9789241548120 physicians&nurses

8/2/2019 9789241548120 Physicians&Nurses

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Hihihs for physiias

ad urss xrad

fro h WHO guidelines

on the pharmacologicaltreatment of persisting

pain in children with

medical illnesses

Prsisi pai

i hidr

Important InformatIon for physIcIans and nursesall health-care professIonals who treat or care for chIldren wIth paIn


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who lib cgig-i-pbii d

piig i i i kg: who gii gi iig i i i i i i.

c: who gii gi iig i i i i i i - t b i i iifor physicians and nurses; pharmacists; policy-makers and medicines regulatory authorities, hospital managers and health insurance managers - Dosing card -pi s i (4 g ) - pi s i (6 - 10 ) - w iig

1.Pain - drug therapy. 2.Pain - classication. 3.Pain measurement. 4.Analgesics, Opioid. 5.Drugs, Essential. 6.Drug and narcotic control. 7.Palliative care.8.ci. 9.Gii. I.w h ogizi.

ISBN 978 92 4 154812 0 (NLM classication: WL 704)

Word Hah Oraizaio 2012

All rights reserved. Publications of the World Health Organization are available on the WHO web site (www.who.int) or can be purchased from WHO Press,World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]).

rq ii who bii i iibi b who pthrough the WHO web site (http://www.who.int/about/licensing/copyright_form/en/index.html).

The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of thew h ogizi ig g , i, i i ii, ig iii i ior boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.

The mention of specic companies or of certain manufacturers products does not imply that they are endorsed or recommended by the World HealthOrganization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products areiigi b iii i .

All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published

material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lieswith the reader. In no event shall the World Health Organization be liable for damages arising from its use.

pi i ( )


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c

Iroduio .................................................... 1

1. Wha is w i h uidis ..................... 3

2. Rodd iia approah ................. 5

3. Hah sys rodaios ............... 10

4. Spia issus ............................................ 12

Ax 1 ......................................................... 15

c WHO guidelines onthe pharmacological treatment of persisting pain in

children with medical illnesses

Ax 2 ......................................................... 17

dg b qik

Ax 3 ......................................................... 21

pi

Ax 4 ......................................................... 23

Pharmacological proles

Ax 5 ......................................................... 41

s ii i

Akowds ........................................ 43

Rfrs .................................................... 43
http://-/?-http://-/?-http://-/?-http://-/?-


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Iit b Persisting pain in children ii i ii

which is extracted from the WHO guidelines on the pharmacological treatment of persisting

pain in children with medical illnesses (1) i .

t who gii i bi ii, ii i

i. ti b igig i i i

- i i i i.

t WHO guidelines on the pharmacological treatment of persisting pain in children with

medical illnesses gi iig i, iig

cancer pain. As such, it replaces the previous guidelines Cancer pain and palliative care

in children, which exclusively covered cancer pain. The new guidelines on persisting pain

in children are the rst of a series of three guidelines documents on all types of pain in

b i. t i gii i b iig i i i. t bi ii gii i i i i,

iig i, b i i gi -gi

techniques, irrespective of whether the underlying cause can be identied.

The World Health Organization (WHO) estimates that around 5.7 billion people live

in countries where moderate and severe pain is not adequately treated. Data from the

Ii ni c B (IncB) 2009 90

gb i g ii i ai, c, n Z,

United States of America, the United Kingdom and several other European countries. This

means that their availability was very limited in many countries and regions. Over 80% of

the world population will have insufcient analgesia.


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mii ii gi, i, bj ii gcontrol conventions and as a result, the focus has historically been on prevention of

misuse, dependence and diversion while medical access has been neglected. In recent

, gig gii gii b i

scientic purposes has resulted in a shift in emphasis.

mi bi i ii gi ii

are of various natures. They include legal and policy issues, and various educational issues

at all levels, from patients and their families to physicians, pharmacists and policy-makers.

Doctors and nurses have an important role to play in overcoming these barriers and

expanding pain relief treatment to all patients who need treatment.

This brochure provides background information on the treatment of pain in children that

can be helpful to doctors and nurses for ensuring adequate access to pain treatment. Formore detailed information and additional references we refer to the formal guidelines

document. This formal guidelines document is available as hardcopy at the WHO Bookshop1

and online at www.who.int/medicines. In case of any discrepancy between this brochure

and the guidelines document, the guidelines document should be the reference.

sii igig b bi i i-k.

1 tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]; web: http://apps.who.int/bookorders/


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W

hatisnew

intheguid

elines

1


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All patients with pain, including children, should be treated, irrespective of whether or not theunderlying cause can be identied. Inability to establish an underlying cause should not be a i i bi.

The new guidelines recommend using analgesic treatments in two steps according to the childslevel of pain severity. Paracetamol and ibuprofen are the medicines of choice in the rst step: thetreatment of mild pain. In the second step, the treatment of moderate to severe pain, morphineis the medicine of choice. Correct use of analgesic medicines will relieve pain in most childreni iig i i i.

I gii, who i g b children. The effects of codeine are unpredictable because of intra-individual metabolic differencesand therefore pose a safety risk. For tramadol, there is currently no available evidence for its

comparative effectiveness and safety in children. In the previous guidelines, Cancer pain andpalliative care in children, k ig ii ik i ii b i -ii ib gii ik i.

pii i i b.

pii i iii g g ii. t g b who .

The term persisting pain as used in these guidelines is intended to cover long-term pain relatedto medical illness. Medical illnesses refers to specic situations of ongoing tissue damage where i gi .


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Reco

mme

nded

clinicalapp

roach

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oi i g bgi i g i .Following the assessment, a treatment plan is developed, including pharmacological andnon-pharmacological interventions. This is then implemented and evaluated by a new, i j .

PAIn ASSeSSment

The pain assessment process involves the child, the parents or caregivers and the health-careproviders. The way a child perceives pain is an outcome of biological, psychological, social, culturaland spiritual factors. Therefore, a comprehensive approach to pain assessment is required.

The initial pain assessment of a child reporting or presenting behavioural signs of pain includes adetailed pain history, a physical examination, the diagnosis of the causes, and the measurement

of pain severity using an age-appropriate pain measurement tool, usually a pain intensity scale.Measurements should be recorded over time in the childs clinical chart or by the child or his/hercaregivers in a journal.

Several questions that should be raised are presented in Table 1, below. The health-care providershould investigate the association of pain with any triggering factors by asking about anyknown aggravating and relieving factors. The health-care provider should also ask what painmanagement treatments have previously been used, as well as the efcacy of any treatments.

fig i , i i g b itogether with the childs primary caregiver. Pain measurement should be performed at regularintervals during the implementation of the pain management plan. This permits the measurementof changes in the severity of pain over time, and the assessment of the adequacy and efcacy of , b j b , .


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7

tab 1 Suary of qusios by h hah-ar providr duri iia vauaio

w i i i?

What verbal and behavioural cues does the child use to express pain? What do the parents and/or caregivers do when the child has pain? What do the parents and/or caregivers not do when the child has pain? What works best in relieving the pain? Where is the pain and what are the characteristics (site, severity, character ofi ib b i/, .g. , big, ig, bbig,ig, bbig)?

h i i ( i /g)? h g i b (i i )?

w i i (ig/i i)? Is the pain disturbing the childs sleep/emotional state? Is the pain restricting the childs ability to perform normal physical activities (sit,, k, )?

Is the pain restricting the childs ability/willingness to interact with others, andbii ?

