A randomised, double-blind, crossover, dose ranging study to determine the optimal dose of oral opioid to treat breakthrough pain for patients with advanced cancer already established on regular opioids,
Running title: Opioids for breakthrough cancer pain
D C Currow1,2 K Clark3 S Louw4 B Fazekas1,5 A Greene5 C R Sanderson1,6
1 IMPACCT, Faculty of Health, University of Technology Sydney, Ultimo, New South Wales. Australia.
2 Australian national Cancer Symptom Trials Group, University of Technology Sydney, Ultimo, New South Wales, Sydney. Australia.
3 University of Sydney, Northern Clinical School, Royal North Shore Hospital, St Leonard’s.
New South Wales.
4 McCloud Consulting Group, Narabang Way, Belrose, New South Wales, Australia.
5 Southern Adelaide Palliative Services, Goodwood Rd, Daw Park. South Australia.
6
Calvary Health Care Kogarah, Kogarah, New South Wales
Corresponding author:
David C. Currow
IMPACCT, Faculty of Health University of Technology Sydney
P O Box 123, Ultimo, New South Wales. Australia 2007 Phone (02) 9514 4862
Email [email protected]
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This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:
10.1002/ejp.1548
Category: Original article
Funding: This study was funded by discretionary funds at each participating site. The study was an investigator-initiated study with no commercial connections.
Conflict of Interest statement: All authors declare no conflict of interest.
Significance: Despite the widespread use of immediate release morphine solution for breakthrough cancer pain, the ideal dose derived from background dose has not been determined in an adequately powered randomised, double-blind, crossover, dose ranging study. This study tested three dose levels in people with advanced cancer. Given no differences in time to onset, level of analgesia achieved, nor side effects, the lowest dose tested (1/12th of the daily dose) should be used.
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Abstract
Pain in people with advanced cancer is prevalent. When a stable dose of opioids is established, people still experience episodic breakthrough pain for which dosing of an immediate release opioid is usually a proportion of the total daily dose.
This multi-site, double blind, randomised trial tested three dose proportions (1/6, 1/8, 1/12 of total daily dose) in two blocks, each block with three dose proportions in random order (6 numbered bottles in total). When participants required opioid breakthrough doses and it was their first breakthrough dose for that study day, they took the next numbered bottle rather than their usual breakthrough dose. (Subsequent doses on that day reverted to their usual dose.)
Eighty five people were randomised in this study of whom 81 took at least one dose and 73 (90%) took at least block one (one of each dose proportion). No dose was found to be optimal at 30 minutes with approximately one third of participants showing maximal reduction with each dose proportion. Median time to pain relief was 120 minutes. There were no differences in harms: drowsiness, confusion, nausea or vomiting at 30, 60 or 120 minutes.
This adequately powered study did not show any difference with three dose proportions for reduction in pain intensity, time to pain relief, pain control on the subsequent day nor any difference in harms. From first principles, this suggests 1/12 the 24 hourly dose should be used as the lowest dose that delivers benefit. Future studies should include a placebo arm.
Key words: pain, randomised controlled trial, breakthrough pain, immediate release opioids, harms
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Background
Pain remains one of the most prevalent and feared symptoms experienced by patients in palliative care. Approximately 84% of patients with cancer and 67% of patients with non- malignant disease experience pain in the last year of life [Seale and Cartwright, 1994]. In opioid-responsive pain, effective pain management for this population requires identification of a stable regular dose of opioid to achieve adequate pain control while minimising any adverse effects. In addition, the provision of supplemental doses of opioid (“breakthrough” or
“rescue” medication) is recommended to treat episodes of breakthrough pain given their prevalence [Zeppetella et al, 2001] occurring in a person with otherwise largely stable pain [Hanks et al, 2001].
Breakthrough pain is a complex and heterogeneous symptom that may be related to inadequate opioid dosing (end-of-dose failure), incident pain caused by patient activity, associated with a non-volitional precipitant such as voiding or, at times, with no obvious precipitant [Portenoy and Hagen, 1990]. It is typically a transitory flare of pain, in the setting of chronic pain [Portenoy and Hagen, 1990; Caraceni and Portenoy, 1999; Deandrea et al, 2014] although definitions vary widely, leading to very different estimates of prevalence.
