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2012 : WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses World Health Organization, 2012

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ISBN: 978-960-86307-7-2

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3.3 Treating pain at regular intervals ....................................................................................... 403.4 Treating pain by the appropriate route ............................................................................... 403.5 Tailoring pain treatment to the individual child .................................................................. 40

3.5.1 Non-opioid analgesics .............................................................................................. 403.5.2 Opioid analgesics ..................................................................................................... 41

3.6 Strong opioids essential in pain treatment .......................................................................... 423.7 Choice of strong opioids .................................................................................................... 423.8 Immediate-release and prolonged-release oral morphine ....................................................433.9 Opioid switching ................................................................................................................ 443.10 Routes of administration ....................................................................................................453.11 Treatment of breakthrough pain ......................................................................................... 463.12 Tolerance, withdrawal and dependence syndrome ............................................................... 463.13 Opioid overdose ................................................................................................................ 473.14 Adjuvant medicines ...........................................................................................................50

3.14.1 Steroids ..................................................................................................................503.14.2 Bone pain ...............................................................................................................503.14.3 Neuropathic pain ....................................................................................................513.14.4 Pain associated with muscle spasm and spasticity ....................................................52

3.15 Research agenda ...............................................................................................................53

4. IMPROVING ACCESS TO PAIN RELIEF IN HEALTH SYSTEMS .......................544.1 The right to health, the right to be spared avoidable pain ...................................................554.2 International regulations on opioid analgesics ....................................................................554.3 Dimensions of a national pain treatment policy ..................................................................564.4 Financing pain relief within the national system .................................................................564.5 Estimating needs for pain relief .........................................................................................574.6 Saving resources by treating pain .......................................................................................584.7 Pain management coverage ...............................................................................................594.8 Human resources for pain management .............................................................................594.9 What treatment should be available ................................................................................... 60

ANNEX 1. PHARMACOLOGICAL PROFILES ....................................................62A1.1 Fentanyl .............................................................................................................................63A1.2 Hydromorphone ................................................................................................................. 66A1.3 Ibuprofen ........................................................................................................................... 69A1.4 Methadone ......................................................................................................................... 70A1.5 Morphine ...........................................................................................................................73A1.6 Naloxone ............................................................................................................................ 76A1.7 Oxycodone ......................................................................................................................... 78A1.8 Paracetamol ....................................................................................................................... 80

> 2

3.3 .............................................................................................403.4 .................................................................................403.5 .......................................................................................40

3.5.1 ..............................................................................................................................403.5.2 .....................................................................................................................................41

3.6 ...............................................................423.7 ..........................................................................................................................423.8 .....................................................433.9 ..........................................................................................................443.10 .........................................................................................................................................................453.11 ..........................................................................................................463.12 , ....................................................................................................463.13 .....................................................................................................................................473.14 ...................................................................................................................................50

3.14.1 .........................................................................................................................................................503.14.2 ................................................................................................................................................503.14.3 ..............................................................................................................................513.14.4 ............................................................................52

3.15 .....................................................................................................................................................53

4. ........................................................................................544.1 , .........................................554.2 ...........................................................................................554.3 .....................................................564.4 ........................................564.5 .............................................................................574.6 ..............................................................................584.7 .........................................................................................................................594.8 ..............................................................................594.9 ................................................................................................60

1. ............................................................62 1.1 ................................................................................................................................................................631.2 .......................................................................................................................................................................651.3 ..........................................................................................................................................................................671.4 ........................................................................................................................................................................701.5 .....................................................................................................................................................................721.6 ..............................................................................................................................................................741.7 ...............................................................................................................................................................751.8 .....................................................................................................................................................................77

> 4> 4

A6.8 The import/export system for strong opioids .....................................................................135A6.9 Requirements for import/export authorizations or certifi cates ............................................136A6.10 The reporting system following exportation, importation and consumption of opioids .......137A6.11 Distribution of strong opioids ..........................................................................................137A6.12 Usual requirements for prescribing and dispensing opioids .............................................138

ANNEX 7. LIST OF CONTRIBUTORS TO THIS PUBLICATION..........................140A7.1 Guidelines development group meeting ............................................................................ 141A.7.2 Other contributors ........................................................................................................... 142A7.3 Declaration of interest and management of potential confl ict of interest ............................143

SUMMARY OF PRINCIPLES AND RECOMMENDATIONS ................................146

REFERENCES ............................................................................................148

INDEX .....................................................................................................156

6.9 / ................................................... 1366.10 , ....................... 1376.11 .............................................................................................................................. 1376.12 .................................... 138

7. .................................................................................................................. 1407.1 .................................................................. 1417.2 ............................................................................................................................................. 1427.3. ..................................... 143

........................................................ 146

............................................................................................................. 148

................................................................................................................... 156

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: American Hospital Formulary Service drug information updates [Online database]. Gurnee, IL, Medicines Complete, 2007.

