Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Jul 19;7(7):CD012564.
doi: 10.1002/14651858.CD012564.pub2.

Opioids for cancer-related pain in children and adolescents

Affiliations

Opioids for cancer-related pain in children and adolescents

Philip J Wiffen et al. Cochrane Database Syst Rev. .

Abstract

Background: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. Views on children's pain have changed over time and relief of pain is now seen as important. In the past, pain was largely dismissed and was frequently left untreated, and it was assumed that children quickly forgot about painful experiences.We designed a suite of seven reviews in chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) to review the evidence for children's pain using pharmacological interventions.As one of the leading causes of mortality and morbidity for children and adolescents in the world today, childhood cancer (and its associated pain) is a major health concern. Cancer pain in infants, children, and adolescents is primarily nociceptive pain with negative long term effects. Cancer-related pain is generally caused directly by the tumour itself such as compressing on the nerve or inflammation of the organs. Cancer-related pain generally occurs as a result of perioperative procedures, nerve damage caused by radiation or chemotherapy treatments, or mucositis. However, this review focused on pain caused directly by the tumour itself such as nerve infiltration, external nerve compression, and other inflammatory events.Opioids are used worldwide for the treatment of pain. Currently available opioids include: buprenorphine, codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. Opioids are generally available in healthcare settings across most developed countries but access may be restricted in developing countries. To achieve adequate pain relief in children using opioids, with an acceptable grade of adverse effects, the recommended method is to start with a low dose gradually titrated to effect or unacceptable adverse effect in the child.

Objectives: To assess the analgesic efficacy, and adverse events, of opioids used to treat cancer-related pain in children and adolescents aged between birth and 17 years, in any setting.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid and Embase via Ovid from inception to 22 February 2017. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries.

Selection criteria: Randomised controlled trials (RCTs), with or without blinding, of any dose, and any route, treating cancer-related pain in children and adolescents, comparing opioids with placebo or an active comparator.

Data collection and analysis: Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table.

Main results: No studies were identified that were eligible for inclusion in this review (very low quality evidence). Several studies tested opioids on adults with cancer-related pain, but none in participants aged from birth to 17 years.We rated the quality of evidence as very low, downgraded due to a lack of available data; no analyses could be undertaken.

Authors' conclusions: No conclusions can be drawn about efficacy or harm in the use of opioids to treat cancer-related pain in children and adolescents. As a result, there is no RCT evidence to support or refute the use of opioids to treat cancer-related pain in children and adolescents.

PubMed Disclaimer

Conflict of interest statement

PW: none known.

TC: none known.

AKA: none known; AKA is a specialist paediatric palliative care consultant and manages children and adolescents with advanced cancer and non‐cancer conditions which are life limiting.

AG: none known; AG serves on medicines regulatory and selection bodies, and previously contributed to WHO guidance on the management of pain in children.

MCG: none known; MCG is a specialist paediatric pain and palliative care physician and treats patients with complex pain.

GL: none known; GL is a specialist paediatric oncologist and paediatric pain physician and manages patients with cancer and cancer pain.

BZ has received personal funding from Grünenthal (2014 to 2016), and Pfizer (2016) in designing and monitoring paediatric investigator plans. BZ is a specialist paediatric pain researcher and clinician and treats patients with cancer pain.

This review was identified in a 2019 audit as not meeting the current definition of the Cochrane Commercial Sponsorship policy. At the time of its publication it was compliant with the interpretation of the existing policy. As with all reviews, new and updated, at update this review will be revised according to 2020 policy update.

Figures

1
1
Study flow diagram.

