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References

References to studies included in this review

Beaver 1967 {published data only}

Beaver WT, Wallenstein SL, Houde RW, Rogers A. A clinical comparison of the analgesic effects of methadone and morphine administered intramuscularly, and of orally and parenterally administered methadone. Clinical Pharmacololgy and Therapeutics 1967;8(3):415‐26. [PUBMED: 5338385]CENTRAL

Bruera 2004 {published data only}

Bruera E, Palmer JL, Bosnjak S, Rico MA, Moyano J, Sweeney C, et al. Methadone versus morphine as a first‐line strong opioid for cancer pain: a randomized, double‐blind study. Journal of Clinical Oncology 2004;22(1):185‐92. [DOI: 10.1200/JCO.2004.03.172]CENTRAL

Mercadante 1998 {published data only}

Mercadante S, Casuccio A, Agnello A, Serretta R, Calderone L, Barresi L. Morphine versus methadone in the pain treatment of advanced cancer patients followed up at home. Journal of Clinical Oncology 1998;16(11):3656‐61. [PUBMED: 9817288]CENTRAL

Mercadante 2008 {published data only}

Mercadante S, Porzio G, Ferrera P, Fulfaro F, Aielli F, Verna L, et al. Sustained‐release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management. European Journal of Pain 2008;12:1040‐6. [DOI: 10.1016/j.ejpain.2008.01.013]CENTRAL

Twycross 1977 {published data only}

Twycross R. A comparison of diamorphine with cocaine and methadone (letter). British Journal of Clinical Practice 1977;4:691‐93. [PUBMED: 69292]CENTRAL

Ventafridda 1986 {published data only}

Ventafridda V, Ripamonti C, Bianchi M, Sbanotto A, De Conno F. A randomized study on oral administration of morphine and methadone in the treatment of cancer pain. Journal of Pain and Symptom Management 1986;1(4):203‐7. [DOI: 10.1016/S0885‐3924(86)80042‐2]CENTRAL

References to studies excluded from this review

Cubero 2010 {published data only}

Cubero DIG, del Giglio A. Early switching from morphine to methadone is not improved by acetaminophen in the analgesia of oncologic patients: a prospective, randomized, double‐blind, placebo‐controlled study. Supportive Care in Cancer 2010;18(2):235‐42. [DOI: 10.1007/s00520‐009‐0649‐8]CENTRAL

Ferrer‐Brechner 1984 {published data only}

Ferrer‐Brechner T, Ganz P. Combination therapy with ibuprofen and methadone for chronic cancer pain. American Journal of Medicine 1984;77(1A):78‐83. [DOI: 10.1016/S0002‐9343(84)80023‐6]CENTRAL

Gourlay 1986 {published data only}

Gourlay GK, Cherry DA, Cousins MJ. A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in the treatment of severe pain in patients with cancer. Pain 1986;25(3):297‐312. [DOI: 10.1016/0304‐3959(86)90234‐4]CENTRAL

Grochow 1989 {published data only}

Grochow L, Sheidler V, Grossman S, Green L, Enterline J. Does intravenous methadone provide longer lasting analgesia than intravenous morphine? A randomised, double blind study. Pain 1989;38(2):151‐7. [DOI: 10.1016/0304‐3959(89)90233‐9]CENTRAL

Lauretti 2013 {published data only}

Lauretti GR, Rizzo CC, Mattos AL, Rodrigues SW. Epidural methadone results in dose‐dependent analgesia in cancer pain, further enhanced by epidural dexamethasone. British Journal of Cancer 2013;108(2):259‐64. [DOI: 10.1038/bjc.2012.593]CENTRAL

Matts 1964 {published data only}

Matts SGF, Swan CHF, Wharton BA. Double blind trial of dextromoramide, methadone and pethidine in the treatment of severe pain. Postgraduate Medical Journal 1964;40:103‐5. [PUBMED: 14122903]CENTRAL