Andrews S, Cranswick N, Hill S et al. eds. WHO model formulary for children. Geneva, World Health Organization, 2008.

Charles L et al. Drug information handbook, a comprehensive resource for all clinicians and healthcare professionals. Hudson, OH, Lexicomp, 2007.

Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook, 16th ed. Hudson, OH, Lexicomp, 2009.

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http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf, 19 2011).

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: : 25-50 mcg/kgr 6 , 1-6 : 100mcg/kgr 6 , 6 -2 : 100 mcg/kgr 4 . 2-12 : 100-200 mcg/kgr 4 , 2,5 mg.

IV 5 : : 25-50 mcg/kgr 6 , 1-6 : 100mcg/kgr 6 , 6 -12 : 100mcg/kgr 4 , 2,5 mg.

IV : : 5 25-50 mcg/kgr,

5-10 mcg/kgr/, 1-6 : 5 100mcg/kgr,

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: Anderson BJ, Persson MA, Anderson M. Rationalising intravenous morphine prescriptions in children. Acute Pain, 1999, 2:5967.

Bouwmeester NJ et al. Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. British Journal of Anaesthesia, 2004, 92:208217.

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Cherny NI, Foley KM, eds. Nonopioid and opioid analgesic pharmacotherapy of cancer pain. Haematology/Oncology Clinics of North America, 1996, 10:79102.

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Hara Y et al. Morphine glucuronosyltransferase activity in human liver microsomes is inhibited by a variety of drugs that are co-administered with morphine. Drug Metabolism and Pharmacokinetics, 2007, 22:103112.


Johnson SJ. Opioid safety in patients with renal or hepatic dysfunction. Pain treatment topics, June 2007 (http://pain-topics.org/pdf/Opioids-Renal-Hepatic-Dysfunction.pdf, 19 2011).

MIMS [online database]. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, 10 2011).


Ripamonti C et al. Normal release oral morphine starting dose in cancer patients with pain. Clinical Journal of Pain, 2009, 25:386390.

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Taddio A et al. Safety of morphine in nonintubated infants in the neonatal intensive care unit. Clinical Journal of Pain, 2009, 25:418422.

Ventafridda V et al. Studies on the effects of antidepressant drugs on the antinociceptive action of morphine and on plasma morphine in rat and man. Pain, 1990, 43:155162.

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: Ashley C, Currie A, eds. The renal drug handbook, 3rd ed. Oxford, Radcliffe Publishing, 2009.

Drugdex in Micromedex Healthcare Series [Internet]. New York, NY, Thomson Reuters, 19742010 (http://micromedex.hcn.net.au/mdx-full/, 18 A 2011).


MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, 10 2010).


Twycross R, Wilcock A, eds. Palliative care formulary, 3rd ed. Nottingham, palliativedrugs.com, 2007.

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: Ashley C, Currie A, eds. The renal drug handbook, 3rd ed. Oxford, Radcliffe Publishing, 2009.

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Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008.


eTG complete [online database]. Melbourne, Therapeutic Guidelines Limited, 2009 (http://etg.tg.org.au/ip/, 6 A 2011).

MIMS [online database]. Sydney, UBM Medica, 2009 (https://www.mimsonline.com.au/Search/Search.aspx, 6 A 2011).


Twycross R, Wilcock A, eds. Palliative care formulary, 3rd ed. Nottingham, palliativedrugs.com, 2007.

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: Wiffen PJ: 16-04-2009: ( ); : 12 .: , , , . : Clark E et al. A randomized controlled trial of acetaminophen, ibuprofen and codeine for acute pain relief in children with musculoskeletal trauma. Pediatrics, 2007, 119:460467.

