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Fentanyl Buccal Tablet vs. Oral Morphine in Doses Proportional to the Basal Opioid Regimen for the Management of Breakthrough Cancer Pain: A Randomized, Crossover, Comparison Study
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Journal of Pain and Symptom Management
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Original Article
Fentanyl Buccal Tablet vs. Oral Morphine in Doses Proportional to the Basal Opioid Regimen for the Management of Breakthrough Cancer Pain: A Randomized, Crossover, Comparison Study Sebastiano Mercadante, MD, Claudio Adile, MD, Arturo Cuomo, MD, Federica Aielli, MD, Andrea Cortegiani, MD, Alessandra Casuccio, BS, and Giampiero Porzio, MD Anesthesia and Intensive Care Unit and Pain Relief and Palliative Care Unit (S.M., C.A.), La Maddalena Cancer Center, Palermo; Anesthesia and Pain Therapy (A.Cu.), National Cancer Institute Pascale, Naples; Department of Biotechnological and Applied Clinical Sciences (F.A., G.P.), University of L’Aquila, L’Aquila; Section of Anesthesia, Analgesia, Intensive Care and Emergency (A.Co.), Department of Biopathology, Medical and Forensic Biotechnologies, Policlinico P. Giaccone, University of Palermo, Palermo; and Department of Experimental Biomedicine and Clinical Neuroscience (A.Ca.), University of Palermo, Palermo, Italy
Abstract Context. Fentanyl products have shown superiority to oral opioids for the management of breakthrough cancer pain (BTcP). However, these studies did not use appropriate patient selection, and drugs have been compared by using different rationales. Objectives. The aim of this randomized, crossover, controlled study was to compare efficacy and safety of fentanyl buccal tablets (FBTs) and oral morphine (OM), given in doses proportional to opioid daily doses. Methods. Cancer patients with pain receiving $60 mg or more of oral morphine equivalents per day and presenting with #3 episodes of BTcP per day were included. In a randomized, crossover manner, patients received FBT or OM at doses proportional to the daily opioid regimen in four consecutive episodes of BTcP. Pain intensity was measured before (T0) and 15 (T15) and 30 minutes (T30), after study drugs. Results. In total, 263 episodes of BTcP were treated. A statistical difference in changes in pain intensityddecrease of $33% and $50%dbetween the two groups was observed at T15 and T30 (P < 0.0005). No severe adverse effects after study drug administration were observed. Conclusion. When used in doses proportional to the basal opioid regimen, FBT showed a clear superiority and was well tolerated when compared with OM during the first 30 minutes, which is the approximate target for a timely intervention required for a BTcP medication. J Pain Symptom Manage 2015;-:-e-. Ó 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. Key Words Cancer pain, breakthrough pain, fentanyl buccal tablet, oral morphine
Introduction Breakthrough cancer pain (BTcP) has been defined as a transitory increase in pain intensity that occurs either spontaneously or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain.1 BTcP is a common problem in patients with cancer Address correspondence to: Sebastiano Mercadante, MD, Anesthesia and Intensive Care Unit and Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, Via san Lorenzo Ó 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.
and is associated with significant morbidity. In a recent report in which a pragmatic definition of BTcP was used,2 the prevalence of BTcP was 75%.3 Oral morphine (OM) has been traditionally offered as a BTcP medication in doses of about 1/6 of the daily opioid regimen, although this approach has never been supported by any evidence.4 Different
312, 90145 Palermo, Italy. E-mail: terapiadeldolore@ lamaddalenanet.it Accepted for publication: May 31, 2015. 0885-3924/$ - see front matter http://dx.doi.org/10.1016/j.jpainsymman.2015.05.016
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technologies have been developed to provide a rapid onset of effect with potent opioid drugs such as fentanyl (rapid onset opioids [ROOs]) delivered by noninvasive routes. It has been suggested that the dose of fentanyl should be individually titrated to enable effective analgesia to be delivered while minimizing the risk of clinically significant adverse effects.2 However, there is no evidence for dose titration as these studies were aimed to demonstrate superiority of ROOs over placebo or OM. 5 The need for dose titration with ROOs has never been appropriately assessed, as evidenced by a series of weaknesses in articles published for regulatory reasons.6,7 Indeed, the only existing study comparing dose titration and proportional doses reported that proportional doses of fentanyl buccal tablets (FBTs) are more effective and safer than a dose titration method, particularly in patients receiving higher doses of opioids for background pain8; this confirms data reported with different fentanyl products, at home, in high doses, and in the elderly.9e14 From a practical point of view, the need to titrate opioid doses for BTcP may make the practical use of ROOs difficult in daily practice, particularly at home or in outpatient setting, and most patients could prefer, in the end, to use OM. 15 All the studies have shown the superiority of the different ROOs over OM. 16e25 NICE guidelines, however, did not provide evidence for that, at least at certain time intervals after administration.26 To scientifically compare ROOs and OM, a similar approach should be used, while using a strict selection of patients, according to a more specific algorithm for a diagnosis of BTcP.3,27,28 The aim of this randomized, crossover, controlled study was to compare the efficacy and safety of FBT and OM, both given in doses proportional to daily opioid doses, for the management of BTcP. The primary outcomes were the changes in pain intensity, and the number of episodes with a decrease in pain intensity of $33% and $50%, recorded 15 and 30 minutes after study medication. The secondary outcome was the number of episodes in which patients reported adverse effects attributed to study medication and the level of satisfaction with the treatments.
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$60 mg oral morphine equivalents (OMEs) per day for background pain, had stable well-controlled pain, with background of mild intensity (#4 on a 0e10 numerical rating scale [NRS]), and had one to three episodes of BTcP per day. Patients with unstable or uncontrolled pain (>4 on a 0e10 NRS) were not eligible for the study. Exclusion criteria also included past inability to tolerate the study drugs, treatment with monoamine oxidase inhibitors, recent antineoplastic treatment, history of alcohol or substance abuse, an expected short survival, and cognitive impairment. Other pharmacologic treatments were maintained if administered for at least two weeks. Patients with relevant problems of the oral mucosa also were not eligible.
Interventions
This was a multicenter, randomized, crossover, controlled study, performed in acute palliative care or pain therapy units. The study was approved by Institutional Review Board of the University of Palermo, and all participating patients provided informed consent.
Consenting patients who met the inclusion criteria were assessed for four consecutive BTcP episodes. Patients were treated according to a routine protocol. After establishing around-the-clock opioid medication according to an opioid titration process and achieving a stable analgesia, with a mean pain intensity #4/10 on a 0e10 NRS for two consecutive days, patients were instructed to call for a BTcP medication when their pain got severe or was clearly distinguishable from their background pain. The study period was three days. Patients randomly received FBT or OM in a crossover design (two episodes for each study drug), in doses proportional to those used for background analgesia for two episodes. For example, the minimal existing dose of 100 mg of FBT or OM 10 mg was given to patients receiving 60 mg of OME; 200 mg of FBT or 20 mg of OM were given to patients receiving 120 mg of OME; 300 mg of FBT or 30 mg of OM were given to patients receiving 180 mg of OME and so on. Intermediate dosing was done with the lower rounded dose. The choice of the doses was based on previous experiences, the availability of FBT and OM, and studies comparing BTcP medications.10,28,29 For example, 100 mg of FBT and 10 mg of OM are commonly suggested for patients receiving 60 mg OME, and the same approach was used for higher doses. For each BTcP episode, nurses recorded pain intensity (0e10 NRS) and severe enough adverse effects intensity to require medical intervention, just before (T0) and 15 minutes (T15) and 30 minutes (T30) after starting the FBT or OM medication. Patients who were not satisfied with the treatment could stop the procedure and ask for their previous effective BTcP medication.