Update of

  • doi: 10.1002/14651858.CD012564

References

References to studies excluded from this review

Argoff 2015 {published data only}
    1. Argoff C, Arnstein P, Stanos S, Robinson CY, Galer BS, Gould E, et al. Relationship between change in pain intensity and functional outcomes in patients with chronic pain receiving twice daily extended‐release hydrocodone birtartrate. Journal of Opioid Management 2015;11(5):417‐24. - PubMed
Collins 1999 {published data only}
    1. Collins JJ, Dunkel IJ, Gupta SK, Inturrisi CE, Lapin J, Palmer LN, et al. Transdermal fentanyl in children with cancer pain: feasibility, tolerability, and pharmacokinetic correlates. Journal of Pediatrics 1999;134(3):319‐23. - PubMed
Finkel 2007 {published data only}
    1. Finkel JC, Pestieau SR, Quezado ZMN. Ketamine as an adjuvant for treatment of cancer pain in children and adolescents. Journal of Pain 2007;8(6):515‐21. - PubMed
Geeta 2009 {published data only}
    1. Geeta MG, Geetha P, Ajithkumar VT, Krishnakumar P, Suresh Kumar K, Mathews L. Management of pain in leukemic children using the WHO analgesic ladder. Indian Journal of Pediatrics 2009;77(6):665‐8. - PubMed
Marinangeli 2004 {published data only}
    1. Marinangeli F, Ciccozzi A, Leonardis M, Aloisio L, Mazzei A, Paladini A, et al. Use of strong opioids in advanced cancer pain: a randomized trial. Journal of Pain and Symptom Management 2004;27(5):409‐16. - PubMed