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8/104

-,

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-

CI: , VAS: , ITT: . . : 15mg/kgr (max 650 mg), 1 mg/kgr (max 60 mg).

. . .

> 108

GRADE 3

: Wiffen PJ: 08-12-2008: 7-15 ; : , . : Borland M et al. A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department. Annals of Emergency Medicine, 2007, 49:335340.

.

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> 110

GRADE 5 ( , )

: Wiffen PJ: 17-04-2009: 319 ; : , , , .: Goodarzi M. Comparison of epidural morphine, hydromorphone and fentanyl for postoperative pain control in children undergoing orthopaedic surgery. Pediatric Anesthesia, 1999, 9:419422.

.

(9

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30 30

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.

> 112

: 2B: Maunuksela E-L, Korpela R, Olkkola KT. Comparison of buprenorphine with morphine in the treatment of postoperative pain in children. Anesthesia & Analgesia, 1988, 67:233239.

.

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> 114

GRADE 8 ( )

: Wiffen PJ: 07-01-2009: ( ) placebo 415 ; : , .: Kokki H et al. Oxycodone versus placebo in children with undifferentiated abdominal pain. Archives of Pediatrics & Adolescent Medicine, 2005, 159:320325.

.

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> 116

GRADE 10

: Wiffen PJ: 17-04-2009: ; : 18 .: Wiffen PJ, McQuay HJ. Oral morphine for cancer pain. Cochrane Database of Systematic Reviews, 2007 (4):CD003868.

.

-

-

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-

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CI: . , 18 (11 , 3 , 2 2 ). .

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GRADE 12

: Wiffen PJ: 15-02-2010: PCA ;: .: Peters JWB et al. Patient controlled analgesia in children and adolescents: a randomized controlled trial. Paediatric Anaesthesia, 1999, 9:235241.

.

P

CA

(9

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I)

A

2 (follow-up: 2 , VASPI)

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7/24(29,2%)

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PCA: , CI: , VASPI: (Visual Analogue Scale of Pain Intensity). 2.

1 . . , . : PCA bolus 15 mcg/kg, 10 15 mcg/kg/,

2040 mcg/kg/.

> 120

GRADE 14

: Wiffen PJ: 08-12-2008: V , 6 -17 ; : , , .: Miner JR et al. Randomized clinical trial of nebulized fentanyl citrate versus i.v. fentanyl citrate in children presenting to the emergency department with acute pain. Academic Emergency Medicine, 2007, 14:895898.

.

IV

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> 122

GRADE 16

: Wiffen PJ: 27-04-2009: (CBT) , , ;: .: Eccleston C et al. Psychological therapies for the management of chronic and recurrent pain in children and adolescents. Cochrane Database of Systematic Reviews, 2009, (2):CD003968.

.

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> 124

Sarawak, M

, , , .

. , .

, .

Devi BCR, Tang TS, Corbe M. Setting up home-based palliative care in countries with limited resources: a model from Sarawak, Malaysia. Annals of Oncology, 2008, 19:20612066.

Kerala, I

N.

( ) . .

Rajagopal MR, Joranson DE, Gilson AM. Medical use, misuse, and diversion of opioids in India. Lancet, 2001, 358:139143.

: (.. ).

A4.3

, 2, A2.1. .

, , . , .

nderson BJ, Palmer GM. Recent pharmacological advances in paediatric analgesics. Biomedicine & Pharmacotherapy, 2006, 60:303309.

Berde CB, Sethna NF. Analgesics for the treatment of pain in children. New England Journal of Medicine, 2002, 347:1542.

Olkkola KT, Hamunen K, Maunuksela EL. Clinical pharmacokinetics and pharmacodynamics of opioid analgesics in infants and children. Clinical Pharmacokinetics, 1995, 28:385404.

Schiessl C et al. Use of patient-controlled analgesia for pain control in dying children. Supportive Care in Cancer, 2008, 16:531536.

> 126

Bertin L et al. Randomized, double-blind, multicenter, controlled trial of ibuprofen versus acetaminophen (paracetamol) and placebo for treatment of symptoms of tonsillitis and pharyngitis in children. Journal of Pediatrics, 1991, 119:811814.

Kelley MT et al. Pharmacokinetics and pharmacodynamics of ibuprofen isomers and acetaminophen in febrile children. Clinical Pharmacology & Therapeutics, 1992, 52:181189.