Participants
Outcomes
Adults were eligible if they had a diagnosis of cancer, were receiving opioids at doses that were
The principal outcome was the change in pain intensity of events treated with study medications, and
Methods
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the evaluation of the number of patients who benefited from the use of FBT or OM with a decrease in pain intensity of $33% and $50% at different time intervals. Secondary end points were the patientaveraged summed pain intensity difference 30 minutes after dosing (SPID30), defined as the cumulative sum of the recorded differences between pain intensity and baseline at each time point from 15 to 30 minutes after dose. Moreover, patients who received both treatments were asked about their preference.
Safety and Tolerability Assessment Intensity of adverse effects on a scale from 0 to 3 was recorded at each time interval. The occurrence of adverse effects severe enough in intensity (2e3 on a verbal scale) or requiring a medical intervention was recorded.
Statistical Analysis For treatment allocation, a central computergenerated sequence was used in blocks of four (two for each study drug). Center sites telephoned to be informed about the sequence of drugs for each patient. To achieve the primary end point, a sample size of 65 evaluable patients (considering at least one couple of episodes of BTcP for patient to achieve in total 65 couples of episodes of BTcP) yields a statistical power of 80% with a Type 1 error of 0.05, allowing the detection of a difference of 15% in pain intensity score reduction from baseline of $33% or $50% between two treatment groups with BTcP episodes 15 minutes after study medications. Statistical analysis of quantitative data, including descriptive statistics, was performed for all the items. All continuous data were expressed as mean SD. Frequency analysis was performed using Pearson’s chi-square test and Fisher exact test, as needed. The one-way analysis of variance (ANOVA) and KruskalWallis test were used to compare the different parametric or nonparametric variables between treatment groups. One-way and mixed model ANOVAs were used to examine within- and between-group effects, respectively, at the different time intervals. The possibility of a carryover effect in patients on FBT as their first treatment was assessed by a comparison with patients on OM first by means of an independent t-test. The presence of period effect, residual effect, or the interaction between period and residual effect was analyzed according to the Hills and Armitage test for crossover trials. Data were analyzed using Epi Info, version 3.2.2 (Centers for Disease Control and Prevention, Atlanta, GA), and SPSS, version 21.0 (IBM Corp., Armonk, NY). All P-values were two sided, and P-values less than 0.05 were considered statistically significant.
3
Results A total of 81 patients were screened for the study. Patient characteristics are shown in Table 1. The type of BTcP was available for all 81 patients: idiopathic (n ¼ 53), incident (n ¼ 28), both (n ¼ 0). Participant flow through the study is shown in Fig. 1. Nine patients did not have episodes of BTcP during the study period. Four patients received only one study medication because they had only one episode of BTcP (n ¼ 2) or refused to continue due to adverse effects (n ¼ 1) or inefficacy (n ¼ 1). Sixty-eight patients took both study medications and were included for comparative analysis. Four patients and one patient had two and three episodes of BTcP, respectively, and 63 patients had four episodes. A total of 263 episodes were treated: 132 with FBT and 131 with OM. No differences in the number of episodes treated with the two drugs and age (ANOVA test, P ¼ 0.688), gender (Pearson chi square, P ¼ 0.800), primary diagnosis (Pearson chi square, P ¼ 0.980), doses of opioids used for background analgesia (Pearson chi square, P ¼ 1.0), pain mechanism (Pearson chi square, P ¼ 0.985), and type of BTcP (P ¼ 0.938) were found. The mean SD doses of FBT and OM were 198.7 120 mg and 20.5 11.2 mg, respectively.
Changes in Pain Intensity After Study Medications The changes in pain intensity (on a 0e10 NRS) after FBT and OM at the different time intervals are shown in Table 2. Pain intensity significantly changed with both drugs (P ¼ 0.0005). A statistical difference between the two groups was observed at T15 and T30 (P < 0.0005). There was a pain decrease of $33% in a higher number of episodes treated with FBT in comparison with OM after 15 and 30 minutes (76.5% vs. 32.8%, and 89% vs. 54.9%, respectively). The difference was highly significant (P < 0.0005). Similar differences were found for the decrease in pain intensity Table 1 Patients’ Demographics and Baseline Characteristics Age, yrs, mean (SD) Male, n (%) Karnofsky, mean (SD) Background pain, mean (SD) OME Primary tumor, n (%) Lung/respiratory Gastrointestinal Breast Head and neck Urogenital Pancreas Liver Others OME ¼ oral morphine equivalents in milligram. Sixty-five patients were receiving oral morphine.
62.1 49 57.2 2.6 105.8
(12.3) (60.5) (9.1) (1.1) (57.9)
11 17 9 4 20 8 4 8
(13.6) (21.0) (11.1) (4.9) (24.7) (9.9) (4.9) (9.9)
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Fig. 1. CONSORT flowdiagram.
of $50% after 15 and 30 minutes (52.3% vs. 11.4%, and 75% vs. 45.8%, respectively; Table 3). The mean SD SPID15 of FBT and OM were 3.25 1.6 and 1.44 1.7, whereas the mean SD SPID30 of FBT and OM were 4.4 1.8 and 2.8 2.7, respectively. The difference was highly significant (P < 0.0005) both between times for each treatment and between treatments at each time. No training or residual effect was detected at the end of the crossover trial.
Adverse Effects and Patients’ Preferences The changes in intensity of the principal adverse effects are shown in Table 4. In both groups, an increase in intensity of nausea/vomiting was found at T30, but adverse effects after study drug administration were never severe (2e3 on the verbal scale). No statistical differences between the two groups were found at any time interval. Of patients who received both treatments, 44 and 20 patients preferred FBT and OM, respectively. Four patients did not provide any preference.
Table 2 Changes in Pain Intensity at the Different Time Intervals Drugs FBT (n ¼ 132) OM (n ¼ 131)
T0
T15
T30
7.7 (1.1) 7.7 (1.2)
4.4 (1.3)* 6.1 (1.9)*
3.2 (1.7)*,** 4.7 (2.8)*,**
FBT ¼ fentanyl buccal tablet; OM ¼ oral morphine. Statistical differences between the two groups were at T0, P ¼ 0.889; at T15 and T30, P < 0.0005. *P # 0.0005 vs. T0. **P < 0.0005 vs. T15.
Discussion This comparative study has shown that, when giving drugs for BTcP in doses proportional to the opioid regimen for background pain, FBT was clearly superior for efficacy and rapidity in comparison with OM. The analgesic effect was more intense at both 15 and 30 minutes after study medications were given. A larger number of episodes treated with FBT presented a decrease in pain intensity of $33% and $50% in comparison with episodes treated with OM, and a relevant difference in SPID30 was reported. Adverse effects commonly observed in patients receiving opioids were not severe and did not differ between the treatments, suggesting that the use of proportional doses of both drugs is safe; this reflects what has been found with the long experience with OM.4 Whether 15 minutes is acceptable for achieving pain relief, it has been found that patients are satisfied with a treatment when they achieve about a 50% decrease in pain intensity, something approaching the level of their background pain intensity.30 After 15 minutes, this cutoff was obtained in only 11% of
Table 3 Number of Episodes in the Two Groups With a Decrease of $33% and $50% in Pain Intensity at the Different Time Points Drugs FBT (n ¼ 132) OM (n ¼ 131)
$33% $33%
T15
T30
101* 43
118* 72
FBT ¼ fentanyl buccal tablet; OM ¼ oral morphine *P < 0.0005.