A thorough physical examination is essential and each location of pain should be carefullyevaluated. During the examination, the examiner should watch carefully for any reactions fromthe child, such as facial grimacing, abdominal rigidity, involuntary exion, and verbal cues, which ii i. a g i i i b i b .

The information gathered from the history and physical examination will help to identify aii igi () i, gi i b radiological investigations to conrm diagnosis, if not yet established.

The main behavioural indicators of acute pain are facial expression, body movement and bodyposture, inability to be consoled, crying and groaning. These behavioural responses may bereduced in persisting pain, except during acute exacerbations. Behaviour in children with chronicpain can include abnormal posturing, fear of being moved, lack of facial expression, lack ofi i ig, qi, i iibii, , ii,g, g i i .

However, children may display none of the expected clues. They may deny their pain for fear ofmore painful treatment, for example, they may be fearful of injections. Absence of these signs

does not mean absence of pain and care should be taken to avoid underestimating pain.


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PHARmAcOlOgIcAl tReAtment

Correct use of analgesic medicines will relieve pain in most children with persisting pain i i i ig k :

1. ig - g2. dosing at regular intervals3. ig i iii4. adapting treatment to the individual child.

Usi a wo-sp srayWHO recommends treating pain in two steps, based on pain severity assessment:

s 1 i i i. t ii -ii gi ik

and ibuprofen. These substances have a xed maximum dosage and can provide onlyii gi. Step 2 is for moderate and severe pain. Strong opioids are used, e.g. morphine, using

ig-i ig . t g b who than those recommended elsewhere. As long as the pain is not sufciently addressed,the dosage needs to be increased in steps of no more than 50% per 24 hours.

Dosi a ruar irvasOpioids should be administered at regular intervals and not on an as-needed basis.

Usi h appropria rou of adiisraioAlthough in many countries the prevailing route of administration is by injection, oraliii ii i i b . tsubcutaneous route could be a valuable alternative for other patients.

Adapi ra o h idividua hidTreatment with strong opioids needs to be individually adjusted and there is no xed

maximum dosage. This may also include small rescue dosages in addition to the regulardosages for use in cases when additional pain is experienced (so-called breakthroughi).

Alternative strong opioids may be needed instead in case a patient has dose-limiting side-effects to morphine. Several alternative strong opioids are discussed in the pharmacologicalproles on page 23.


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9

OtHeR ASPectS tO cOnSIDeR WHIle tReAtIng PAIn IncHIlDRen

lo-r opioid uslg- ii i i i ii. t, i also receive a combination of a stimulant laxative and a stool softener prophylactically.

WaiPatients can wean from opioids safely in 510 days after short-term therapy without posingsignicant health risks. After long-term therapy the weaning period will take weeks. The i b i i ig b .

AidoNaloxone is a specic antidote, but care in its administration is needed in order not toprecipitate opioid withdrawal syndrome. Moderate opioid overdose can be managed withassisted ventilation, while naloxone doses starting at 1 microgram (mcg)/kg are titratedover time, e.g. every 3 minutes, until the necessary dose is found. A low-dose infusion iig b qi ii k i adverse effect of the opioid overdose resolves.

It is recommended for physicians and nurses to read the entire Chapters 1, 2 and 3 of the

newwho gii gi iig i i i ii i, which deal with classication of pain in children, evaluation of persistingpain in the paediatric population and pharmacological treatment strategies.

3


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Healthsystem

recom

mend

ations

3


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Opioid analgesics such as morphine and pain management services should be available at all levels of. t, ib ii, iig g ii, b i b i ii, .g. gi hIV ii .

nd for duaio ad raiit ii ii gi i ii ii ii.When used rationally for medical purposes, strong opioids are safe medicines. However, certainiii b k i ib si 2, Recommended clinicalapproach, in particular the maximum daily increase and the importance of weaning gradually.Therefore training and education on how to prescribe opioids is very important.

For methadone, additional training on the dosage is important as it has a long

half-life in the body and tends to accumulate, with a risk of overdosage.

Assessment and measurement of pain is essential for estimating pain severity, and hence, foriig i ii ib j g. t, i i i, i i i i, i i. ci i i i i , i i b giz.

Us of orphi ora souioSome countries with extremely low resources for health care use morphine oral solution, whichi b i . B ig i ipowder as the starting material, the cost per patient can be as low as USD 0.05 a day. Expiry dates b g k .

Ipora of siai ds for pai rifEvery year, the national authorities must prepare estimates for the following calendar year of theirqi i g ii. ti i i i i ii gi i i qii i i

medicines. Although the production of estimates is a government responsibility, when requested,i - i i b i i.

Siuaioa aaysisA crucial step towards expanding pain relief treatment in the health system is to assess thei i g i , girestricting the availability or accessibility of opioid analgesics. Countries that have very strict lawsand policies that do not allow ready access to pain treatment should endeavour to make them lessrestrictive and more practicable. The World Health Organization has developed guidelines thatelaborate on the policy aspects of improving access to ensure the balance between the adequateavailability for medical and scientic purposes while simultaneously preventing abuse, diversionand trafcking (2). I i - k big ii access to pain treatment services to the attention of the authorities.

4


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Sp

ecial

issues

4


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This section addresses special issues that need to be taken into account in improving access i i.

Risk of dpd

d i i . aigto the denition of dependence syndrome, other symptoms need to exist, including astrong desire to take a substance, difculties in controlling its use, persisting in its usedespite harmful consequences, and a higher priority given to substance use than to otheractivities and obligations (ICD-10 denition).

Withdrawal can be prevented by gradually reducing the dose instead of making an abruptinterruption. Tolerance (a need for higher doses in order to achieve the same effect) may i ii gi, g ig g b

related to an increased severity of the disease and the pain.

Prevalence of the dependence syndrome in pain patients is rare. The possibility thatdependence might occur should not be a reason for not addressing the patients pain, and i i , b ,j ik i- i b .

Risk of divrsio

While opioids are potent medicines for the relief of moderate and severe pain, there is arisk of misuse and diversion, which can be low or high, depending on the country. Measures ik i ii ii i i ibii appropriate prescribing, including careful patient selection. To prevent accidental overdose


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by family members, the caregivers and the patient should be warned to store the medicinesin a safe place in child-proof containers. The possibility that one of the parents may haveopioid dependence and may be taking the opioids themselves should also be considered.

Sudd irrupio of suppy of sro opioid diisSudden interruption of treatment with strong opioids leads to severe withdrawal syndrome.sig ii i i ig, ig,lacrimation, rhinorrhea, anxiety, restlessness, insomnia, dilated pupils, piloerection, chills,tachycardia, hypertension, nausea and vomiting, cramping abdominal pains, diarrhoea, i. wi ii ig, i iextremely important to ensure the quality of the procurement system in order to minimize ik ii.

Rsarh adaMany aspects of the pharmacological treatment of pain in children are insufcientlyinvestigated. For this reason the guidelines development group of experts that developed gii g i ii i i i.

It is recommended for physicians, nurses and pharmacists who conduct research

to read Annex 5 of the guidelines, Research agenda.

Foruas for orphi ora souioConsiderable savings can be achieved by compounding an oral solution in the pharmacy as big i i. o i b ig i i i . w ig isolution, the biological and chemical shelf-life should be considered. The preservation isin particular important. Several circulating formulas use carcinogenic or ineffective waysof preservation, such as with bronopol (2-bromo-2-nitropropane-1.3-diol) or chloroform

.