Lesko SM, Mitchell AA. An assessment of the safety of pediatric ibuprofen. A practitioner-based randomized clinical trial. Journal of the American Medical Association, 1995, 273:929933.

Perrott DA et al. Efficacy and safety of acetaminophen vs ibuprofen for treating childrens pain or fever: a meta-analysis. Archives of Pediatrics & Adolescent Medicine, 2004, 158:521526.

Alegaert et al. Tramadol disposition in the very young: an attempt to assess in vivo cytochrome P-450 2D6 activity. British Journal of Anaesthesia, 2005, 95:231239.

Bozkurt P. Review article: use of tramadol in children. Pediatric Anesthesia, 2005, 15:10411047 doi:10.1111

Brown, SC, Stinson J. Treatment of pediatric chronic pain with tramadol hydrochloride: siblings with Ehlers-Danlos syndrome Hypermobility type (case report). Pain Research & Management, 2004, 9:209211.

Garrido MJ et al. Population pharmacokinetic/pharmacodynamic modelling of the analgesic effects of tramadol in pediatrics. Pharmaceutical Research, 2006, 23:20142023.

Kamel C. Tramadol en analgesia pdiatrica. Revista Iberoamerican del Dolor, 2008, 3:3645.

Rose JB et al. Oral tramadol for the treatment of pain of 730 days duration in children. Anesthesia & Analgesia, 2003, 96:7881.

Tremlett M, Anderson BJ, Wolf A. Pro-con debate: is codeine a drug that still has a useful role in pediatric practice? Paediatric Anaesthesia, 2010, 20:183194.

Williams DG, Hatch DJ, Howard RF. Codeine phosphate in paediatric medicine. British Journal of Anaesthesia, 2001, 86:413421.

+

Drendel AL et al. A randomized clinical trial of ibuprofen versus acetaminophen with codeine for acute pediatric arm fracture pain. Annals of Emergency Medicine, 2009, 54:553560.

Anderson BJ et al. The dose-effect relationship for morphine and vomiting after day-stay tonsillectomy in children. Anaesthesia and Intensive Care, 2000, 28:155160.

Bhandari V et al. Morphine administration and short-term pulmonary outcomes among ventilated preterm infants. Pediatrics, 2005, 116:352359.

> 128

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7.2 Akiiki Bitalabeho, , HIV, Meena Cherian, , , icolas Clark, , , Tarun Dua, , , Shaffiq Essajee, , IV, Barbara Milani, , , Lulu Muhe, , , Willem Scholten, , (), Cecilia Sepulveda, , .

Gauhar Afshan (), Hendrina Jacomina Albertyn ( ), Jane Ballantyne (), Rae Frances Bell (), Robert Bennett (), Mariela S. Bertolino (A), Kin-Sang Chan (), David Christopher Currow (A), Henry Ddungu (), Liliana de Lima (/), Julia Downing ( /), Marie Therese Fallon ( ), Allen Finley (), Nanna Finnerup (), Kathleen Foley (), Ajunan Ganesh (), Huda Abu-Saad Huijer (), Mary Korula (I), Leora Kuttner (), John Lee ( ), Elizabeth Molyneux (), Bart Morlion (B), Srinivasa Raja (), Rajat Ray (I), Carla Ripamonti (I), Ashok Kumar Saxena (I), Neil Schechter (), Hardo Sorgatz (), George Tharion (I), Monique Maria Verduijn ( ), Chantal Wood (), Boris Zernikow (). Hoppu Kalle (), Greg Kearns (), Marcus Reidenberg ().

Dele Abegunde (), Patricia Aguilar-Martinez (), Jehan Al-Fannah (), Michael Angastiniotis (), Maha Arnaout (), Lena L. Bergqvist (),Romesh Bhattacharji (I), Patricia Bonilla (), Hama Boureima-Sambo (), Rosa Buitrago de Tello (), Mei-Yoke Chan (), Roger Chou (), Jacqui Clinch ( ), Mark Connelly (), Hadeel Fakhri Ahmad Daghash ( ), Silvia Maria de Macedo Barbosa (B), C.R. Beena Devi (M), Christopher Drasbek (), Verna Edwards (), Ivanhoe C. Escartin (), Eunice Garanganga (), Ral Gonzlez (), Ruth Guinsburg

Andrew L. Gray KwaZulu-Natal Durban, ( : )

Nicola Magrini (CeVEAS)Modena, I( : )

Barbara Milani ,

Lulu Muhe

Willem Scholten ,

> 144

O (IASP). US$ 3500 Johnson & Johnson.