$50% $50%
T15
T30
69* 15
99* 60
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Table 4 Mean Intensity of the Most Common Adverse Effects at the Different Time Intervals FBT Symptoms Nausea/vomiting Drowsiness Confusion
OM
T0
T15
T30
T0
T15
T30
0.01(0.09) 0.14(0.4) 0.07(0.3)
0.03(0.2) 0.16(0.4) 0.05(0.3)
0.14(0.7)* 0.18(0.4) 0.05(0.2)
0.09(0.6) 0.12(0.3) 0.08(0.3)
0.08(0.3) 0.13(0.4) 0.07(0.3)
0.19(0.7)** 0.14(0.4) 0.07(0.3)
FBT ¼ fentanyl buccal tablet; OM ¼ oral morphine. No differences between the groups. *P < 0.05 vs. T0. **P < 0.05 vs. T15.
episodes treated with OM. The number of episodes with such a decrease in pain intensity increased after 30 minutes (45%). However, this cannot be considered a good performance of OM for those with BTcP, as most patients will remain unsatisfied with the treatment. Indeed, FBT produced a decrease of >50% in 52% and 75% of episodes after 15 and 30 minutes, respectively, which translates in the real world to a good analgesic performance. Finally, more than twice the number of subjects who preferred FBT to OM. The differences observed could be explained by the pharmacokinetic differences between the drugs, although differences in the equianalgesic potency of drugs may be an alternative. There are no specific studies confirming equivalencies between oral transmucosal fentanyl preparations and OM. In postoperative studies of opioid-na€ıve patients, it has been calculated that the oral transmucosal fentanyl citrate (OTFC) to intravenous morphine (IVMO) ratio was 1:10e20.28,31 A ratio of about 1:20 was used in a previous study of OTFC and IVMO in cancer patients after preliminary testing,10 also considering that in previous studies the starting dose of OTFC for patients receiving equivalent doses of OM was 200 mg. As with IVMO, which was found to be safe in several observational studies,9,11e13 OTFC doses did not exceed 20% of patients’ around-the-clock medication, which should be at least 60 mg of OM. Similarly, the minimal FBT strength is 100 mg, with about double the fentanyl availability in comparison with OTFC. In the case of FBT, we can argue that about 65% of the FBT dose is available for the treatment of BTcP (about 65 mg) and 3.5 mg of OM will be available (about 30% of the total oral dose because of the first-pass effect), with a ratio of about 1:20. The choice of the dose also was based on a presumed equivalency, given that 100 mg of FBT and 10 mg of OM are commonly suggested for patients receiving 60 mg or OMEs. Regardless of the equivalency problems, both drugs were safe when administered in doses proportional to the basal opioid regimen. Previous studies have shown that ROOs provide faster analgesia than placebo and oral opioids. In the case
of FBT, there are several studies that have shown that FBT was efficacious, well tolerated and demonstrated rapid onset of analgesia in comparison with placebo.19e22 However, several limitations biased the results, which seem to be inferior to those expected in terms of efficacy. They include unclear distinction between background pain intensity and BTcP intensity, and the high number of patients who failed dose titration. FBT also was compared with oral opioids.23 In a randomized, double-blind, double-dummy comparison study with oral oxycodone, the differences in the decrease of pain intensity after 15 and 30 minutes, 0.22e0.33 points on NRS, respectively, although significant, were clinically negligible because they were largely less of one point. After 15 and 30 minutes, meaningful pain relief was observed in 16% and 45%, respectively, of episodes treated with FBT; at the same time intervals, only in 13% and 41% of episodes was there a pain decrease $33% and $50%, respectively. After dose titration, 81% reached a successful oxycodone dose, and such doses were greater than the prestudy oxycodone doses, considered to be effective. Although no linear relationship was observed between successful doses achieved during the titration phase for FBT and oral oxycodone and the basal opioid regimen, the mean doses of oxycodone or FBT were about 1/6 of the background opioid doses (relatively proportional, as those used in the present study). Moreover, as with other ROOs studies, well-controlled pain was defined as having moderate pain (#6 on an 11-point NRS), and about 30% did not achieve a successful dose. Thus, the interpretation of these results may be altered because of the variability of each single episode in patients with pain that was not well controlled, also reflecting the minimal but clinically negligible advantage of FBT over oral oxycodone. Other studies of FBT showed the same limitations, including the minimal clinical impact (less than one point reduction in pain intensity) after FBT in comparison with placebo or oral opioids and the recruitment of patients with relatively high levels of background pain intensity.19e23
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These data justify the concerns raised by the NICE guidelines, which did not provide evidence to suggest that fentanyl products were more effective than OM for the management of BTcP.26 This statement was based on a nonrelevant decrease in pain intensity at the same time intervals; 45e60 minutes after administration, there are no significant differences. However, BTcP duration is often time limited, and as most episodes auto-resolve, oral opioids are expected to provide some pain relief after 30e 45 minutes.32,33 Differences are unlikely to be found at these intervals, when most episodes vanish spontaneously. Therefore, these time intervals are not useful to settle the question and should be focused on the first 15e30 minutes. It has been reported that a decrease in pain intensity of $33% represents a moderate improvement and $50% represents a substantial improvement. Alternately, a two-point difference may have a clinical meaning.34e36 By using proportional doses of both study drugs, the number-needed-to-treat with FBT at 15 and 30 minutes was 1.9 and 1.3, respectively. This outcome represents a relevant analgesic performance in comparison to OM, which produced a number-neededto-treat of 8.7 and 2.18 at the same time intervals. As outlined by NICE guidelines, these changes in pain intensity may justify the use of more expensive drugs. It seems clear that the definition of effective dose after dose titration does not correspond to pain measurement performed in the subsequent controlled phases, and that a dose proportional to the opioid basal regimen is able to cover the variability of BTcP in most cases, providing better efficacy in comparison with the titration method. For instance, the only existing controlled study, performed with FBT, has shown that proportional doses are more effective than the dose titration approach, without higher risks of adverse effects,8 confirming a series of open-label studies in which proportional doses were highly effective and well tolerated.9e14,37e39 Most studies of BTcP medications have suggested to titrate the dose of ROOs.2 However, these randomized trials have never specifically examined this issue, and the information gathered is just consequential to the study design aimed to demonstrate superiority of ROOs over placebo or oral opioids. Moreover, the lack of a clear distinction between background pain intensity (mild to moderate) and BTcP intensity (moderate to severe) strongly biased the results, which were in any case inferior to those expected. Indeed, more recently, a more detailed definition has been provided: Background pain should be none or mild, and BTcP should be severe or clearly distinguishable from background pain.3,27,29,30,40
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Doses proportional to the basal opioid regimen have been proposed as an alternative to dose titration,6,7 based on meaningful considerations, including the level of opioid tolerance. Of interest, by simulating the calculation of doses of opioids used for background analgesia and those achieved after individual titration, the mean values of proportional doses were quite similar to those found after titration.7 In a clinical scenario, the dose of the oral opioid used as a rescue medication was 18% of the around-the-clock opioid dose. When using an ROO, the effective dose found after dose titration was about 35% of the around-the-clock dose.33 In a recent controlled study, two different nasal fentanyl products, given in doses proportional to the basal opioid regimen, were similarly effective and safe.39 Limitations of this study include the lack of blinding or double-dummy technique. However, such types of studies are complex and require economic support from the pharmaceutical industry, which was not involved in this case. The study also was designed to assess the patients’ preference. Finally, incomplete data are common in such kinds of studies. However, the number of the ‘‘couples’’ of episodes with both treatments was adequate. In conclusion, when used in doses proportional to the basal opioid regimen, FBT showed a clear superiority over OM in the first 30 minutes, the approximate target for a timely intervention required for a BTcP medication. Both treatments were well tolerated, and adverse effects were minimal. More studies with other fentanyl products should be performed to confirm these findings.
Disclosures and Acknowledgments No funding was received for this study and the authors declare no conflicts of interest.
References 1. Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain 1999;81:129e134. 2. Davies A, Dickman A, Reid C, Stevens A, Zeppetella J. The management of cancer-related breakthrough pain: recommendations of a task group of the Association of Palliative Medicine of Great Britain and Ireland. Eur J Pain 2009;13:331e338. 3. Mercadante S, Valle A, Porzio G, et al. Relationship between background cancer pain, breakthrough pain, and analgesic treatment: a preliminary study for a better interpretation of epidemiological and clinical studies. Curr Med Res Opin 2013;29:667e671.
