3G concentrationssuggest that renal function is not animportant predictor of glucuronideconcentrations until the GFR falls to<65 mL/min/1.73m2. A slight fall inglucuronide clearance was observed in4 children whose GFR was predictedto be between 33 and 65 mL/min/1.73m2. Clinical problems at this levelof renal impairment would not be ex-pected, provided the initial dose wasnot too high and the dose was titratedaccording to pain. A GFR of 30mL/min/1.73m2 or below may have amore marked effect on morphine glu-curonide pharmacokinetics.

The relationship of plasma concen-tration with dose was linear within therange 0.3 to 4 mg/kg/d. The averageplasma morphine concentration withinthis range was equal to dose (mil-ligrams per kilogram per day) × 8.6(95% confidence interval 7.4 to 9.9).Thirlwell et al23 report average plasmamorphine concentration = dose (mil-ligrams per kilogram per day) × 11.9(95% confidence interval 10.7 to 13.1)in adults with cancer receiving oralmorphine solution and sustained-re-lease tablets. Plasma morphine concen-trations of at least 12 to 65 ng/mL ap-pear to be necessary for minimaleffective concentrations with regard to

52



analgesia.14,18,24,25 Based on the datafor IRMS, this study would also sug-gest that plasma morphine concentra-tions <12 ng/mL are unlikely to pro-vide good analgesia in children withcancer pain. From the regression equa-tion derived here (Figure), it is pre-dicted that to provide average plasmamorphine concentrations above 12ng/mL, a dose of at least 1.5 mg/kg/dwould be required. In comparison, theregression equation calculated byThirlwell et al23 suggests that an adultwould require 1 mg/kg/d to provide anaverage plasma concentration in theregion of 12 ng/mL.

Because of limited data in children, ithas been a tendency to extrapolatefrom practice with adult patients. Adultpatients with cancer tend to be in theolder age range. Differences both in re-sponse to morphine and in pharmaco-kinetics have been demonstrated withage in adults, with younger adults hav-ing higher morphine requirements26

and increased morphine clearance overolder adult patients.27 Older adults arealso likely to have less efficient renalfunction. Extrapolation of practicefrom older patients is therefore unlike-ly to produce optimal treatment forchildren. Recent literature suggestsempirically a starting dose for childrenof 0.3 mg/kg/dose for IRMS28 and 1mg/kg/dose for MST29 (ie, 1.8 and 2mg/kg/d). This study supports theserecommendations. The dose can thenbe titrated according to effect. Al-though most children will not requiremore than a doubling of their dose,29

occasionally children do require excep-tionally high doses.29,30 The reasonsthese particularly high doses may beneeded are not fully understood but areprobably more related to pain that isonly partly opioid-responsive or to tol-erance than to differences in pharma-cokinetics.

The peak to trough ratios in childrenafter MST were surprisingly high in thisstudy. In addition, several children inthis group did require additional med-ication for breakthrough pain. Fluctua-

tion may be particularly marked in chil-dren, because once the drug is released,the elimination half-life in children isshorter (2.3 hours in children vs 3.2hours in adults). This result might sug-gest that dosing at more frequent inter-vals than every 12 hours may be appro-priate in children, and indeed somepediatricians empirically do prescribeMST every 8 hours. Studies in adultshave demonstrated differences betweensustained-release preparations in therate of drug release,31 with Kapanol(Glaxo Wellcome) having significantlyless fluctuation than MS Contin (Per-due Frederick) in plasma morphine con-centration. Although most studies donot identify pharmacodynamic differ-ences relating to different products, cau-tion is advised in moving towards once-daily sustained-release preparations forchildren without sufficient previous re-search and adequate pain assessment.

When assessed, a third of childrenhad significant pain despite opioidanalgesia. Possible reasons include theuse of lower than currently recom-mended starting doses and the infre-quent use of formal pain assessmenttools in this population. Regular painassessment might enable more effec-tive and timely response to pain.

The P-PHARM software has beenrecently developed and has proved use-ful in establishing pharmacokinetic pa-rameters in a group of children whocould provide only sparse plasma con-centration data and for whom conven-tional pharmacokinetic analysis wouldnot be possible. Other methods for de-termining population parameters fromsparse data such as the NONMEMprogram have been described.32 Al-though both approaches involve nonlin-ear mixed effects modeling of popula-tion parameters, the algorithm used toderive these parameters differs. NON-MEM uses a first-order approach inearlier versions and a first-order condi-tional estimation in later versions,32

whereas P-PHARM uses the 2-step ex-pectation-maximization algorithm.11

From a practical viewpoint NONMEM

has been more widely used, but P-PHARM is a Windows-based, menu-driven package. Comparison of the 2approaches found good agreement be-tween the 2 with some simulations butnot others.33 The importance of usingthe correct model was highlighted forboth methods. In this study the simplestmodel (1 compartment, homoscedasticerror) was used.