[Løhre et al., 2018] The onset of breakthrough pain can be gradual or paroxysmal with variable durations ranging from seconds to hours, occurring infrequently or many times a day [Deandrea et al, 2014]. A survey of patients with cancer found that 50% of patients
experienced breakthrough pain lasting longer than 60 minutes [Bedard et al, 2013]. Patients generally report such pain as distressing and of moderate to severe intensity, with visual analogue scores (VAS) of >50 (0-100mm scale).
Most guidelines recommend regular long-acting opioid preparations for chronic cancer pain at a dose determined by individual titration for efficacy, paired with readily available short- acting preparations of the same opioid agent to be used as required for breakthrough pain [Hanks et al, 2001; Cancer Council Aust, 2016; World Health Organisation 2018].
Breakthrough doses are typically calculated as a fixed proportion of the regular dose [Hanks et al, 2001; Cancer Council Aust, 2016] and suggested ratios vary between one sixth and one twelfth of the total daily regular opioid dose. More recently, studies of oral transmucosal fentanyl suggest that breakthrough opioids should be individually titrated [Mercadante et al, 2009]. Building on this, rapid onset opioids have also been recommended for breakthrough pain [Zeppetella, 2009; Caraceni et al, 2013]. However these formulations are considerably
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more expensive than oral opioids, less easily available, and lack pharmaco-economic evidence of benefit.
As oral opioids continue to be the mainstay of managing breakthrough pain for many situations [Zeppetella, 2009], the lack of evidence to guide clinical practice is problematic, and persists despite interrogation of large pooled datasets [Hagen et al, 2007; Caraceni et al, 2004]. Inappropriate dosing may result in inadequate analgesia or significant adverse events potentially affecting quality of life and compliance with treatment. This study aimed to improve the clinical outcomes of people with opioid responsive pain by defining an optimal oral proportion of the daily dose of regular oral opioid to be prescribed as a breakthrough dose, and gaining a better understanding of the side-effect profile of immediate release opioids in the setting of breakthrough pain.
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Methods
Study design
This multi-centre, double-blind, dose ranging study of oral oxycodone or oral immediate release morphine for breakthrough pain involved participants from palliative care inpatient and community settings. Participants had been stabilised on regular background morphine or oxycodone for opioid-responsive pain (although this did not include Targin), and
breakthrough pain episodes were therefore not attributable to end-of dose failure but could reflect either incident pain or spontaneous events [Portenoy, 1990]. Participants continued to take their regular background opioid during the study. This study tested three dose
proportions (1/6, 1/8, 1/12 of total daily dose) in two blocks, each block with the three dose proportions in random order (6 numbered bottles in total) of the same opioid they were taking regularly. When participants required opioid breakthrough doses and it was their first
breakthrough dose for that study day, they took the next numbered bottle rather than their usual breakthrough dose. (Subsequent doses on that day reverted to their usual dose as prescribed by their physician.)
The study was conducted at six sites in two countries for inpatients and outpatients:
Australia: Southern Adelaide Palliative Services (SAPS) at Repatriation General Hospital and Flinders Medical Centre and Royal Adelaide Hospital, Adelaide; Mater Hospital, Brisbane;
St Vincent’s Hospital / Sacred Heart Hospice, Sydney and Singapore (the National Cancer Centre).
The study was conducted according to Good Clinical Practice and the Declaration of
Helsinki. All participants provided written informed consent before commencing the study.
Participants were identified by their clinical teams as potential participants and recruited by study nurses who were independent of their day-to-day clinical care. The independent ethics committee for each participating centre approved the protocol. The study was registered before the first participant was enrolled with the Australian and New Zealand Clinical Trials Registry (ACTRN12605000366651).
The primary outcome was to determine the optimal dose of opioid for breakthrough pain - the dose with the greatest percentage reduction in Visual Analogue Scale (VAS) pain scores at 30 minutes after administration of the breakthrough dose. The secondary outcomes for this
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study were: pain at 60 and 120 minutes; time from breakthrough dose to pain relief (>20mm reduction on a 0mm-100mm VAS was considered a clinically significant change for an acute exacerbation of chronic pain although there is still debate with a wide range of figures quoted for this [Olsen et al, 2017]); and scores for nausea, vomiting, drowsiness and confusion at 30, 60 and 120 minutes after the study dose. Benefit and harms were combined in order to define the optimal dose of breakthrough opioid as a percentage of the 24 hourly dose.