Henry Lu , Pfizer, . .

Rajat Ray Addnok-N ( ) Rusan Pharma Ltd., . .

.

Andy Gray Nicola Magrini. Andy Gray Scheduling and Naming Expert Committee () LIFELab, ast Coast Biotechnology Regional Innovation Centre Trust, . LIFELab . .

Allen Finley . Mariela Bertolino .

Rosa Buitrago Product Patrimony Manager Sanofi-Aventis 2007 2010. .

Stuart MacLeod ritish Columbia 2003 2010. US$ 50 000 . .

Gary Walco . : US$ 6500 Purdue Pharma US$ 2500 Pfizer 2010, US$ 1500 Neuromed 2008, US$ 2000 Anesiva US$ 1000 Endo 2007, US$ 2500 Cephalon 2006.

Boris Zernikow : 2000 Reckitt Benckiser 2007, 2000 Janssen 2008, 1500 Wyeth 2008, 20 000 Grunenthal 2008, 1000 Schwarz Pharma. 2006 16 000 , 2007, 2009 2010, 116 000 , .

> 146

, , . .

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> 148

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6. McGrath PJ, Finley GA, eds. Chronic and recurrent pain in children and adolescents. Seattle, WA, International Association for the Study of Pain (IASP) Press, 1999.

7. Haanp M, Treede F-D. Diagnosis and classification of neuropathic pain. IASP Clinical Updates, 2010, 18:16.

8. Ingelmo PM, Fumagalli R. Neuropathic pain in children. Minerva Anestesiologica, 2004, 70:393398.

9. Walco GA et al. Neuropathic pain in children: special considerations. Mayo Clinic Proceedings, 2010, 85 (Suppl. 3):S33S41.

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11. Mishra S et al. Breakthrough cancer pain: review of prevalence, characteristics and management. Indian Journal of Palliative Care, 2009, 15:1418.

12. Svendsen KB et al. Breakthrough pain in malignant and non-malignant diseases: a review of prevalence, characteristics and mechanisms. European Journal of Pain, 2005, 9:195206.

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14. Cancer pain relief with a guide to opioid availability, 2nd ed., Geneva, World Health Organization, 1996.

15. Scadding J. Neuropathic pain. Advances in Clinical Neuroscience & Rehabilitation, 2003, 3:814.

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17. Gaughan DM et al. The prevalence of pain in pediatric human immunodeficiency virus/acquired immunodeficiency syndrome as reported by participants in the Pediatric Late Outcomes Study (PACTG 219). Pediatrics, 2002, 109:11441152.

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19. Breitbart W, DiBiase L. Current perspectives on pain in AIDS, Part 1. Oncology, 2002, 16:818835.

> 150

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39. von Baeyer CL. Childrens self-reports of pain intensity: scale selection, limitations and interpretation. Pain Research & Management, 2006, 11:157162.

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41. Hicks CL et al. The Faces Pain Scale revised: toward a common metric in pediatric pain measurement.Pain, 2001, 93:173183.

42. Hester NO et al. Measurement of childrens pain by children, parents, and nurses: psychometric and clinical issues related to the Poker Chip tool and Pain Ladder. Final grant report. Generalizability of procedures assessing pain in children. Denver, CO, Center for Nursing Research, School of Nursing, University of Colorado, 1989.

43. Scott PJ, Ansell BM, Huskisson EC. Measurement of pain in juvenile chronic polyarthritis. Annals of the Rheumatic Diseases, 1977, 36:186187.

44. Odole AC, Akinpelu AO. Translation and alternate forms reliability of the Visual Analogue Scale in the three major Nigerian languages. The Internet Journal of Allied Health Sciences and Practice, 2009, 7.

45. von Baeyer CL et al. Three new datasets supporting use of the Numerical Rating Scale (NRS-11) for childrens self-reports of pain intensity. Pain, 2009, 143:223227.

46. Crellin D et al. Analysis of the validation of existing behavioral pain and distress scales for use in the procedural setting, Pediatric Anesthesia, 2007, 17:720733.