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4. Hanks GW, de Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 2001;84:587e593. 5. Mercadante S. Breakthrough pain: on the road again. Eur J Pain 2009;13:329e330. 6. Mercadante S. Rapid onset opioids for breakthrough pain. Titrating or not titrating, this is the question? Eur J Pain 2011;5:443e448. 7. Mercadante S. The use of rapid onset opioids for breakthrough cancer pain: the challenge of its dosing. Crit Rev Oncol Hematol 2011;80:460e465. 8. Mercadante S, Gatti A, Porzio G, et al. Dosing fentanyl buccal tablet for breakthrough cancer pain: dose titration versus proportional doses. Curr Med Res Opin 2012;28: 963e968. 9. Mercadante S, Villari P, Ferrera P, et al. Safety and effectiveness of intravenous morphine for episodic breakthrough pain in patients receiving transdermal buprenorphine. J Pain Symptom Manage 2006;32:175e179. 10. Mercadante S, Villari P, Ferrera P, et al. Transmucosal fentanyl vs intravenous morphine in doses proportional to basal opioid regimen for episodic-breakthrough pain. Br J Cancer 2007;96:1828e1833. 11. Mercadante S, Intravaia G, Villari P, et al. Intravenous morphine for breakthrough (episodic-) pain in an acute palliative care unit: a confirmatory study. J Pain Symptom Manage 2008;35:307e313. 12. Mercadante S, Villari P, Ferrera P, Bianchi M, Casuccio A. Safety and effectiveness of intravenous morphine for episodic (breakthrough) pain using a fixed ratio with the oral daily morphine dose. J Pain Symptom Manage 2004;27:352e359. 13. Mercadante S, Villari P, Ferrera P, Mangione S, Casuccio A. The use of opioids for breakthrough pain in acute palliative care unit by using doses proportional to opioid basal regimen. Clin J Pain 2010;26:306e309. 14. Mercadante S, Ferrera P, Adile C, Casuccio A. Fentanyl buccal tablets for breakthrough pain in highly tolerant cancer patients: preliminary data on the proportionality between breakthrough pain dose and background dose. J Pain Symptom Manage 2011;42:464e469. 15. Davies AN, Vriens J, Kennett A, McTaggart M. An observational study of oncology patients’ utilization of breakthrough pain medication. J Pain Symptom Manage 2008; 35:406e411. 16. Coluzzi PH, Schwartzberg L, Conroy JD, et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain 2001;91:123e130. 17. Davies A, Sitte T, Elsner F, et al. Consistency of efficacy, patient acceptability, and nasal tolerability of fentanyl pectin nasal spray compared with immediate-release morphine sulfate in breakthrough cancer pain. J Pain Symptom Manage 2011;41:358e366. 18. Fallon M, Reale C, Davies A, et al. Efficacy and safety of fentanyl pectin nasal spray compared with immediate-release morphine sulfate tablets in the treatment of breakthrough cancer pain: a multicenter, randomized, controlled, double-blind, double-dummy multiple-crossover study. J Support Oncol 2011;9:224e231.
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19. Kosugi T, Hamada S, Takigawa C, et al. A randomized, double-blind, placebo-controlled study of fentanyl buccal tablets for breakthrough pain: efficacy and safety in Japanese cancer patients. J Pain Symptom Manage 2014;47:990e1000. 20. Portenoy RK, Taylor D, Messina J, Tremmel L. A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clin J Pain 2006;22:805e811. 21. Slatkin NE, Xie F, Messina J, Segal TJ. Fentanyl buccal tablet for relief of breakthrough pain in opioid-tolerant patients with cancer-related chronic pain. J Support Oncol 2007;5:327e334. 22. Webster LR, Slevin KA, Narayana A, Earl CQ, Yang R. Fentanyl buccal tablet compared with immediate-release oxycodone for the management of breakthrough pain in opioid-tolerant patients with chronic cancer and noncancer pain: a randomized, double-blind, crossover study followed by a 12-week open-label phase to evaluate patient outcomes. Pain Med 2013;14:1332e1345. 23. Ashburn M, Slevin K, Messina J, Xie F. The efficacy and safety of fentanyl buccal tablet compared with immediaterelease oxycodone for the management of breakthrough pain in opioid-tolerant patients with chronic pain. Anesth Analg 2011;112:693e702. 24. Jandhyala R, Fullarton JR, Bennett MI. Efficacy of rapidonset oral fentanyl formulations vs. oral morphine for cancer-related breakthrough pain: a meta-analysis of comparative trials. J Pain Symptom Manage 2013;46: 573e580. 25. Zeppetella G, Davies A, Eijgelshoven I, Jansen JP. Network meta-analysis of the efficacy of opioid analgesics for the management of breakthrough cancer pain episodes. J Pain Symptom Manage 2014;47:772e785. 26. Available at: www.nice.org.uk/cg140. Accessed May 2014. 27. Davies A, Zeppetella G, Andersen S, et al. Multicentre European study of breakthrough cancer pain: characteristics and patient perceptions of current and potential management strategies. Eur J Pain 2011;15:756e763. 28. Lichtor J, Sevarino F, Joshi G, et al. The relative potency of oral transmucosal fentanyl citrate compared with intravenous morphine in the treatment of moderate to severe postoperative pain. Anesth Analg 1999;89:732e738. 29. Davies A, Buchanan A, Zeppetella G, et al. Breakthrough cancer pain: an observational study of 1000 European oncology patients. J Pain Symptom Manage 2013;46: 619e628. 30. Mercadante S, Adile C, Torta R, et al. Meaningful cut-off pain intensity for breakthrough pain changes in advanced cancer patients. Curr Med Res Opin 2013;29:93e97. 31. Lu JK, Bailey PL. Dose-related respiratory pharmacology of oral transmucosal fentanyl citrate (OTFC) versus intravenous morphine: a randomized, double-blind, doubledummy study. Anesthesiology 2003;99:A967. 32. Zeppetella G. Dynamics of breakthrough pain vs. pharmacokinetics of oral morphine: implications for management. Eur J Cancer Care 2009;18:331e337. 33. Zeppetella GB. Opioids for cancer breakthrough pain: a pilot study reporting patient assessment of time to meaningful pain relief. J Pain Symptom Manage 2008;35:563e567.
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34. Farrar J, Polomano R, Berlin J, Strom B. A comparison of change in the 0-10 numeric rating scale to a pain relief scale and global medication performance scale in a shortterm clinical trial of breakthrough pain intensity. Anesthesiology 2010;11:1464e1472. 35. Farrar J, Portenoy RK, Berlin J, Kinman J, Strom B. Defining the clinically important difference in pain out come measure. Pain 2000;88:287e294. 36. Farrar J, Young J, LaMoreaux L, Werth J, Poole M. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001;94:149e158. 37. Mercadante S, Prestia G, Casuccio A. The use of sublingual fentanyl for breakthrough pain by using doses
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proportional to opioid basal regimen. Curr Med Res Opin 2013;29:1527e1532. 38. Mercadante S, Porzio G, Aielli F, et al. The use of fentanyl buccal tablets for breakthrough pain by using doses proportional to opioid basal regimen in a home care setting. Support Care Cancer 2013;21:2335e2339. 39. Mercadante S, Prestia G, Adile C, Casuccio A. Intranasal fentanyl versus fentanyl pectin nasal spray for the management of breakthrough cancer pain in doses proportional to basal opioid regimen. J Pain 2014;15:602e607. 40. Mercadante S, Lazzari M, Reale C, et al. IOPS Study Group. Italian Oncological Pain Survey (IOPS): a multicentre Italian study of breakthrough pain performed in different settings. Clin J Pain 2015;31:214e221.