As described in the Methods section,certain assumptions had to be made tofit the data, particularly with regard toF, ka, and lag time. More samplestaken earlier in the interval may haveenabled modelling of ka and lag time inaddition to Cl and volume. It is possi-ble that the estimates fixed were notoptimal to the child population studiedhere and that some of the differences inpharmacokinetics between childrenand adults and between children at dif-ferent ages may have been attributableto differences in F, ka, or lag time.However, this study does identify dif-ferences between younger and olderchildren and between children withcancer and an adult cancer populationthat have implications for the use ofmorphine in children. Whether thesedifferences are attributable to modeledparameters such as Cl or VD or incor-rect assumptions regarding the fixedparameters such as bioavailability, thedifferences are real.

Further studies in this population areclearly required. They may include theuse of rational dosing schedules thatcould be compared with those suggest-ed by the regression analysis describedhere. Bioavailability of oral morphinerelative to intravenous administrationhas not been established in children.This knowledge could be particularlyhelpful when transferring from 1 routeto another during different phases oftreatment or palliative care. There islimited understanding of the subgroupof children who have exceptional anal-gesic requirements and of childrenwith organ dysfunction. In this studyno assessment was made of morphineside effects such as drowsiness, nausea,

53


JULY 1999

or hypoventilation. Despite the practi-cal difficulties encountered in carryingout such studies in this population, fur-ther pharmacokinetic and pharmaco-dynamic studies are important. Withpatience drug research in children ispossible and is essential for improve-ment in treatment.34

In conclusion, our study suggests thatwhen given an equivalent dose forweight, younger children are likely tohave significantly lower plasma mor-phine and metabolite concentrations.The lower AUC in young children mayresult from reduced bioavailability oforal preparations, increased Cl, or larg-er VD. A starting dose for oral morphineof 1.5 to 2 mg/kg/d is recommended forchildren with pain unrelieved by mildor moderate strength analgesics. Dos-ing of MST at 8-hour intervals may beappropriate in children.

The authors thank the Pediatric Oncology De-partments of The Royal Marsden Hospital,Surrey; The Children’s Hospital, Birming-ham; The Oxford Radcliffe Hospital; StBartholomew’s Hospital, London; Southamp-ton General Hospital; Great Ormond StreetHospital, London and Helen House Hospice forChildren, Oxford for their support and partici-pation. We thank all the children who tookpart and their parents. We are greatly indebtedto them. We are grateful to Anna Gloyn,Simon Clark, and Stephen Beckwith for carry-ing out the high-performance liquid chro-matography assays in the IRCF ClinicalOncology Laboratory, St Bartholomew’s Hos-pital, London. The authors especially want tothank Drs Peter Hoskin and Philippe Poulainfor allowing us to use their data from adults inthis study.

REFERENCES1. Schecter NL. Pain in children with

cancer. In: Foley KM, editor. Ad-vances in pain research and therapy.Vol 16. New York: Raven Press Ltd;1990. p. 57-71.

2. Hanna MH, Peat SJ, Woodham M,Knibb A, Fung C. Analgesic efficacyand CSF pharmacokinetics of intrathe-cal morphine-6-glucuronide; compari-son with morphine. Br J Anaesth1990;64:547-50.

3. Osborne R, Thompson P, Joel S, TrewD, Patel N, Slevin M. The analgesic

activity of morphine-6-glucuronide. BrJ Clin Pharmacol 1992;34:130-8.

4. Nicholson RH. Medical research withchildren: ethics, law and practice. Thereport of an Institute of Medical Ethicsworking party on the ethics of clinicalresearch investigations on children.Oxford: Oxford University Press;1986.

5. Counahan R, Chantler C, Ghazali S,Kirkwood B, Rose F, Barratt TM. Esti-mation of glomerular filtration rate fromplasma creatinine concentration in chil-dren. Arch Dis Child 1976;51:875-8.

6. Taylor CM. Assessment of the glomeru-lar filtration rate. In: Postlethwaite RJ,editor. Clinical paediatric nephrology.2nd ed. Boston, MA: Butterworth-Heinemann Ltd; 1994. p. 89-100.

7. Joel SP, Osborne RJ, Slevin M. Animproved method for the simultaneousdetermination of morphine and itsprincipal glucuronide metabolites. JChromatogr 1988;430:394-9.

8. McGrath PA, deVeber LL, Hearn MT.Multidimensional pain assessment inchildren. In: Fields HL, Dubner R,Cervero F, editors. Advances in painresearch and therapy. vol 9. New York:Raven Press; 1985. p. 387-93.