Moksnes 2011 {published data only}

Moksnes K, Dale O, Rosland JH, Paulsen O, Klepstad P, Kaasa S. How to switch from morphine or oxycodone to methadone in cancer patients? A randomised clinical phase II trial. European Journal of Cancer 2011;47(16):2463‐70. [DOI: 10.1016/j.ejca.2011.06.047]CENTRAL

Morley 2003 {unpublished data only}

Morley JS, Bridson J, Nash TP, Miles JB, White S, Makin MK. Low‐dose methadone has an analgesic effect in neuropathic pain: a double‐blind randomized controlled crossover trial. Palliative Medicine2003; Vol. 17, issue 7:576‐87. [PUBMED: 14594148]CENTRAL

NCT00573937 {unpublished data only}

Prommer E (lead investigator). Methadone versus morphine for cancer related pain. clinicaltrials.gov/ct2/show/NCT00573937 (accessed 21 April 2016)2016. [CTG: NCT00573937]CENTRAL

NCT00726830 {unpublished data only}

Fisch MJ (lead investigator). Methadone, morphine, or oxycodone in treating pain in patients with cancer. clinicaltrials.gov/ct2/show/NCT00726830 (accessed 21 April 2016)2012. [CTG: NCT00726830]CENTRAL

Raptis 2013 {published data only}

Raptis E, Vadalouca A, Stavropoulou E, Argyra E, Melemeni A, Siafaka I. Pregabalin vs. opioids for the treatment of neuropathic cancer pain: a prospective, head‐to‐head, randomized, open‐label study. Pain Practice 2014;14(1):32‐42. [DOI: 10.1111/papr.12045]CENTRAL

Bruera 1991

Bruera E, Fainsinger R, Moore M, Thibault R, Spoldi E, Ventafridda V. Local toxicity with subcutaneous methadone. Experience of two centers. Pain 1991;45(2):141‐3. [DOI: 10.1016/0304‐3959(91)90179‐2]

Bruera 2002

Bruera E, Sweeney C. Methadone use in cancer patients with pain: a review. Journal of Palliative Medicine 2002;5(1):127‐38. [DOI: 10.1089/10966210252785097]

Cruciani 2008

Cruciani RA. Methadone: to ECG or not to ECG.... That is still the question. Journal of Pain and Symptom Management 2008;36(5):545‐52. [DOI: 10.1016/j.jpainsymman.2007.11.003]

Davis 2001

Davis MP, Walsh D. Methadone for relief of cancer pain: a review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration. Supportive Care in Cancer 2001;9(2):73‐83. [DOI: 10.1007/s005200000180]

DH 2013

Anon. More care, less pathway. A review of the Liverpool Care Pathway. Report by Baroness Julia Neuberger (Chair), available at www.gov.uk/government/uploads/system/uploads/attachment_data/file/212450/Liverpool_Care_Pathway.pdf (accessed 21 April 2016).

Fainsinger 1993

Fainsinger R, Schoeller T, Bruera E. Methadone in the management of cancer pain: a review. Pain 1993;51(2):137‐47. [DOI: 10.1016/0304‐3959(93)90125‐9]

Gannon 1997

Gannon C. The use of methadone in the care of the dying. European Journal of Palliative Care 1997;4(5):152‐8.

Good 2014

Good P, Afsharimani B, Movva R, Haywood A, Khan S Hardy J. Therapeutic challenges in cancer pain management: a systematic review of methadone. Journal of Pain and Palliative Care Pharmacotherapy 2014;28(3):197‐205. [DOI: 10.3109/15360288.2014.938883]

Gorman 1997

Gorman AL, Elliott KJ, Inturrisi CE. The d‐ and l‐isomers of methadone bind to the non‐competitive site on the N‐methyl‐D‐aspartate (NMDA) receptor in rat forebrain and spinal cord. Neuroscience Letters 1997;223(1):5‐8.

