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Opioids for the management of breakthrough pain in cancer patients

  1. Giovambattista Zeppetella1,*,
  2. Andrew N Davies2

Editorial Group: Cochrane Pain, Palliative and Supportive Care Group

Published Online: 21 OCT 2013

Assessed as up-to-date: 18 OCT 2013

DOI: 10.1002/14651858.CD004311.pub3


How to Cite

Zeppetella G, Davies AN. Opioids for the management of breakthrough pain in cancer patients. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD004311. DOI: 10.1002/14651858.CD004311.pub3.

Author Information

  1. 1

    St Clare Hospice, Hastingwood, Essex, UK

  2. 2

    Royal Surrey County Hospital, Department of Palliative Medicine, Guildford, UK

*Giovambattista Zeppetella, St Clare Hospice, Hastingwood Road, Hastingwood, Essex, CM17 9JX, UK. John.Zeppetella@stclarehospice.org.uk.

Publication History

  1. Publication Status: Edited (no change to conclusions), comment added to review
  2. Published Online: 21 OCT 2013

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This is not the most recent version of the article. View current version (14 AUG 2015)

 
Characteristics of included studies [ordered by study ID]
Christie 1998

MethodsMulticentre, randomised, double-blind, dose titration of OTFC


Participants62 adult cancer patients from 11 sites. Patients had stable background pain and were using Fentanyl-TTS 50-300 μg/h for ATC medication


InterventionsFollowing 2 days of baseline data, 33 patients were assigned to 200 μg of OTFC (as they were using less than 100 μg/h Fentanyl-TTS as ATC medication) and 29 were randomly allocated to 200 or 400 μg OTFC

Patients were then titrated to an effective dose. Maximum of OTFC dose was 1600 μg; the need to increase the dose was randomly ignored one-third of the time


OutcomesPI measured by 11-point categorical rating scale; PR by 5-point VRS and global satisfaction was assessed with 5-point VRS

Results

47 patients were successfully titrated (26 assigned and 22 randomised)

In 4 patients, episodic pain remained uncontrolled with 1600 μg OTFC (1 assigned and 3 randomised)

No significant difference between the assigned and randomised groups with final titration dose

No meaningful relationship between the dose of fentanyl-TTS and the successful dose of OTFC

Non-blinded comparisons with usual rescue medication showed OTFC produced markedly lower PI scores and higher PR scores at 15, 30 and 60 min

Global satisfaction ratings were significantly higher for OTFC than for usual rescue medication (2.6 vs. 2.0; P value = 0.001)

The most common AE possible, probably or almost certainly related to OTFC at all stages of the study were somnolence (18%), nausea (11%), dizziness (10%) and vomiting (5%). Once OTFC had been appropriately titrated, the prevalence was somnolence (11%), nausea (10%) and dizziness (5%). 11 patients withdrew because of AE; including 3 patients where AE were directly related to OTFC. 4 patients required hospitalisation during the study, 1 of which the investigator could not rule out as being possibly related to OTFC


NotesQuality score 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation method not described

Allocation concealment (selection bias)Unclear riskAllocation concealment not described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskThe patient and the study personnel who interacted with the patient were not aware of the dose

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

SizeUnclear risk62 participants

Coluzzi 2001

MethodsMulticentre, randomised, double-blind, double-dummy, multiple-cross-over comparison of NR-morphine versus OTFC


Participants134 adult cancer outpatients from 19 American university- and community-based hospitals and clinics

Patients using an oral opioid equivalent to 60-100 mg oral morphine per day or 50-300 μg/h of Fentanyl-TTS


InterventionsFirst phase was open-label OTFC dose titration to identify successful rescue medication dose

In the double-blind cross-over phase patients were given 10 pre-numbered randomised sets of rescue medication: 5 successful OTFC with 5 placebo NR-morphine and 5 successful NR-morphine, with 5 placebo OTFC


OutcomesPI measured by 11-point NRS rating scale; PR by 5-point VRS and global satisfaction with a 5-point VRS. Use of additional rescue medication was also recorded

Results
93 patients were titrated to a successful OTFC dose, 89 patients used at least 1 set of study medication and 75 patients were treated at least 1 BTP with both OTFC and NR-morphine. No relationship with OTFC and NR-morphine doses or with either OTFC or NR-morphine and ATC medication. PI scores at each time point were lower for OTFC than NR-morphine (P value = 0.033). PI scores for OTFC across all time points were significantly lower than NR-morphine (P value = 0.008) and PR was higher at each time point for OTFC than NR-morphine (P value = 0.009). PI and PR scores for ITT population were similar to efficacy population. Mean GMP rating for OTFC was higher than NR-morphine (P value = 0.001). The percentage of BTP that required additional rescue medication were the same for both OTFC and NR-morphine (P value = 0.54)