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Original Article
Fentanyl Buccal Tablet vs. Oral Morphine in Doses Proportional to the Basal Opioid Regimen for the Management of Breakthrough Cancer Pain: A Randomized, Crossover, Comparison Study Sebastiano Mercadante, MD, Claudio Adile, MD, Arturo Cuomo, MD, Federica Aielli, MD, Andrea Cortegiani, MD, Alessandra Casuccio, BS, and Giampiero Porzio, MD Anesthesia and Intensive Care Unit and Pain Relief and Palliative Care Unit (S.M., C.A.), La Maddalena Cancer Center, Palermo; Anesthesia and Pain Therapy (A.Cu.), National Cancer Institute Pascale, Naples; Department of Biotechnological and Applied Clinical Sciences (F.A., G.P.), University of L’Aquila, L’Aquila; Section of Anesthesia, Analgesia, Intensive Care and Emergency (A.Co.), Department of Biopathology, Medical and Forensic Biotechnologies, Policlinico P. Giaccone, University of Palermo, Palermo; and Department of Experimental Biomedicine and Clinical Neuroscience (A.Ca.), University of Palermo, Palermo, Italy
Abstract Context. Fentanyl products have shown superiority to oral opioids for the management of breakthrough cancer pain (BTcP). However, these studies did not use appropriate patient selection, and drugs have been compared by using different rationales. Objectives. The aim of this randomized, crossover, controlled study was to compare efficacy and safety of fentanyl buccal tablets (FBTs) and oral morphine (OM), given in doses proportional to opioid daily doses. Methods. Cancer patients with pain receiving $60 mg or more of oral morphine equivalents per day and presenting with #3 episodes of BTcP per day were included. In a randomized, crossover manner, patients received FBT or OM at doses proportional to the daily opioid regimen in four consecutive episodes of BTcP. Pain intensity was measured before (T0) and 15 (T15) and 30 minutes (T30), after study drugs. Results. In total, 263 episodes of BTcP were treated. A statistical difference in changes in pain intensityddecrease of $33% and $50%dbetween the two groups was observed at T15 and T30 (P < 0.0005). No severe adverse effects after study drug administration were observed. Conclusion. When used in doses proportional to the basal opioid regimen, FBT showed a clear superiority and was well tolerated when compared with OM during the first 30 minutes, which is the approximate target for a timely intervention required for a BTcP medication. J Pain Symptom Manage 2015;-:-e-. Ó 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. Key Words Cancer pain, breakthrough pain, fentanyl buccal tablet, oral morphine
Introduction Breakthrough cancer pain (BTcP) has been defined as a transitory increase in pain intensity that occurs either spontaneously or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain.1 BTcP is a common problem in patients with cancer Address correspondence to: Sebastiano Mercadante, MD, Anesthesia and Intensive Care Unit and Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, Via san Lorenzo Ó 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.
and is associated with significant morbidity. In a recent report in which a pragmatic definition of BTcP was used,2 the prevalence of BTcP was 75%.3 Oral morphine (OM) has been traditionally offered as a BTcP medication in doses of about 1/6 of the daily opioid regimen, although this approach has never been supported by any evidence.4 Different
312, 90145 Palermo, Italy. E-mail: terapiadeldolore@ lamaddalenanet.it Accepted for publication: May 31, 2015. 0885-3924/$ - see front matter http://dx.doi.org/10.1016/j.jpainsymman.2015.05.016
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technologies have been developed to provide a rapid onset of effect with potent opioid drugs such as fentanyl (rapid onset opioids [ROOs]) delivered by noninvasive routes. It has been suggested that the dose of fentanyl should be individually titrated to enable effective analgesia to be delivered while minimizing the risk of clinically significant adverse effects.2 However, there is no evidence for dose titration as these studies were aimed to demonstrate superiority of ROOs over placebo or OM. 5 The need for dose titration with ROOs has never been appropriately assessed, as evidenced by a series of weaknesses in articles published for regulatory reasons.6,7 Indeed, the only existing study comparing dose titration and proportional doses reported that proportional doses of fentanyl buccal tablets (FBTs) are more effective and safer than a dose titration method, particularly in patients receiving higher doses of opioids for background pain8; this confirms data reported with different fentanyl products, at home, in high doses, and in the elderly.9e14 From a practical point of view, the need to titrate opioid doses for BTcP may make the practical use of ROOs difficult in daily practice, particularly at home or in outpatient setting, and most patients could prefer, in the end, to use OM. 15 All the studies have shown the superiority of the different ROOs over OM. 16e25 NICE guidelines, however, did not provide evidence for that, at least at certain time intervals after administration.26 To scientifically compare ROOs and OM, a similar approach should be used, while using a strict selection of patients, according to a more specific algorithm for a diagnosis of BTcP.3,27,28 The aim of this randomized, crossover, controlled study was to compare the efficacy and safety of FBT and OM, both given in doses proportional to daily opioid doses, for the management of BTcP. The primary outcomes were the changes in pain intensity, and the number of episodes with a decrease in pain intensity of $33% and $50%, recorded 15 and 30 minutes after study medication. The secondary outcome was the number of episodes in which patients reported adverse effects attributed to study medication and the level of satisfaction with the treatments.
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$60 mg oral morphine equivalents (OMEs) per day for background pain, had stable well-controlled pain, with background of mild intensity (#4 on a 0e10 numerical rating scale [NRS]), and had one to three episodes of BTcP per day. Patients with unstable or uncontrolled pain (>4 on a 0e10 NRS) were not eligible for the study. Exclusion criteria also included past inability to tolerate the study drugs, treatment with monoamine oxidase inhibitors, recent antineoplastic treatment, history of alcohol or substance abuse, an expected short survival, and cognitive impairment. Other pharmacologic treatments were maintained if administered for at least two weeks. Patients with relevant problems of the oral mucosa also were not eligible.
Interventions
This was a multicenter, randomized, crossover, controlled study, performed in acute palliative care or pain therapy units. The study was approved by Institutional Review Board of the University of Palermo, and all participating patients provided informed consent.
Consenting patients who met the inclusion criteria were assessed for four consecutive BTcP episodes. Patients were treated according to a routine protocol. After establishing around-the-clock opioid medication according to an opioid titration process and achieving a stable analgesia, with a mean pain intensity #4/10 on a 0e10 NRS for two consecutive days, patients were instructed to call for a BTcP medication when their pain got severe or was clearly distinguishable from their background pain. The study period was three days. Patients randomly received FBT or OM in a crossover design (two episodes for each study drug), in doses proportional to those used for background analgesia for two episodes. For example, the minimal existing dose of 100 mg of FBT or OM 10 mg was given to patients receiving 60 mg of OME; 200 mg of FBT or 20 mg of OM were given to patients receiving 120 mg of OME; 300 mg of FBT or 30 mg of OM were given to patients receiving 180 mg of OME and so on. Intermediate dosing was done with the lower rounded dose. The choice of the doses was based on previous experiences, the availability of FBT and OM, and studies comparing BTcP medications.10,28,29 For example, 100 mg of FBT and 10 mg of OM are commonly suggested for patients receiving 60 mg OME, and the same approach was used for higher doses. For each BTcP episode, nurses recorded pain intensity (0e10 NRS) and severe enough adverse effects intensity to require medical intervention, just before (T0) and 15 minutes (T15) and 30 minutes (T30) after starting the FBT or OM medication. Patients who were not satisfied with the treatment could stop the procedure and ask for their previous effective BTcP medication.