Participants
Eligible participants had received a stable dose of either long-acting morphine or oxycodone for cancer pain for the four days preceding the screening visit and were able to successfully use breakthrough doses at a dose prescribed according to the usual clinical practice of their prescriber, as demonstrated by having taken at least one breakthrough dose of the same opioid in the last seven days with symptomatic benefit. Participants were required to be English-speaking adults, able to swallow oral medications with modified Australia-modified Karnofsky Performance Status score 30 -100, with a calculated creatinine clearance
>20mL/min, and physically able to complete a pain diary. Participants were ineligible to participate in the study if they experienced confusion with a Mini Mental State examination (MMSE) score of less than 24, had uncontrolled nausea or vomiting, suspected
gastrointestinal obstruction, a known history of hypersensitivity to morphine or oxycodone, or a history of substance misuse.
Study medication
Each morphine dose was supplied in identical 25ml bottles as liquid morphine solution (Ordine ™) 5mg/mL or 10mg/mL diluted to identical volumes or liquid oxycodone solution (OxyNorm ™) 10mg/mL depending on each participant’s background opioid.
Randomisation
The six doses of study opioid were randomised and numbered in sequence. There were two blocks each with one of each of the three dose levels (1/6, 1/8, 1/12 of the total daily dose of background opioid) randomly assigned from a computer generated random number generator.
Only the study pharmacist (who had no patient contact) was aware of the allocation. At no times were patients, caregivers nor clinical staff aware of the allocation. All bottles of breakthrough were identical in size and the volume of liquid that they contained. Block randomisation was performed to minimise the power reduction due to withdrawal from the
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study, as a participant who only completed three doses would still contribute data for each dose level.
All labelled containers were returned to the dispensary of origin for accounting and disposal at the end of the study.
The intervention
Participants continued to take their regular long-acting (‘background’) and breakthrough opioid as needed. However, for the first episode of breakthrough pain on any given study day, participants were asked to take the entire dose from the next mixture bottle in the numbered sequence. If pain was not controlled within two hours, the participant took a dose of their usual breakthrough medication as previously prescribed and continued to use their regular medication for any subsequent episodes of breakthrough pain on the same day.
Upon completing all six study doses, or at the completion of the study at day 28 for each participant, even if all study doses had not been taken, the participant reverted to their pre- study prescribed breakthrough.
Assessments and study procedures
Participants were visited by a study nurse for screening and to provide written, informed consent to participate in the study. The following day (study day 1) eligible participants were visited again and provided with study medication, a pain diary and a Breakthrough
Information Card. Participants were followed up by telephone on days 2, 7, 14 and 21, to check if medications had been taken and to review adverse events. Participants were visited on day 28 or at completion of all six study doses, whichever occurred first, to complete exit data and collect data forms and medication bottles. It was possible for the exit visit to occur on day 6 of the study if a participant required breakthrough medication every day.
At eligibility, the following data were collected: participant age, tumour diagnosis,
medications including form and total dose of regular opioid, other adjuvant medications for pain, other concomitant medications. Pain was assessed using a 0-100mm Visual Analogue scale (VAS) anchored with ‘no pain’ and ‘worst possible pain’ for pain. Functional status was assessed using the Australia-modified Karnofsky Performance Score (AKPS). A serum creatinine concentration from within four weeks of entering the study was required.
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During the study, participants completed a Breakthrough Information Card each time a study medication was taken. The dose number, date and time of dose were recorded. The
following were also recorded at the time the medication was taken, then at 30 minutes, 60 minutes and two hours after the dose: pain relief experienced, and visual analogue scales for pain, nausea, vomiting, drowsiness and confusion. Participants completed a simple pain diary each day of the study to record background information about their daily pain, about any other episodes of breakthrough pain, and any medications taken for these episodes.
Statistical considerations Sample size
The primary outcome was the percentage reduction in pain, measured on a 0mm-100 mm VAS, 30 minutes after the ‘breakthrough’ dose. The null hypothesis was that each dose size was optimal for one-third of participants (assuming complete data for all participants). The alternate hypothesis was that one dose size is optimal for at least 50% of participants and the other two doses are optimal for less than 25% of participants. This was seeking a clinical effect in acute-on-chronic pain of approximately 10mm difference. For 80% power, and a 2- sided test at the 0.05 significance level, the required sample size was 78 participants
completing at least one block (one dose at each of the three levels).
Analysis plan
There was no imputation of missing data. Data for participants who withdrew early was used in the analysis up to the point of their discontinuation. All statistical tests were two-sided tests at the 5% significance level.
All analyses used an intention-to-treat population and included all participants who were randomised and took at least one dose of study medication. Participants’ data were analysed in the randomised dose groups; however, subjects were only included in dose groups for which they received treatment.