Most reported AE were considered unrelated to OTFC, the most frequent were somnolence (20 patients), nausea (18), constipation (14) and dizziness (10) and were generally mild to moderate in intensity. The study design made it difficult to differentiate AE resulting from ATC and rescue opioids. 18 (13%) patients were withdrawn from the study due to an AE, 6 possibly related to OTFC. 1 patient was withdrawn due to a hospitalisation for intractable pain, hallucinations and confusion during the OTFC titration phase of the study, probably related to OTFC


NotesQuality score 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe order in which the patient received treatments was determined by a computer-generated randomisation code

Allocation concealment (selection bias)Unclear riskAllocation concealment not described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe placebo doses for OTFC and MSIR were formulated and packaged identically to the respective active medication

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskMissing primary outcome data were accounted for using imputed scores with the last-observation-carried-forward

SizeUnclear risk134 participants

Fallon 2011

MethodsA double-blind, double-dummy, multiple-cross-over study comparing FPNS versus NR-morphine in breakthrough cancer pain


Participants110 patients experiencing 1-4 episodes daily of BTP while taking ≥ 60 mg/d oral morphine (or equivalent) for background pain, 80 completed titration, 79 completed efficacy phase


InterventionsBaseline data collected on BTP episodes, and use of rescue medication

Open-label titration phase to identify successful dose of FPNS

Efficacy phase where 10 BTP episodes were treated (5 with FPNS and encapsulated oral placebo, 5 with NR-morphine and nasal spray placebo)


OutcomesPrimary: patient-averaged PI difference 15 min after dosing (PID15)

Secondary: PI, PID difference from baseline, SPID, PR, TOTPAR, the percentage of episodes showing clinically meaningful PR (≥ 2 point reduction in PI)

Results

FPNS significantly improved mean SPID from 10 min (P value < 0.05) until 60 min (P value < 0.0001), including the primary endpoint at 30 min (P value < 0.0001)

FPNS significantly improved PI scores as early as 5 min (P value < 0.05); PID from 10 min (P value < 0.01); and PR scores from 10 min (P value < 0.001)

More patients showed a clinically meaningful (≥ 2-point reduction in PI) pain reduction from 10 min onwards (P ≤ 0.01) and 90.6% of the FPNS-treated vs. 80.0% of placebo-treated BTP episodes did not require rescue medication (P value < 0.001)

Approximately 70% of patients were satisfied or very satisfied with the convenience and ease of use of FPNS

5.3% of patients withdrew from treatment due to AE, no significant nasal effects were reported

87% of patients elected to continue open-label treatment post study


NotesQuality score 4 (randomisation method not described)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation method not described

Allocation concealment (selection bias)Unclear riskAllocation concealment not described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskTreatments matched in appearance

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe last-observation-carried-forward was used to input missing data before mean values were calculated for each patient

SizeUnclear risk110 participants

Farrar 1998

MethodsMulticentre, randomised, double-blinded, placebo-controlled trial comparing OTFC versus placebo


Participants130 adult cancer patients from 23 different community and academic cancer centres

Relatively stable background pain requiring at least the equivalent of 60 mg morphine daily or at least 50 μg/h of Fentanyl-TTS


InterventionsOpen-label titration to determine effective dose of OTFC

In the double-blind phase, patients were given 10 sequentially numbered units, 7 contained the successful OTFC dose and 3 were placebo. 93 patients completed open-label titration 92 of which agreed to participate in the second phase


OutcomesPI measured by 11-point NRS rating scale; PR by 5-point VRS and global satisfaction with a 5-point VRS. Use of additional rescue medication was documented

Results

72 patients completed all 10 doses, 2 completed 7 doses, 4 completed 6 doses, 4 completed 5 doses and 8 completed 4 doses or fewer

For all time periods, statistically significant differences were seen for both PI and PR pain for episodes treated with OTFC compared with those treated with placebo (P value < 0.0001)

Global evaluation showed OTFC to be significantly better than placebo (P value < 0.0001)

BTP treated with placebo were significantly more likely to require additional rescue medication than those treated with OTFC (P value < 0.0001)

The more frequent opioid-related AE reported as possibly related to OTFC were dizziness (17%), nausea (14%), somnolence (8%), constipation (5%), asthenia (5%), confusion (4%), vomiting (3%) and pruritus (3%)


NotesQuality score 4 (randomisation method not described)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation method not described

Allocation concealment (selection bias)Unclear riskAllocation concealment not described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe placebo doses were formulated identically (i.e. colour, taste and texture) and packaged identically to the active drug