Participants
Outcomes
Adults were eligible if they had a diagnosis of cancer, were receiving opioids at doses that were
The principal outcome was the change in pain intensity of events treated with study medications, and
Methods
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the evaluation of the number of patients who benefited from the use of FBT or OM with a decrease in pain intensity of $33% and $50% at different time intervals. Secondary end points were the patientaveraged summed pain intensity difference 30 minutes after dosing (SPID30), defined as the cumulative sum of the recorded differences between pain intensity and baseline at each time point from 15 to 30 minutes after dose. Moreover, patients who received both treatments were asked about their preference.
Safety and Tolerability Assessment Intensity of adverse effects on a scale from 0 to 3 was recorded at each time interval. The occurrence of adverse effects severe enough in intensity (2e3 on a verbal scale) or requiring a medical intervention was recorded.
Statistical Analysis For treatment allocation, a central computergenerated sequence was used in blocks of four (two for each study drug). Center sites telephoned to be informed about the sequence of drugs for each patient. To achieve the primary end point, a sample size of 65 evaluable patients (considering at least one couple of episodes of BTcP for patient to achieve in total 65 couples of episodes of BTcP) yields a statistical power of 80% with a Type 1 error of 0.05, allowing the detection of a difference of 15% in pain intensity score reduction from baseline of $33% or $50% between two treatment groups with BTcP episodes 15 minutes after study medications. Statistical analysis of quantitative data, including descriptive statistics, was performed for all the items. All continuous data were expressed as mean SD. Frequency analysis was performed using Pearson’s chi-square test and Fisher exact test, as needed. The one-way analysis of variance (ANOVA) and KruskalWallis test were used to compare the different parametric or nonparametric variables between treatment groups. One-way and mixed model ANOVAs were used to examine within- and between-group effects, respectively, at the different time intervals. The possibility of a carryover effect in patients on FBT as their first treatment was assessed by a comparison with patients on OM first by means of an independent t-test. The presence of period effect, residual effect, or the interaction between period and residual effect was analyzed according to the Hills and Armitage test for crossover trials. Data were analyzed using Epi Info, version 3.2.2 (Centers for Disease Control and Prevention, Atlanta, GA), and SPSS, version 21.0 (IBM Corp., Armonk, NY). All P-values were two sided, and P-values less than 0.05 were considered statistically significant.
3
Results A total of 81 patients were screened for the study. Patient characteristics are shown in Table 1. The type of BTcP was available for all 81 patients: idiopathic (n ¼ 53), incident (n ¼ 28), both (n ¼ 0). Participant flow through the study is shown in Fig. 1. Nine patients did not have episodes of BTcP during the study period. Four patients received only one study medication because they had only one episode of BTcP (n ¼ 2) or refused to continue due to adverse effects (n ¼ 1) or inefficacy (n ¼ 1). Sixty-eight patients took both study medications and were included for comparative analysis. Four patients and one patient had two and three episodes of BTcP, respectively, and 63 patients had four episodes. A total of 263 episodes were treated: 132 with FBT and 131 with OM. No differences in the number of episodes treated with the two drugs and age (ANOVA test, P ¼ 0.688), gender (Pearson chi square, P ¼ 0.800), primary diagnosis (Pearson chi square, P ¼ 0.980), doses of opioids used for background analgesia (Pearson chi square, P ¼ 1.0), pain mechanism (Pearson chi square, P ¼ 0.985), and type of BTcP (P ¼ 0.938) were found. The mean SD doses of FBT and OM were 198.7 120 mg and 20.5 11.2 mg, respectively.
Changes in Pain Intensity After Study Medications The changes in pain intensity (on a 0e10 NRS) after FBT and OM at the different time intervals are shown in Table 2. Pain intensity significantly changed with both drugs (P ¼ 0.0005). A statistical difference between the two groups was observed at T15 and T30 (P < 0.0005). There was a pain decrease of $33% in a higher number of episodes treated with FBT in comparison with OM after 15 and 30 minutes (76.5% vs. 32.8%, and 89% vs. 54.9%, respectively). The difference was highly significant (P < 0.0005). Similar differences were found for the decrease in pain intensity Table 1 Patients’ Demographics and Baseline Characteristics Age, yrs, mean (SD) Male, n (%) Karnofsky, mean (SD) Background pain, mean (SD) OME Primary tumor, n (%) Lung/respiratory Gastrointestinal Breast Head and neck Urogenital Pancreas Liver Others OME ¼ oral morphine equivalents in milligram. Sixty-five patients were receiving oral morphine.
62.1 49 57.2 2.6 105.8
(12.3) (60.5) (9.1) (1.1) (57.9)
11 17 9 4 20 8 4 8
(13.6) (21.0) (11.1) (4.9) (24.7) (9.9) (4.9) (9.9)
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Fig. 1. CONSORT flowdiagram.
of $50% after 15 and 30 minutes (52.3% vs. 11.4%, and 75% vs. 45.8%, respectively; Table 3). The mean SD SPID15 of FBT and OM were 3.25 1.6 and 1.44 1.7, whereas the mean SD SPID30 of FBT and OM were 4.4 1.8 and 2.8 2.7, respectively. The difference was highly significant (P < 0.0005) both between times for each treatment and between treatments at each time. No training or residual effect was detected at the end of the crossover trial.
Adverse Effects and Patients’ Preferences The changes in intensity of the principal adverse effects are shown in Table 4. In both groups, an increase in intensity of nausea/vomiting was found at T30, but adverse effects after study drug administration were never severe (2e3 on the verbal scale). No statistical differences between the two groups were found at any time interval. Of patients who received both treatments, 44 and 20 patients preferred FBT and OM, respectively. Four patients did not provide any preference.
Table 2 Changes in Pain Intensity at the Different Time Intervals Drugs FBT (n ¼ 132) OM (n ¼ 131)
T0
T15
T30
7.7 (1.1) 7.7 (1.2)
4.4 (1.3)* 6.1 (1.9)*
3.2 (1.7)*,** 4.7 (2.8)*,**
FBT ¼ fentanyl buccal tablet; OM ¼ oral morphine. Statistical differences between the two groups were at T0, P ¼ 0.889; at T15 and T30, P < 0.0005. *P # 0.0005 vs. T0. **P < 0.0005 vs. T15.
Discussion This comparative study has shown that, when giving drugs for BTcP in doses proportional to the opioid regimen for background pain, FBT was clearly superior for efficacy and rapidity in comparison with OM. The analgesic effect was more intense at both 15 and 30 minutes after study medications were given. A larger number of episodes treated with FBT presented a decrease in pain intensity of $33% and $50% in comparison with episodes treated with OM, and a relevant difference in SPID30 was reported. Adverse effects commonly observed in patients receiving opioids were not severe and did not differ between the treatments, suggesting that the use of proportional doses of both drugs is safe; this reflects what has been found with the long experience with OM.4 Whether 15 minutes is acceptable for achieving pain relief, it has been found that patients are satisfied with a treatment when they achieve about a 50% decrease in pain intensity, something approaching the level of their background pain intensity.30 After 15 minutes, this cutoff was obtained in only 11% of
Table 3 Number of Episodes in the Two Groups With a Decrease of $33% and $50% in Pain Intensity at the Different Time Points Drugs FBT (n ¼ 132) OM (n ¼ 131)
$33% $33%
T15
T30
101* 43
118* 72
FBT ¼ fentanyl buccal tablet; OM ¼ oral morphine *P < 0.0005.
