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Transdermal fentanyl for cancer pain

  1. Gina Hadley*,
  2. Sheena Derry,
  3. R Andrew Moore,
  4. Philip J Wiffen

Editorial Group: Cochrane Pain, Palliative and Supportive Care Group

Published Online: 5 OCT 2013

Assessed as up-to-date: 3 SEP 2013

DOI: 10.1002/14651858.CD010270.pub2


How to Cite

Hadley G, Derry S, Moore RA, Wiffen PJ. Transdermal fentanyl for cancer pain. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD010270. DOI: 10.1002/14651858.CD010270.pub2.

Author Information

  1. University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences, Oxford, Oxfordshire, UK

*Gina Hadley, Pain Research and Nuffield Department of Clinical Neurosciences, University of Oxford, Pain Research Unit, Churchill Hospital, Oxford, Oxfordshire, OX3 7LE, UK. glhadley@doctors.org.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 5 OCT 2013

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Characteristics of included studies [ordered by study ID]
Ahmedzai 1997

MethodsMulticentre, randomised, open, two period cross-over study: each period lasted 15 days with no washout between periods. Initial opioid dose calculated using manufacturers recommendations, with dose titration at start of each period to achieve pain control

Setting: Palliative care centres, UK

Assessed at baseline and 8, 16, 23, 31 days, and by daily patient diary


ParticipantsAdult cancer patients requiring strong opioid analgesia and receiving stable dose of morphine for at least 48 hours

Life expectancy > 1 month

N = 202

Mean age 62 years (range 18 to 89)

M 112, F 90


InterventionsTransdermal fentanyl patch (new patch every 72 hours)

Sustained release oral morphine, given every 12 hours

One treatment for 15 days followed immediately by other for 15 days.

Immediate release morphine was used freely to titrate pain at the start of study and at cross-over

Where possible other medication remained unchanged, but other analgesics allowed: e.g. NSAIDs, permitted radiotherapy, nerve blocks


OutcomesSleep, rescue medication, drowsiness using VAS, daily diary

Pain and mood using Memorial Pain Assessment Card (MPAC), twice daily

QoL (self-rated) using EORTC QLQ-C30

Performance status (clinician rated) using WHO scale

Treatment preference

Adverse events


NotesOxford Quality Score: R1, DB0, W1. Total = 2/5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not described

Allocation concealment (selection bias)Unclear riskMethod not described

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
High riskAppears to be a completer analysis. "Patients who withdrew before the end of the study were included in the analysis to the fullest extent possible"

SizeUnclear risk50 to 200 participants per treatment arm

Kongsgaard 1998

MethodsMulticentre, enriched enrolment, randomised withdrawal study: 7 day stabilisation phase, 15 day open label titration phase, and 9 day double blind, placebo controlled, parallel group phase

Assessment by daily patient diary and clinical visits at trial entry, beginning and end of double blind period, and 3 month intervals for follow-up


ParticipantsAdult cancer patients with pain caused by malignancy recurring after potentially curative therapy, not currently amenable to curative therapy. Requiring equivalent of 60 to 300 mg oral morphine daily, with acceptable toxicity and pain relief (pain no worse than moderate, assessed by investigator using 7-point scale at end of stabilisation phase). Karnofsky performance > 50

Site of cancer: head and neck, prostate, colon, lung, breast, uterus, gastrointestinal, liver, other

Titration phase: N = 138 (131 enrolled after stabilisation, 7 directly)

Mean age 59 years (range 24 to 83)

M 85, F 53


InterventionsStabilisation phase: oral morphine (≥60 mg to ≤ 300 mg daily) titrated to provide adequate pain control with acceptable adverse effects

 

15 day dose-titration period: fixed conversion table used to convert morphine to fentanyl and titration to maintain adequate pain control with acceptable adverse effects. New patch applied every 72 hours

 

9 day double blind period using fentanyl or placebo at same dose as at end of titration period (median dose 50 μg/h)

 

Rescue medication (rapid release morphine) available. Medication for concurrent illness continued


OutcomesWithdrawals due to inadequate analgesia (patient required x2 mean daily dose of rescue morphine that was administered at end of open treatment phase, or if no rescue morphine required at that stage, when patient required > 50% of mean morphine dose administered during stabilisation period)