The primary efficacy endpoint was analysed using a log linear model (Poisson regression model) of the frequency of participants with each optimal dose size. The model tested the null hypothesis that the proportion of participants with each optimal dose size was the same for each dose group. Secondary analyses included descriptive statistics of the raw values for VAS pain, nausea, vomiting, drowsiness and confusion scores, and change from baseline values by timepoint (30, 60 and 120 minutes) and dose group. Average scores were used for
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participants who took the same level breakthrough dose in each block, so that each participant was only counted once in each dose group.
Change from baseline VAS scores at 30 minutes were modelled using a random effects model for crossover designs. The global association between dose group and change from baseline at 30 minutes was tested using the F-test. Pairwise treatment comparisons of 1/6 versus 1/8, 1/6 versus 1/12 and 1/8 versus 1/12 were tested using paired t-tests if the p-value from the F-test was significant.
The number and percentage of participants who experienced pain relief at each time point were presented by dose group where pain relief for acute-on-chronic pain is defined as a reduction of at least 20 mm on the VAS pain scale [Salaffi et al, 2004]. A Kaplan Meier analysis was performed for time to pain relief.
A post-hoc sensitivity analysis was conducted to exclude participants with a minimum VAS pain score of ≤20 mm at the time a study breakthrough dose was taken given that the primary response was set at a 20mm reduction.
All analyses were performed using SAS version 9.4 or later. The study reporting complies with the CONSORT guidelines for presenting randomized controlled trials [Schulz et al, 2010].
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Results
Participants
Eighty-five participants were assigned a randomised drug sequence, of whom 81 took at least one dose of study treatment (intention-to-treat population). Participants were in the study for a mean 11.3 days (standard deviation (SD) 7.8) with a median 8.0 days (range 1-28). Ninety percent (73 participants) took at least three study doses, and 67% of participants (n=54) took all six doses. Fourteen participants (17%) were taking long-acting morphine as their regular opioid and all other 67 (83%) were taking long-acting oxycodone. (Figure 1) The median daily oral morphine equivalent dose of background opioid (using a 1.33 multiplier adjustment for oxycodone to morphine) was 80mg (range 13mg-1200mg; Table 1). Excluding the one outlier, the mean dose was 103 mg (standard deviation (SD) 79) of morphine equivalent per 24 hours. The trial completed recruitment to its intended cohort.
Efficacy
There was no dose proportion that was found to be optimal: 35.6% (95% confidence interval (95%CI) 24.7%, 47.7%) of participants had most reduction in VAS score from the 1/6 total daily dose, 34.2% (95%CI 23.5%, 46.3%) from the 1/8 dose, and 30.1% (95%CI 19.9%, 42.0%) from the 1/12 dose (p=0.567; Figure 2; Table 2). There was no difference between the dose proportions in change from baseline to 30, 60 nor 120 minutes for VAS pain scores.
(Figure 3) Results for time to pain relief showed a median time to pain relief of 120 minutes (95% CI 60 minutes, infinity) for the one-eighth and one-twelfth daily dose size. The median time to pain relief was not reached for the one-sixth daily dose. The proportion of participants having no change in pain scores from the beginning of the episode that generated the need to take a breakthrough opioid at 30 and 120 minutes decreased from 79% to 52% in the 1/6 proportion group, 82% to 44% in the 1/8 proportion group and 73% to 48% in the 1/12 proportion group.
The sensitivity analysis excluding those with baseline pain score of ≤20mm VAS score at the time the breakthrough dose was taken (n=66 for 1/6 dose, n=67 for 1/8 dose, n=64 for 1/12 dose) also found no significant difference in change in pain score by dose. The mean change in pain score was -13.316.4 for 1/6 proportion, -14.113.9 for 1/8 and -16.616.5 for 1/12 (p=0.845).
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Additionally, there were also no differences in the levels of pain from the daily diaries on the day immediately preceding the day on which a breakthrough dose was taken nor the day after. (Figure 4)
Adverse effects
No differences between the dose proportions in change from baseline in VAS nausea or vomiting were seen. There were statistically significant differences between the three dose groups overall in change from baseline to 30 mins for VAS drowsiness (p=0.044) and confusion (p=0.011). The one eighth group reduced VAS drowsiness and confusion more than the one twelfth dose group, however, the pairwise differences were not statistically different (p=0.087 and 0.076 respectively). In the sensitivity analysis, the overall p values dropped even further for drowsiness and confusion: 0.011 and 0.002 respectively.