9. Gauvin-Piquard A, Rodary C, RezuaniA, Lemerle J. Pain in children 2-6 years:a new observational rating scale elabo-rated in a pediatric oncology unit - pre-liminary report. Pain 1987;31:177-88.

10. Poulain P, Hoskin PJ, Hanks GW, A-Omar O, Walker VA, Johnston A, etal. Relative bioavailability of con-trolled release morphine tablets (MSTContinus) in cancer patients. Br JAnaesth 1988;61:569-74.

11. Gomeni R, Pineau G, Mentre F. Popu-lation kinetics and conditional assess-ment of the optimal dosage regimenusing the P-PHARM software pack-age. Anticancer Res 1994;14:2321-6.

12. Robieux IC, Kellner JD, Coppes MJ,Shaw D, Brown E, Good C, et al.Analgesia in children with sickle cellcrisis: comparison of intermittent opi-oids vs. continuous intravenous infu-sion of morphine and placebo-con-trolled study of oxygen inhalation.Pediatr Hematol Oncol 1992;9:317-26.

13. Dampier CD, Setty BN, Logan J, IoliJG, Dean R. Intravenous morphinepharmacokinetics in pediatric patientswith sickle cell disease. J Pediatr1995;126:461-7.

14. Nahata MC, Miser AW, Miser JS, Re-uning RH. Variation in morphine phar-macokinetics in children with cancer.Dev Pharmacol Ther 1985;8:182-8.

15. Greene RF, Miser AW, Lester CM,Balis FM, Poplack DG. Cerebrospinalfluid and plasma pharmacokinetics ofmorphine infusions in pediatric cancerpatients and rhesus monkeys. Pain1987;30:339-48.

16. Kart T, Christrup LL, Rasmussen M.Recommended use of morphine inneonates, infants and children based ona literature review: part 1 - pharmaco-kinetics. Pediatr Anaesth 1997;7:5-11.

17. Chinyanga HM, Vandenberg H, BohnD, Macleod S, Soldin S. Pharmacoki-netics of morphine in young childrenfollowing cardiac surgery. Anesthesiol-ogy 1983;59:A447.

18. Lynn AM, Opheim K, E, Tyler DC.Morphine infusion after pediatric car-diac surgery. Crit Care Med 1984;12:863-6.

19. McRorie TI, Lynn AM, Nespeca MK,Opheim KE, Slattery JT. The matura-tion of morphine clearance and metab-olism (published erratum appears inAm J Dis Child 1992 Nov;146:1305).Am J Dis Child 1992;146:972-6.

20. Kelly HW. Pharmacotherapy of paedi-atric lung disease: differences betweenchildren and adults. Clin Chest Med1987;8:681-94.

21. Jacobson SJ, Koren G. Pharmacologyof symptom control in children. In:Doyle D, Hanks G, MacDonald N,editors. Oxford textbook of palliativemedicine. Oxford: Oxford UniversityPress; 1993. p. 691-3.

22. Burne R, Hunt A. Use of opiates interminally ill children. Palliat Med1987;1:27-30.

23. Thirlwell MP, Sloan PA, Maroun JA,Boos GJ, Besner J, Stewart JH, et al.Pharmacokinetics and clinical efficacyof oral morphine solution and con-trolled-release morphine tablets in can-cer patients. Cancer 1989;63:2275-83.

24. Nahata MC, Miser AW, Miser JC, Re-uning RH. Analgesic plasma concen-trations of morphine in children withterminal malignancy receiving contin-uous subcutaneous infusion of mor-phine sulphate to control severe pain.Pain 1984;18:109-14.

25. Collins JJ, Geake J, Grier HE,Houck, CS, Thaler HT, Weinstein HJ,et al. Patient-controlled analgesia formucositis pain in children: a three-pe-riod crossover study comparing mor-phine and hydromorphone. J Pediatr1996;129:722-8.

26. Hoskin PJ, Hanks GW. The manage-ment of symptoms in advanced cancer:experience in a hospital-based contin-

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uing care unit. J R Soc Med 1988;81:341-4.

27. Baillie SP, Bateman DN, Coates PE,Woodhouse KW. Age and the pharma-cokinetics of morphine. Age Ageing1989;18:258-62.

28. AHCPR. Acute Pain Management ininfants, children, and adolescents: Op-erative and medical procedures. Quickreference guide for clinicians.Rockville, MD; Agency for HealthCare Policy and Research, PublicHeath Service, U.S. Department ofHealth and Human Sciences, 1992.

29. Goldman A, Bowman A. The role oforal controlled-release morphine inpain relief in children with cancer. Pal-liat Med 1990;4:279-85.

30. Collins JJ, Grier HE, Kinney HC,Berde CB. Control of severe pain inchildren with terminal malignancy. JPediatr 1995;126:653-7.