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskWe used the conservative last occurrence carry forwards method to impute missing values

SizeUnclear risk130 participants

Kress 2009

MethodsA multinational, randomised, double-blind, placebo-controlled, cross-over of INFS for BTP in patients with cancer


Participants120 inpatient or outpatient cancer patients enrolled from pain centres, anaesthesiology departments, palliative care units and oncology clinics on a stable dose of background opioid medication equivalent to 60-500 mg/d of oral morphine or 25-200 μg/h of transdermal fentanyl; 113 randomised, 100 completed double-blind efficacy phase


InterventionsOpen-label titration to determine effective dose of INFS

Randomised to treatment sequences composed of 2 sets of 4 administrations with each set comprising 3 INFS administrations and 1 placebo administration


OutcomesPrimary: PID at 10 min (PID10) 

Secondary: SPID0-60, GI

Results

Use of INFS at all doses was associated with PID10 scores that were significantly higher than those with placebo (2.36, 95% CI 2.16 to 2.56 vs. 1.10, 95% CI 0.84 to 1.36)

Mean PID scores with INFS (pooled doses) were significantly higher compared with those with placebo at 10, 20, 40 and 60 min after administration (all, P value < 0.001) and mean PID scores at 20, 40 and 60 min were significantly higher with each dose of INFS compared with placebo (at all time points, P value < 0.05 for 50 μg vs. placebo and P value < 0.001 for 100 and 200 μg vs. placebo)

Mean PID scores were significantly increased with increases in dose and time after administration with INFS compared with placebo (all, P value < 0.001). SPID60 scores were significantly higher with INFS (pooled doses) than with placebo (3.63 vs. 1.89; adjusted difference, 1.70, 95% CI 1.45 to 1.94; P value < 0.001)

Mean GI scores at 60 min after administration were increased with increasing INFS dose and was significantly higher with INFS (pooled doses) than with placebo (1.88 vs. 0.95; adjusted difference, 0.93, 95% CI 0.77 to 1.08; P value < 0.001)

The proportions of patients who rated GI as good, very good or excellent were 75.4% with INFS (pooled doses) compared with 30.9% with placebo

The prevalence of AE was 22/111 (19.8%) during the efficacy period, during which the most frequently reported were nausea (5 (4.5%)) and vertigo (2 (1.8%)). No serious AE were considered related to the study drugs


NotesQuality score 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation method not described

Allocation concealment (selection bias)Unclear riskAllocation concealment not described

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

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskMissing data were imputed using the last-observation-carried-forward method

SizeUnclear risk120 participants

Lennernäs 2010

MethodsA phase II randomised, double-blind, cross-over study of fentanyl sublingual tablet for BTP in cancer patients


Participants38 adults with locally advanced or metastatic cancer experiencing at least 4 episodes of BTP and taking a fixed-schedule opioid regimen equivalent to 30-1000 mg/d oral morphine or 25-300 µg /h transdermal fentanyl recruited, 23 completed


InterventionsBaseline data collected on BTP episodes, and use of rescue medication

1 dose of placebo or SLF 100, 200 or 400 µg was given to patients in a random order for 4 BTP episodes; treatment periods were separated by a washout period of at least 1 d


OutcomesPrimary: PID from baseline

Secondary: global assessment, need for rescue medication

Results

Overall PID increased significantly with SLF 400 µg versus placebo (8.57 mm, P value < 0.0001). Improvements were statistically different from placebo at 15 min (P value = 0.005)

SLF 100 and 200 µg were not statistically different from placebo (P value = 0.137 and P value = 0.402, respectively)

A dose that gave a clinically important reduction in pain (PID > 20 mm) was identified by 95% of patients

Reduced use of rescue medication (P value < 0.001, SLF 400 µg) and improved global assessment of treatment (P value = 0.0146, SLF 400 µg) confirmed these differences as clinically important

15 AE were reported by 13 patients the most frequent were pain (4 participants) and vomiting (2). 2 events were considered to be study-drug-related (nausea/vomiting and dizziness); both occurred within 30-60 min of administration of SLF 400 μg and were classified as moderate and mild in severity, respectively


NotesQuality score 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskActive treatment or placebo were given to patients in a random order, according to a computer-generated randomisation list

Allocation concealment (selection bias)Low riskThe order in which the treatments were administered was random and unknown to patients and investigators

Blinding of participants and personnel (performance bias)
All outcomes
Low riskAppearance, packaging and labelling of the active and placebo tablets were identical to ensure blinding

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskITT population was analysed using the random-intercept model of analysis

SizeHigh risk38 participants

Mercadante 2007

MethodsA randomised, cross-over, controlled study comparing IV morphine with OTFC given in doses proportional to the background opioid regimen for the management of BTP