$50% $50%
T15
T30
69* 15
99* 60
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Table 4 Mean Intensity of the Most Common Adverse Effects at the Different Time Intervals FBT Symptoms Nausea/vomiting Drowsiness Confusion
OM
T0
T15
T30
T0
T15
T30
0.01(0.09) 0.14(0.4) 0.07(0.3)
0.03(0.2) 0.16(0.4) 0.05(0.3)
0.14(0.7)* 0.18(0.4) 0.05(0.2)
0.09(0.6) 0.12(0.3) 0.08(0.3)
0.08(0.3) 0.13(0.4) 0.07(0.3)
0.19(0.7)** 0.14(0.4) 0.07(0.3)
FBT ¼ fentanyl buccal tablet; OM ¼ oral morphine. No differences between the groups. *P < 0.05 vs. T0. **P < 0.05 vs. T15.
episodes treated with OM. The number of episodes with such a decrease in pain intensity increased after 30 minutes (45%). However, this cannot be considered a good performance of OM for those with BTcP, as most patients will remain unsatisfied with the treatment. Indeed, FBT produced a decrease of >50% in 52% and 75% of episodes after 15 and 30 minutes, respectively, which translates in the real world to a good analgesic performance. Finally, more than twice the number of subjects who preferred FBT to OM. The differences observed could be explained by the pharmacokinetic differences between the drugs, although differences in the equianalgesic potency of drugs may be an alternative. There are no specific studies confirming equivalencies between oral transmucosal fentanyl preparations and OM. In postoperative studies of opioid-na€ıve patients, it has been calculated that the oral transmucosal fentanyl citrate (OTFC) to intravenous morphine (IVMO) ratio was 1:10e20.28,31 A ratio of about 1:20 was used in a previous study of OTFC and IVMO in cancer patients after preliminary testing,10 also considering that in previous studies the starting dose of OTFC for patients receiving equivalent doses of OM was 200 mg. As with IVMO, which was found to be safe in several observational studies,9,11e13 OTFC doses did not exceed 20% of patients’ around-the-clock medication, which should be at least 60 mg of OM. Similarly, the minimal FBT strength is 100 mg, with about double the fentanyl availability in comparison with OTFC. In the case of FBT, we can argue that about 65% of the FBT dose is available for the treatment of BTcP (about 65 mg) and 3.5 mg of OM will be available (about 30% of the total oral dose because of the first-pass effect), with a ratio of about 1:20. The choice of the dose also was based on a presumed equivalency, given that 100 mg of FBT and 10 mg of OM are commonly suggested for patients receiving 60 mg or OMEs. Regardless of the equivalency problems, both drugs were safe when administered in doses proportional to the basal opioid regimen. Previous studies have shown that ROOs provide faster analgesia than placebo and oral opioids. In the case
of FBT, there are several studies that have shown that FBT was efficacious, well tolerated and demonstrated rapid onset of analgesia in comparison with placebo.19e22 However, several limitations biased the results, which seem to be inferior to those expected in terms of efficacy. They include unclear distinction between background pain intensity and BTcP intensity, and the high number of patients who failed dose titration. FBT also was compared with oral opioids.23 In a randomized, double-blind, double-dummy comparison study with oral oxycodone, the differences in the decrease of pain intensity after 15 and 30 minutes, 0.22e0.33 points on NRS, respectively, although significant, were clinically negligible because they were largely less of one point. After 15 and 30 minutes, meaningful pain relief was observed in 16% and 45%, respectively, of episodes treated with FBT; at the same time intervals, only in 13% and 41% of episodes was there a pain decrease $33% and $50%, respectively. After dose titration, 81% reached a successful oxycodone dose, and such doses were greater than the prestudy oxycodone doses, considered to be effective. Although no linear relationship was observed between successful doses achieved during the titration phase for FBT and oral oxycodone and the basal opioid regimen, the mean doses of oxycodone or FBT were about 1/6 of the background opioid doses (relatively proportional, as those used in the present study). Moreover, as with other ROOs studies, well-controlled pain was defined as having moderate pain (#6 on an 11-point NRS), and about 30% did not achieve a successful dose. Thus, the interpretation of these results may be altered because of the variability of each single episode in patients with pain that was not well controlled, also reflecting the minimal but clinically negligible advantage of FBT over oral oxycodone. Other studies of FBT showed the same limitations, including the minimal clinical impact (less than one point reduction in pain intensity) after FBT in comparison with placebo or oral opioids and the recruitment of patients with relatively high levels of background pain intensity.19e23
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These data justify the concerns raised by the NICE guidelines, which did not provide evidence to suggest that fentanyl products were more effective than OM for the management of BTcP.26 This statement was based on a nonrelevant decrease in pain intensity at the same time intervals; 45e60 minutes after administration, there are no significant differences. However, BTcP duration is often time limited, and as most episodes auto-resolve, oral opioids are expected to provide some pain relief after 30e 45 minutes.32,33 Differences are unlikely to be found at these intervals, when most episodes vanish spontaneously. Therefore, these time intervals are not useful to settle the question and should be focused on the first 15e30 minutes. It has been reported that a decrease in pain intensity of $33% represents a moderate improvement and $50% represents a substantial improvement. Alternately, a two-point difference may have a clinical meaning.34e36 By using proportional doses of both study drugs, the number-needed-to-treat with FBT at 15 and 30 minutes was 1.9 and 1.3, respectively. This outcome represents a relevant analgesic performance in comparison to OM, which produced a number-neededto-treat of 8.7 and 2.18 at the same time intervals. As outlined by NICE guidelines, these changes in pain intensity may justify the use of more expensive drugs. It seems clear that the definition of effective dose after dose titration does not correspond to pain measurement performed in the subsequent controlled phases, and that a dose proportional to the opioid basal regimen is able to cover the variability of BTcP in most cases, providing better efficacy in comparison with the titration method. For instance, the only existing controlled study, performed with FBT, has shown that proportional doses are more effective than the dose titration approach, without higher risks of adverse effects,8 confirming a series of open-label studies in which proportional doses were highly effective and well tolerated.9e14,37e39 Most studies of BTcP medications have suggested to titrate the dose of ROOs.2 However, these randomized trials have never specifically examined this issue, and the information gathered is just consequential to the study design aimed to demonstrate superiority of ROOs over placebo or oral opioids. Moreover, the lack of a clear distinction between background pain intensity (mild to moderate) and BTcP intensity (moderate to severe) strongly biased the results, which were in any case inferior to those expected. Indeed, more recently, a more detailed definition has been provided: Background pain should be none or mild, and BTcP should be severe or clearly distinguishable from background pain.3,27,29,30,40
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Doses proportional to the basal opioid regimen have been proposed as an alternative to dose titration,6,7 based on meaningful considerations, including the level of opioid tolerance. Of interest, by simulating the calculation of doses of opioids used for background analgesia and those achieved after individual titration, the mean values of proportional doses were quite similar to those found after titration.7 In a clinical scenario, the dose of the oral opioid used as a rescue medication was 18% of the around-the-clock opioid dose. When using an ROO, the effective dose found after dose titration was about 35% of the around-the-clock dose.33 In a recent controlled study, two different nasal fentanyl products, given in doses proportional to the basal opioid regimen, were similarly effective and safe.39 Limitations of this study include the lack of blinding or double-dummy technique. However, such types of studies are complex and require economic support from the pharmaceutical industry, which was not involved in this case. The study also was designed to assess the patients’ preference. Finally, incomplete data are common in such kinds of studies. However, the number of the ‘‘couples’’ of episodes with both treatments was adequate. In conclusion, when used in doses proportional to the basal opioid regimen, FBT showed a clear superiority over OM in the first 30 minutes, the approximate target for a timely intervention required for a BTcP medication. Both treatments were well tolerated, and adverse effects were minimal. More studies with other fentanyl products should be performed to confirm these findings.
Disclosures and Acknowledgments No funding was received for this study and the authors declare no conflicts of interest.
References 1. Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain 1999;81:129e134. 2. Davies A, Dickman A, Reid C, Stevens A, Zeppetella J. The management of cancer-related breakthrough pain: recommendations of a task group of the Association of Palliative Medicine of Great Britain and Ireland. Eur J Pain 2009;13:331e338. 3. Mercadante S, Valle A, Porzio G, et al. Relationship between background cancer pain, breakthrough pain, and analgesic treatment: a preliminary study for a better interpretation of epidemiological and clinical studies. Curr Med Res Opin 2013;29:667e671.