31. Gourlay GK, Plummer JL, CherryDA, Onley MA. A comparison of Ka-panol (a new sustained-release mor-phine formulation), MST Continus,and morphine solution in cancer pa-tients: pharmacokinetic aspects ofmorphine and morphine metabolites.In: Gebhart GF, Hammond DL,Jensen TS, editors. Proceedings of theSeventh World Congress on Pain.Paris: IASP Press, 1994: p. 631-43.

32. Sheiner LB, Beal SL. Evaluation ofmethods for estimating populationpharmacokinetic parameters. 111. Mo-

noexponential model: routine clinicalpharmacokinetic data. J Pharma-cokinet Biopharm 1983;11:303-19.

33. Bennett JE, Wakefield JC. A compar-ison of a Bayesian population methodwith two methods as implemented incommercially available software. JPharmacokinet Biopharm 1996;24:403-32.

34. BPA and ABPI. Licensing medicinesfor children. London: British Paedi-atric Association and the Associationof the British Pharmaceutical Industry,1996.

55

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19-

Medical and nursing problems of children withneurodegenerative diseaseAnne Hunt Helen House Hospice for Children, Oxford and Roger Burne General Practitioner and Medical Director, HelenHouse Hospice for Children, Oxford

Address for correspondence: Anne Hunt, Helen House Hos-pice for Children, 37 Leopold Street, Oxford OX4 1QT,UK.

Key words: child; hospice care; neurodegenerative disease (non-MeSH);terminal care

Little is written on the management of problems encountered by children withneurodegenerative disease. Whilst the conditions are individually rare, as agroup of diseases they pose a considerable burden on the child, the family andthe community. This study describes the 127 children with neurodegenerativedisease who were admitted to Helen House, a hospice for children, from thetime of opening in November 1982 until the end of 1993. The great majority ofthe conditions were genetic in origin and nearly one-third of the families hadhad two or more children with the same disease. Seventy-four (58%) of thechildren have died, with nearly half dying at home. The course of the diseasewas in many cases chronic and these children presented with multiple medicaland nursing problems. Examination of the problems recorded in 1993 revealedthat nearly all the children had no speech, or speech was impaired. Most wereeither totally immobile or had considerably reduced mobility. Seventy percent of the children had feeding problems and one-quarter were fed througha nasogastric tube or gastrostomy. Thirty-five per cent of the children sufferedpain on occasions, with muscle spasm being the main identifiable source of pain.Practical suggestions are made for the management of these children.

Mots-cl6s: enfant; soins d’hospice; maladie neuro-d6g6n6rative; soins en fin devie

II existe tres peu de documentation sur les problemes des enfants atteints d’unemaladie neuro-d6g6n6rative. Bien que ces maladies soient individuellementrares, quand elles sont vues comme un groupe de maladies, elles pbsentconsid6rablement sur I’Enfant, la Famille et la Societe. Cette etude d6crit les127 enfants atteints d’une maladie neuro-d6g6n6rative qui ont ete admis 6Helen House, un hospice p6diatrique entre l’ouverture au mois de novembre1982 jusqu’a la fin de I’annee 1993. La plupart des maladies 6talent d’origineg6n6tique et presque un tiers des families ont eu au moins deux enfants atteints



20

de la meme maladie. Soixante-quatorze (soit 58%) des enfants sont d6c6d6s,dont presque la molti6 6 la maison. Dans beaucoup de cas, 1’6volution de lamaladie etait chronique et ces enfants pr6sentalent des problbmes multiples tantau plan m6dical que des soins 6 apporter. Un examen des probi6mes constat6sen 1993 a r6v6l6 que pour presque tous ces enfants, soit la parole btalt perdue,soit cette fonction etait d6t6rior6e. La plupart 6talent compl6tement paralys6sou avaient une mobilit6 consid6rablement diminu6e. Soixante-dix pour centdes enfants avaient des problbmes pour se nourrir, un quart d’entre eux 6tantaliment6s par voie naso-gastrique ou par gastrotomie. Trente-cinq pour cent desenfants souffraient de douleurs 6pisodlques, dues dans la plupart des cas 6 desspasmes musculaires. Des suggestions pratiques sont mises en avant pour lagestion m6dicale de ces enfants.