Patient diary card:

Pain intensity using 100 mm VAS, x2 daily

Rescue medication, daily

Well-being using 100 mm VAS, x2 daily

Clinical visit:

Investigator assessment of pain intensity using 7-point scale (no pain-intolerable pain)

Investigator global assessment of trial medication (excellent, good, moderate, poor)

Adverse events


NotesOxford Quality Score: R1, DB1, W1. Total = 3/5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not described

Allocation concealment (selection bias)Unclear riskMethod not described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskMethod not described

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskMethod not described

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskITT analysis, but imputation method not described. Withdrawals ˜ 10%

SizeHigh risk< 50 participants per treatment arm

Kress 2008

MethodsMulticentre, randomised, open, parallel group study: 30 days of treatment plus 7 days follow-up

Assessment by daily patient diary and weekly clinic visits

Aim to determine non-inferiority and compare safety of new formulation patch (FIT) with standard formulation patch and oral morphine. Participants switched to FIT using standardised conversion ratio, based on previous 24 hour intake or 12.5 μg/h if opioid naïve; previous analgesics phased out

Dose adjustment allowed throughout study to meet needs of individual participants

 

ITT – participants who took at least one dose of medication


ParticipantsAdult cancer patients (in or out patients) with chronic cancer-related pain requiring long term (> 30 days) strong (WHO Step 3) opioid treatment, either step up or rotation. Karnofsky score >50/100 at baseline

N = 220

Mean age 63 (±11) years

M 132, F 88


InterventionsFentanyl Improved Transdermal (FIT) patch, n = 117

Standard opioid treatment, n = 103 (65 transdermal fentanyl (Durogesic patch), 38 Oramorph)

New patches applied every 72 hours, oramorph given every 12 hours

 

Dose adjustment permitted if breakthrough pain became regular (upward) or if significant adverse events were experienced alongside adequate pain control and no rescue medication (downward)

Other treatment continued, including radiotherapy and chemotherapy, and both pharmacological and non-pharmacological pain-modulating interventions.

Rescue medication: morphine, administered as preferred by participant or investigator


OutcomesPatient diary:

Pain intensity using 0 to 10 numerical rating scale, daily

Tolerability (constipation, nausea sleep disturbance, daytime drowsiness), using 4-point ordinal scale (absent, mild, moderate, severe)

Rescue medication

Adverse events, serious adverse events

Primary endpoint was relative area under the curve of PI expressed as a % maximum possible area under the curve


NotesOxford Quality Score: R1, DB0, W1. Total = 2/5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not described

Allocation concealment (selection bias)Low riskInteractive voice response system

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThis was not a true ITT analysis patients with missing values did not contribute to that analysis - 16% for primary endpoint - but losses to each group approximately the same

SizeUnclear risk50 to 200 participants per treatment arm

Mercadante 2008

MethodsMulticentre, randomised, open, parallel group study: 4 weeks

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

Assessment at baseline and weekly intervals


ParticipantsAdult cancer patients 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 patients), and mixed nociceptive-neuropathic syndromes (18 patients) the most dominant pain type

N = 108

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

M 36, F 34 (completers)


InterventionsTransdermal fentanyl patch, initially 0.6 mg/day 25 μg/h, n = 36

Sustained release oral morphine, initially 60 mg/day, n = 36

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

 

Rescue medication: oral morphine at 1/6 daily 24 hour oral equivalent requirement

Use of other medication permitted, including those for palliation of symptoms


OutcomesSymptoms associated with opioid therapy (e.g. nausea, drowsiness, confusion) using 4-point scale (not at all, slight, a lot, severe)

Constipation using 4-point scale (0 = 1 passage every 1 to 2 days, 1 = one passage every 3 to 4 days, 2 = one passage > 4 days, 3 = rectal measures)

Distress score calculated from sum of symptom intensities

 

Pain intensity using numerical rating scale (0 to 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 to 2)

Cost


NotesOxford Quality Score: R2, DB0, W1. Total = 3/5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"computer generated"

Allocation concealment (selection bias)Unclear riskMethod not described

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
High riskCompleter analysis

SizeHigh risk< 50 participants per treatment arm

Mystakidou 2005

MethodsRansomised, open label, parallel group study: 2 months

All participants underwent palliative radiotherapy before randomisation. Fixed starting dose of study medication, adjusted to patient requirements