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Discussion
From first principles of prescribing, this current study suggests that the lowest dose proportion (1/12) should be used for breakthrough pain when people are stabilised on a background dose of opioid for pain secondary to cancer or its treatments, given that there was no greater benefit from giving a larger dose proportion. No dose proportion of breakthrough opioid tested was found to be superior, whether in terms of greater reduction in pain, shorter time to pain reduction, or lower levels of harms when compared to baseline. Approximately one half of participants received no significant pain relief from breakthrough opioid treatment at any of the dose proportions. This is an important finding in itself as it supports other work which has concluded that a meaningful relationship between the background opioid dose and the successful dose proportion for breakthrough pain does has not yet been demonstrated [Zeppetella and Ribeiro, 2006]. It suggests that the optimal titration strategy is to identify the lowest dose that achieves benefit while prospectively measuring harms of interest
[Zeppetella, 2013]. One previous double-blind study compared immediate release oral morphine solution with oral trans-mucosal fentanyl, but dose titration in that study was done as an open-label run into the study [Coluzzi et al, 2001]. The current study therefore
complements this earlier work, providing blinded data on within-person titration in a randomised study.
While there did not seem not be a relationship with the breakthrough dose proportion calculated as a proportion of the 24 hourly background dose in terms of pain relief, neither did there seem to be a relationship with the dose in terms of adverse effects. It might be expected that adverse effects might differ over time and by dose proportion, however the study accounted for this by examining the effects at three time-points (30, 60 and 120 minutes) and three dose proportions.
Further, the work was limited to morphine and oxycodone and therefore cannot be extrapolated to other opioids.
Breakthrough pain is a prevalent problem for people with cancer pain. Such pain is
heterogeneous in nature (characteristics of the pain, exacerbating factors, temporal patterns) and highly subjective, with higher functional status suggested as one factor associated with more breakthrough pain [Mercadante et al, 2018]. A recent study reported an average daily number of breakthrough pain episodes of 2.4, with mean intensity 75 mm on a 0-100 mm
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VAS and mean duration of 43.3 minutes [Mercadante et al, 2018] although fewer than one third of participants could predict when an episode of breakthrough pain may occur. This incidence was much higher than the episodes of pain seen in this current study although another large study had one third of people taking regular analgesia with no breakthrough pain [Caraceni et al, 2004]. One explanation for this difference is that this study excluded people whose background opioid was being initiated or titrated, and therefore often using breakthrough opioid for end-of-dose failure, as they needed to be on stable doses of opioids.
Mercadante et al., reported the mean time to meaningful pain relief was 16.5 minutes
[Mercadante et al, 2018]. However, what constitutes ‘meaningful’ pain relief varies between studies. Further, the known pharmacokinetics and pharmacodynamics of oral morphine or oxycodone, which are the agents that are used for the majority of breakthrough pains that are unrelated to end-of-dose failure, do not really support the current clinical recommendations.
For oral morphine, peak plasma levels occur 30 to 90 minutes after administration, and although this study used a primary end point of 30 minutes in line with usual practice, the time course of pain relief suggests benefits at 60 minutes are more likely [Davies et al, 2008].
This current study suggests that there is no appreciable dose/response relationship and therefore questions the widespread practice of current dosing recommendations for
breakthrough pain when people are on an established, regular and (largely) effective dose of opioid.
Study strengths
This pragmatic study has explored, in a double blind study for the first time, three dose proportions of breakthrough, immediate release oral opioid formulations to determine prospectively the net effect on breakthrough cancer pain. As a multi-site study, it
encompassed a range of participants in a range of clinical settings with a range of pains. The study objectively measures the net effect of clinical recommendations that are widely used.
Study limitations
This study was limited by the 40 of 81 participants who took at least one breakthrough dose when their pain score was ≤30mm on a 0-100mm VAS, limiting their contribution to the analysis given that their pain scores at the time of taking the breakthrough dose were relatively low. The sensitivity analysis did not show any signal for differences in the subset of participants when these data were excluded.
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Implications for clinical practice
Given that the duration of most breakthrough pain reported in the literature is much shorter than the pharmacological onset of action of immediate release oral opioid formulations used for breakthrough cancer pain, the way that these medications are currently used needs further exploration. How much of the pain relief was caused by the immediate release opioid
medication, and how much was due to regression to the mean (a return to baseline measurements that were going to occur in any case)?