WHO recommends using formulas with safe ingredients only, an effective preservationand an established biological and chemical shelf-life. An example of such a formula is theOral Morphine Solution from the Formulary of the Dutch Pharmacists (FNA). A modiedversion is included in the WHO highlights brochure Persisting pain in children: importantinformation for pharmacists.


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Annex1 Content of the document WHO guidelines

on the pharmacological treatment of

persisting pain in children with medical

illnessesThis brochure is extracted from the WHO guidelines on the pharmacological treatment ofpersisting pain in children with medical illnesses. In order to give the reader an impression i , i i iz b.

Pain in children is a public health concern of major signicance in most parts of theworld. Although the means and knowledge to relieve pain exists, childrens pain is oftennot recognized, is ignored or even denied. These guidelines address the pharmacologicalmanagement of persisting pain in children with medical illnesses. They include severalii i, iig - gi. t gii i i g qi igig ii .

All moderate and severe pain in children should always be addressed. Depending on the

situation, the treatment of moderate to severe pain may include non-pharmacological, i -ii gi i ii gi. t iirecommendations are unlikely to be effective unless accompanied by the necessary policychanges, which are not all covered in these guidelines.

tIroduiostates the objective of these guidelines and a description of their scope,including which types of pain are specically included and excluded. It also describes thepatients to which they apply and the audience for whom the guidelines were developed.

chapr 1.Classication of pain in children provides a description of pain classication.

chapr 2. Evaluation of persisting pain in the paediatric population gives generalguidance and key concepts on the assessment and evaluation of pain in children.


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chapr 3. Pharmacological treatment strategies provides clinical guidance to healthprofessionals. It presents the recommendations for pharmacological interventions,emphasizing that moderate and severe pain in children should always be addressed.t i gi i i b

iig i b , j ii ( hIV/aIds), ik i,b, i i ig i, i -step approach based on the severity of pain. Paracetamol or ibuprofen are the medicinesof choice in the rst step and are used for treatment of mild pain.mi, gii, i ii i i i to severe pain. Both strong opioids and non-opioid analgesics should always be availableat all levels of health care. With the publication of these guidelines, WHOs three-stepgi i i b b i.

chapr 4. Improving access to pain relief in health systems b considerations regarding how to improve access to pain treatment and includes four policyi.

Ax 1.Provides Pharmacological proles ii.Ax 2.Backgroundto the clinical recommendations, gives a description of the development process ofthe document, the considerations included by the Guidelines Development Group ig i bi -gi

interventions. Ax 3.Background to the health system recommendations provides theconsiderations by the Guidelines Development Group when formulating the recommendations c 4. Ax 4.Evidence retrieval and appraisal, Grade bwhich were developed for using the retrieved literature, and the observational studiesthat were retrieved on topics for which there were no systematic reviews and randomizedii i. Ax 5. i Research agenda. Ii qi ig i ii gi i i ib i Ax 6.fi, i Ax 7, individuals who contributed to thegii i.


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Annex2 Dosage tables for quick reference

(see also the pharmacological proles)

tab 2 Sari dosas for opioid aasis for opioid-aiv oas

mdii Rou of adiisraio Sari dos

mi

IV iji

2550 mcg/kg every 6 hrs

sc iji

IV iiIii IV 2550 mcg/kg, then

510 mcg/kg/hr

f

IV ijib 12 mcg/kg every 24 hrs

IV iibIii IV 12 g/kg,

0.51 mcg/kg/hr

Administer IV morphine slowly over at least 5 minutes.b The intravenous doses for neonates are based on acute pain management and sedation

dosing information. Lower doses are required for non-ventilated neonates. Administer IV fentanyl slowly over 3 5 minutes.


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tab 3 Sari dosas for opioid aasis i opioid-aiv ifas

(1 month1 year)

mdii Rou of adiisraio Sari dos

mi

o (ii ) 80200 mcg/kg every 4 hrs

IV iji16 months: 100 mcg/kg every 6 hrs612 months: 100 mcg/kg every 4 hrs

(max 2.5 mg /dose)sc iji

IV ii

16 months: Initial IV dose: 50 mcg/kg,

then: 1030 mcg/kg/hr612 months: Iii IV : 100200 mcg/kg, then: 2030 mcg/kg/hr

sc ii13 months: 10 mcg/kg/hr312 months: 20 mcg/kg/hr

fb

IV iji 12 mcg/kg every 24 hrs

IV iiIii IV 12 g/kg,

0.51 mcg/kg/hr

Oxycodone o (ii ) 50125 mcg/kg every 4 hrs

Administer IV morphine slowly over at least 5 minutes.b The intravenous doses of fentanyl for infants are based on acute pain management and

i ig ii. Administer IV fentanyl slowly over 35 minutes.


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tab 4 Starting dosages for opioid analgesics in opioid-naive children (112 years)

mdiiRou of

adiisraioSari dos

mi

o (ii)

12 years: 200400 mcg/kg every 4 hrs212 years: 200500 mcg/kg every 4 hrs (max 5 mg)

o (g)


IV iji 12 years: 100 mcg/kg every 4 hrs212 years: 100200 mcg/kg every 4 hrs

(max 2.5 mg)sc iji

IV iiIii IV : 100200g/kg,

2030 mcg/kg/hr

sc ii 20 g/kg/

f

IV iji 12 g/kgb, repeated every 3060 minutes

IV ii Iii IV 12 g/kgb

, then 1 mcg/kg/hr

h

o (ii)

3080 mcg/kg every 34 hrs(max 2 mg/dose)

IV iji sc iji


m

o (ii) 100200 g/kg

every 4 hrs for the rst 23 doses, then every612 hrs (max 5 mg/dose initially)IV ijig

sc iji

Oxycodone

o (ii)

125200 mcg/kg every 4 hrs (max 5 mg/dose)

o (g)

5 mg every 12 hrs

Administer IV morphine slowly over at least 5 minutes.b Administer IV fentanyl slowly over 35 minutes.


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Hydromorphone is a potent opioid and signicant differences exist between oral andintravenous dosing. Use extreme caution when converting from one route to another. Inconverting from parenteral hydromorphone to oral hydromorphone, doses may need tobe titrated up to 5 times the IV dose.

Administer IV hydromorphone slowly over 23 minutes. Due to the complex nature and wide inter-individual variation in the pharmacokinetics

of methadone, methadone should only be commenced by practitioners experienced withi .

m iii b i ik g ii. t g to be reduced by 50% 23 days after the effective dose has been found to preventadverse effects due to methadone accumulation. From then on dosage increases shouldbe performed at intervals of one week or over and with a maximum increase of 50%.

g Administer IV methadone slowly over 35 minutes.

tab 5 Approxia dos raios for swihi bw parra ad ora

dosa fors

mdii Dose ratio (parenteral:oral)

mi 1:21:3

h 1:21:5

m 1:11:2

Hydromorphone is a potent opioid and signicant differences exist between oral and

intravenous dosing. Use extreme caution when converting from one route to another. Inconverting from parenteral hydromorphone to oral hydromorphone, doses may need tobe titrated up to 5 times the IV dose.

3


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A

nne

x3 Preparations

Preparation availability

For providing adequate pain treatment the following preparations need to be available:

Step 1 analgesics (non-opioids)

For step one both paracetamol and ibuprofen should be available.

Paraao

Oral liquid: 25 mg/ml.si: 100 g.Tablet: 100500 mg.

Ibuprof

tb: 200 g, 400 g.o iqi: 40 g/.