Graner 2016

Graner KM, Rolim GS, Moraes AB, Padovani CR, Lopes MA, Santos‐Silva AR, et al. Feelings, perceptions, and expectations of patients during the process of oral cancer diagnosis. Support Care Cancer 2016;24:2323‐32. [DOI: 10.1007/s00520‐015‐3030‐0]

Guyatt 2013a

Guyatt G, Oxman AD, Sultan S, Brozek J, Glasziou P, Alonso‐Coello P, et al. GRADE guidelines: 11. Making an overall rating of 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]

Guyatt 2013b

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]

Hanks 1998

Hanks GWC, Cherny N. Opioid analgesic therapy. In: Doyle D, Hanks GWC, MacDonald N editor(s). Oxford Textbook of Palliative Medicine. Oxford: Oxford University Press, 1998:331‐51.

Higgins 2011

Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: 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.

Ma 2016

Ma H, Liu Y, Huang L, Zeng XT, Jin SH, Yue GJ, et al. The adverse events of oxycodone in cancer‐related pain: a systematic review and meta‐analysis of randomized controlled trials. Medicine (Baltimore) 2016;95(15):e3341. [DOI: 10.1097/MD.0000000000003341]

Mathew 1999

Mathew P, Storey P. Subcutaneous methadone in terminally ill patients: manageable local toxicity. Journal of Pain and Symptom Management 1999;18(1):49‐52. [DOI: 10.1016/S0885‐3924(99)00020‐2]

Moher 2009

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. [DOI: 10.1371/journal.pmed1000097]

Payne 1998

Payne R, Gonzales GR. Pathophysiology of pain in cancer and other terminal diseases. In: Doyle D, Hanks GWC, MacDonald N editor(s). Oxford Textbook of Palliative Medicine. Oxford: Oxford University Press, 1998:299‐310.

RevMan 2014 [Computer program]

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Ripamonti 1997

Ripamonti C, Zecca E, Bruera E. An update on the clinical use of methadone for cancer pain. Pain 1997;70(2‐3):109‐15. [DOI: 10.1016/S0304‐3959(96)03286‐1]

Twycross 1998

Twycross R, Wilcock A, Thorpe S. Palliative Care Formulary. Oxford: Radcliffe Medical Press, 1998.

Twycross 2014

Twycross R, Wilcock A (Eds). PCF5 Palliative Care Formulary. Fifth. Nottingham: palliativedrugs.com Ltd, 2014. [ISBN: 978‐0‐9552547‐9‐6]

van den Beuken‐van Everdingen 2007

van den Beuken‐van Everdingen MH, de Rijke JM, Kessels AG, Schouten HC, van Kleef M, Patijn J. High prevalence of pain in patients with cancer in a large population‐based study in The Netherlands. Pain 2007;132:312‐20.

van den Beuken‐van Everdingen 2013

van den Beuken‐van Everdingen MH, Geurts JW, Patijn J. Prolonged QT interval by methadone: relevance for daily practice? A prospective study in patients with cancer and noncancer pain. Journal of Opioid Management 2013;9(4):263‐7. [DOI: 10.5055/jom.2013.0167]

Ventafridda 1987

Ventafridda V, Tamburini M, Caraceni A, De Conno F, Naldi F. A validation study of the WHO method for cancer pain relief. Cancer 1987;59(4):850‐6. [PUBMED: 3802043]

Weschules 2008

Weschules DJ, Bain KT, Richeimer S. Actual and potential drug interactions associated with methadone. Pain Medicine 2008;9(3):315‐44. [DOI: 10.1111/j.1526‐4637.2006.00289.x]

Wiffen 2014

Wiffen PJ, Derry S, Moore RA. Impact of morphine, fentanyl, oxycodone or codeine on patient consciousness, appetite and thirst when used to treat cancer pain. Cochrane Database of Systematic Reviews 2014, Issue 5. [DOI: 10.1002/14651858.CD011056.pub2]

References to other published versions of this review

Nicholson 2002

Nicholson A, Davies A, Reid C. Methadone for cancer pain. Cochrane Database of Systematic Reviews 2002, Issue 11. [DOI: 10.1002/14651858.CD003971]

