Effectiveness of fentanyl buccal soluble film in cancer patients with inadequate breakthrough pain control.

BACKGROUND: Clinical evidence for the rapidity and effectiveness of fentanyl buccal soluble film (FBSF) in reducing pain intensity of breakthrough cancer pain (BTcP) remains inadequate. This study aimed to evaluate the efficacy of FBSF proportional to the around-the-clock (ATC) opioid regimens in rapidly relieving the intensity of BTcP episodes by determining the percentage of patients requiring further dose titration. METHODS: The study procedure included a dose-finding period followed by a 14-day observation period. Pain intensity was recorded with a Numeric Rating Scale (NRS) at onset and 5, 10, 15, and 30 min after FBSF self-administration. Meaningful pain relief was defined as the final NRS score ≤ 3. Satisfaction survey was conducted for each patient after treatment using the Global Satisfaction Scale. RESULTS: A total of 63 BTcP episodes occurred in 30 cancer patients. Only one patient required rescue medication at first BTcP episode and then achieved meaningful pain relief after titrating FBSF by 200 µg. Most BTcP episodes relieved within 10 min. Of 63 BTcP episodes, 30 (47.6%), 46 (73.0%), and 53 (84.1%) relieved within 5, 10, and 15 min after FBSF administration. Only grade 1/2 adverse events were reported, including somnolence, malaise, and dizziness. Of the 63 BTcP episodes, 82.6% were rated as excellent/good satisfaction with FBSF. CONCLUSION: FBSF can be administrated "on demand" by cancer patients at the onset of BTcP, providing rapid analgesia by achieving meaningful pain relief within 10 min. TRIAL REGISTRATION: This study was retrospectively registered 24 December, 2021 at Clinicaltrial.gov (NCT05209906): https://clinicaltrials.gov/study/NCT05209906 .

A systematic review of qualitative research exploring patient and health professional perspectives of breakthrough cancer pain.

PURPOSE: Breakthrough cancer pain (BtCP) is a prevalent health issue which is difficult to manage. A plethora of quantitative research in this area exists. There is a paucity of research on the perspectives of health professionals and patients surrounding domains impacting effective treatment, including definitions of BtCP, treatment, and education opportunities. This review aims to identify and synthesize the extent of qualitative research exploring health professional and patient perspectives of BtCP. METHODS: A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) approach was undertaken. The approach was registered with Prospero. MEDLINE, EMBASE, and Web of Science were searched for peer-reviewed literature published any date prior to May 19, 2022. Eligible sources must have considered health professional and/or patient perspectives of BtCP. A narrative synthesis approach was utilized. RESULTS: Three sources met the review criteria. One source explored nurse perspectives, while two sources explored patient perspectives. Study quality was moderate to high. Overlapping themes across the three studies included communication, defining BtCP, impact of BtCP, management of BtCP, perceptions of BtCP, analgesia and pain relief, and training and professional development. CONCLUSION: Given limited research investigating clinician and patient perspectives of BtCP, a rich understanding informed by exploratory qualitative methods around identification, best management strategies, professional development, and factors promoting and inhibiting best practice remains unclear. Further qualitative inquiry is warranted, and it is expected such research will inform BtCP clinical guidelines.

Automated mandatory bolus versus basal infusion for maintenance of epidural analgesia in labour.