Step 2 analgesics (strong opioids)

Morphine should always be available as immediate release dosage forms (oral liquid,

immediate release (IR) tablets 10 mg and injections). Additionally, prolonged release

tablets and granules should be available if affordable.

morphi

o iqi: 2 g ( i )/.tb: 10 g ( ).Iji: 10 g ( i ) i 1 .

Tablet (prolonged release): 10 mg, 30 mg, 60 mg, 100mg, 200mg (as sulfate).Granules: (prolonged release, to mix with water): 20 mg, 30 mg, 60 mg, 100 mg, 200 mg

(i ).

Additionally, one or more other strong opioids should be available as an alternative to

morphine in step two. There are many options, including:

Fay

t zg: 200 g, 400 g, 600 g, 800 g, 1200 g, 1600 g (i).Transdermal patch (extended release): 12.5 mcg/hr, 25 mcg/hr, 50 mcg/hr, 75 mcg/hr,

100 g/ ( b).Injection: 50 mcg/ml in various vial sizes (as citrate).


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Hydroorpho

Iji: 1 g i 1 , 2 g i 1 , 4 g i 1 , 10 g i1 ( i).tb: 2 g, 4 g, 8 g ( i).

o iqi: 1 g ( i)/.

mhado (WARNING: requires additional training for dosing)

Injection: 10 mg/ml in various vial sizes (as hydrochloride).Tablet: 5 mg, 10 mg, 40 mg (as hydrochloride).Oral liquid: 1 mg/ml, 2 mg/ml, 5 mg/ml (as hydrochloride).o : 10 g/ ( i).

Oxyodo

Tablet: 5 mg, 10 mg, 15 mg, 20 mg, 30 mg (as hydrochloride).Tablet (modied release): 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg,160 g ( i).Capsule: 5 mg, 10 mg, 20 mg (as hydrochloride).o iqi: 1 g/ ( i).c iqi: 10 g/, 20 g/ ( i).

The use ofpethidine is not recommended.

Antagonist

For use in opioid overdosage

naoxo

Iji: 400 g/ (i) i 1 .

4


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A

nne

x4 Pharmacological profles

Please see Annex 1 of the who gii gi iig

i i i i i i for further details on interactions with othermedicines.

This section gives the pharmacological proles of the non-opioid and opioid analgesicii i iig i i i i i i. I ithe prole of naloxone, the antidote in case of opioid overdose.

The formulations and strengths in this section are indicative of medicines generallyavailable on the market.Countries may have access to different formulations and strengths.t i i g k iig i i i. f ii i i WHO model list of essential medicines for children, ii i.

A4.1 FayAtc cod:n01ah01trasuosa oz: 200 g, 400 g, 600 g, 800 g, 1200 g, 1600 g( i).

Transdermal patch (extended release): 12.5 mcg/hr, 25 mcg/hr, 50 mcg/hr, 75 mcg/, 100 g/ ( b).Ijio: 50 mcg/ml in various vial sizes (as citrate).

Idiaios: moderate to severe persisting pain.

coraidiaios: hypersensitivity to opioid agonists or to any component of thei; i i; ; i i; i of, or use within 14 days after ending monoamine oxidase inhibitors; raised intracranial

pressure and/or head injury, if ventilation not controlled; coma; use within 24 hours before g.

Prauios: impaired respiratory function; avoid rapid injection which may precipitatechest wall rigidity and difculty with ventilation; bradycardia; asthma; hypotension; shock;obstructive or inammatory bowel disorders; biliary tract disease; convulsive disorders;hypothyroidism; adrenocortical insufciency; avoid abrupt withdrawal after prolonged; ib i; ii i; ii; igravis; hepatic impairment; renal impairment; toxic psychosis; (patches:) increased serumlevels in patients with fever > 40 C (104 F).

Skid asks: warn the patient or caregiver about the risk of undertaking tasks requiringattention or coordination, for example, riding a bike.


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Dosa:

Sari dos for opioid-aiv pais:

IV injection: oa ifa 12 mcg/kg per dose slowly over 35 minutes;repeated every 24 hours;

hid 12 mcg/kg per dose, repeated every 3060 i.Continuous IV infusion:

oa ifa iii IV b 12 mcg/kg (slowly over35 minutes), followed by 0.51 g/kg/;

hid iii IVb 12 mcg/kg (slowly over 35 minutes), followed by1 g/kg/ (i i ).

coiuaio: after a starting dose according to the dosages above, the dosageshould be adjusted to the level that is effective (with no maximum), but themaximum dosage increase is 50% per 24 hours in outpatient settings. Experiencedprescribers can increase up to 100% under monitoring of the patient. (The usualIV i 13 mcg/kg/hr,some children require up to 5 mcg/kg/hr.)

Dos for brakhrouh pai

Transmucosal lozenge (oral transmucosal fentanyl citrate or OTFC):

hid ovr 2 yars ad ovr 10 k body wih 1520 g/kg single dose (maximum 400 mcg); if more than 4 doses of breakthrough painii , j bkg gi.

Dos wh swihi fro orphi:

t : hid 2 yars or ovr,who is opioid tolerant and on at least 4560 mgof oral morphine equivalent per dayuse 25 mcg/hr system (or higher,based on conversion to fentanyl equivalents see Notes); the child shouldhave stable pain management with a short-acting opioid at least for 24 hoursi ig (i qi bkg i); i ; b i (b bkg i

needs); use a ratio of 45 mg of oral morphine equivalents per 12.5 mcg/hri i g ( b qigi ). cgpatch every 72 hours; a 48-hour schedule is not recommended in children.


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Dosa disoiuaio: after short-term therapy (714 days), the original dose can bedecreased by 1020% of the original dose every 8 hours increasing gradually the time interval.After long-term therapy, the dose should be reduced not more than 1020% per week.

Ra ipair: moderate (glomerular ltration rate (GFR) 1020ml/min or serumcreatinine 300700 micromol/l) reduce dose by 25%; severe (GFR 700 micromol/l) reduce dose by 50%.

Hpai ipair: avoid or reduce dose, may precipitate coma.

Advrs ffs:

oo nausea, vomiting, constipation, dry mouth, biliary spasm, respiratorydepression, muscle rigidity, apnoea, myoclonic movements, bradycardia, hypotension,

abdominal pain, anorexia, dyspepsia, mouth ulcer, taste disturbance, vasodilation,anxiety, drowsiness, diaphoresis;

uoo atulence, diarrhoea, laryngospasm, dyspnoea, hypoventilation,ii, i, i, iii, i, i,gii, , k, i, izzi, iig, b;

rar i i, i , i, i, i i,haemoptysis, psychosis, seizures, shock, asystole, pyrexia, ataxia, muscle fasciculation, iii (i ).

Iraios wih ohr diis*:

i, beta-adrenergic blockers, calcium channel blockers, central nervous system, imidazole antifungals, macrolide antibiotics, monoamine oxidase inhibitors*,naloxone*, naltrexone*, neuroleptics, nitrous oxide, opioid antagonists/partial agonists,i, iibi.

* Indicates severe.

nos:

Fentanyl is subject to international control under the Single Convention on Narcoticdg, 1961. Other dose forms of fentanyl are available but these currently have no role in the

g ii iig i i b i. Grapefruit juice should be avoided as fentanyl serum concentrations may be

signicantly increased. IV iii:- Administer by slow intravenous injection over 35 minutes or by continuous infusion.

- The intravenous doses for neonates, infants and children are based on acute pain

g i ig ii; b qi ipatients without ventilatory support.