Introduction

Neurodegenerative disease in children is takento mean disease characterized both by loss ofskills and by symptoms arising mainly fromcentral nervous system disease. Each conditionis individually rare in the population but, as agroup, neurodegenerative disease is significant asa cause of death in children. Perhaps becauseof the rarity of each condition little has beenwritten on the problems encountered by childrensuffering from neurodegenerative conditions.1-5Of 307 children admitted to Helen House (achildren’s hospice) over a period of 11 years fromNovember 1982 to the end of 1993, 127 (41%)had a neurodegenerative disease. These childrenformed the largest diagnostic group. For everyone child admitted with cancer between two andthree were admitted with a neurodegenerativecondition. The children in this study received careat the hospice for periods from a few days to a fewweeks each year.During their stay, each child was cared for and

assessed by a multidisciplinary team, includingregistered sick children’s nurses, nursery nurses,general practitioners, a teacher, a social worker, aphysiotherapist and other experienced carers. Theaim was to ensure the comfort of the child andto relieve the stresses on the family, thus helpingthem to continue caring for the child at home. Thegreat majority of admissions were for respite care.The children’s home care team remained respon-sible for specialist assessments and treatments.

Methods

From 1987, demographic information on all chil-dren admitted was entered onto a computerdatabase. Information on children admitted priorto 1987 was also entered retrospectively. Since1987, the clinical problems and details of medi-cation of children admitted have been recorded

during each admission. The database has beenanalysed for demographic information relating to127 children admitted with a neurodegenerativedisease from November 1982 to the end of

1993, and for clinical information relating to thesubgroup of 45 children admitted in 1993. Theproportion of children affected by the problemsin each year varied little and the subgroup isbelieved to be typical of the whole group ofchildren.

Results

PatientsThere were 127 children (77 male, 50 female)

whose age on first admission was between oneand 19 years of age (median five to nine years)(Table 1). Of the 127 children, 74 (58%) haddied by the end of 1993. The median age at

death was between ten and 14 years (range 1-25).The median time from first admission to deathwas between two and three years, with a rangefrom a few days to nine years. Of the 74 childrenwho have died, 36 (49%) died at home. Seven-teen (23%) died at the hospice and 15 (20%) inhospital. Six (8%) died in other situations. Chil-dren were referred through many sources, with



21

the largest number (33%) being referred by thefamilies themselves (Table 2). All children werebeing cared for at home by their parents. Themain reason for referral was for respite care andemotional support.Of the 127 children, 31% were suffering

from one of the mucopolysaccharide storagediseases. Sixteen per cent of children had oneof the forms of Batten’s disease (neuronalceroid liopfuscinosis) and 13% one of the

leucodystrophies. Twenty-three per cent sufferedfrom various other named disorders, and a further17% from a neurodegenerative disease that hadnot been sufficiently defined to name (Table 3).The children belonged to 107 families; 28 (26%)families had two affected children, and two fami-lies had three children with the same disease. The

average number of visits per child over the studyyears was 13, with a range of from one to 101visits. In 1993, 45 children stayed for on average21 days (range 1-92 days) spread over an averageof four to five visits (range 1-10 visits).

Table 1 Age at first admission of 127 children withneurodegenerative disease

Table 2 Sources of referral of 127 children withneurodegenerative disease

Table 3 Diagnoses of 127 children with neurodegenerative disease



22

Clinical problemsThe clinical problems in 45 children with

neurodegenerative disease who were admittedin 1993 are shown in Table 4. The medicationschildren received during admission are listed inTable 5. The number of medications received

by each child ranged from one to 13 (median4). Administration of medication was difficult inchildren whose swallowing was impaired. Liquidmedications presented particular difficulties andchildren often managed crushed tablets mixed ina little food (e.g. fromage-frais) with greaterease.

Communication

Speech was impaired in all children, with over70% having no speech. Whilst difficult to assess,some 20% of children retained their intellectualskills despite motor and speech impairment. Itwas vital to acknowledge the independence andautonomy of these children and to allow them toparticipate in decision-making, both in everydaylife and regarding their future care. Even whenthe children were greatly intellectually impaired,most parents were able to preserve the essence oftheir child’s personality and identity and to remainengaged with them.6 6While most children had no effective means of

communication, a few with little or no speechcould use some sign language, usually their own,

Table 4 Problems recorded in 45 children in 1993

or more occasionally, formal signing such as

Makaton. Three children who were intellectuallyable to communicate did have some sort of com-munication aid such as a ’Bliss’ book, a book thatcontained symbols, words and photographs repre-senting subjects about which the child was mostlikely to want to communicate. With decreasingvoluntary movement, use of these books becamemore difficult and simple sign language, such asraising an arm for a ’yes’ or a movement of theeyes in a particular direction, was substituted.Where more sophisticated aids could help, insuf-ficient knowledge about what was available, orinsufficient funding, made it unlikely that thechild would receive these aids.

Feeding problemsFeeding problems were encountered in nearly

70% of the children. Whether a child is fed orallyor by tube, the main aim should be the child’scomfort and pleasure, rather than the achieve-ment of what may be arbitrary nutritional values.The variety, flavour, temperature, texture andconsistency of food and drink, as well as the

position in which the child is fed and the shape ofthe spoon and cup, are all important in maintain-ing the child’s comfort, nutrition and hydration.Great care and skill was required in feeding thesechildren.