Assessment at baseline, 3, 7, 14, 28 days, and 2 months


ParticipantsAdult cancer patients with painful bony metastasis and moderate/severe chronic cancer pain requiring strong opioids

Primary cancer location: lung, kidney/bladder, gastrointestinal, breast, unknown, other)

Site of bony metastasis: thoracic spine, lumbar spine, cervical spine, thoracic and lumbar spine, pelvis, femur, scapula

Other metastases: brain, gastrointestinal, lung, adrenal

N = 460 (422 eligible)

Mean age 61 (25 to 88) years (eligible)

M 219, F 203 (eligible)


InterventionsTransdermal fentanyl, initially 25 μg/h every 72 hours, n = 201

Paracetamol 500 mg plus codeine 30 mg, to maximum of 4 times per day, n = 221

 

Fentanyl dose was increased when treatment satisfaction ≤ 2 and pain score ≥ 3

Fentanyl-treated participants could receive paracetamol and codeine twice in first 12 hours after patch application, as rescue medication


OutcomesDiary cards:

Greek brief pain inventory (G-BPI), 0 to 10

Overall treatment satisfaction, 1 to 4 (not at all satisfied, fairly satisfied, satisfied, completely satisfied)

QoL using VAS, 0 to 10 (0 = high, 10 = low)

European Collaborative Oncology Group status

Adverse events


NotesOxford Quality Score: R1, DB0, W1. Total = 2/5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not described

Allocation concealment (selection bias)Unclear riskMethod not described

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
High riskCompleter analysis

SizeLow risk≥ 200 participants per treatment arm (before withdrawals)

Oztürk 2008

MethodsRandomised, open label, parallel group. Duration 15 days


ParticipantsLung cancer requiring WHO step 3 opioids for pain; 18 of fentanyl patients were treated in hospital, and 16 of morphine patients were treated in hospital, others were visited by doctors at home

N = 50

Mean age 55 years (completers, range not stated)

M/F not reported


InterventionsTransdermal fentanyl patch

Sustained relief oral morphine

Starting level:

Participants requiring 200 to 400 mg tramadol used 25 μg/h TDF patches

Participants requiring 500 to 600 mg oral tramadol used 50 μg/h TDF patches

120 mg slow release morphine

Dose increased if inadequate response to maximum 100 mg/h TDF or 180 mg SRM (41% and 23% changed, two participants in each group increased dose twice)

Rescue medication: both groups given subcutaneous morphine if pain ‘unbearable’ (NRS > 3)


OutcomesPain: NRS (0-10)

ADLs using ECOG

Adverse events


NotesOxford Quality Score: R1, DB0, W1. Total = 2/5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskMethod not described

Allocation concealment (selection bias)Unclear riskMethod not described

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
High riskCompleter analysis

SizeHigh risk25 participants per treatment arm

Pistevou-Gompaki 2004

MethodsMulticentre, randomised, open, parallel group study

All participants received palliative radiotherapy (unclear whether before or during medication)

Assessed at baseline (before radiotherapy), at 2-weekly intervals during and after radiotherapy, for 3 months


ParticipantsAdult cancer patients with painful bony metastasis. Moderate/severe pain refractory to common analgesics, no previous strong opioids

Primary cancer location (lung, prostate, breast, stomach/gallbladder, kidney, multiple myeloma, unknown); site of bony metastasis (thoracic spine, lumbar spine, cervical spine, thoracic and lumbar spine, pelvis, limbs, scapula); other metastases (brain, lymph, lung, liver)

N = 26 (24 eligible)

Age range 54 to 72 years

M 19, F 7


InterventionsRadiotherapy plus:

Transdermal fentanyl 25 μg/hour, every 72 hours, n = 13

Paracetamol 500 mg plus codeine 30 mg, x4 daily, n = 13

3 fentanyl and 2 paracetamol plus codeine participants also received iv bisphosphonates


OutcomesPain intensity using VAS (0 to 10)

QoL using Greek brief pain inventory (G-BPI) 0 to 10


NotesOxford Quality Score: R1, DB0, W1. Total = 2/5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not described

Allocation concealment (selection bias)Unclear riskMethod not described

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskImputation method not described