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26

t :- Reservoir type transdermal patches should not be cut because damage to the rate-

controlling membrane can lead to a rapid release of fentanyl and overdose.

- a , , -i, -ii, i ki ;

remove after 72 hours and apply replacement patch on a different area (avoid thesame area for several days).

- When patches are removed, they should be folded in half with the adhesive side facingi i i qi iig i can be signicant and enough to poison a child or animal if not disposed of properly.

- t b i i i i i b bi.

- Some patients experience withdrawal symptoms (e.g. diarrhoea, colic, nausea,

ig, ) g i i i i i, i i i b until symptoms resolve (usually a few days).

o i:- To achieve maximum mucosal exposure to the fentanyl, the lozenge should be

placed inside the mouth against the buccal mucosa and moved constantly up anddown, and changed at intervals from one side to the other.

- t zg b b i i zg ii

15 minutes. Naloxone is used as an antidote in case of opioid overdose.

equiaasi doss:

t ig 24 i b i bapproximately equal to the fentanyl transdermal patches shown*:

morphine salt 45 mg daily = fentanyl 12.5 mcg patch morphine salt 90 mg daily = fentanyl 25 mcg patch morphine salt 180 mg daily = fentanyl 50 mcg patch morphine salt 270 mg daily = fentanyl 75 mcg patch morphine salt 360 mg daily = fentanyl 100 mcg patch.

*This table represents a conservative conversion to fentanyl transdermal patch

and should NOT be used to convert from transdermal fentanyl to other analgesic

therapies; overestimation of the dose of the new agent and possibly overdose

with the new analgesic agent may result. The dosing conversion above from oralmorphine to transdermal fentanyl is conservative to minimize the potential for

overdosing patients with the rst dose, and therefore approximately 50% of

patients are likely to require a higher dose following the initial application.


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27

A4.2 HydroorphoAtc cod: N02AA03Ijio: 1 g i 1 , 2 g i 1 , 4 g i 1 , 10 gi 1 ( i).

tab: 2 g, 4 g, 8 g ( i).Ora iquid: 1 g ( i)/.


coraidiaios: hypersensitivity to opioid agonists or to any component of the formulation; i i; ; i i; i , ii14 days after ending monoamine oxidase inhibitors; raised intracranial pressure and/or headinjury, if ventilation not controlled; coma; use within 24 hours before or after surgery.

Prauios: impaired respiratory function; avoid rapid injection which may precipitatechest wall rigidity and difculty with ventilation; bradycardia; asthma; hypotension; shock;obstructive or inammatory bowel disorders; biliary tract disease; convulsive disorders;hypothyroidism; adrenocortical insufciency; avoid abrupt withdrawal after prolonged; ib i; ii i; ii; igravis; hepatic impairment; renal impairment; toxic psychosis.


Dosa:


Oral (using immediate-release formulations):

hid initially 3080 mcg/kg per dose (maximum 2 mg per dose) every34 hours.

Subcutaneous or intravenous:

hid initially 15 mcg/kg per dose slowly over at least 23 minutes every36 hours.

coiuaio: after a starting dose according to the dosages above, the dosageshould be adjusted to the level that is effective (with no maximum), but themaximum dosage increase is 50% per 24 hours in outpatient settings. Experiencedprescribers can increase up to 100% with close monitoring of the patient.

Dosa disoiuaio: after short-term therapy (714 days), the original dose can bedecreased by 1020% of the original dose every 8 hours increasing gradually the time interval.After long-term therapy, the dose should be reduced not more than 1020% per week.


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Ra ipair: moderate (GFR 1020ml/min or serum creatinine 300700 micromol/l)and severe (GFR 700 micromol/l) reduce dose, start with i ig .

Hpai ipair: i i iii i g ii.

Advrs ffs:

oo nausea, vomiting, constipation, dry mouth, sedation, biliary spasm, respiratorydepression, muscle rigidity, apnoea, myoclonic movements, asthenia, dizziness, confusion,i, i, ig, i, , , ig;

uoo i, i, bi, i, ii,oedema, postural hypotension, miosis, visual disturbances, abdominal cramps, anorexia,paraesthesia, malaise, agitation, tremor, muscle weakness, hallucinations, vertigo, moodchanges, dependence, drowsiness, anxiety, sleep disturbances, headache, taste disturbance,

gii, i i, g, b; rar i i, i , i , k, i i, iz.

Iraios wih ohr diis:central nervous system depressants, ethanol*, monoamine oxidase inhibitors*, naloxone*,naltrexone*,opioid antagonists/partial agonists*.

* Indicates severe.

nos: Hydromorphone is subject to international control under the Single Convention on Narcotic

dg, 1961. Hydromorphone is a potent opioid and signicant differences exist between oral and

intravenous dosing. Use extreme caution when converting from one route to another. Give with food or milk to decrease gastrointestinal upset. Extended-release preparations are available; however, these are not indicated for use in

ii ig. Naloxone is used as an antidote in case of opioid overdose.

equiaasi doss:

Hydromorphone morphine vice versa

According to manufacturers, oral hydromorphone is 7.5 times more potent thanmorphine; however, when switching from morphine to hydromorphone, some suggestthe ratio is 5:1 (i.e. the dose of hydromorphone should be 1/5 of the morphine dose), iig i i 1:4 b (i.. i b 4 i ).

Parenteral hydromorphone to oral hydromorphone

I iig , less than one-half as effective as parenteral doses (may only be 1/5 as effective). Doses may needto be titrated up to 5 times the IV dose.


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A4.3 IbuprofAtc od: m01ae01tab: 200 g, 400 g.Ora iquid: 100 mg/5 ml.

Idiaios: i iig i.

coraidiaios: hypersensitivity (including asthma, angioedema, urticaria or rhinitis)to acetylsalicylic acid or any other non-opioids and non-steroidal anti-inammatorymedicines (NSAIDs); active peptic ulceration or upper gastrointestinal bleeding; severe i, i i i i.

Prauios: asthma; cardiac disease; volume depletion, such as in gastroenteritis or

i (i ik ii); i g irisk of bleeding; previous peptic ulceration; coagulation defects; allergic disorders; renalii; i ii.

Dosa:

Oral:

ifa ovr 3 ohs hid 510 mg/kg three or four times daily with

or after food; maximum total daily dose is 40 mg/kg/day divided into 4 doses.

Ra ipair: mild (GFR 2050 ml/min or approximate serum creatinine 150300micromol/l) use lowest effective dose and monitor renal function; sodium and wateri ii i i ib ig failure; moderate (GFR 1020ml/min or serum creatinine 300700 micromol/l) to severe(GFR 700 micromol/l) avoid.

Hpai ipair: i i, i i ik giibleeding; can cause uid retention; avoid in severe liver disease.

Advrs ffs:

oo nausea, diarrhoea, dyspepsia, headache, abdominal pain, anorexia,constipation, stomatitis, atulence, dizziness, uid retention, raised blood pressure,, gii i big;

uoo urticaria, photosensitivity, anaphylactic reactions, renal impairment;

rar angioedema, bronchospasm, hepatic damage, alveolitis, pulmonaryeosinophilia, pancreatitis, visual disturbances, erythema multiforme (Stevens-Johnsonsyndrome), toxic epidermal necrolysis (Lyell syndrome), colitis, aseptic meningitis.