Nicholson 2004

Nicholson AB. Methadone for cancer pain. Cochrane Database of Systematic Reviews 2004, Issue 1. [DOI: 10.1002/14651858.CD003971.pub2]

Nicholson 2007

Nicholson AB. Methadone for cancer pain. Cochrane Database of Systematic Reviews 2007, Issue 10. [DOI: 10.1002/14651858.CD003971.pub3]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Jump to:

Beaver 1967

Methods

Randomised, double‐blind (double dummy), cross‐over study

Single doses with assessment at 6 h

Participants

Chronic pain due to cancer

N = 43 started, 37 completed at least 1 series (M: 11, F: 26)

Mean age 48 years (range 34‐59 years)

Interventions

Morphine (IM or oral) or methadone (IM or oral) in a range of doses from 8 mg to 48 mg

4 doses for each series and 4 different series

Outcomes

PI: categorical scale (5 points), measured over 6 h

50% pain relief

Adverse events

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Stated to be randomised

Allocation concealment (selection bias)

Unclear risk

Not stated

Blinding of participants and personnel (performance bias)

Low risk

"in the oral‐parenteral study both capsules and an injection, one of which was a dummy, were administered"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"in the oral‐parenteral study both capsules and an injection, one of which was a dummy, were administered"

Incomplete outcome data (attrition bias)
All outcomes

High risk

Only completed cross‐overs were analysed for efficacy

Selective reporting (reporting bias)

Unclear risk

Some participants contributed more than one set of data

Size

High risk

< 50 participants per treatment arm

Bruera 2004

Methods

Randomised, double‐blind, parallel‐group; duration 28 days

Participants

Outpatients with cancer pain determined by a validated clinical assessment. Differentiated between neuropathic and non‐neuropathic pain

N = 103 patients randomised (methadone 49, morphine 54), 66 completed (methadone 29, morphine 37)

M: 37, F: 66

Age: methadone median age 59 years (range 26‐84 years); morphine median age 60 years (range 31‐87 years)
Excluded participants who had previously been treated with strong opioids
All non‐opioids discontinued on recruitment; titration of antiemetics and laxatives allowed

Interventions

Oral methadone 7.5 mg twice daily with 5 mg 4‐hourly as needed. Oral morphine 15 mg twice daily with 5 mg 4‐hourly as needed
Titration based on use of 'as needed' doses and physicians' assessment daily for days 1 to 8, then weekly

Outcomes

Participant‐reported data, daily on days 1 to 8, then weekly thereafter: pain, sedation, confusion, nausea, constipation, recorded on 0‐10 NRS
Weekly assessment of cognitive function (tool not specified) and global assessment of overall benefit on VRS with 7 points and descriptors
End of study outcomes:
Pain response of 20% NRS reduction considered clinically relevant
Composite toxicity calculated as sum of NRS for side effects ‐ worsening by 20% or more considered clinically relevant
Pain response and stable composite toxicity deemed to be 'obvious benefit'
Participant‐reported global benefit ‐ VRS 4 or more on 7‐point scale

Adverse events

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"generated centrally by computer generated numbers stratified by center"

Allocation concealment (selection bias)

Low risk

Pharmacy at each centre advised of treatment assigned but the code was kept in a sealed envelope and not released to clinicians unless clinical emergency

Blinding of participants and personnel (performance bias)

Low risk

Stated to be double blind, "in identical capsules"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Stated to be double blind, "in identical capsules"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Similar rates of withdrawals in both groups and for similar reasons. BOCF for dichotomised end points

Selective reporting (reporting bias)

Low risk

All intended outcomes reported upon

Size

High risk

49 participants in one arm and 54 in the other

Mercadante 1998

Methods

Prospective randomised parallel‐group study

Participants treated until death

Participants

Advanced cancer requiring strong opioids for pain management

N = 40

M: 19, F: 21

Age: morphine mean age 65 years ± 2.7; methadone mean age 61 years ± 2.9

Interventions

Oral morphine modified‐release, titrated to need

Oral methadone solution, titrated to need

Other palliative care drugs allowed including non‐opioid analgesics. No anticancer therapy