47. Blount RL, Loiselle KA.Behavioural assessment of pediatric pain. Pain Research & Management, 2009, 14:4752.

48. Stinson J et al. Review of systematic reviews on acute procedural pain in children in the hospital setting. Acute Pain, 2008, 10:105106.

49. Ramelet A-S et al. Clinical validation of the Multidimensional Assessment of Pain Scale. Pediatric Anesthesia,2007, 17:11561165.

50. Beyer JE et al. Practice guidelines for the assessment of children with sickle cell pain. Journal of the Society of Pediatric Nurses, 1999, 4:6173.

51. Franck LS et al. Assessment of sickle cell pain in children and young adults using the adolescent pediatric pain tool. Journal of Pain and Symptom Management, 2002, 23:114120.

52. Palermo TM. Impact of recurrent and chronic pain on child and family daily functioning: a critical review of the literature. Journal of Developmental and Behavioral Pediatrics, 2000, 21:5869.

53. Vetter TR. A primer on health-related quality of life in chronic pain medicine. Anesthesia and Analgesia, 2007, 104:703718.

54. Palermo TM. Commentary: assessment of functional status and disability in pediatric chronic and recurrent pain. Pediatric Pain Letter, 2000, 4:3738.

55. Jordhoy Ms et al. Assessing physical functioning: a systematic review of quality of life measures developed for use in palliative care. Palliative Medicine, 2007, 21:673682.

> 152

73. WHO Expert Committee on the Selection and Use of Essential Medicines. WHO model list of essential medicines for children: 2nd list (updated) March 2010. Geneva, World Health Organization, 2010.

74. WHO Expert Committee on the Selection and Use of Essential Medicines. The selection and use of essential medicines: report of the WHO Expert Committee, 2003 (including the 13th model list of essential medicines). Geneva, World Health Organization, 2003 (http://whqlibdoc.who.int/trs/WHO_TRS_920.pdf, 7 2011).

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76. Finnegan LP et al. Neonatal abstinence syndrome: assessment and management. Journal of Addictive Diseases, 1975, 2:141158.

77. Katz R, Kelly HW, Hsi A. Prospective study on the occurrence of withdrawal in critically ill children who receive fentanyl by continuous infusion. Critical Care Medicine, 1994, 22:763767.

78. Tobias JT. Out-patient therapy of iatrogenic opioid dependency following prolonged sedation in the pediatric intensive care unit. Intensive Care Medicine, 1996, 11:284287.

79. Robertson RC et al. Evaluation of an opiate-weaning protocol using methadone in pediatric intensive care unit patients. Pediatric Critical Care Medicine, 2000, 1:119123.

80. Anand KJ et al. Tolerance and withdrawal from prolonged opioid use in critically ill children. Pediatrics, 2010, 125:12081225.

81. Berde CB, Sethna NF. Analgesics for the treatment of pain in children. New England Journal of Medicine, 2002, 347:1542.

82. Wong RKS, Wiffen PJ. Bisphosphonates for the relief of pain secondary to bone metastases. Cochrane Database of Systematic Reviews, 2002, (2):CD002068.

83. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database of Systematic Reviews, 2007, (4):CD005454.

84. Hetrick SE et al. Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents. Cochrane Database of Systematic Reviews, 2007, (3):CD004851.

85. The selection and use of essential medicines. Report of the WHO Expert Committee. October 2007 (including the model list of essential medicines for children). Geneva, World Health Organization, 2008 (WHO Technical Report Series, No. 950).

86. Wiffen PJ, McQuay HJ, Moore RA. Carbamazepine for acute and chronic pain in adults. Cochrane Database of Systematic Reviews, 2005, (3):CD005451.

87. Vedula SS et al. Outcome reporting in industry-sponsored trials of gabapentin for off-label use. The New England Journal of Medicine, 2009, 361:19631971.

88. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database of Systematic Reviews, 2003, (1):CD003351.

89. Challapalli V et al. Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Database of Systematic Reviews, 2005, (4):CD003345.

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106. Smith BH et al. The impact of chronic pain in the community. Family Practice, 2001, 18:292299.

107. Ho, IK et al. Healthcare utilization and indirect burden among families of pediatric patients with chronic pain. Journal of Musculoskeletal Pain, 2008, 16:155164.