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Dosa:


Oral, subcutaneous or intravenous:

hid initially 100200 mcg/kg every 4 hours for the rst 23 doses, then100200 mcg/kg every 612 hours; maximum of 5 mg per dose initially.Administer IV methadone slowly over 35 minutes.

coiuaio: after a starting dose according to the dosages above, the dosageshould be adjusted to the level that is effective (with no maximum), but themaximum dosage increase is 50% per 24 hours in outpatient settings. Experiencedprescribers can increase up to 100% with close monitoring of the patient. Then,

the dosage may need to be reduced by 50% 23 days after the effective dose hasbeen found to prevent adverse effects due to methadone accumulation. From thenon dosage increases should be performed at intervals of one week or over and witha maximum increase of 50%. (see Notes for important information regarding doseii).

Dosa disoiuaio: after short-term therapy (714 days), the original dose can bedecreased by 1020% of the original dose every 8 hours, increasing gradually the time interval.

After long-term therapy, the dose should be reduced not more than 1020% per week.Ra ipair: severe (GFR 700 micromol/l) reducedose by 50% and titrate according to response; signicant accumulation is not likely in renalfailure, as elimination is primarily via the liver.

Hpai ipair: avoid or reduce dose; may precipitate coma.

Advrs ffs:

oo nausea, vomiting, constipation, dry mouth, biliary spasm, respiratoryi, i, igii, i, bi, i, ii,oedema, postural hypotension, hallucinations, vertigo, euphoria, dyshporia, dependence,i, i i, i ;

uoo restlessness, dyspnoea, hypoventilation, depersonalisation,i, i, iii, i, i, gii, , k, i, izzi, iig, b, , ,ii;

rar QT interval prolongation, torsades de pointes, hypothermia, circulatory depression,i , i, i, i i, i, i, iz, k,

asystole, pyrexia, ataxia, muscle fasciculation, raised intracranial pressure.Iraios wih ohr diis:

abacavir, amiodarone, atomoxetine, carbamazepine, central nervous system depressants,efavirenz, uvoxamine, fosamprenavir, medicines that prolong the QT interval, monoamine


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32

oxidase inhibitors*, naloxone*, naltrexone*, nelnavir, nevirapine, opioid antagonists/partialagonists, phenobarbital, phenytoin, quinine, rifampicin, ritonavir, voriconazole, zidovudine.

* Indicates severe.

nos: Methadone is subject to international control under the Single Convention on Narcotic

dg, 1961. The dosage should be titrated clinically with close observation of the patient. Because of

the large volume of distribution, higher doses are required for the rst few days while theb i b ; i i , i i bsufcient. Continuing on the initial daily dose is likely to result in sedation within a fewdays, possibly respiratory depression, and even death.

aii i ji .

Dispersible tablet should be completely dissolved before administration. Methadone has a long and variable half-life and potentially lethal drug interactions with

g. Care needs to be taken with methadone to avoid toxicity because the time to reach steady

i ig g i g b 12 . Particular attention is required during initiation of treatment, during conversion from one

ii ig ii. Prolongation of the QT interval or torsade de pointes (especially at high doses) may occur. Use with caution as methadones effect on respiration lasts longer than analgesic effects.

Naloxone is used as an antidote in case of opioid overdose. As methadone has a long half-life, infusion of naloxone may be required to treat opioid

overdose.

equiaasi doss:

Dose conversion ratios from other opioids are not static but are a function of previousopioid exposure, and are highly variable.pbi b qigi ii, bi i -iitolerant individuals, indicate that methadone is 12 times as potent as morphinein single dose studies, but in individuals on long-term (and high dose) morphine,methadone is closer to 10 times as potent as morphine; it can be 30 times more potentor occasionally even more. The potency ratio tends to increase as the dose of morphineincreases. If considering methadone, thought should be given to the potential difculty bq iig ii.

Other opioids should be considered rst if switching from morphine due to unacceptableeffects or inadequate analgesia. Consultation with a pain clinic or palliative-care serviceis advised.


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A4.5 morphiAtc od: n02aa01Ora iquid: 2 g ( i )/.tab: 10 g ( ).

Tablet (prolonged release): 10 mg, 30 mg, 60 mg, 100 mg, 200 mg (as sulfate).Granules: (prolonged release, to mix with water): 20 mg, 30 mg, 60 mg, 100 mg,200 g (i ).Ijio: 10 g ( i ) i 1 .


coraidiaios: hypersensitivity to opioid agonists or to any component of the formulation; i i; ; i i; i , ii

14 days after ending monoamine oxidase inhibitors; raised intracranial pressure and/or headinjury, if ventilation not controlled; coma; use within 24 hours before or after surgery.

Prauios: impaired respiratory function; avoid rapid injection which may precipitatechest wall rigidity and difculty with ventilation; bradycardia; asthma; hypotension; shock;obstructive or inammatory bowel disorders; biliary tract disease; convulsive disorders;hypothyroidism; adrenocortical insufciency; avoid abrupt withdrawal after prolonged; ib i; ii i; ii; igravis; hepatic impairment; renal impairment; toxic psychosis.

Skid asks: i b ik kig k qiigattention or coordination, for example, riding a bike.


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34

Dosa:


Oral (immediate-release formulation):

infant 112 months 80200 mcg/kg every 4 hours; child 12 years 200400 mcg/kg every 4 hours; child 212 years 200500 mcg/kg every 4 hours; maximum oral starting

dose is 5 mg.

Oral (prolonged-release formulation):

child 112 years initially 200800 mcg/kg every 12 hours.

Subcutaneous injection:

oa 2550 mcg/kg every 6 hours; infant 16 months 100 mcg/kg every 6 hours; ifa child 6 months2 years 100 mcg/kg every 4 hours; child 212 years 100200 mcg/kg every 4 hours; maximum starting

dose is 2.5 mg.

IV injection over at least 5 minutes:

oa 2550 mcg/kg every 6 hours; infant 16 months 100 mcg/kg every 6 hours; ifa child 6 months12 years 100 mcg/kg every 4 hours; maximum

starting dose is 2.5 mg.

IV injection and infusion:

oa iii b intravenous injection over at least 5 minutes 2550g/kg, b continuous intravenous infusion 510 mcg/kg/hr;

infant 16 months iii b intravenous injection over at least 5 minutes100 g/kg, b continuous intravenous infusion 1030g/kg/;

ifa child 6 months12 years iii b intravenous injectionover at least 5 minutes 100200 mcg/kg, b continuous intravenous

infusion 2030 mcg/kg/hr.

Continuous SC infusion:

infant 13 months 10 g/kg/; ifa child 3 months12 years 20 g/kg/.

coiuaio: after a starting dose according to the dosages above, the dosageshould be adjusted to the level that is effective (with no maximum), but the maximumdosage increase is 50% per 24 hours in outpatient settings. Experienced prescriberscan increase up to 100% with close monitoring of the patient.


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Oral (immediate-release formulation), IV injection, or subcutaneous:

aii i b ii q qi i

maximum of 510% of the regular daily baseline morphine dose. If repeatedbkg qi, j g bi i gi b i qi bkg i i maximum increase of 50% per 24 hours.

Dosa disoiuaio: after short-term therapy (714 days), the original dose can bedecreased by 1020% of the original dose every 8 hours, increasing gradually the time

interval. After long-term therapy, the dose should be reduced not more than 1020% perk.

Ra ipair: mild (GRF 2050 ml/min or approximate serum creatinine 150300micromol/l) to moderate (GFR 1020 ml/min or serum creatinine 300700 micromol/l) reducedose by 25%; severe (GFR 700 micromol/l) reduce dose by50% or consider switching to alternative opioid analgesics which have less renal elimination,such as methadone and fentanyl; increased and prolonged effect; increased neurotoxicity.