SizeHigh risk< 50 participants per treatment arm

van Seventer 2003

MethodsMulticentre, randomised, open, parallel group study. Duration 4 weeks

Assessements by investigator and participant at baseline, 7 and 28 days. Participants also kept a daily diary


ParticipantsAdults with moderate-severe cancer related pain requiring opioid treatment, with life expectancy ≥ 3 months. Participants could be opioid naïve or using opioids for mild-to-moderate pain before entry. Participants using opioids for moderate-to-severe pain in 30 days preceding study entry were excluded

N = 131

Mean age 65 (±12) years

M 85, F 46


InterventionsTransdermal fentanyl, initially 25 μg/h every 72 hours, n = 67

(dose increments of 25 μg/h to achieve adequate pain control)

Sustained release oral morphine, initially 30 mg every 12 hours, n = 64

(dose increments of 30% to 50% 12 hours after previous administration to achieve adequate pain control)

Rescue medication: 10 mg severedol every 2 to 4 hours, as required

Concomitant medication recorded


OutcomesPain control using Shortened Wisconsin brief pain inventory: 11-point scale (0 = no, 10 = extreme), daily

Global assessment of pain relief, sleep, interruption of daily activities and caregiver's activities, troublesome side effects using 4-point scale (1 = not at all, 4 = very much) at start and 28 days

Overall assessment using 11-point scale (0 = very poor, 10 = very good)

Constipation using questionnaire (bowel function normal, constipated, diarrhoeal) at start, 7 and 28 days

Adverse events


NotesOxford Quality Score: R1, DB0, W1. Total = 2/5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not adequately described but states "centrally randomised"

Allocation concealment (selection bias)Unclear riskMethod not adequately described but states "centrally randomised"

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
High riskLOCF imputation

SizeUnclear risk50 to 200 participants per treatment arm

Wong 1997

MethodsRandomised, open, parallel group study. Duration 7 day stabilisation phase (if necessary), 14 day treatment phase

Assessment during stabilisation, at start of treatment phase, and in immediate and final phases of treatment


ParticipantsAdult cancer patients with estimated survival time ≥ 2 months, and pain requiring oral morphine or equivalent ≤ 404 mg per day

Site of primary cancer: head and neck, liver, cervix, pancreas, lung, kidney, bladder

Metastatic sites: bone, lung, liver

Pain not directly related to disease or treatment: fentanyl 9, morphine 5

Location of pain: back, abdomen, lower extremities, head/neck, spine

Type of pain:

Fentanyl: somatic 18, visceral 8, deafferentation 7

Morphine: somatic 18, visceral 7, deafferentation 6

N = 47 (40 completed)

Mean age 59 years (range 30 to 79)

M 29, F 11 (completers)


InterventionsDuring stabilisation phase, current opioid was converted to immediate release morphine hydrochloride (if necessary), which was then converted using standard charts for treatment phase

Transdermal fentanyl patch, every 3 days, n = 20 (completers)

Controlled-release morphine, every 12 hours, n = 20 (completers)

Rescue medication: immediate release morphine


OutcomesPain intensity using 5-point scale (no pain, mild, moderate, severe, excruciating)

Frequency of pain using 4-point scale (no pain, occasional, always, persistent)

Degree of pain improvement using 5-point scale (no pain, obvious, moderate, little, no improvement)

Profile of mood state as effected by the pain using 4-point scale (no, mild, moderate, severe interference)

Quality of sleep using 4-point scale (normal, occasionally awakened by pain, always awakened by pain, insomnia)

Activity status using Eastern Cooperative oncology group (ECOG) 5-point scale (0 = fully active, 4 = completely disabled)

Use of rescue medication

Patient satisfaction

Treatment preference

Adverse events


NotesOxford Quality Score: R1, DB0, W0 (withdrawals not reported per treatment arm). Total = 1/5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not described

Allocation concealment (selection bias)Unclear riskMethod not described

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
High riskCompleter analysis

SizeHigh risk< 50 participants per treatment group

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Ergenoglu 2010Pain not due to cancer

Sarhan 2009Conference abstract

Wirz 2009Not a randomised controlled trial

 
Comparison 1. Fentanyl versus sustained release morphine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Constipation4484Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.47, 0.78]