ParticipantsA consecutive sample of 105 cancer patients receiving opioids regularly at doses > 60 mg of oral morphine equivalents, 40 enrolled, 25 completed


InterventionsPatients presenting a couple of BTP episodes occurring between 7am and 7pm received IV morphine and OTFC for each couple of BTP events with a washout period between the episodes of at least 6 h

The IV morphine dose was based on the author's previous experience and the OTFC dose based previous studies of OTFC

The IV morphine dose was administered for about 5 min at 20% of the oral daily dose, converted using an equianalgesic ratio of 1/3


OutcomesPrimary: SPID30

Secondary: PID (0-60), PR (0-60), TOTPAR (0-60), % BTP episodes > 33% improvement, % BTP episodes > 50% improvement, % BTP episodes requiring rescue, GMP

Results

53 couples of breakthrough events, each treated with IV morphine and OTFC were recorded

IV morphine decreased PI from a mean of 6.9 to 3.3 and to 1.7 at 15 and 30 min respectively;  a reduction of > 33% in 39 (74%) and in 46 episodes (87%) and > 50% in 29 (55%) and in 40 episodes (75%) at 15 and 30 min, respectively

OTFC decreased PI from a mean of 6.9 to 4.1 and to 2.4 at 15 and 30 min, respectively; a reduction of > 33% in 30 (57%) and 45 episodes (85%) and > 50% in 20 (38%) and in 40 episodes (75%) at 15 and 30 min, respectively

Statistical differences between the 2 treatments were found at 15 min (P value = 0.013), but not at 30 min (P value = 0.059)

The outcome was unrelated to the background medication, and as a consequence to IV morphine and OTFC doses, or differences in age, gender, pain mechanism, time of events or type of opioid used as background analgesic

In most patients, it was not possible to distinguish AE from the study and background opioid. Moderate AE in episodes treated with OTFC were: nausea (4 episodes), drowsiness (7), and confusion (1), and with IV morphine nausea (2), drowsiness (10) and confusion (3). No severe AE were recorded


NotesQuality score 3


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe order of administration was computer-generated to produce equivalent sequence orders

Allocation concealment (selection bias)High riskNot blinded

Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded

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

SizeHigh risk25 participants

Mercadante 2009

MethodsOpen-label, randomised, cross-over comparison of INFS with OTFC for the treatment of breakthrough cancer pain


Participants196 inpatients or outpatients cancer patients enrolled from pain centres, anaesthesiology departments, palliative care units and oncology clinics on a stable dose of background opioid medication equivalent to 60-500 mg/d of oral morphine or 25-200 μg/h of Fentanyl-TTS; 139 randomised, 86 completed


InterventionsBaseline data collected on background PI, BTP episodes and use of rescue medication

A titration phase (up to 5 weeks for INFS and up to 8 weeks for OTFC) using the agreed titration schedule for each drug

An efficacy phase (approximately 2 weeks) when 6 BTP episodes were treated with the identified effective INFS/OTFC doses. Time to onset of meaningful PR, PI and the use of rescue medication were recorded for each episode

Following completion of the titration and efficacy phases with INFS or OTFC, the patient repeated the titration and efficacy phases with the other study drug


OutcomesPrimary: PID at 10 min (PID10) 

Secondary: PI, PID10, PID30, SPID0-30 and SPID0-60, patient's GI, ease of drug administration and patient preference. The relationship between the background opioid doses and the effective BTP doses of INFS was also explored

Results

Among the ITT population (139 participants), median time to onset of meaningful PR was 11 min with INFS vs. 16 min with OTFC; 65.7% of patients attained faster time to 'meaningful' pain-relief onset with INFS (P value < 0.001)

PID was statistically significantly greater for INFS than OTFC from 5 min post dosing. Significantly more INFS-treated BTP episodes achieved clinically important PR (≥ 33% and ≥ 50% PI reduction) up to 30 min post dosing

The proportions of episodes treated with INFS and OTFC achieving a PI reduction of ≥ 33% at 5 min were 25.3% versus 6.8% (P value < 0.001), and at 10 min were 51.0% versus 23.6% (P value < 0.001), respectively; the proportions of episodes treated with INFS and OTFC achieving a ≥ 50% PI reduction at 5 min were 12.8% versus 2.1% (P value < 0.001), and at 10 min were 36.9% versus 9.7% (P value < 0.001), respectively

Higher SPID0-15 and SPID0-60 scores were achieved with INFS (P value < 0.001). More patients preferred INFS than OTFC (P value < 0.001) and more patients found it very easy/easy to use. Both treatments were well tolerated