BACKGROUND: Epidural analgesia is often used for pain relief during labour and childbirth, and involves administration of local anaesthetics (LA) into the epidural space resulting in sensory blockade of the abdomen, pelvis, and perineum. Epidural opioids are often co-administered to improve analgesia. Administration of epidural medications can be accomplished by basal infusion (BI) or automated mandatory bolus (AMB). With BI, medications are administered continuously, while AMB involves injecting medications at set time intervals. Patient-controlled epidural analgesia (PCEA) on top of AMB or BI enables patients to initiate additional boluses of epidural medications.  The superior method of delivering epidural medications would result in lower incidence of pain requiring anaesthesiologist intervention (breakthrough pain). Also, it should be associated with lower incidence of epidural-related adverse effects including caesarean delivery, instrumental delivery (use of forceps or vacuum devices), prolonged duration of labour analgesia, and LA consumption. However, clear evidence of the superiority of one technique over the other is lacking. Also, differences in the initiation of epidural analgesia such as combined spinal-epidural (CSE) (medications given into the intrathecal space in addition to the epidural space) compared to epidural only, and medications used (types and doses of LA or opioids) may not have been accounted for in previous reviews.  Our prior systematic review suggested that AMB reduces the incidence of breakthrough pain compared to BI with no significant difference in the incidence of caesarean delivery or instrumental delivery, duration of labour analgesia, and LA consumption. However, several studies comparing AMB and BI have been performed since then, and inclusion of their data may improve the precision of our effect estimates. OBJECTIVES: To assess the benefits and harms of AMB versus BI for maintaining labour epidural analgesia in women at term. SEARCH METHODS: We searched CENTRAL, Wiley Cochrane Library), MEDLINE, (National Library of Medicine), Embase(Elseiver), Web of Science (Clarivate), the WHO-ICTRP (World Health Organization) and ClinicalTrials.gov (National Library of Medicine) on 31 December 2022. Additionally, we screened the reference lists of relevant trials and reviews for eligible citations, and we contacted authors of included studies to identify unpublished research and ongoing trials. SELECTION CRITERIA: We included all randomised controlled studies that compared bolus dosing AMB with continuous BI during epidural analgesia. We excluded studies of women in preterm labour, with multiple pregnancies, with fetal malposition, intrathecal catheters, those that did not use automated delivery of medications, and those where AMB and BI were combined. DATA COLLECTION AND ANALYSIS: We used standard methodology for systematic review and meta-analysis described by Cochrane. Primary outcomes included: incidence of breakthrough pain requiring anaesthesiologist intervention; incidence of caesarean delivery; and incidence of instrumental delivery. Secondly, we assessed the duration of labour; hourly LA consumption in bupivacaine equivalents, maternal satisfaction after fetal delivery, and neonatal Apgar scores.  The following subgroup analyses were chosen a priori: epidural alone versus CSE technique; regimens that used PCEA versus those that did not; and nulliparous versus combination of nulli- and multi-parous women. We used the GRADE system to assess the certainty of evidence associated with our outcome measures. MAIN RESULTS: We included 18 studies of 4590 women, of which 13 enrolled healthy nulliparous women and five included healthy nulli- and multiparous women. All studies excluded women with preterm or complicated pregnancies. Techniques used to initiate epidural analgesia differed between the studies: seven used combined spinal epidural, 10 used epidural, and one used dural puncture epidural (DPE). There was also variation in analgesics used. Eight studies utilised ropivacaine with fentanyl, three used ropivacaine with sufentanil, two utilised levobupivacaine with sufentanil, one used levobupivacaine with fentanyl, and four utilised bupivacaine with fentanyl. Most of the studies were assessed to have low risk of randomisation, blinding, attrition, and reporting biases, except for allocation concealment where eight studies were assessed to have uncertain risk and three with high risk. Our results showed that AMB was associated with lower incidence of breakthrough pain compared to BI (risk ratio (RR) 0.71; 95% confidence interval (CI) 0.55 to 0.91; I2 = 57%) (16 studies, 1528 participants), and lower hourly LA consumption in bupivacaine equivalents (mean difference (MD) -0.84 mg/h; 95% CI -1.29 to -0.38, I2 = 87%) (16 studies, 1642 participants), both with moderate certainty. AMB was associated with an estimated reduction in breakthrough pain incidence of 29.1% (incidence 202 per 1000, 95% CI 157 to 259), and was therefore considered clinically significant. The incidence of caesarean delivery (RR 0.85; 95% CI 0.69 to 1.06; I2 = 0%) (16 studies, 1735 participants) and instrumental delivery (RR 0.85; 95% CI 0.71 to 1.01; I2 = 0%) (17 studies, 4550 participants) were not significantly, both with moderate certainty. There was no significant difference in duration of labour analgesia (MD -8.81 min; 95% CI -19.38 to 1.77; I2 = 50%) (17 studies, 4544 participants) with moderate certainty. Due to differences in the methods and timing of outcome measurements, we did not pool data for maternal satisfaction and Apgar scores. Results reported narratively suggest AMB may be associated with increased maternal satisfaction (eight studies reported increased satisfaction and six reported no difference), and all studies showed no difference in Apgar scores. WIth the exception of epidural alone versus CSE which found significant subgroup differences in LA consumption between AMB and BI, no significant differences were detected in the remaining subgroup analyses. AUTHORS' CONCLUSIONS: Overall, AMB is associated with lower incidence of breakthrough pain, reduced LA consumption, and may improve maternal satisfaction. There were no significant differences between AMB and BI in the incidence of caesarean delivery, instrumental delivery, duration of labour analgesia, and Apgar scores. Larger studies assessing the incidence of caesarean and instrumental delivery are required.

High-volume patient-controlled epidural vs. programmed intermittent epidural bolus for labour analgesia: a randomised controlled study.