Hpai ipair: avoid or reduce dose, may precipitate coma.

Advrs ffs:

oo nausea, vomiting, constipation, lightheadedness, drowsiness, dizziness,sedation, sweating, dysphoria, euphoria, dry mouth, anorexia, spasm of urinary andbii , i, , ig, ii, bi, i,ii;

uoo i i (-), i, ii; rar ii iii i (sIadh),

anaphylaxis.

Iraios wih ohr diis*:

amitriptyline, chlorpromazine, ciprooxacin, diazepam, haloperidol, metoclopramide,naloxone*, naltrexone*, opioid antagonists/partial agonists, ritonavir*.

* Indicates severe.

nos:

Morphine is subject to international control under the Single Convention on Narcoticdg, 1961. pg- i i b ; i

be able to swallow the whole tablet; alternatively, prolonged-release granules can be used.


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sb iji i ib i. For continuous intravenous infusion, dilute with glucose 5% or 10% or sodium

chloride 0.9%. High strength modied-release tablets and capsules should only be used in patients

ii . aiii g -ii i i i. Naloxone is used as an antidote in case of opioid overdose.

A4.6 naoxoAtc od: V03AB15Ijio: 400 g/ (i) i 1 .

Idiaios: opioid overdose.

coraidiaios: there are no contraindications to the use of naloxone for treatmentof opioid toxicity.

Prauios: cautious dosing is needed to avoid severe withdrawal syndrome afterprolonged administration of opioids and in opioid-tolerant children; cardiovasculardisease; post-operative patients (may reverse analgesia and increase blood pressure).

Dosa:

Dos i opioid-ora pais

Intravenous:

oa, ifa hid 1 mcg/kg titrated over time, e.g. every3 minutes, until the child is breathing spontaneously and maintainingadequate oxygenation; a low dose infusion may be required thereafter tomaintain adequate respiration and level of consciousness until the effect ofoverdose has resolved; close monitoring is needed.

Dos i opioid-aiv pais

Intravenous:

oa, ifa hid 10 mcg/kg; if no response, give subsequent dose of100 mcg/kg (resuscitation doses); review diagnosis if respiratory function does notimprove; further doses may be required if respiratory function deteriorates.

Continuous IV infusion using an infusion pump:

oa, ifa hid 520 mcg/kg/hr, adjusted according to response.


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Ra ipair: excretion of some opiods and/or their active metabolites (codeine,dextropropoxyphene, dihydrocodeine, morphine, pethidine, oxycodone) is delayed inimpairment so these opioids will accumulate; extended treatment with naloxone infusionmay be required to reverse opioid effect.

Hpai ipair: j .

Advrs ffs:

oo nausea, vomiting, sweating; uoo tachycardia, ventricular arrhythmias; rar i .

Iraios wih ohr diis: there are no known interactions where it is advised

to avoid concomitant use.

nos:

Naloxone hydrochloride may be administered in the same doses as for intravenousinjection by subcutaneous injection, but only if the intravenous route is not feasible( i).

For continuous intravenous infusion, dilute to a concentration of 4 mcg/ml withglucose 5% or sodium chloride 0.9%.

For intravenous bolus, administer over 30 seconds as undiluted preparation.

The intravenous dose may be repeated every 23 minutes until response. After initial response, the intravenous dose may need to be repeated every

2060 i i i. Do not administer naloxone to neonates of mothers who have been taking methadone

i.

A4.7 OxyodoAtc cod: N02AA05

tab: 5 mg, 10 mg, 15 mg, 20 mg, 30 mg (as hydrochloride).Tablet (modied release): 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg,160 g ( i).capsu: 5 mg, 10 mg, 20 mg (as hydrochloride).Ora iquid: 1 g/ ( i).corad ora iquid: 10 g/, 20 g/ ( i).


coraidiaios: hypersensitivity to opioid agonists or to any component of the formulation; i i; ; i i; i , ii 14days after ending monoamine oxidase inhibitors; raised intracranial pressure and/or head injury,if ventilation not controlled; coma; use within 24 hours before or after surgery.


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Prauios: impaired respiratory function; avoid rapid injection which may precipitatechest wall rigidity and difculty with ventilation; bradycardia; asthma; hypotension; shock;obstructive or inammatory bowel disorders; biliary tract disease; convulsive disorders;hypothyroidism; adrenocortical insufciency; avoid abrupt withdrawal after prolonged

; ib i; ii i; ii; igravis; hepatic impairment; renal impairment; toxic psychosis.


Dosa:


Oral (immediate-release formulation):

infant 112 months 50125 mcg/kg every 4 hours; child 112 years 125200 mcg/kg every 4 hours, max 5 mg.

Oral (prolonged-release formulation):

hid ovr 8 yars 5 mg every 12 hours.

coiuaio: after a starting dose according to the dosages above, the dosage

should be adjusted to the level that is effective (with no maximum), but themaximum dosage increase is 50% per 24 hours in outpatient settings. Experiencedprescribers can increase up to 100% with careful monitoring of the patient.


Oral (using immediate-release preparation):

ifa hid:additional oxycodone may be administered as frequently as

required with a maximum of 510% of the regular daily baseline oxycodone. I bkg qi, j gbaseline oxycodone dose guided by the amount of oxycodone required forbreakthrough pain with a maximum increase of 50% per 24 hours.

Dosa disoiuaio: for short-term therapy (714 days), the original dose can be decreasedby 1020% of the original dose every 8 hours increasing gradually the time interval. In the caseof a long-term therapy protocol, the dose should be reduced not more than 1020% per week.

Ra ipair: mild (GFR 2050 ml/min or approximate serum creatinine 150300micromol/l) to severe (GFR 700 micromol/l) dose reduction b qi; i i ig .

H i i i d d d d b 50% id


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Hpai ipair: moderate and severe; reduce dose by 50% or avoid use.

Advrs ffs:

oo nausea, vomiting, constipation, diarrhoea, dry mouth, sedation, biliary

spasm, abdominal pain, anorexia, dyspepsia, pruritus, somnolence, dizziness; ss oo igii, i, i i, b,dyspnoea, impaired cough reex, asthenia, anxiety, chills, muscle fasciculation, posturalhypotension, hallucinations, vertigo, euphoria, dysphoria, dizziness, confusion;

uoo bi, i, ii, , g,dependence, drowsiness, sleep disturbances, headache, miosis, visual disturbances,sweating, ushing, rash, urticaria, restlessness, difculty with micturition, urinaryretention, ureteric spasm, gastritis, atulence, dysphagia, taste disturbance, belching,hiccups, vasodilation, supraventricular tachycardia, syncope, amnesia, hypoesthesia,

pyrexia, amenorrhoea, hypotonia, paraesthesia, disorientation, malaise, agitation, i, , ki;

rar i ii , i i, i , i, k, i i, iz.

Iraios wih ohr diis:

central nervous system depressants, monoamine oxidase inhibitors*, naloxone*, naltrexone*,opioid antagonists/partial agonists*.

* Indicates severe.

nos: Oxycodone is subject to international control under the Single Convention on Narcotic

dg, 1961. Prolonged-release oxycodone preparations must not be crushed or chewed; the child must

b b b. t ii i gii . Oxycodone is partially metabolized to an active metabolite, oxymorphone, via CYP2D6

pathway; slow or ultra-fast metabolizers may experience reduced or enhanced analgesia - i-.

High strength modied-release tablets should only be used in patients who are opioid. aiii g -ii i i i.