In the safety population (139 participants), 56.8% (79) of patients experienced ≥ 1 AE during the trial. The only AE that occurred in ≥ 5% of patients in either treatment group was nausea. Among those patients who experienced serious AE (13.7%, 19), none were considered to be related to either study medication

There was a weak correlation between effective INFS doses and background opioid doses


NotesQuality score 3


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPatients were randomised to receive INFS followed by OTFC, or vice versa, using block randomisation stratified by centre

Allocation concealment (selection bias)High riskNot blinded

Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe last value prior to dropping out/taking rescue medication was carried forward

SizeUnclear risk139 participants

Portenoy 1999a

MethodsMulticentre, randomised double-blind dose titration of OTFC


Participants67 adult cancer patients using an oral opioid equivalent to 60-100 mg oral morphine daily


InterventionsBaseline data collected for usual rescue medication

Patients were then randomly allocated to either 200 or 400 μg OTFC and then titrated to a successful dose

The maximum dose of OTFC was 1600 μg; the need to increase the dose was randomly ignored one-third of the time


OutcomesPI measured by 11-point NRS rating scale; PR by 5-point VRS and global satisfaction with a 5-point VRS

Results
67 patients met the eligibility criteria

65 patients began the OTFC titration phase, 32 randomised to 200 μg and 33 to 400 μg

48 patients were successfully titrated

No significant difference was seen in the final OTFC dose in patients randomised to 200 μg compared with those randomised to 400 μg (P value = 0.13)

56% of the total falls in PI occurred in the first 15 min and 78% within 30min

64% of PR occurred within 15 min following use of OTFC and 84% within 30 min

No relationship between the successful dose of OTFC and ATC medication

AE were somnolence, nausea and dizziness


NotesQuality score 4 (randomisation method not described)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation method not described

Allocation concealment (selection bias)Low riskBoth the patient and the investigator were blind to the dose

Blinding of participants and personnel (performance bias)
All outcomes
Low riskAll units were identical in appearance

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

SizeUnclear risk67 participants

Portenoy 2006

MethodsRandomised, placebo-controlled study of FBT for BTP in opioid-treated patients with cancer


Participants139 screened (123 enrolled) adult cancer patients using an oral opioid equivalent to 60-100 mg oral morphine daily


InterventionsOpen-label titration to identify an effective FBT dose

Randomisation to 1 of 18 prespecified dose sequences of 10 tablets (7 FBT and 3 placebo)


OutcomesPrimary: SPID30

Secondary: PID (0-60), PR (0-60), TOTPAR (0-60), % BTP episodes > 33% improvement, % BTP episodes > 50% improvement, % BTP episodes requiring rescue, GMP

Results

65% (80/123) of patients were titrated to an effective dose

493 BTP episodes were treated with FBT and 208 episodes with placebo

Mean (± SE) PID scores and PR scores at each time point were significantly higher for FBT than for placebo

Mean (± SE) SPID and TOTPAR scores (P value < 0.003 at 15 min and P value < 0.0001 for 30, 45 and 60 min)

Mean SPID30 (± SE) was 3.0 ± 0.12 and 1.8 ± 0.18 for FBT and placebo doses, respectively (P value < 0.0001)

A ≥ 33% improvement was seen in more FBT treated episodes than placebo at both 15 and 30 min (P value = 0.045 and P value < 0.0001, respectively)

A ≥ 50% reduction was reported in more FBT treated episodes than placebo (P value = 0.0023)

GMP ratings for FBT were superior to placebo at both 30 and 60 min (P value < 0.0001)

There seemed to be no relationship between effective FBT dose and either the dose of the baseline opioid regimen or the supplemental opioid taken at the start of the study

The most commonly reported AE were those associated with opioid use: nausea, vomiting, dizziness, constipation and somnolence; most of these AE were mild to moderate in severity

4% of patients withdrew from the study as a result of nausea and/or vomiting, and 2% withdrew because of dizziness

2 (2%) patients had application site ulcers of the oral mucosa that were considered by the investigator to be definitely


NotesQuality score 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation method not described

Allocation concealment (selection bias)Low riskPatients and investigators were blinded to the order in which FBT and placebo tablets were taken

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskWe used the last-observation-carried-forward method

SizeUnclear risk123 participants

Portenoy 2010

MethodsA multicentre, placebo-controlled, double-blind, multiple-cross-over study of FPNS in the treatment of breakthrough cancer pain


Participants139 adults with cancer receiving a fixed-schedule opioid regimen at a total daily dose equivalent ≥ 60 mg oral morphine per day for background pain, and had 1-4 episodes of moderate-to-severe BTP per day were screened, 114 titrated, 83 entered efficacy phase, 76 completed