108. Sleed M et al. The economic impact of chronic pain in adolescence: methodological considerations and a preliminary costs-of-illness study. Pain, 2005, 119:183190.

109. A community health approach to palliative care for HIV/AIDS and cancer patients in sub-Saharan Africa. Geneva, World Health Organization, 2004.

110. Palliative care. Geneva, World Health Organization, 2007 (Cancer control, knowledge into action: WHO guide for effective programmes, module 5) (http://www.who.int/cancer/media/FINAL-Palliative%20Care%20Module.pdf, 9 2011).

111. Task shifting: global recommendations and guidelines rational redistribution of tasks among health workforce teams. Geneva, World Health Organization/U.S. Presidents Emergency Plan for AIDS Relief (PEPFAR)/Joint United Nations Programme on HIV (UNAIDS), 2008.

112. WHO handbook for guideline development. Geneva, WHO Guidelines Review Committee, World Health Organization. October 2009.

113. Scoping document for the WHO treatment guidelines for chronic pain in children. Geneva, World Health Organization, 2008.

114. Atkins D. et al. Systems for grading the quality of evidence and the strength of recommendations I: critical appraisal of existing approaches The GRADE Working Group. BMC Health Services Research, 2004, 4:38.

115. Wiffen PJ, McQuay HJ. Oral morphine for cancer pain. Cochrane Database of Systematic Reviews, 2007, (4):CD003868.

116. Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database of Systematic Reviews, 2004, (3):CD004847.

117. Mercadante S, Bruera E. Opioid switching: a systematic and critical review. Cancer Treatment Reviews, 2006, 32:304315.

118. Laurant M et al. Substitution of doctors by nurses in primary care. Cochrane Database of Systematic Reviews, 2005, (2):CD001271.

119. Convention on Psychotropic Substances, 1971. New York, NY, United Nations, http://www.incb.org/pdf/e/conv/convention_1971_en.pdf, 23 2011).

120. United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1988. New York, NY, United Nations, 1988 (http://www.incb.org/pdf/e/conv/1988_convention_en.pdf, 23 2011).

121. Guidelines for the WHO review of psychoactive substances for international control. Geneva, World Health Organization, 2007.

122. Report of the International Narcotics Control Board: demand for and supply of opiates for medical and scientific needs. Vienna, International Narcotics Control Board, 1989.

123. International Narcotics Control Board. The report of the International Narcotics Control Board for 2004. New York, NY, United Nations, 2005.

> 156

EYA - 56 37, 40 13 ( 23) 5960, 101, 147 19 51, 96 51 51 104127 124127 GRADE 105122 122

109 IV 108 110 IV PCA PCA 107 116 IV

119

111 PCA PCA

113 IM

117 PCA 118 / 115 , placebo 114 105 106 , 121 , IV 120

124 124 146 4850 146 (. ) 37 (. ) 37, 134 41 41 38, 146 41 41 44-45, 146 146 41 40 41 40 40 41 146 , 129 146 / 133 146 8 ( ) 37, 146,

7 8 41 47, 6380 59 59 () 7 51, 147 , 13, 2425,

, 96 ( 10) 4445,

9192, 146 ( 10) 4445, 9192, 146

, 142143 ( 21) 5960, 101102, 147 ( ) 37, 146 ( ) 13 () 7 37, 146 () 7 6580 65-80

> 158

9697 7 51, 9697, 147 ( 20) 5960, 123124, 147 , 131 8 8 56 56 , () 56 56 42, 44, 56 ( 12)

4445, 91, 146 ( 6 7)

4243, 8889, 146 40 7 40 ( 15) 45, 9293, 146 7 40 CYP2D6 8 39 131 134135 132 / , 138 ( ) 13 ( 14) 45,

9293, 146 131 131-137 7 134

124, 142 , 55 2005/25 55 53, 60, 129 , , 9394 23 6 13 8

123

I 64 6364 63 41, 63 41 41, 63 106 63 63 ATC 63 126 ( GRADE) 105 63 GRADE 105, 115 63 63 38 6364 () 8 56 , erala ( ) 124 13 13 137

42, 55 51 97 13 24 25 24 2425 , GRADE 121 55 WHA 58.22 55 133 , 133 55 , 61, 131 10, 131 , 131 98 52, 98, 147 98 GRADE 113 13 13 37, 39, 84 84