Many families faced considerable difficulties infeeding their child, especially when the childbecame unable to swallow without choking.Certain techniques could delay this phase; for

Table 5 Medications received by 45 children in 1993



23

example, when swallowing thin liquids became aproblem, the addition of a thickening agent oftenmade swallowing easier. Additional attention tomouth care was necessary, as oral thrush and

gingivitis could make feeding more painful anddifficult. Regular dental checks and treatmentof dental caries continued to be important andcould be forgotten in the face of all the otherdifficulties.Twelve (27%) of the children were tube fed.

The decision whether or not to feed their child bytube, be it by nasogastric tube or by gastrostomy,was a difficult one for each family. Some familieswere certain that they did not want to tube-feedtheir child, while others saw no alternative. Thisdichotomy of views was also expressed by someprofessionals working with the families. Whilstartificial feeding might have prolonged the child’slife it did not necessarily improve its quality.Usually artificial feeding is reserved for thosechildren where significant distress will be allevi-ated or where it will extend a child’s useful and

enjoyable life.7With improved surgical techniques, percuta-

neous gastrostomy, which can give rise to less

difficulty with secretions, may now be prefer-able to prolonged nasogastric feeding for manychildren. This route may be considered less ormore invasive by each individual concerned andeach family’s perceptions will be different. Theprofessional’s role is to enable the parents to lookat, and talk through, the options and help them todecide which is appropriate for their child in theirfamily.

Respiratory problemsRespiratory problems were recorded in

38% of these children. Limited mobility,swallowing difficulty, muscular weakness and

gross kyphoscoliosis were all contributory fac-tors. Chest infections were frequent problems.They were treated with oral antibiotics and

physiotherapy in nearly all but terminal events.Dyspnoea was often a problem for children in

the terminal phase. Of 17 children who died atHelen House from 1982 to 1993, 11 received

strong opiate drugs for the relief of respiratorydistress.8,9 Occasionally, morphine sulphate wasgiven orally but most children at this stage oftheir illness were not able to take oral medica-tion. Some had morphine via a nasogastric tube

if one was already in situ; for others, diamorphinewas given by subcutaneous injection. Where morethan one dose of diamorphine was thought to berequired, subcutaneous diamorphine was admin-istered by syringe driver, usually in combinationwith hyoscine. A starting dose of oral morphinesulphate suggested in this situation is 0.15 mg/kgper four-hourly dose. If subcutaneous injection isneeded, diamorphine is preferred using a syringedriver starting at 0.3 mg/kg/24 h (0.05 mg/kg perfour-hourly dose).

Several children in this group experiencedsevere and distressing infection with chickenpox,and recent practice has been to give a course oforal acyclovir immediately on diagnosis.10 Thistreatment does appear to have resulted in anattenuated illness.

Excess secretions

Thirty-one per cent of the children had diffi-culty in swallowing even their own oral secretions.Drooling and choking could be troublesome anddifficult to control. Some children required fre-quent suction to keep their airway clear, althoughthis could exacerbate the situation. We had usedhyoscine in earlier years, sublingually or by subcu-taneous injection, to reduce secretions. Prolongedusage did, however, on occasions result in toler-ance or paralytic ileus. Hyoscine hydrobromidepatches have been used in adult patients to

manage excess secretions, i and in children withSanfilippo syndromes (mucopolysaccharidosestype III). Although not licensed for this indi-cation, we have used the patches over extendedperiods for several children, using from one-halfto one patch for three days and allowing oneday’s break before another patch is applied; byusing this regimen tolerance does not seem to bea problem.

SeizuresSeizures were a problem for 60% of the chil-

dren. For most, these were well controlled bytheir oral anticonvulsant regimen. However, fora few, seizure control, especially in the termi-nal period, was difficult. For most of these themanagement of prolonged seizures with rectal

diazepam was effective. For a few, diazepamhad little effect and status epilepticus developed.Those conditions in which seizure control was

particularly difficult were late infantile Batten’s



24

disease and subacute sclerosing panencephalitis.Paraldehyde administered rectally in an equalquantity of arachis oil was an effective drugfor these children in the late stage of theirdisease. Two families were able to continue tocare for their child at home for several weeks,administering rectal paraldehyde every threeto four hours to control seizures. General sup-portive care for the child is also needed withmaintenance of hydration, control of fever, sim-ple analgesia and treatment of any apparentprecipitating factor for the seizures. The routineanticonvulsant regimen should also be continuedif possible.