InterventionsBaseline data collected on BTP episodes, and use of rescue medication

Open-label titration phase to identify successful dose of FPNS

Efficacy phase where 10 BTP episodes were treated with this effective dose (7) or placebo (3)


OutcomesPrimary: patient-averaged SPID 30 min after dosing (SPID30)

Secondary: PI, PID, SPID, onset of analgesia, PR, TOTPAR, use of additional rescue medication and clinically meaningful PR

Results

FPNS significantly improved mean SPID from 10 min (P value < 0.05) to 60 min (P value < 0.0001), including the primary endpoint at 30 min (P value < 0.0001)

FPNS significantly improved PI scores as early as 5 min (P value < 0.05); PID from 10 min (P value < 0.01) and PR scores from 10 min (P value < 0.001)

More patients showed a clinically meaningful (≥ 2-point reduction in PI) pain reduction from 10 min onwards (P value ≤ 0.01) and 90.6% of the FPNS-treated vs. 80.0% of placebo-treated BTP episodes did not require rescue medication (P value < 0.001)

Approximately 70% of patients were satisfied or very satisfied with the convenience and ease of use of FPNS

5.3% of patients withdrew from treatment due to AE, no significant nasal effects were reported

87% of patients elected to continue open-label treatment post study


NotesQuality score 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPatients were instructed to use the bottles in the order designated, which was established by a computer-generated schedule of active drug and placebo in a 7:3 ratio

Allocation concealment (selection bias)Low riskThe patient and all personnel involved with the study (including investigators and investigation site personnel) were blinded to the medication codes

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskPatients received separate 'blinded' bottles, each of which contained either FPNS at the effective dose or placebo

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe last-observation-carried-forward method was used to input missing data prior to calculating the mean values for each patient

SizeUnclear risk139 participants

Rauch 2009

MethodsA randomised, placebo-controlled, multicentre, multiple-dose study of fentanyl sublingual tablet in the treatment of breakthrough cancer pain


Participants136 adults with cancer-related pain regularly experiencing 1-4 episodes of BTP daily, while receiving a fixed-schedule oral opioid regimen equivalent to 60-1000 mg oral morphine per day or transdermal fentanyl equivalent to 50-300 µg/h screened, 131 enrolled, 78 successfully titrated, 60 completed efficacy phase


Interventions2-week open-label titration phase

Double-blind efficacy phase, during which patients received 7 fentanyl sublingual tablet or  3 placebo, in a random order


OutcomesPrimary: SPID over 30 min

Secondary: SPID over 60 min, PID, PR, patient overall satisfaction with medication, percentage of responders and the use of rescue medication

Results

Fentanyl sublingual tablet provided significant improvements in SPID relative to placebo at 30 min (49.5 vs. 36.6, P value = 0.0004) and 60 min post administration (143.0 vs. 104.5, P value = 0.0002)

Fentanyl sublingual tablet provided significant improvements in PID and PR compared with placebo, from 10 min post dose (P value = 0.0055 and P value = 0.049 for PID and PR, respectively)

Patient recruitment was stopped early, due to positive interim analysis results (significant at prespecified level, P value ≤ 0.0414)

41 patients experiencing ≥ 1 study-drug-related AE most commonly nausea (12.2%), vomiting (5.3%) and somnolence (4.6%). 1 serious AE (mild affect lability) was considered possibly related to study medication


NotesQuality score 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation method not described

Allocation concealment (selection bias)Unclear riskAllocation concealment not described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo tablets and their packaging were identical in appearance to the matching active treatment

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskEfficacy analyses were conducted using the ITT population

SizeUnclear risk131 participants

Rauch 2010

MethodsA randomised, double-blind, placebo-controlled study of FBSF for BTP in patients with cancer


Participants152 adults with cancer-related pain regularly experiencing 1-4 episodes of BTP daily, while receiving a fixed-schedule oral opioid regimen equivalent to 60-1000 mg oral morphine per day or transdermal fentanyl equivalent to 50-300 μg/h screened, 82 titrated, 70 completed efficacy phase


Interventions1-week screening period followed by an open-label titration period of up to 2 weeks, a double-blind period of up to 2 weeks during which patients received 6 FBSF or 3 placebo, in a random order


OutcomesPrimary: SPID30 determined by the least-squares mean

Secondary: PID and PR calculated at various time points throughout the study period and the SPID were calculated over various intervals. Global satisfaction was assessed on a 5-point scale at the time of rescue or 60 min after study dose