The aim of neuraxial analgesia is to achieve excellent pain relief with the fewest adverse effects. The most recently introduced technique for epidural analgesia maintenance is the programmed intermittent epidural bolus. In a recent study, we compared this with patient-controlled epidural analgesia without a background infusion and found that a programmed intermittent epidural bolus was associated with less breakthrough pain, lower pain scores, higher local anaesthetic consumption and comparable motor block. However, we had compared 10 ml programmed intermittent epidural boluses with 5 ml patient-controlled epidural analgesia boluses. To overcome this potential limitation, we designed a randomised, multicentre non-inferiority trial using 10 ml boluses in each group. The primary outcome was the incidence of breakthrough pain and total analgesic intake. Secondary outcomes included motor block; pain scores; patient satisfaction; and obstetric and neonatal outcomes. The trial was considered positive if two endpoints were met: non-inferiority of patient-controlled epidural analgesia with respect to breakthrough pain; and superiority of patient-controlled epidural analgesia with respect to local anaesthetic consumption. A total of 360 nulliparous women were allocated randomly to patient-controlled epidural analgesia-only or programmed intermittent epidural bolus groups. The patient-controlled group received 10 ml boluses of ropivacaine 0.12% with sufentanil 0.75 µg.ml-1 ; the programmed intermittent group received 10 ml boluses supplemented by 5 ml patient-controlled boluses. The lockout period was 30 min in each group and the maximum allowed hourly local anaesthetic/opioid consumption was identical between the groups. Breakthrough pain was similar between groups (11.2% patient controlled vs. 10.8% programmed intermittent, p = 0.003 for non-inferiority). Total ropivacaine consumption was lower in the PCEA-group (mean difference 15.3 mg, p < 0.001). Motor block, patient satisfaction scores and maternal and neonatal outcomes were similar across both groups. In conclusion, patient-controlled epidural analgesia is non-inferior to programmed intermittent epidural bolus if equal volumes of patient-controlled epidural analgesia are used to maintain labour analgesia and superior with respect to local anaesthetic consumption.

Efficacy of reconstituted intravenous fentanyl to sublingual solution versus oral morphine syrup for breakthrough pain among patients with chronic gynecologic cancer pain: A randomized, double-blind, placebo-controlled trial.

Rapid-acting fentanyl formulations are superior to oral morphine (OM) syrup in controlling breakthrough pain among patients with cancer, but they are expensive and unavailable in many countries. OBJECTIVE: To evaluate the efficacy of reconstituted intravenous fentanyl to sublingual solution (IFS) in relieving breakthrough pain as compared with OM. METHODS: In this randomized, double-blind, double-dummy, placebo-controlled trial, patients with gynecologic cancer aged ≥18 years experiencing chronic cancer pain with breakthrough pain were enrolled. Patients were randomly allocated (1:1) to receive either 50 µg IFS or 5 mg OM. Pain intensity level was assessed at 5, 15, 30, 45, 60, and 120 min after treatment. The primary outcome was the reduction in pain intensity at 15 min in the intention-to-treat population (ClinicalTrials.gov, NCT05037539). RESULTS: Between June 15, 2021 and December 30, 2021, 40 participants were equally and randomly assigned to receive IFS or OM. The primary outcome was significantly higher in the IFS group (4.25 vs. 1.05, p < 0.0001). The secondary outcomes also showed higher reduction in pain intensity at 5 min in the IFS group. Subsequent breakthrough pain did not differ between the two groups. However, the reduction in pain was lower in the IFS group at 45, 60, and 120 min, where pain was classified as mild. No severe adverse effects were observed in both groups. Burning sensation without noticeable lesion was found in 20% of the IFS group. CONCLUSION: IFS can reduce early breakthrough pain. IFS may be considered for breakthrough pain when rapid-acting fentanyl formulations are unavailable.

Low-dose sublingual fentanyl improves quality of life in patients with breakthrough cancer pain in palliative care.

Aim: This subanalysis of the CAVIDIOPAL study evaluated the impact of individualized management of breakthrough cancer pain (BTcP) with fentanyl on the quality of life (QoL) of advanced cancer patients in Spanish palliative care units. Patients & methods: This was a prospective, observational, multicenter study. The European Organization for Research and Treatment of Cancer's QLQ-C30 questionnaire was used at baseline (V0) and visit 28 (V28). Results: Ninety-five patients were mainly treated with 67-133 µg fentanyl, showing a notable reduction in intensity (visual analog scale: 8.0 [V0] to 4.6 [V28]), frequency and duration of BTcP episodes shortly after the first 1-2 weeks of treatment, with significantly improved QoL (global health status: 31.1 [V0] to 53.1 [V28]). Conclusion: Low-dose sublingual fentanyl effectively reduced BTcP in advanced cancer patients in palliative care units, significantly improving QoL. Clinical trial registration: NCT02840500 (ClinicalTrials.gov).