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4. Hanks GW, de Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 2001;84:587e593. 5. Mercadante S. Breakthrough pain: on the road again. Eur J Pain 2009;13:329e330. 6. Mercadante S. Rapid onset opioids for breakthrough pain. Titrating or not titrating, this is the question? Eur J Pain 2011;5:443e448. 7. Mercadante S. The use of rapid onset opioids for breakthrough cancer pain: the challenge of its dosing. Crit Rev Oncol Hematol 2011;80:460e465. 8. Mercadante S, Gatti A, Porzio G, et al. Dosing fentanyl buccal tablet for breakthrough cancer pain: dose titration versus proportional doses. Curr Med Res Opin 2012;28: 963e968. 9. Mercadante S, Villari P, Ferrera P, et al. Safety and effectiveness of intravenous morphine for episodic breakthrough pain in patients receiving transdermal buprenorphine. J Pain Symptom Manage 2006;32:175e179. 10. Mercadante S, Villari P, Ferrera P, et al. Transmucosal fentanyl vs intravenous morphine in doses proportional to basal opioid regimen for episodic-breakthrough pain. Br J Cancer 2007;96:1828e1833. 11. Mercadante S, Intravaia G, Villari P, et al. Intravenous morphine for breakthrough (episodic-) pain in an acute palliative care unit: a confirmatory study. J Pain Symptom Manage 2008;35:307e313. 12. Mercadante S, Villari P, Ferrera P, Bianchi M, Casuccio A. Safety and effectiveness of intravenous morphine for episodic (breakthrough) pain using a fixed ratio with the oral daily morphine dose. J Pain Symptom Manage 2004;27:352e359. 13. Mercadante S, Villari P, Ferrera P, Mangione S, Casuccio A. The use of opioids for breakthrough pain in acute palliative care unit by using doses proportional to opioid basal regimen. Clin J Pain 2010;26:306e309. 14. Mercadante S, Ferrera P, Adile C, Casuccio A. Fentanyl buccal tablets for breakthrough pain in highly tolerant cancer patients: preliminary data on the proportionality between breakthrough pain dose and background dose. J Pain Symptom Manage 2011;42:464e469. 15. Davies AN, Vriens J, Kennett A, McTaggart M. An observational study of oncology patients’ utilization of breakthrough pain medication. J Pain Symptom Manage 2008; 35:406e411. 16. Coluzzi PH, Schwartzberg L, Conroy JD, et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain 2001;91:123e130. 17. Davies A, Sitte T, Elsner F, et al. Consistency of efficacy, patient acceptability, and nasal tolerability of fentanyl pectin nasal spray compared with immediate-release morphine sulfate in breakthrough cancer pain. J Pain Symptom Manage 2011;41:358e366. 18. Fallon M, Reale C, Davies A, et al. Efficacy and safety of fentanyl pectin nasal spray compared with immediate-release morphine sulfate tablets in the treatment of breakthrough cancer pain: a multicenter, randomized, controlled, double-blind, double-dummy multiple-crossover study. J Support Oncol 2011;9:224e231.
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19. Kosugi T, Hamada S, Takigawa C, et al. A randomized, double-blind, placebo-controlled study of fentanyl buccal tablets for breakthrough pain: efficacy and safety in Japanese cancer patients. J Pain Symptom Manage 2014;47:990e1000. 20. Portenoy RK, Taylor D, Messina J, Tremmel L. A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clin J Pain 2006;22:805e811. 21. Slatkin NE, Xie F, Messina J, Segal TJ. Fentanyl buccal tablet for relief of breakthrough pain in opioid-tolerant patients with cancer-related chronic pain. J Support Oncol 2007;5:327e334. 22. Webster LR, Slevin KA, Narayana A, Earl CQ, Yang R. Fentanyl buccal tablet compared with immediate-release oxycodone for the management of breakthrough pain in opioid-tolerant patients with chronic cancer and noncancer pain: a randomized, double-blind, crossover study followed by a 12-week open-label phase to evaluate patient outcomes. Pain Med 2013;14:1332e1345. 23. Ashburn M, Slevin K, Messina J, Xie F. The efficacy and safety of fentanyl buccal tablet compared with immediaterelease oxycodone for the management of breakthrough pain in opioid-tolerant patients with chronic pain. Anesth Analg 2011;112:693e702. 24. Jandhyala R, Fullarton JR, Bennett MI. Efficacy of rapidonset oral fentanyl formulations vs. oral morphine for cancer-related breakthrough pain: a meta-analysis of comparative trials. J Pain Symptom Manage 2013;46: 573e580. 25. Zeppetella G, Davies A, Eijgelshoven I, Jansen JP. Network meta-analysis of the efficacy of opioid analgesics for the management of breakthrough cancer pain episodes. J Pain Symptom Manage 2014;47:772e785. 26. Available at: www.nice.org.uk/cg140. Accessed May 2014. 27. Davies A, Zeppetella G, Andersen S, et al. Multicentre European study of breakthrough cancer pain: characteristics and patient perceptions of current and potential management strategies. Eur J Pain 2011;15:756e763. 28. Lichtor J, Sevarino F, Joshi G, et al. The relative potency of oral transmucosal fentanyl citrate compared with intravenous morphine in the treatment of moderate to severe postoperative pain. Anesth Analg 1999;89:732e738. 29. Davies A, Buchanan A, Zeppetella G, et al. Breakthrough cancer pain: an observational study of 1000 European oncology patients. J Pain Symptom Manage 2013;46: 619e628. 30. Mercadante S, Adile C, Torta R, et al. Meaningful cut-off pain intensity for breakthrough pain changes in advanced cancer patients. Curr Med Res Opin 2013;29:93e97. 31. Lu JK, Bailey PL. Dose-related respiratory pharmacology of oral transmucosal fentanyl citrate (OTFC) versus intravenous morphine: a randomized, double-blind, doubledummy study. Anesthesiology 2003;99:A967. 32. Zeppetella G. Dynamics of breakthrough pain vs. pharmacokinetics of oral morphine: implications for management. Eur J Cancer Care 2009;18:331e337. 33. Zeppetella GB. Opioids for cancer breakthrough pain: a pilot study reporting patient assessment of time to meaningful pain relief. J Pain Symptom Manage 2008;35:563e567.
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Mercadante et al.
34. Farrar J, Polomano R, Berlin J, Strom B. A comparison of change in the 0-10 numeric rating scale to a pain relief scale and global medication performance scale in a shortterm clinical trial of breakthrough pain intensity. Anesthesiology 2010;11:1464e1472. 35. Farrar J, Portenoy RK, Berlin J, Kinman J, Strom B. Defining the clinically important difference in pain out come measure. Pain 2000;88:287e294. 36. Farrar J, Young J, LaMoreaux L, Werth J, Poole M. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001;94:149e158. 37. Mercadante S, Prestia G, Casuccio A. The use of sublingual fentanyl for breakthrough pain by using doses
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proportional to opioid basal regimen. Curr Med Res Opin 2013;29:1527e1532. 38. Mercadante S, Porzio G, Aielli F, et al. The use of fentanyl buccal tablets for breakthrough pain by using doses proportional to opioid basal regimen in a home care setting. Support Care Cancer 2013;21:2335e2339. 39. Mercadante S, Prestia G, Adile C, Casuccio A. Intranasal fentanyl versus fentanyl pectin nasal spray for the management of breakthrough cancer pain in doses proportional to basal opioid regimen. J Pain 2014;15:602e607. 40. Mercadante S, Lazzari M, Reale C, et al. IOPS Study Group. Italian Oncological Pain Survey (IOPS): a multicentre Italian study of breakthrough pain performed in different settings. Clin J Pain 2015;31:214e221.