Results

The SPID30 was significantly greater for FBSF-treated episodes of BTP than for placebo-treated episodes (47.9 ± 3.9 vs. 38.1 ± 4.3; P value = 0.004). The SPID values for FBSF-treated episodes were consistently greater compared with placebo-treated episodes at all post-dose time points with a statistically significant separation from placebo starting at 15 min post dose (P value < 0.05) to 60 min post dose (P value < 0.001). PID values for FBSF-treated episodes were consistently greater compared with placebo-treated episodes at 10 min post dose and all time points beyond, with the difference reaching statistical significance at 30 min. The PR values were statistically significant from placebo starting at 30 min post dose (P value < 0.01) and continuing until the last assessment (P value < 0.01). The percentage of episodes with a 33% or 50% decrease in pain was also significantly greater with FBSF than with placebo. Overall satisfaction with the study drug was significantly greater with FBSF than with placebo (mean score 2.0 vs. 1.5, respectively; P value < 0.001). Moreover, more patients rated their overall satisfaction with FBSF as good, very good or excellent compared with placebo

Treatment-emergent AE were reported by 75 patients during the titration period (nausea (9.3%), vomiting (9.3%), somnolence (6.0%), dizziness (4.6%) and headache (4.0%)), and 34 patients during the double-blind period (nausea (9.9%), vomiting (9.9%) and headache (1.2%)). Most AE were not considered to be drug related although 1 patient had 4 AE, where it could not be determined whether they were drug related. 5 patients reported oral AE but considered to be unrelated to FBSF


NotesQuality score 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe order in which the patient received FBSF or placebo was determined by a computer-generated randomisation code

Allocation concealment (selection bias)Unclear riskAllocation concealment not described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskMissing data were handled using last-observation-carried-forward

SizeUnclear risk152 participants

Rauch 2012

MethodsA randomised, double-blind, placebo-controlled study of fentanyl sublingual spray for BTP in patients with cancer


Participants130 adults with no more than moderate cancer-related pain regularly experiencing 1-4 episodes of BTP daily at least partially controlled by supplemental medication equivalent to ≥ 5 mg NR-morphine, while receiving a fixed-schedule oral opioid regimen equivalent to at least 60 mg oral morphine for at least 1 week. 130 enrolled, 98 successfully titrated, 95 completed efficacy phase


InterventionsOpen-label dose titration period followed by a double-blind treatment period, both of up to 26 days, with a follow-up safety assessment 30 days after completion of treatment. During the efficacy period, patients treated 10 episodes of BTP using 7 fentanyl sublingual spray and 3 placebo doses in random order


OutcomesPrimary: SPID30

Secondary: PID and PR calculated at various time points throughout the study period. GMP was assessed on a 5-point scale and patient satisfaction with treatment was assessed by means of the TSQM

Results

Mean SPID30 score was significantly higher with fentanyl sublingual spray than placebo (P value < 0.0001), as was PID, SPID, PR and TOTPAR scores from 5 to 60 min. The use of rescue medication within 60 min of treatment was significantly lower for episodes treated with fentanyl sublingual spray vs. placebo (P value < 0.0001). Patient impression of treatment effectiveness evaluated at 30 and 60 min also favoured fentanyl sublingual spray (P value < 0.0001) as did the TSQM

The most commonly reported AE during titration were nausea (13.0%), somnolence (8.5%), dizziness (7.7%) and vomiting (7.7%) and during the efficacy phase were nausea (7.1%), hyperhidrosis (5.1%) and peripheral oedema (5.1%); the majority were mild or moderate in intensity. Application site irritation occurred in 3 (2.3%) patients during the titration period; this AE led to study discontinuation in 1 patient


NotesQuality score 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe order of the double-blind doses was randomised according to a computer-generated schedule prepared by a contract research organisation

Allocation concealment (selection bias)Low riskAll investigators, study staff and patients remained blinded to treatment allocation throughout the study

Blinding of participants and personnel (performance bias)
All outcomes
Low riskTo maintain blinding, fentanyl sublingual spray and placebo were packaged and labelled identically

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskEfficacy analyses were performed on the ITT population

SizeUnclear risk130 participants

Slatkin 2007

MethodsRandomised, placebo-controlled study of FBT for BTP in opioid-treated patients with cancer


Participants129 patients enrolled (87 randomised) adult cancer patients using an oral opioid equivalent to 60-100 mg oral morphine daily


InterventionsOpen-label titration to identify an effective FBT dose

Randomisation to 1 of 18 prespecified dose sequences of 10 tablets (7 FBT and 3 placebo)


OutcomesPrimary: SPID60

Secondary: PID (0-120), PR (0-120), TOTPAR (0-120), % BTP episodes > 33% improvement, % BTP episodes > 50% improvement, % BTP episodes requiring rescue, GMP