After the CAVIDIOPAL study, we carried out an additional analysis to evaluate the impact of individualized management of breakthrough cancer pain, using the analgesic drug fentanyl, on quality of life (QoL) of advanced cancer patients receiving palliative care in Spain. We performed a prospective, observational, multicenter study, in which patients' QoL was assessed using a validated questionnaire at baseline (day 0) and after 28 days of fentanyl treatment. Of the 95 patients included in the study, the majority were treated with low doses of fentanyl and showed significant pain relief. The intensity, frequency and duration of breakthrough cancer pain episodes were notably reduced shortly after the first 1­2 weeks of treatment. Moreover, patients' QoL significantly improved during fentanyl treatment from baseline to day 28. A global impression of improvement was reported by both patients and clinicians.

Increased quality of life in patients with breakthrough cancer pain after individualized therapy: the CAVIDIOM study.

Aim: To evaluate the quality of life (QoL) in patients with breakthrough cancer pain (BTcP) in Spanish medical oncology departments. Patients & methods: In a prospective, observational, multicenter study, we assessed QoL using the EQ-5D-5L instrument at baseline and after 15 and 30 days of individualized BTcP therapy, as well as BTcP characteristics and treatment. Results: Patients (n = 118) were mainly women, over 64 years old and with advanced cancer. QoL improved at 15 (p = 0.013) and 30 days (p = 0.011) versus baseline. Individualized BTcP therapy consisted mostly of rapid-onset opioids (transmucosal fentanyl at doses of 67-800 µg) according to the physician evaluation. BTcP improved, including statistically significant reductions in intensity, duration, number of episodes in the last 24 h and time to onset of BTcP relief. Conclusion: QoL increased after individualized pain therapy in patients with advanced cancer and BTcP in medical oncology departments.

Cancer patients can experience flares of pain, called breakthrough pain (BTcP), despite treatment with painkillers. Although BTcP can be excruciating, its intensity and other characteristics depend on several factors, including its treatment. However, even if treated, BTcP can impair quality of life for cancer patients. We assessed quality of life in 118 patients with advanced cancer and BTcP treated in 13 medical oncology departments across Spain. We treated BTcP with individualized therapy, taking into account both pain-related and patient-related factors. We also measured quality of life using a specific, widely-used questionnaire at the study visits: at onset of individualized pain therapy and after 3, 15 and 30 days' treatment. At each visit, flare-up pain therapy was adjusted or maintained as necessary. Throughout the study, quality of life and sleep quality improved for all participants. Furthermore, there was a greater reduction in intensity, duration and frequency of BTcP. The most common treatments for flare-ups were low doses of rapid-onset opioids (fentanyl given by sublingual, buccal or nasal administration), which were much better tolerated than high-dose opioids. Overall, the study showed that quality of life in patients with advanced cancer and BTcP increased after individualized pain therapy, mainly with low doses of rapid-onset opioids.

Light-Induced Activation of a Specific Type-5 Metabotropic Glutamate Receptor Antagonist in the Ventrobasal Thalamus Causes Analgesia in a Mouse Model of Breakthrough Cancer Pain.

Breakthrough cancer pain (BTcP) refers to a sudden and transient exacerbation of pain, which develops in patients treated with opioid analgesics. Fast-onset analgesia is required for the treatment of BTcP. Light-activated drugs offer a novel potential strategy for the rapid control of pain without the typical adverse effects of systemic analgesic drugs. mGlu5 metabotropic glutamate receptor antagonists display potent analgesic activity, and light-induced activation of one of these compounds (JF-NP-26) in the thalamus was found to induce analgesia in models of inflammatory and neuropathic pain. We used an established mouse model of BTcP based on the injection of cancer cells into the femur, followed, 16 days later, by systemic administration of morphine. BTcP was induced by injection of endothelin-1 (ET-1) into the tumor, 20 min after morphine administration. Mice were implanted with optic fibers delivering light in the visible spectrum (405 nm) in the thalamus or prelimbic cortex to locally activate systemically injected JF-NP-26. Light delivery in the thalamus caused rapid and substantial analgesia, and this effect was specific because light delivery in the prelimbic cortex did not relieve BTcP. This finding lays the groundwork for the use of optopharmacology in the treatment of BTcP.

Quality of life in patients with breakthrough cancer pain in radiation oncology departments in Spain: the CAVIDIOR study.