ConstipationConstipation was a problem for 44% of the chil-

dren. Dietary measures such as increased intakeof fibre and fluids were often hard to maintainbecause of feeding difficulties, and laxatives wereoften needed. Constipation was usually managedby a combination of regular lactulose and sennaand by the use of microenemas (docusate sodiumor sodium citrate). The enemas, when given onevery second or third day, kept the constipationunder control and prevented continuous soilingresulting from overflow (most of the children wereincontinent of both urine and faeces). As timeprogressed the microenemas, which had formerlyworked very successfully, became ineffective inmany of the children. Phosphate enemas werethen used with good effect.

Pain

Thirty-five per cent of the children were iden-tified as experiencing pain. Most children couldnot talk to say they hurt or describe their pain,but, even where the source of pain cannot beidentified, treatment is essential. Self-report painassessment tools such as visual analogue scales,faces scales, and body mapsl2 can be used, withthe help of the carer, to improve communicationwith intellectually able children, even those withboth speech and motor impairment. At presentthere is no tool that is suitable for children whohave both intellectual and motor impairment,most behavioural scales requiring observation ofthe child’s voluntary movements. There is a needfor carers to be particularly sensitive to the signsof pain that each child displays, and to make theirbest judgement about what the source of pain may

be. If in doubt, a therapeutic trial of regular anal-gesics may be worthwhile after a careful clinicalexamination.The most frequently identified factor as a

cause of pain was muscle spasm. Children withSanfilippo syndrome and the leucodystrophieswere particularly prone to muscular spasm.Regular oral diazepam has been the most

effective measure, although it sometimes causedunacceptable drowsiness. The benefit of baclofenalone was less obvious, but a combination withdiazepam seemed helpful. Where muscle spasmand spasticity is poorly controlled, dislocation ofthe hips may occur, resulting in further pain anddifficulty in maintaining the child’s comfort.

Joint pain was another important cause of

pain in these children, especially those with

mucopolysaccharide disease. Nonsteroidal anti-

inflammatory drugs (NSAIDs), such as ibuprofenand dicloflenac, were helpful and their use

allowed some children who had stopped walkingto become mobile again for a time.Only three children in this group required a

strong opioid drug for pain. One of these wasa child with metachromatic leucodystrophy whocould not tolerate handling and was thought tohave a peripheral neuropathy. Despite the likeli-hood of a neuropathic pain, morphine at low dosewas effective and has allowed her to be handledwithout distress for several months.

Constipation, gastritis or oesophagitis fromreflux were also recognized as causes of

pain. Children who were generally unwelland fretful were sometimes found to havean otitis media or oral thrush. Adolescent

girls occasionally required an oral contraceptivepill or medroxyprogesterone acetate injectionsto regulate and moderate their periods andto prevent premenstrual symptoms. NSAIDssuch as ibuprofen were helpful in alleviatingdysmenorrhoea.

Movement disordersOver one-third of these children had movement

disorders, for example ataxia, dystonic posturing,or jerky uncontrolled movements that could bedifficult to distinguish from seizures or mus-

cle spasms. The management of movementdisorders can be complex and requires both

paediatric and neurological expertise. A com-bination of antiparkinsonian, muscle relaxant



25

and anticholinergic medications was sometimesrequired.

Sleep disordersSleep problems were reported in 31 % of the

children. These were most frequently seen inthose with mucopolysaccharidoses; often inthese conditions night sedation is ineffective.Behavioural approaches, however, can help, forinstance, by establishing a routine, and by reduc-ing stimulation to a minimum by cutting out lightand noise. Often the young child with Sanfilipposyndrome may not sleep for many consecutivenights, and making a safe environment for thechild in a room, chair or bed may be the only waythe parents can maintain their own health.

Skin careThe geat majority of children were immobile,

so they could not turn themselves in bed. None,however, developed pressure sores of a kind thatmight occur in a similarly affected adult. Changingthe child’s position was important and the useof special mattresses (hollow core fibre-type orripple beds) helped to maintain intact skin. Mostchildren were incontinent and therefore wore dis-

posable nappies. Whilst napkin rash as such wasrare, thrush was occasionally a problem requiringtreatment with an antifungal cream.

Problems experienced by familiesLoss and bereavementThe genetic origin of many neurodegenerative

diseases occurring in children means that familiesface difficult decisions regarding future pregnan-cies if they are to avoid another affected child. 13Where more than one child in a family has the dis-ease, the presenting symptoms may not have beenrecognized until after a second affected child wasborn. Once the diagnosis is known or suspected inone child, and where no antenatal test is available,many parents decide to have no further children.Where testing is available, some families take therisk and face the subsequent decision of whetherto end the pregnancy if the test proves positive.Few families decide to have further children with-out any tests.