Outcomes

Pain intensity self report (when possible, otherwise doctor‐rated)

Symptoms related to cancer or adverse events

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Stated to be 'randomised'

Allocation concealment (selection bias)

Unclear risk

Not stated

Blinding of participants and personnel (performance bias)

High risk

Commercially available products used

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Commercially available products used

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No problems identified

Selective reporting (reporting bias)

Unclear risk

Some pain measurements may have been physician‐ or carer‐assessed but not clearly specified

Size

High risk

20 participants per treatment arm

Mercadante 2008

Methods

Multicentre, randomised, open, parallel‐group study: duration 4 weeks

Fixed starting dose of study medication, adjusted to balance analgesia and adverse effects

Assessment at baseline and weekly intervals

Participants

Adults with advanced cancer requiring strong opioids who had received opioids for mild to moderate pain, including tramadol and codeine at doses of at least 300 mg and 180 mg respectively, without adequate analgesia. Expected survival > 3 months

Breast cancer was the most frequent diagnosis (16 participants), and mixed nociceptive‐neuropathic syndromes (18 participants) the most dominant pain type

N = 108 (70 completed)

M: 36, F: 34 (completers)

Mean age 59 years (range 18‐78) (completers)

Interventions

Oral methadone, 15 mg/d in 3 divided doses, n = 36

Modified‐release oral morphine, initially 60 mg/d, n = 36

Transdermal fentanyl patch, initially 0.6 mg/d (25 μg/h), n = 36

Rescue medication: oral morphine at 1/6 24‐h oral equivalent requirement

Outcomes

Symptoms associated with opioid therapy (e.g. nausea, drowsiness, confusion): 4‐point scale (not at all, slight, a lot, severe)

Constipation: 4‐point scale (0 = 1 passage every 1‐2 days, 1 = one passage every 3‐4 days, 2 = one passage > 4 days, 3 = rectal measures)

Distress score calculated from sum of symptom intensities

PI: NRS (0‐10)

Time to achieve dose stabilisation

Number of daily dose changes

Opioid escalation index

QoL using Spitzer QoL index (activity, daily life, health perceptions, social support, Behaviour rated on Likert 3‐point scale (0‐2)

Cost

Notes

Other medication for 'symptoms' were allowed during the study, which included anti‐inflammatories, antidepressants and anticonvulsants, which may have an impact on pain; these were either continued or introduced as needed during the study

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"computer‐generated"

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)

High risk

Not blinded; used "commercially available" products

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Not blinded; used "commercially available" products

Incomplete outcome data (attrition bias)
All outcomes

High risk

Efficacy data (group means) for participants remaining in study (completers). States numbers of dropouts equally distributed between groups

Selective reporting (reporting bias)

Low risk

No problems identified

Size

High risk

36 per treatment arm

Twycross 1977

Methods

Randomised, double‐blind, parallel‐group: duration 4 weeks approximately

Participants

Cancer pain; participants with terminal cancer with severe pain
N = 46. Gender mix stated to be 'comparable'

Median age 63 years

Interventions

Diamorphine elixir with cocaine 10 mg, n = 26

Oral methadone, n = 20

Dose titrated to pain relief

Outcomes

VAS for pain, nausea and mood, assessed twice daily

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"randomly allocated"; method not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)

Low risk

"drugs were dispensed in undistinguishable solutions"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"drugs were dispensed in undistinguishable solutions"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants accounted for

Selective reporting (reporting bias)

Low risk

No problems identified

Size

High risk

< 50 participants per treatment arm (20 and 26)

Ventafridda 1986

Methods

Randomised, parallel‐group: duration 14 days

Participants

Advanced cancer requiring strong opioids for "excruciating pain"