> 160

/ 89 ATC 67 126-127 PCA PCA 113 , 118 69 133 9091 44 GRADE 107113, 116119 68 67, 85 43 44 43 EMLc 44 44 4245, 8891, 146 11 ( ) 45, 9192, 146 5 ( ) 4243, 8889, 146 8 ( , ) 4344, 9091, 146 9 ( , ) 4344, 9091, 146 6770 40 42 9394 ( 5) 4243, 8889, 146 ( 8) 4344,

9091, 146 ( 9)

4344, 9091, 146 52, 147 52, 147 52, 147 , 99 ( ,

GRADE) 106

47, 7071 71 71 70 47 7071 70 71 ATC 70 71

70 70 7071 132 , 133 9 133 48 9 . , 55 51 51

131 1112 40 4445, 146 4445, 146 4445, 146 40, 92 ( ) 9293 40, 92 45, 92, 146 40, 45, 47, 92, 146 45, 9293 45, 9293 40, 45, 9293, 146 ,

40, 9293 40, 45, 9293 45 45 37, 146 37, 83, 129, 141, 143145 7 6 141 6 142143 45, 7274 73 73 72 72 72 72 placebo, GRADE 114 /, 115 / , GRADE 115

> 162

, . 43 1012 50 () 14 40 20 HIV/AIDS 2324 5758 , , 58 , , 57 , 57 58 57 , 58 58 56 21 13, 2425 , 56 59 59 59 , 59 59 124 24 24 , GRADE 109 46, 147 40 17 () 25 , GRADE 119 13 56 57 13 13 27-35 27 35 27 29 29 35 29

30 30 35 30 30 30 30 , 35 , , 34 30 , 30 , 30 30, 35 30, 34 , 30 30 2930 30 30 30 35 , 30, 35 30 30 34, 35 8 21 13, 21, 40 21 10 27, 28 , 27 27 29 29 27, 29 29 27 27, 29 27, 29 1011 , 42 8 27 , GRADE 110 3033 3132 33 31 , 3132 (Faces Pain Scale - Revised) 31 0-10 32 Pieces of Hurt/Poker Chip 31 (Visual Analogue Scale) 32 Oucher 32

> 164

13 7

38 9 38 ( ) 13 ( 17) 46, 9394, 147 , 129 ( ) 38, 146 39, 146 84 38, 84, 146 84 ( ) 38, 146 , 129 38, 39, 146 39 1 38, 8485, 146, 131138 132 133 132 134135 / 135 /, 136 134 INCB/ 134 134 133134 132 132, 133 / 138 133 137 133 131 9 131 131 131 55 55

142 () 9 (. ) 5052 ( 22) 5960, 101102, 147 24 () 7 () 9 141145 142 143145 143 123 6 142 3853, 5960, 8499, 101102, 146147 ( 23) 5960, 101102, 147 ( 10) 4445, 9192, 146 ( 10) 4445, 9192, 146 ( 21) 5960, 101 102, 147 ( 11) 4445, 9192, 146 ( 3) 38, 8687, 146 ( 16) 46, 9394, 147 83 ( 19) 5051, 9596, 147 ( 20) 5960, 101102, 147 83 ( 12) 4445, 9192, 146 ( 6 7) 4243, 8889, 146 ( 15) 45, 9293, 146 ( 14) 45, 9293, 146 14 14 3853, 8499, 146147 83 83 83 83 / 84 8499 83 1 38, 8485, 146

> 166

( ) 80 121 ATC 77 127 ( IV ) 120 64 GRADE 108110, 120121 77 77 7780 37, 83 10 14, 41, 6380 6364 6567 6770 7071 7274 7475 7577 7780 42, 56

40 40 ( 13) 45, 9293, 146 37, 146

( 2) 38, 8687, 146 ( 4) 42, 8788, 146

2005/25 55 58.22 55 () 9 131

AAIDS 7ATC 7

EMLc 42 7

G GDG 7GFR 7GRADE 14 7 83 105122

HHIV 7HIV/AIDS 24 23 24 , 24 24 23 23 23 24 , 23 24 23 24 24

IIM 7INCB 7ITT 7IV 7

Mmcg 7

NNeonatal Abstinence Score 47NRS 7

PPCA 7RCT 7

SSC 7SSRI 7

TTCA 7 147 , 9697

VVAS 7

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