Aim: The CAVIDIOR study evaluated quality of life (QoL) in patients with breakthrough cancer pain receiving palliative radiation therapy in radiation oncology departments (RODs) in Spain. Patients & methods: Prospective observational study at 11 Spanish RODs (July 2016-November 2017). QoL was assessed using Short Form Health Survey 12. Secondary end points were sleep quality, caregiver burden and patient/perception of improvement. Results: QoL improved according to the Short Form Health Survey 12 mental component. Sleep quality and caregivers' burden improved significantly. Conclusion: Breakthrough cancer pain is highly prevalent and can be substantially reduced with appropriate diagnosis and management in RODs. Along with the QoL questionnaire, sleep quality and caregiver burden provide a more comprehensive assessment of overall health status in patients receiving radiation therapy in RODs. Clinical trial registration: NCT02836379 (ClinicalTrials.gov).

Pain management in patients with end-stage renal disease and calciphylaxis- a survey of clinical practices among physicians.

BACKGROUND: Calciphylaxis is a rare condition usually seen in patients with end-stage renal disease. Pain is a hallmark of this condition and can be extremely difficult to control. Anecdotal data suggests that pain management in calciphylaxis is challenging with variable approaches across the United Kingdom (UK) and internationally. A knowledge and practice survey was conducted to establish current practice in the management of pain in patients with calciphylaxis, in the UK. Based on the results and clinical experience the authors suggest a clinical practice guideline. METHODS: An online questionnaire was circulated among physicians (renal and palliative care) involved in the management of pain in calciphylaxis. The questionnaire included a mix of open-ended questions and questions with drop down options. RESULTS: One hundred and six clinicians responded to the survey of which 60 (57%) respondents were from palliative medicine; the remaining 46 (43%) were from renal medicine. 31 (30%) respondents across both specialties had not encountered any patients with a diagnosis of calciphylaxis (renal-2, palliative care-29). A referral to the palliative care team was undertaken by 18% of renal physicians, 32% referred to the pain team and 50% referred to both. Only 3% of the palliative medicine respondents indicated that they had received a referral from the renal team at the time of diagnosis. Opioids were the preferred initial drug of choice for the management of all types of pain. Paracetamol was universally selected as the preferred first-choice adjuvant agent for management of all types of pain. The importance of advance care planning was highlighted with 72% undertaking advanced care planning discussions often or most of the time. CONCLUSION: There was wide variation in the current practice of pain management in patients with calciphylaxis, with variation between renal specialists and palliative care specialists. Referral to specialists in pain management is not universal despite the severe nature of the pain experienced by patients with calciphylaxis. The data generated has facilitated the development of a clinical practice guideline to support complex pain management in a group of patients with multiple comorbidities.

Reducing breakthrough pain during labour epidural analgesia: an update.

PURPOSE OF REVIEW: Neuraxial techniques are the current gold standard for labour analgesia, but are associated with up to 25% incidence of breakthrough pain. In this review, we aim to update clinicians on the latest research pertaining to the optimization of neuraxial labour analgesia. RECENT FINDINGS: Attempts to improve the efficacy and reliability of epidural analgesia while minimizing adverse effects have resulted in the rising popularity of combined spinal epidural and the dural puncture epidural (DPE). Recent studies have focused on determining the safety, efficacy, and optimization of the DPE technique.Another research focus is on the development of individualized therapy in which patients may titrate their own labour analgesia according to their varying requirements, possibly augmented with computer-aided feedback systems and automated mandatory bolus techniques that automatically adjust drug delivery to the patients' analgesic requirements. The addition of a risk-stratification model based on maternal, anaesthetic, and obstetric factors will facilitate early institution of individualized therapy to forestall breakthrough pain in higher risk patients. SUMMARY: Recent advances in combined spinal epidural, DPE, automated mandatory bolus, and individualized therapies have advanced our goal of providing effective labour analgesia that is titrated to changing analgesic requirements during labour and delivery and reducing breakthrough pain.

Breakthrough Pain: A Qualitative Study of Patients with Advanced Cancer in Northwest China.

BACKGROUND: Breakthrough pain is an extremely painful symptom that impairs quality of life in cancer patients. It negatively impacts their emotional wellbeing, physical function, and mental health. The aim of this study is to use a qualitative methodology to examine the perception of cancer patients with breakthrough pain in the Northwest of China. METHODS: A semi-structured, face-to-face interview was conducted with nine cancer patients who experienced breakthrough pain; and a qualitative content analysis was performed. RESULTS: Five themes were generated: (1) sufferings from breakthrough cancer pain, (2) hopelessness and helplessness, (3) perception of breakthrough cancer pain and analgesia, (4) strong as a Chinese, and (5) support needed from health care system. CONCLUSION: Although certain traditional cultural worldviews increase patients' acceptance of pain, healthcare providers need proper treatment guidelines to improve the quality of cancer patient care in Northwest China. We recommend that healthcare workers and hospital managers place cancer pain management in higher priority. Relevant pain management education programs should be provided to both healthcare providers and patients to improve their knowledge in these area. Healthcare professionals need to establish a mutual communication channel between patients and healthcare workers to meet patients' needs during breakthrough pain episodes in order to improve pain management. Nevertheless, the government and the healthcare system need to recognize the importance and urgency of palliative care services.