Naloxone is used as an antidote in case of opioid overdose.

equiaasi doss:

When converting from oral morphine to oral oxycodone, use an initial doseconversion ratio of 1.51 (e.g. replace 15 mg morphine with 10 mg oxycodone).t i iiz gi.

A4 8 P


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A4.8 ParaaoAtc od: n02Be01Ora iquid: 25 mg/ml.Supposiory: 100 g.

tab: 100500 mg. i.

Idiaios: i i.

Prauios: hepatic impairment, renal impairment, overdose.

Dos:

Oral or rectal:

oa 10 mg/kg every 68 hours as necessary; maximum dose is4 i 24 ;

ifa hid 15 mg/kg, up to 1 g, every 46 hours as necessary,maximum dose is 4 doses, or 4 g,i 24 .

Hpai ipair: dose-related toxicity;do not exceed the daily recommended dose.

Advrs ffs:

rar rash, pruritus, urticaria, hypersensitivity, anaphylactic reactions, neutropenia,bi, i.Hepatotoxicity (and less frequently renal damage) can occur after paracetamoloverdose and can even occur at standard doses in children with the conditionsdescribed above.

Iraios wih ohr diis:

bzi, i, bbi, i, i

nos:

Infants under 3 months should not be given paracetamol unless advised by a doctor. Shake suspension well before use and use a measuring device provided with the

i. Children may be at an increased risk of liver damage from paracetamol overdose

i i, b, ig bi i, kig g

course of treatment, have poor oral intake (nutrition and hydration), or are takingliver enzyme inducing drugs. Acetylcysteine is used as an antidote in case of overdose.

S f i i l d d ti5


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Summary of principles and recommendations

Priips

Optimal pain management may require a comprehensive approach comprising a combination ofnon-opioid, opioid analgesics, adjuvants and non-pharmacological strategies. A comprehensiveapproach is possible even in resource-limited settings.

Correct use of analgesic medicines will relieve pain in most children with persisting pain due toi i i ig k :

ig - g dosing at regular intervals (by the clock) ig i iii (b )

tailoring treatment to the individual child (by the individual).

ciia rodaios1. It is recommended to use the analgesic treatment in two steps according to the childs level

of pain severity.2. Paracetamol and ibuprofen are the medicines of choice in the rst step (mild pain).3. Both paracetamol and ibuprofen need to be made available for treatment in the rst step.4. The use of strong opioid analgesics is recommended for the relief of moderate to severe

iig i i i i i i.5. Morphine is recommended as the rst-line strong opioid for the treatment of persisting

moderate to severe pain in children with medical illnesses.6. There is insufcient evidence to recommend any alternative opioid in preference to morphine

as the opioid of rst choice.7. Selection of alternative opioid analgesics to morphine should be guided by considerations of

safety, availability, cost and suitability, including patient-related factors.8. It is strongly recommended that immediate-release oral morphine formulations be available

i i i i i i i.

9. I i i-i g- g bavailable, if affordable.

10. siig ii / iii i i i g i iq gi i ib i-.

11. Alternative opioids and/or dosage forms as an alternative to oral morphine should beavailable to practitioners, in addition to morphine, if possible.

12. ri i ii i .13. Oral administration of opioids is the recommended route of administration.14. The choice of alternative routes of administration when the oral route is not available should

be based on clinical judgement, availability, feasibility and patient preference.15. The intramuscular route of administration is to be avoided in children.

A

nne

x5

16 A careful distinction between end-of-dose pain episodes incident pain related to movement


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42

16. A careful distinction between end of dose pain episodes, incident pain related to movement , bkg i i .

17. It is strongly recommended that children with persisting pain receive regular medication to i i ii bkg i.

There is insufcient evidence to recommend a particular opioid or route of administration for

breakthrough pain in children. There is a need to make an appropriate choice of treatment

modality based on clinical judgement, availability, pharmacological considerations and patient-

related factors.

18. The use of corticosteroids as adjuvant medicines is o i iig i i i i i i.

19. The use of bisphosphonates as adjuvant medicines is o i

b i i i.

At present, it is not possible to make recommendations:

- for or against the use of tricyclic antidepressants (TCAs) and selective serotonin reuptake

inhibitors (SSRIs) as adjuvant medicines in the treatment of neuropathic pain in children.

- for any anticonvulsant as an adjuvant in the management of neuropathic pain in children.

- regarding the benets and risks of ketamine as an adjuvant to opioids for neuropathic pain

in children.

- regarding the benets and risks of the systemic use of local anaesthetics for persisting

neuropathic pain in children.- for the use of benzodiazepines and/or baclofen as an adjuvant in the management of pain

in children with muscle spasm and spasticity.

Hah sys rodaios20. ei i i iz g iig i

i i i i i i ig ii,iig ii gi, i g.

21. h i i b ii ii i i i b i g i i i iiiig qi.

22. I ii, i i, bj i ii, ig i ig, ib, ii / i ii exibility, efciency, increased coverage of services and/or improved quality of care.

23. The conditions under which such permission is granted should be based on thedemonstration of competence, sufcient training, and personal accountability fori .

Acknowledgements


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Acknowledgementst ig iii ib i b: h ab-s hij,John J. Collins, Stephanie Dowden, Shafq Essajee, G. Allen Finley, Andrew L. Gray, Cleotilde

h. h, l m, ai ni, pik dig, Vii pzk, wi s,Dorothy van Schooneveld, Cecilia Sepulveda Bermedo, Brittany Wegener, Chantal Wood, ii, ib WHO guidelines on the pharmacologicaltreatment of persisting pain in children with medical illnesses.

Generous nancial support was received for the development of these brochures from theIi aii s pi (Iasp), s, wa, usa; m f,n yk, ny, usa; mii h, w s, t hg, n; t t c t, l, ui Kig.

Photos: Dr Srivieng Pairojkul of Khon Kran University (cover, pages 4, 10 and 13); Dr ArmandoGarduno (page 3); with permission from Mr and Mrs Ahmad Rozelan bin Yunus, Malacca,Malaysia (page 5); Mildmay Uganda (page 6); Dr E. Hamzah, Hospis Malaysia (page 12). MrsLindsey J. Woodworth and Dr Caprice A Knapp of the International Childrens Palliative CareNetwork provided the photographs and mediated in obtaining permission of the photographers ii i i i i b.

References1. WHO guidelines on the pharmacological treatment of persisting pain in children with

medical illnesses. Geneva, World Health Organization, 2012.ti i b who mii bi (..int/medicines). Hard copies are available from the WHO Bookshop (http://apps.who.int/bookorders/anglais/home1.jsp?sesslan=1).

2. Ensuring balance in national policies on controlled substances: guidance for availabilityand accessibility of controlled medicines. Geneva, World Health Organization, 2011.

Hard copies are available from the WHO Bookshop:http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1&codcol=15&codcch=807; i b ii gg : ://..i/ii//qi_/guide_nocp_sanend/en/index.html.
http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1&codcol=15&codcch=807http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1&codcol=15&codcch=807http://www.who.int/medicines/areas/quality_safety/guide_nocp_sanend/en/index.htmlhttp://www.who.int/medicines/areas/quality_safety/guide_nocp_sanend/en/index.htmlhttp://www.who.int/medicines/areas/quality_safety/guide_nocp_sanend/en/index.htmlhttp://www.who.int/medicines/areas/quality_safety/guide_nocp_sanend/en/index.htmlhttp://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1&codcol=15&codcch=807http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1&codcol=15&codcch=807


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