It could be argued that the lack of difference between the three arms in this study show that oral breakthrough analgesics may be equally ineffective for changing the course of pain for most people. Careful evaluation of the time course of breakthrough pain is required in each patient, and any use of breakthrough pain medications needs to be adapted accordingly. Even with careful titration, it may be that for most people, breakthrough pain medication might only produce harmful effects, while pain is subsiding spontaneously due to its natural course.
This study reiterates once more that pain management is a much more complex process than titrating to a pre-determined dose of an opioid. We do not yet understand all the factors that contribute to effective pain management in people with cancer-related pain.
Implications for further research
Definitions and the taxonomy of breakthrough pain have continued to evolve over the life of this study. As definitions are agreed internationally, the characterisation of breakthrough pain will be tighter in future studies.
Conclusion
As others have suggested, this study found no meaningful relationship between the effective dose of breakthrough medication and the background opioid dose for patients with chronic cancer pain. Doses of breakthrough medication should be titrated for each patient based on their individual needs starting at 1/12 the 24 hourly dose to minimize any harms while still delivering the same benefit in relief of pain.
Acknowledgements
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Medical writing services provided by Sophie Gibb, PhD CMPP, from WriteSource Medical were funded by PaCCSC in accordance with Good Publication Practice (GPP3) guidelines (http://ismpp.org/gpp3)
We would like to acknowledge the participants and their caregivers and clinical staff for participating in this study.
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Zeppetella, G. (2013). Evidence-based treatment of cancer-related breakthrough pain with opioids. Journal of National Comprehensive Cancer Network, 11, Suppl 1, S37-43.
Accepted Article
Table 1: Participants’ demographics in a randomized, double-blind, dose ranging study of three different proportions of breakthrough dose calculated from the total daily dose of opioid in patients requiring regular opioid analgesia for cancer pain.
n=81
Age at baseline Mean years (SD) 62.8 (13.3) Gender
Female 33 (40.7%)
Male 47 (58.0%)
Missing 1 (1.2%)
Median daily oral morphine equivalent dose 80mg
Range 13mg-1200mg
Type of Cancer
Breast 14 (17.3%)
Colo-rectal 10 (12.3%)
Lung 14 (17.3%)
Prostate 9 (11.1%)
Other 33 (40.7%)
Missing 1 (1.2%)
AKPS
Median 75
Min, Max 30, 90
AKPS – Australia-modified Karnofsky Performance Status
Accepted Article
Table 2 Optimal Dose Size in people on regular opioid analgesia for cancer pain taking immediate release opioid for breakthrough pain.
1/6 Total Daily (N=77)
1/8 Total Daily (N=78)
1/12 Total Daily (N=78)
p-value
Number of participants who took all 3 dose sizes at least
once 73
Number (%) of participants for whom the dose size is optimal [1]
26 (35.6%) 25 (34.2%) 22 (30.1%) 0.567
95% CI for % (24.7% 47.7%) (23.5%, 46.3%) (19.9%, 42.0%)
Accepted Article
Figure 1 – CONSORT diagram participant flow diagram
*doses were 1/6, 1/8 and 1/12 the total daily dose of opioid Consented n = 85
Block 1 – randomised order of one dose of each of three dose levels* (n=81) n = 73/81 (90%) took all three doses
Block 2 – randomised order of one dose of each of three dose levels* (n = 73)
n = 54/81 (67%) took all six doses Consented but took no medication
after consent
n = 4 14/81 (17%) extended
release morphine;
67/81 (83%) extended release oxycodone
ejp_1548_f1.docx
Accepted Article
ejp_1548_f2.docx
Accepted Article
Figure 3
-25 -20 -15 -10 -5 0
Pain scores after taking 1/6, 1/8 or 1/12 the 24 hourly dose of opioid for breakthrough pain
30 minutes 60 minutes 120 minutes
1/6 1/8 1/12
-3 -2 -1 0 1 2
Drowsiness
30 minutes 60 minutes 120 minutes
1/6 1/8 1/12
-3 -2.5 -2 -1.5 -1 -0.5 0
Vomiting
30 minutes 60 minutes 120minutes
1/6 1/8 1/12
-3 -2.5 -2 -1.5 -1 -0.5 0
Nausea
30 minutes 60 minutes 120 minutes
1/6 1/8 1/12
-3 -2.5 -2 -1.5 -1 -0.5 0
30 minutes 60 minutes 120 minutes Confusion
1/6 1/8 1/12
ejp_1548_f3.docx
Accepted Article
Figure 4
ejp_1548_f4.docx