Additional references

ACS 2015
    1. American Cancer Society. Cancer in children. www.cancer.org/cancer/cancerinchildren/detailedguide/cancer‐in‐children‐... (accessed July 2016).
AMA 2013
    1. American Medical Association. Pediatric pain management. https://www.ama‐assn.org/ (accessed 25 January 2016).
AUREF 2012
    1. Cochrane Pain, Palliative and Supportive Care Group. PaPaS author and referee guidance. papas.cochrane.org/papas‐documents (accessed 16 July 2016).
Caes 2016
    1. Caes L, Boemer KE, Chambers CT, Campbell‐Yeo M, Stinson J, Birnie KA, et al. A comprehensive categorical and bibliometric analysis of published research articles on pediatric pain from 1975 to 2010. Pain 2016;157(2):302‐13. [DOI: 10.1097/j.pain.0000000000000403] - DOI - PubMed
Cooper 2017a
    1. Cooper TE, Fisher E, Gray A, Krane E, Sethna NF, Tilburg M, et al. Opioids for chronic non‐cancer pain in children and adolescents. Cochrane Database of Systematic Reviews 2017, Issue 7. [DOI: 10.1002/14651858.CD012538.pub2] - DOI - PMC - PubMed
Cooper 2017b
    1. Cooper TE, Heathcote L, Clinch J, Gold J, Howard R, Lord S, et al. Antidepressants for chronic non‐cancer pain in children and adolescents. Cochrane Database of Systematic Reviews 2017, Issue 8. [DOI: 10.1002/14651858.CD012535.pub2] - DOI - PMC - PubMed
Cooper 2017c
    1. Cooper TE, Heathcote L, Anderson B, Grégoire MC, Ljungman G, Eccleston C. Non‐steroidal anti‐inflammatory drugs (NSAIDs) for cancer‐related pain in children and adolescents. Cochrane Database of Systematic Reviews 2017, Issue 7. [DOI: 10.1002/14651858.CD012563.pub2] - DOI - PMC - PubMed
Cooper 2017d
    1. Cooper TE, Fisher E, Anderson B, Wilkinson N, Williams G, Eccleston C. Paracetamol (acetaminophen) for chronic non‐cancer pain in children and adolescents. Cochrane Database of Systematic Reviews 2017, Issue 8. [DOI: 10.1002/14651858.CD012539.pub2] - DOI - PMC - PubMed
Dowell 2016
    1. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain ‐ United States. JAMA 2016;315(15):1624‐45. - PMC - PubMed
Dworkin 2008
    1. Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. Journal of Pain 2008;9(2):105‐21. [DOI: 10.1016/j.jpain.2007.09.005] - DOI - PubMed
Eccleston 2003
    1. Eccleston C, Malleson PM. Management of chronic pain in children and adolescents. We need to address the embarrassing lack of data for this common problem. BMJ 2003;326(7404):1408‐9. - PMC - PubMed
Eccleston 2017
    1. Eccleston C, Cooper TE, Fisher E, Anderson B, Wilkinson N. Non‐steroidal anti‐inflammatory drugs (NSAIDs) for chronic non‐cancer pain in children and adolescents. Cochrane Database of Systematic Reviews 2017, Issue 8. [DOI: 10.1002/14651858.CD012537.pub2] - DOI - PMC - PubMed
Frankish 2003
    1. Frankish H. 15 million new cancer cases per year by 2020, says WHO. Lancet 2003;361(9365):1278. - PubMed
Guyatt 2008
    1. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck‐Ytter Y, Alonso‐Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650):924‐6. [DOI: 10.1136/bmj.39489.470347.AD] - DOI - PMC - PubMed
Guyatt 2011
    1. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE Guidelines: 1. Introduction‐GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology 2011;64(4):383‐94. [DOI: 10.1016/j.jclinepi.2010.04.026] - DOI - PubMed
Guyatt 2013a
    1. Guyatt G, Oxman AD, Sultan S, Brozek J, Glasziou P, Alonso‐Coelle P, et al. Making an overall rating of the confidence in effect estimates for a single outcome and for all outcomes. Journal of Clinical Epidemiology 2013;66(2):151‐7. [DOI: 10.1016/j.jclinepi.2012.01.006] - DOI - PubMed
Guyatt 2013b
    1. Guyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, et al. GRADE guidelines: 12. Preparing summary of findings tables‐binary outcomes. Journal of Clinical Epidemiology 2013;66(2):158‐72. [DOI: 10.1016/j.jclinepi.2012.01.012] - DOI - PubMed
Higgins 2011
    1. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Hoffman 2010
    1. Hoffman DL, Sadosky A, Dukes EM, Alvir J. How do changes in pain severity levels correspond to changes in health status and function in patients with painful diabetic peripheral neuropathy?. Pain 2010;149(2):194‐201. [DOI: 10.1016/j.pain.2009.09.017] - DOI - PubMed
IARC 2008
    1. International Association on the Research of Cancer. Global cancer facts & figures. www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/doc... (accessed 7 March 2016).
Kaatsch 2010
    1. Kaatsch P. Epidemiology of childhood cancer. Cancer Treatment Reviews 2010;36(4):277‐85. [DOI: 10.1016/ctrv.2010.02.003] - DOI - PubMed