Practice Patterns in Distinguishing Between Background Pain and Breakthrough Pain During Patient Education: a Korean Physician Survey.

This study sought to explore the association between physician practice patterns and patient education, with a focus on breakthrough cancer pain (BTcP). A nationwide online survey was conducted by 92 Korean physicians. Thirteen questions on Korean physician's assessment, prescription, patient education practices, and knowledge regarding BTcP were administered. Based on their responses, physicians were divided using two methods: (1) by their patient education practices, where the "education group" always explained the distinction between background pain and BTcP and the "less education group" which explained it less frequently; and (2) by their definition of BTcP, as occurring "after control of background pain" or "regardless of background pain." We compared practice patterns using Fisher's exact test or Student's t test and performed multiple logistic regression analysis. The "education group" (65 physicians, 70.7 %) was more likely than the "less education group" to assess BTcP meticulously (odds ratio [OR] 17.13, 95 % confidence interval [CI] 4.98-58.94), prepare rescue medications in advance (OR 3.67, 95 % CI 1.36-9.90), and give explicit instructions regarding medications (OR 36.68, 95 % CI 5.63-239.15). Physicians who defined BTcP as occurring "after control of background pain" were more likely to explain how to take rescue medication (P < 0.05) than physicians who defined BTcP as occurring "regardless of background pain." Korean physicians' BTcP practice patterns may be affected by whether they consistently educate patients on the distinction between background pain and BTcP, regardless of their knowledge of the definition of BTcP.

Fentanyl Buccal Tablet: A New Breakthrough Pain Medication in Early Management of Severe Vaso-Occlusive Crisis in Sickle Cell Disease.

BACKGROUND: Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder. The principal clinical manifestations of SCD are the chronic hemolytic anemia and the acute vaso-occlusive crisis (VOCs), which are mainly characterized by ischemic/reperfusion tissue injury. Pain is the main symptom of VOCs, and its management is still a challenge for hematologists, requiring a multidisciplinary approach. METHODS: We carried out a crossover study on adult SCD patients, who received two different types of multimodal analgesia during two separate severe VOCs with time interval between VOCs of at least 6 months. The first VOC episode was treated with ketorolac (0.86 mg/kg/day) and tramadol (7.2 mg/kg/day) (TK treatment). In the second VOC episode, fentanyl buccal tablet (FBT; 100 µg) was introduced in a single dose after three hours from the beginning of TK analgesia (TKF treatment). We focused on the first 24 hours of acute pain management. The primary efficacy measure was the time-weighted-sum of pain intensity differences (SPID24). The secondary efficacy measures included the pain intensity difference (PID), the total pain relief (TOTPAR), and the time-wighted sum of anxiety (SAID24). RESULTS: SPID24 was significantly higher in TKF than in TK treatment. All the secondary measures were significantly ameliorated in TKF compared to TK treatment, without major opioid side effects. Patients satisfaction was higher with TKF treatment than with TK one. CONCLUSIONS: We propose that VOCs might require breakthrough pain drug strategy as vaso-occlusive phenomena and enhanced vasoconstriction promoting acute ischemic pain component exacerbate the continuous pain of VOCs. FBT might be a powerful and feasible tool in early management of acute pain during VOCs in emergency departments.

Efficacy and safety of sublingual fentanyl orally disintegrating tablet at doses determined from oral morphine rescue doses in the treatment of breakthrough cancer pain.