Families of children with neurodegenerativedisease therefore face a continuum of losses. At

diagnosis, there is the loss of the potential adult;later they experience the child’s loss of skills and,

eventually, they face the child’s death. For some,these experiences are repeated as subsequent chil-dren are diagnosed with the same condition. Somewill also undergo termination of much wantedpregnancies. Atkinl4 describes their predicament.A bereavement service with two bereavement

workers is provided by Helen House. Familieswho had already been bereaved on referral tothe hospice, or who had lost one of their affectedchildren whilst using the hospice, often chose notto use this service. They felt the need to postponeor suppress grieving for their first loss whilst theycontinued to care for the remaining sick child. Itwas important to acknowledge their grief and toallow its expression when the time was right forthem.

Following the death of a child, families continueto be supported by visits and phone calls fromtheir ’contacts’ (key workers at the hospice) andby one of the bereavement visitors. This supportis maintained for as long as the family feel it ishelpful, the average length of time being in theregion of two years. A remembrance weekendis held once a year when families may returnto celebrate the life of the child and have the

opportunity to meet again with other parents withwhom they can share their stories. Cards are sentat birthdays and anniversaries of the children.Special attention is directed to the needs of thewell brothers and sisters.6

Conclusion

Chronic degenerative conditions impose a greatburden, both on families and associated profes-sionals. It may be difficult to maintain routinecontacts when there is no great change fromweek to week, or from month to month. It is ourexperience that families valued enormously thecontribution of consultants, general practitionersand community nurses who maintained regularavailability and contact, even in situations wherethere was no specific ’professional’ task to beperformed. 15 In these instances, the professionalswere keeping open the channels of communica-tion that would become essential in times of crisis.Whatever else could or could not be done, afriendly listening ear and commonsense practicalhelp were always valued.

In this study, the median number of years



26

since first admission to the hospice till death wasbetween two and three. These figures emphasizethe often chronic nature of the disease process andthe nature of the burden on the child’s family.They also make apparent the level of commitmentrequired by the health professional in standing bythe family over the years. The skills that the careof children with neurodegenerative disease drawfrom both parents and professionals are many.Our experience has been derived within a chil-dren’s hospice but could equally well be appliedin the home. Whilst caring for these children canpresent both difficulties and challenges, it is sel-dom that nothing can be done to help. Attentionto detail, persistence and imagination in seekingsolutions, willingness to ask advice, and the appli-cation of basic clinical and therapeutic skills, canall help make life easier for both child and family.

AcknowledgementsWe wish to thank Dr Ann Goldman, Con-

sultant in Palliative Care, Great Ormond StreetHospital for Children, London, for her generousadvice and encouragement.

References

1 Muenzer J. Mucopolysaccharidoses. Adv Pediatr1986; 33: 269-302.

2 Jaeken J, Casaer P, DeCock P. Vigabatrin in GABAmetabolism disorders [Letter]. Lancet 1989; i: 1074.

3 Marsden CD, Quinn NP. The dystonias. Br Med J1990;300:139-44.

4 Kurlemann G, Palm DG. Vigabatrin inmetachromatic leucodystrophy; positive influence onspasticity [Letter]. Dev Med Child Neurol 1991; 33:182.

5 Cleary MA, Wraith JE. Management ofmucopolysaccharidosis type III. Arch Dis Child 1993;69:403-406.

6 Worden JW, Monahan JR. Caring for bereavedparents. In: Armstrong-Dailey A, Goltzer SZeds. Hospice care for children. New York: OxfordUniversity Press, 1993: 122-39.

7 Goldman A, Burne R. Symptom management. In:Goldman A ed. Care of the dying child. Oxford:Oxford University Press, 1994: 52-75.

8 Burne R, Hunt A. Use of opiates in terminally illchildren. Palliat Med 1987 ; 1 : 27-30.

9 Hunt A. A survey of signs, symptoms and symptomcontrol in 30 terminally ill children. Dev Med ChildNeurol 1990; 32: 341-46.

10 Sharts-Engel N. Acyclovir in the management ofchickenpox. MCN Am J Mat Child Nurs 1992; 17:280.

11 McCaffery M, Beebe A. Pain in children: specialconsiderations. In: Latham J ed. Pain: clinical manualfor nursing practice. London: Mosby, 1994: 223-59.

12 Dunlop R. Transdermal hyoscine and drooling[Letter]. Palliat Med 1990; 4: 328-29.

13 Clarke A. Dying from genetic disease. In: Hill L. edCaring for dying children and their families. London:Chapman & Hall, 1994: 246-59.

14 Atkin M. The doomed family. In: Burton L ed. Careof the child facing death. London: Routledge & KeganPaul, 1974: 60-73.

15 Howell DA. Role of the primary physician. In:Armstrong-Dailey A, Goltzer SZ eds. Hospice carefor children. New York: Oxford University Press,1993: 172-83.



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