L'Abbé 1987
    1. L'Abbé KA, Detsky AS, O'Rourke K. Meta‐analysis in clinical research. Annals of Internal Medicine 1987;107(2):224‐33. - PubMed
Ljungman 1996
    1. Ljungman G, Kreuger A, Gordh T, Berg T, Sorensen S, Rawal N. Treatment of pain in paediatric oncology: a Swedish nationwide survey. Pain 1996;68(2‐3):385‐94. - PubMed
McQuay 1998
    1. McQuay H, Moore R. An Evidence‐based Resource for Pain Relief. Oxford (UK): Oxford University Press, 1998.
Moher 2009
    1. Moher D, Liberati A, Tetzlaff J, Altman DG, the PRISMA Group. Preferred reporting items for systematic reviews and meta‐analyses: the PRISMA statement. PLoS Medicine 2009;6(7):e1000097. - PMC - PubMed
Moore 2008
    1. Moore RA, Barden J, Derry S, McQuay HJ. Managing potential publication bias. In: McQuay HJ, Kalso E, Moore RA editor(s). Systematic Reviews in Pain Research: Methodology Refined. Seattle (WA): IASP Press, 2008:15‐24. [ISBN: 978‐0‐931092‐69‐5]
Moore 2009
    1. Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic pain in adults. Cochrane Database of Systematic Reviews 2009, Issue 3. [DOI: 10.1002/14651858.CD007076.pub2] - DOI - PMC - PubMed
Moore 2010a
    1. Moore RA, Eccleston C, Derry S, Wiffen P, Bell RF, Straube S, et al. "Evidence" in chronic pain ‐ establishing best practice in the reporting of systematic reviews. Pain 2010;150(3):386‐9. [DOI: 10.1016/j.pain.2010.05.011] - DOI - PubMed
Moore 2010b
    1. Moore RA, Straube S, Paine J, Phillips CJ, Derry S, McQuay HJ. Fibromyalgia: moderate and substantial pain intensity reduction predicts improvement in other outcomes and substantial quality of life gain. Pain 2010;149(2):360‐4. - PubMed
Moore 2010c
    1. Moore RA, Moore OA, Derry S, Peloso PM, Gammaitoni AR, Wang H. Responder analysis for pain relief and numbers needed to treat in a meta‐analysis of etoricoxib osteoarthritis trials: bridging a gap between clinical trials and clinical practice. Annals of the Rheumatic Diseases 2010;69(2):374‐9. [DOI: 10.1136/ard.2009.107805] - DOI - PMC - PubMed
Moore 2010d
    1. Moore RA, Smugar SS, Wang H, Peloso PM, Gammaitoni A. Numbers‐needed‐to‐treat analyses ‐ do timing, dropouts, and outcome matter? Pooled analysis of two randomized, placebo‐controlled chronic low back pain trials. Pain 2010;151(3):592‐7. [DOI: 10.1016/j.pain.2010.07.2013] - DOI - PubMed
Moore 2010e
    1. Moore RA, Derry S, McQuay HJ, Straube S, Aldington D, Wiffen P, et al. ACTINPAIN writing group of the IASP Special Interest Group (SIG) on Systematic Reviews in Pain Relief. Clinical effectiveness: an approach to clinical trial design more relevant to clinical practice, acknowledging the importance of individual differences. Pain 2010;149(2):173‐6. [PUBMED: 19748185] - PubMed
Moore 2011a
    1. Moore RA, Straube S, Paine J, Derry S, McQuay HJ. Minimum efficacy criteria for comparisons between treatments using individual patient meta‐analysis of acute pain trials: examples of etoricoxib, paracetamol, ibuprofen, and ibuprofen/paracetamol combinations after third molar extraction. Pain 2011;152(5):982‐9. [DOI: 10.1016/j.pain.2010.11.030] - DOI - PubMed
Moore 2011b
    1. Moore RA, Mhuircheartaigh RJ, Derry S, McQuay HJ. Mean analgesic consumption is inappropriate for testing analgesic efficacy in post‐operative pain: analysis and alternative suggestion. European Journal of Anaesthesiology 2011;28(6):427‐32. [DOI: 10.1097/EJA.0b013e328343c569] - DOI - PubMed
Moore 2012
    1. Moore RA, Straube S, Eccleston C, Derry S, Aldington D, Wiffen P, et al. Estimate at your peril: imputation methods for patient withdrawal can bias efficacy outcomes in chronic pain trials using responder analyses. Pain 2012;153(2):265‐8. [DOI: 10.1016/j.pain.2011.10.004] - DOI - PubMed
Moore 2013a
    1. Moore RA, Straube S, Aldington D. Pain measures and cut‐offs ‐ 'no worse than mild pain' as a simple, universal outcome. Anaesthesia 2013;68(4):400‐12. [DOI: 10.1111/anae.12148] - DOI - PubMed
Moore 2013b
    1. Moore A, Derry S, Eccleston C, Kalso E. Expect analgesic failure; pursue analgesic success. BMJ 2013;346:f2690. [DOI: 10.1136/bmj.f2690] - DOI - PubMed
Moore 2014a
    1. Moore RA, Derry S, Taylor RS, Straube S, Phillips CJ. The costs and consequences of adequately managed chronic non‐cancer pain and chronic neuropathic pain. Pain Practice 2014;14(1):79‐94. - PubMed
Moore 2014b