OBJECTIVE: A randomized, crossover, double-blinded placebo-controlled and non-blinded active drug-controlled, comparative clinical trial was conducted to evaluate the efficacy and safety of sublingual fentanyl tablet. METHODS: Subjects were patients treated with strong opioids at fixed intervals for chronic cancer pain and with oral morphine as rescue medication for breakthrough pain. Sublingual fentanyl was administered at doses that were 1/25th (high dose) and 1/50th (low dose) of the dose of rescue morphine and was compared with placebo and oral morphine. The primary endpoint was pain intensity difference at 30 min after administration. (Clinical Trials Government; NCT00684632). RESULTS: Fifty-one patients were enrolled in the investigation. Their mean pain intensity in visual analog scale before rescue medication prior to the investigation was 60.96 (16.44, standard deviation) mm. Compared with placebo, the low and high doses of sublingual fentanyl showed significant analgesic effects (least squares mean difference, 4.54 and 8.49 mm; P = 0.014, P < 0.001, respectively). Adverse reactions were observed in 17.6%, the most common being constipation, nausea and somnolence. The incidence of adverse reactions during the high-dose administration period was higher than that during the low-dose and active control drug administration periods. CONCLUSIONS: Patients treated with strong opioid analgesics at fixed intervals for chronic cancer pain and with oral morphine at doses up to 20 mg as rescue medication were investigated. The doses of sublingual fentanyl to treat breakthrough pain were determined from rescue morphine doses by use of conversion ratios. In these patients, administration of sublingual fentanyl at doses determined by a conversion ratio of 1/50 was effective and safe. Further studies are needed to validate the use of this conversion method.

Breakthrough pain management using fentanyl buccal tablet (FBT) in combination with around-the-clock (ATC) opioids based on the efficacy and safety of FBT, and its relationship with ATC opioids: results from an open-label, multi-center study in Japanese cancer patients with detailed evaluation.

OBJECTIVE: Rapid analgesic onset opioids, particularly fentanyl buccal tablet, is preferable for managing breakthrough pain. The efficacy and safety of fentanyl buccal tablet and its association with around-the-clock opioids needs to be explored with an option of dose adjustments, more closely reflecting administration in clinical practice. The aim of the study was to assess the safety and efficacy of fentanyl buccal tablet in breakthrough pain management in combination with around-the-clock opioids with the dose adjustment option, and explore the dose adjustment's influence on breakthrough pain management using detailed evaluation. METHODS: The 12-week open-label, multi-center study was conducted throughout Japan. Cancer patients aged 20 years or older, experiencing persistent pain controlled with around-the-clock opioids and breakthrough pain with supplemental medications were enrolled. Fentanyl buccal tablet and around-the-clock opioid doses could be adjusted under protocol-specified conditions. Efficacy variables were assessed at each fentanyl buccal tablet administration. Safety was assessed mainly by adverse events. RESULTS: All efficacy variables showed sustained analgesic effect. Nearly half the patients stayed on the same dose; most fentanyl buccal tablet administrations did not require additional supplemental medications. Dose increase of fentanyl buccal tablet and around-the-clock opioids seemed to improve breakthrough pain intensity and frequency, respectively. Fentanyl buccal tablet and around-the-clock opioid doses were not strongly associated. Treatment-related adverse events were all common with opioid treatment and did not increase over time. CONCLUSIONS: Fentanyl buccal tablet can stably and safely manage breakthrough pain in cancer patients with independent dose adjustment based on detailed evaluation of each patient's condition. Breakthrough pain management using fentanyl buccal tablet with around-the-clock opioids at optimal doses may be an important factor in palliative care for cancer patients with breakthrough pain.

Improved patient functioning after treatment of breakthrough cancer pain: an open-label study of fentanyl buccal tablet in patients with cancer pain.

PURPOSE: This open-label study evaluated the effects of fentanyl buccal tablet (FBT) on functioning and mood in cancer patients with breakthrough cancer pain (BTcP). METHODS: Opioid-tolerant patients in seven European countries with up to four BTcP episodes/day received FBT doses (100-800 µg) identified during open-label titration to treat up to eight BTcP episodes during an open-label treatment period. In countries where FBT was not commercially available, patients could enter an open-label continuation phase. Functionality and satisfaction assessments included change from baseline to the end of the treatment period in the modified Brief Pain Inventory (BPI-7S) seven-item interference subscale, patient's global assessment of satisfaction and ease of use, and Patient's Global Impression of Change (PGIC). Safety was also assessed. RESULTS: Of 330 randomized patients, 218 completed the treatment period and 88 entered the continuation phase. Median background pain intensity was 4.0 (mild) throughout the study. After the treatment period, mean (SD) global modified BPI-7S score improved from 39.7 (15.9) at baseline to 31.6 (16.8) for a mean change of -8.6 (95% confidence interval CI -10.5, -6.7; P < 0.0001), and 74.5% of patients reported improvement in overall status (PGIC) compared with 25.5% who reported no change or worsening (P < 0.001). Treatment-related adverse events (≥2 patients) during the continuation phase were application site erythema (6.9%), application site swelling (4.6%), and vertigo (4.6%). CONCLUSIONS: FBT may improve patient functioning, mood, and overall satisfaction in the management of BTcP. Long-term data did not indicate new safety concerns with FBT doses up to 800 µg.

Breakthrough cancer pain: a comparison of surveys with European and Canadian patients.