N = 66 (randomised), 54 (completed)

M: 31, F: 23

Interventions

Oral methadone 1 mg/ml, dose 8‐28 mg daily, given as divided dose every 6 h for 3 d, then every 8 h, n = 27

Oral morphine 4 mg/ml dose 4‐24 mg every 4 h, n = 27

All participants received diclofenac 150 mg daily and haloperidol 20 mg daily by injection

Outcomes

PI: 5‐point categorical scale (converted to integrated pain score, which took into account duration)

Achieved no worse than mild pain (VAS ≤ 30/100)

Adverse events

Withdrawals

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Stated to be "randomised", method not described

Allocation concealment (selection bias)

Unclear risk

Method not described

Blinding of participants and personnel (performance bias)

High risk

Not described. Presumed open‐label, since different dosing regimens

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Not described. Presumed open‐label, since different dosing regimens

Incomplete outcome data (attrition bias)
All outcomes

High risk

Completer analysis

Selective reporting (reporting bias)

Low risk

No problems identified

Size

High risk

< 50 participants per treatment arm

BOCF: baseline observation carried forward; F: female; h: hours; IM: intramuscular; M: male; mg: milligrams; N: number of participants in study; n: number of participants in treatment arm; NRS: Numerical Rating Scale; PI: pain intensity; QoL: quality of life; VAS: Visual Analogue Scale; VRS: Verbal Rating Scale

Characteristics of excluded studies [ordered by study ID]

Jump to:

Study

Reason for exclusion

Cubero 2010

Study of methadone in combination with acetaminophen (paracetamol)

Ferrer‐Brechner 1984

28 participants across 4 groups. Likely to be fewer than 10 participants per treatment group

Gourlay 1986

Fewer than 10 participants per treatment group

Grochow 1989

Fewer than 10 participants per treatment group

Lauretti 2013

Study of methadone in combination with other agents

Matts 1964

Not specifically cancer pain ‐ only 15 out of 90 participants reported cancer‐related pain

Moksnes 2011

Study of switching methods using methadone

Morley 2003

Double‐blind randomised controlled cross‐over trial of methadone for neuropathic pain. Excluded cancer pain

NCT00573937

Only 1 participant recruited

NCT00726830

Only 1 participant recruited

Raptis 2013

Not a study of methadone

Study flow diagram
Figures and Tables -
Figure 1

Study flow diagram

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Figures and Tables -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Figures and Tables -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

Summary of findings for the main comparison. Methadone compared to Morphine for cancer pain

Methadone compared to morphine for cancer pain

Patient or population: people with cancer pain
Intervention: methadone
Comparison: morphine

Outcomes

Assumed risk

Corresponding risk

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Morphine

Methadone

Participant‐reported pain intensity

Pain intensity scores:

One study (103 participants) reported > 20% improvement in pain scores for 76% of morphine and 75% methadone participants in those that completed

No worse than mild pain (pain score of 3/10 or less after treatment):

One study (54 participants) reported all achieved no worse than mild pain based on mean pain scores. Two studies (148 participants) reported mean pain scores very close to a score of 3

⊕⊕⊝⊝
low1,2

Downgraded two points for reasons stated

Adverse events: appetite, thirst, somnolence

Not estimable

Not estimable

Not estimable

342
(5 studies)

⊕⊝⊝⊝
very low1,2,3

Downgraded three points for reasons stated

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence

High quality: we are very confident that the true effect lies close to that of the estimate of the effect

Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different

Low quality: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect

Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect

1 Risk of bias: random allocation and allocation concealment unclear, all had sample size of less than 200 per treatment arm.
2 Imprecision: sample size is smaller than optimal information size; confidence interval around estimate of effect is wide and included no effect and appreciable benefit/harm.
3 Indirectness. Surrogates for appetite, thirst and somnolence such as sedation, drowsiness and dry mouth used.

Figures and Tables -
Summary of findings for the main comparison. Methadone compared to Morphine for cancer pain