    1. Moore RA, Cai N, Skljarevski V, Tölle TR. Duloxetine use in chronic painful conditions ‐ individual patient data responder analysis. European Journal of Pain 2014;18(1):67‐75. [DOI: 10.1002/j.1532-2149.2013.00341.x] - DOI - PMC - PubMed
O'Brien 2010
    1. O'Brien EM, Staud RM, Hassinger AD, McCulloch RC, Craggs JG, Atchinson JW, et al. Patient‐centered perspective on treatment outcomes in chronic pain. Pain Medicine 2010;11(1):6‐15. [DOI: 10.1111/j.1526-4637.2009.00685.x] - DOI - PubMed
PCF 2014
    1. Twycross R, Wilcock A, Howard P. Palliative care formulary. Palliativedrugs.com (accessed September 2016).
PedIMMPACT 2008
    1. McGrath PJ, Walco GA, Turk DC, Dworking RH, Brown MT, Davidson K, et al. Core outcome domains and measures for pediatric acute and chronic/recurrent pain clinical trials: PedIMMPACT. Journal of Pain 2008;9(9):771‐83. - PubMed
Review Manager 2014 [Computer program]
    1. Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Ripamonti 2008
    1. Ripamonti C, Bandieri E. Pain therapy. Journal of Hematology & Oncology 2008;70(2):145‐59. [DOI: 10.1016/j.critrevonc.2008.12.005] - DOI - PubMed
Rosenblum 2008
    1. Rosenblum A, Marsch LA, Joseph H, Portenoy RK. Opioids and the treatment of chronic pain: controversies, current status, and future directions. Experimental and Clinical Psychopharmacology 2008;16(5):405‐16. [DOI: 10.1037/a0013628] - DOI - PMC - PubMed
Stinson 2006
    1. Stinson JN, Kavanagh T, Yamada J, Gill N, Stevens B. Systematic review of the psychometric properties, interpretability and feasibility of self‐report pain intensity measures for use in clinical trials in children and adolescents. Pain 2006;125(1‐2):143‐57. [DOI: 10.1016/j.pain.2006.05.006] - DOI - PubMed
Straube 2008
    1. Straube S, Derry S, McQuay HJ, Moore RA. Enriched enrolment: definition and effects of enrichment and dose in trials of pregabalin and gabapentin in neuropathic pain. A systematic review. British Journal of Clinical Pharmacology 2008;66(2):266‐75. [DOI: 10.1111/j.1365-2125.2008.03200.x] - DOI - PMC - PubMed
Straube 2010
    1. Straube S, Derry S, Moore RA, Paine J, McQuay HJ. Pregabalin in fibromyalgia ‐ responder analysis from individual patient data. BMC Musculoskeletal Disorders 2010;11:150. [DOI: 10.1186/1471-2474-11-150] - DOI - PMC - PubMed
Sultan 2008
    1. Sultan A, Gaskell H, Derry S, Moore RA. Duloxetine for painful diabetic neuropathy and fibromyalgia pain: systematic review of randomised trials. BMC Neurology 2008;8:29. [DOI: 10.1186/1471-2377-8-29] - DOI - PMC - PubMed
Tanko 2009
    1. Tanko NM, Echejoh GO, Manasseh NA, Mandong MB, Uba AF. Paediatric solid tumours in Nigerian children: a changing pattern. African Journal of Paediatric Surgery 2009;6(1):7‐10. - PubMed
United Nations 2017
    1. United Nations. World population prospects 2017 ‐ population indicators. esa.un.org/unpd/wpp/Download/Standard/Population (accessed 06 March 2016).
Verghese 2010
    1. Verghese ST, Hannallah RS. Acute pain management in children. Journal of Pain Research 2010;3:105‐23. [DOI: 10.2147/JPR.S4554] - DOI - PMC - PubMed
Von Bayer 2007
    1. Bayer CL, Spagrud LJ. Systematic review of observational (behavioural) measures of pain for children and adolescents aged 3 to 18 years. Pain 2007;127(1‐2):140‐50. [DOI: 10.1016/j.pain.2006.08.014] - DOI - PubMed
WHO 1998
    1. World Health Organization. Cancer pain relief and palliative care in children. apps.who.int/iris/bitstream/10665/42001/1/9241545127.pdf (accessed prior to 4 July 2017).
WHO 2011
    1. World Health Organization. Cancer Fact Sheet N°297. www.who.int/mediacentre/factsheets/fs297/en/ (accessed 12 February 2016).
WHO 2012
    1. World Health Organization. WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses. apps.who.int/iris/bitstream/10665/44540/1/9789241548120_Guidelines.pdf (accessed prior to 4 July 2017). [ISBN 978 92 4 154812 0] - PubMed
Wiffen 2017b
    1. Wiffen PJ, Cooper TE, Heathcote L, Clinch J, Howard R, Krane E, et al. Antiepileptic drugs for chronic non‐cancer pain in children and adolescents. Cochrane Database of Systematic Reviews 2017, Issue 8. [DOI: 10.1002/14651858.CD012536.pub2] - DOI - PMC - PubMed
Wiffen 2017c
    1. Wiffen PJ, Wee B, Derry S, Bell RF, Moore RA. Opioids for cancer pain ‐ an overview of Cochrane reviews. Cochrane Database of Systematic Reviews 2017, Issue 7. [DOI: 10.1002/14651858.CD012592] - DOI - PMC - PubMed
World Bank 2016
    1. The World Bank. Data ‐ population ages 0‐14 (% of total). data.worldbank.org/indicator/SP.POP.0014.TO.ZS (accessed 29 February 2016).

Publication types

Substances

LinkOut - more resources