INTRODUCTION: Breakthrough cancer pain is defined as a transient exacerbation of pain that occurs spontaneously or in response to a trigger, despite stable and controlled background pain. Breakthrough pain often causes significant functional impairments for patients and can decrease quality of life. OBJECTIVE: The objective of the study was to determine differences between breakthrough cancer pain incidence and management in Canada and Europe. METHODS: Data collected from previous studies of breakthrough cancer pain in Canada and Europe was compared. A standard survey with identical inclusion/exclusion criteria was utilized for both patient populations. RESULTS: Both groups of patients had a similar number and duration of breakthrough pain episodes, and similar pain intensity and pain interference with their daily activities. European patients reported better analgesic efficacy and satisfaction with management, and a greater percentage of European patients were prescribed a transmucosal fentanyl formulation (19.1 vs 2.9 %). More European patients (55 %) than Canadian patients (32.5 %) took their rescue medication every time they had a breakthrough pain episode. CONCLUSIONS: Breakthrough cancer pain in both Canadian and European patients greatly impacts their daily living, and both groups of patients had similar experiences with breakthrough cancer pain. Currently, this pain is not adequately managed for many patients. The role for new analgesic treatments in management of breakthrough cancer pain needs further study.

Long-term efficacy and tolerability of intranasal fentanyl in the treatment of breakthrough cancer pain.

PURPOSE: The aim of the present study was to assess the long-term tolerability and efficacy of intranasal fentanyl (INFS) in opioid-tolerant patients with breakthrough cancer pain (BTP). PATIENTS AND METHODS: A 6 months, observational, prospective, cohort study design was employed to follow advanced cancer patients with BTP receiving INFS under routine clinical practice. Eligible adult cancer patients suffering from BTP had been prescribed INFS at effective doses. Data were collected at T0 and at month intervals for six months. The principal outcomes were the evaluation of possible serious adverse effects with prolonged use of INFS, the efficacy of BTP treatment with INFS, the quality of sleep, the rate of INFS discontinuation, and reasons for that. RESULTS: Seventy-five patients were surveyed. Thirty-four patients (45.3 %) had a follow-up at 3 months, and twelve patients (16 %) were followed up at 6 months. The mean opioid doses, expressed as oral morphine equivalents, ranged 111-180 mg/day, while the mean INFS doses were 87-119 µg. Adverse effects were reported in a minority of patients and were considered to be associated with opioid therapy used for background pain. The quality of sleep significantly improved during the first 3-4 months. Finally, efficacy based on a general impression regarding the efficacy of INFS was good-excellent in most patients and statistically improved in time up to the third month. CONCLUSION: The long-term use of INFS in advanced cancer patients is effective and safe. No serious adverse effects were found up to six months of assessment. The level of quality of sleep and patients' satisfaction was relatively good, considering the advanced stage of disease.

Efficacy and safety of sublingual fentanyl orally disintegrating tablet at doses determined by titration for the treatment of breakthrough pain in Japanese cancer patients: a multicenter, randomized, placebo-controlled, double-blind phase III trial.

BACKGROUND: Breakthrough cancer pain typically has a rapid onset and relatively short duration. Due to this temporal profile, it may not be adequately relieved by oral opioid analgesics. The sublingual fentanyl orally disintegrating tablet is a formulation by which fentanyl can be rapidly absorbed across the oral mucosa producing rapid-onset analgesia, and which may be effective for breakthrough pain treatment. METHODS: A multicenter, randomized, placebo-controlled, double-blind comparative study was conducted to evaluate the efficacy and safety of the sublingual fentanyl tablet at optimized doses for breakthrough pain treatment in cancer patients treated with strong opioid analgesics at fixed intervals. The optimal dose was determined by open-label dose titration. The efficacy and safety of a 12-week extended treatment were also evaluated. RESULTS: Eleven of 42 subjects who received the sublingual fentanyl tablet experienced adverse drug reactions. Common reactions were somnolence, constipation, nausea, and vomiting. No serious adverse reactions occurred. Sublingual fentanyl tablets at optimal doses and placebo were administered to 37 subjects in a double-blinded manner. A significant analgesic effect of the sublingual fentanyl tablet was present compared to placebo at 30 min after administration. The sublingual fentanyl tablet was also effective and safe during extended treatment, in which changes in basal opioid doses as well as sublingual fentanyl tablet doses were made as needed. CONCLUSION: Sublingual fentanyl tablets at doses determined by titration were effective and safe for breakthrough pain treatment in cancer patients treated with strong opioid analgesics at fixed intervals. Extended treatment up to 12 weeks was also effective and safe.