Results

493 episodes of BTP were treated with FBT, 223 episodes with placebo

SPID60 was significantly greater for FBT treated compared with placebo (mean ± SE, 9.7 ± 0.63 vs. 4.9 ± 0.50; P value < 0.0001), irrespective of pain pathophysiology

There was a greater reduction in PI following FBT than placebo at 10 min (0.9 vs. 0.5; P value < 0.0001) that increased up to 90 min and was then maintained for 2 h (P value < 0.0001)

PR was significantly better with FBT than with placebo as early as 10 min (0.815 vs. 0.606; P value < 0.0001); increasing to 90 min and maintained for 2 h (P value < 0.0001)

TOTPAR was significantly better (P value < 0.0001) following FBT than placebo at 60, 90 and 120 min

Supplemental medication was used for 11% of FBT-treated episodes with compared with 30% episodes with placebo

A clinically significant improvement in PI scores from baseline of ≥ 33% and ≥ 50% occurred in a larger proportion of BTP episodes treated with FBT compared with placebo at 10 min (P value = 0.007, P value = 0.033), 15 min (P value < 0.0001, P value < 0.0001), and 30 min (P value < 0.0001, P value < 0.0001), respectively

GMP ratings were better for FBT versus placebo at 60 and 120 min, (P value < 0.0001)

AE were reported by 83 of 125 (66%) patients during the study. In total, 10% of patients (12/125) had AE involving the application site of FBT. Most of the application site AE occurred during the dose-titration phase and were of mild intensity and transitory. 1 patient discontinued the study due to an application-site irritation that was considered mild and related to treatment with the study drug


NotesQuality score 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom assignment of treatment sequences to study patients was computer-generated by a statistician not directly involved in the conduct of the study

Allocation concealment (selection bias)Low riskBoth patients and investigators were blinded to the order in which FBT and placebo

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskMatching placebo tablets

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAll efficacy analyses were performed on the full analysis set

SizeUnclear risk129 participants

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Ashburn 2011All but 1 patient had a non-cancer diagnosis

Cleary 1997Duplicate version

Coluzzi 1997Preliminary report of Coluzzi 2001

Coluzzi 2002Duplicate of Coluzzi 2001

Davies 2011Supplement to Fallon 2011

Hagen 2010Not a randomised controlled trial

Johnson 2010Not breakthrough pain

Pasqualucci 1987Chronic pain not breakthrough pain

Rauch 2011Conference abstract

Rauch 2012bConference abstract

Reynolds 2011Conference abstract

Reynolds 2012Reason for exclusion

Shaiova 2004Radiation-induced oral mucositis

Simmonds 1997Preliminary report of Christie 1998

Stanley 2011Conference abstract

Taylor 2010Supplement to Portenoy 2010

 
Comparison 1. Transmucosal opioid versus placebo

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

 1 Pain intensity difference (PID) at 10 min6988Mean Difference (IV, Fixed, 95% CI)0.39 [0.27, 0.52]

 2 PID at 15 min71076Mean Difference (IV, Fixed, 95% CI)0.49 [0.35, 0.62]

 3 PID at 30 min71076Mean Difference (IV, Fixed, 95% CI)0.92 [0.75, 1.09]

 
Comparison 2. Transmucosal opioid versus oral morphine

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

 1 Pain intensity difference (PID) at 15 min2308Mean Difference (IV, Fixed, 95% CI)0.37 [0.00, 0.73]

 
Comparison 3. Intranasal fentanyl spray (INFS) versus oral transmucosal fentanyl citrate (OTFC)

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

 1 Pain intensity difference (PID) at 10 min1201Mean Difference (IV, Fixed, 95% CI)1.19 [1.15, 1.23]

 2 PID at 15 min1201Mean Difference (IV, Fixed, 95% CI)1.43 [1.38, 1.48]

 
Comparison 4. Oral transmucosal fentanyl citrate (OTFC) versus intravenous morphine (IV-MO)

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

 1 Pain intensity difference (PID) at 15 min150Mean Difference (IV, Fixed, 95% CI)0.80 [-0.00, 1.60]

 
Summary of findings for the main comparison. Transmucosal fentanyl compared with placebo for breakthrough pain in cancer patients

Transmucosal fentanyl compared with placebo for breakthrough pain in cancer patients

Patient or population:

Intervention: transmucosal fentanyl compared with placebo

Comparison: the management of breakthrough pain in cancer patients

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

The management of breakthrough pain in cancer patientsTransmucosal fentanyl compared with placebo

PID

change at 15 min
The change in mean PID change in the interventional group was 0.49 standard deviations lower (0.35 to 0.62)1076

(7 studies)
⊕⊕⊕⊕
high
WMD 0.49 (0.35 to 0.62)

*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; PID: pain intensity difference; RR: risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.