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 .

An overview of the current drug treatment strategies for moderate to severe, chronic malignant tumor-related pain.

INTRODUCTION: The pharmacological management of cancer pain is a complex issue that requires knowledge and experience in the use of analgesics. The aim of this expert review is to provide a panorama of the pharmacological strategies in cancer pain management. AREAS COVERED: Opioid dose titration is a delicate process regarding the start of opioid treatment in different clinical conditions. How to improve the opioid response is a fundamental step, which includes different strategies when an initial treatment with opioids fails. The use of adjuvants is another relevant issue that should be considered in some specific circumstances to optimize the management of cancer pain management. Some clinical conditions, such as neuropathic pain and breakthrough pain, deserve a special attention. Relevant literature was selected to provide an overview of cancer pain management strategies. EXPERT OPINION: Opioid therapy still remains the cornerstone of pharmacological management of cancer pain. Opioids should be used according to the level of tolerance, also personalizing the treatment (route, drug, and dosing). Adjuvant drugs may help in specific conditions, although their use should be balanced with the adverse effects. Breakthrough pain requires expertise in tailoring a treatment according to patient's profile and characteristics of episodes.

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.

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.

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.

Association between breakthrough labor pain, patient-controlled epidural analgesia use, and numeracy: A pilot observational study.

OBJECTIVE: Labor analgesia can be maintained with a continuous epidural infusion, supplemented by patient-controlled epidural boluses. patient-controlled epidural boluses use and timing require numeric understanding, as patients need to understand when they can administer supplemental boluses, lockout intervals, and total doses. We hypothesized that women with lower numeric literacy have a higher rate of provider-administered supplemental boluses for breakthrough pain because they do not understand the concept behind patient-controlled epidural boluses. DESIGN: Pilot observational study SETTING: Labor and Delivery Suite PARTICIPANTS: Nulliparous, English-speaking patients with singleton, vertex pregnancies admitted for postdates (gestational age ≥ 41 weeks) induction of labor requesting neuraxial labor analgesia. INTERVENTIONS: Combined spinal-epidural labor analgesia was initiated with intrathecal fentanyl and epidural analgesia was maintained using continuous epidural infusion with patient-controlled epidural boluses. MEASUREMENTS AND FINDINGS: Numeric literacy was assessed using the Lipkus 7-item expanded numeracy test. Patients were stratified by whether or not they required supplemental provider-administered analgesia and patient-controlled epidural boluses use patterns were evaluated. A total of 89 patients completed the study. There were no demographic differences between patients who required supplemental analgesia compared with those who did not. Patients that required supplemental analgesia were more likely to request and receive patient-controlled epidural boluses (P<0.001). Hourly bupivacaine requirement was higher in women with breakthrough pain. There were no differences in numeric literacy between the two groups. KEY CONCLUSIONS: Patients who required treatment of breakthrough pain had higher patient-controlled epidural boluses demands-to-delivery ratio. Numeric literacy was not correlated with the need for provider-administered supplemental boluses. IMPLICATIONS FOR PRACTICE: Easy to understand scripts on how to use patient-controlled epidural boluses allows for understanding of patient-controlled epidural boluses use.

Efficacy of Patient-Controlled Intravenous Analgesia with Esketamine for Herpes Zoster Associated with Breakthrough Pain.

BACKGROUND: Some patients with herpes zoster (HZ) experience an intermittent spontaneous, short-lived and severe pain, which is called breakthrough pain (BTP). The effect of analgesic drugs and invasive procedures is not significant. Therefore, treatment of HZ associated with BTP is challenging. Esketamine is a new N-methyl-D-aspartate receptor antagonist, with enhanced analgesic effects. This study aimed to evaluate the efficacy and adverse reactions of patient-controlled intravenous analgesia (PCIA) with low-dose esketamine for HZ associated with BTP. OBJECTIVES: To evaluate the efficacy and adverse reactions of PCIA with low-dose esketamine for HZ associated with BTP. STUDY DESIGN: A retrospective, observational study. SETTING: The study was carried out in the Pain Department of the Affiliated Hospital of Jiaxing University in Jiaxing, China. METHODS: The clinical data of HZ associated with BTP treated by PCIA with low-dose esketamine at the Pain Department of the Affiliated Hospital of Jiaxing University, between October 2015 to October 2021, were collected retrospectively. The Numeric Rating Scale (NRS-11) scores of rest pain (RP) and BTP, frequency of BTP, Pittsburgh Sleep Quality Index (PSQI) score, and fasting blood glucose (FBG) were recorded and analyzed before treatment (T0) and on days one (T1) and 3 (T2), week one (T3), months one (T4), 3 (T5), and 6 (T6) after treatment. Adverse reactions during the treatment were recorded. RESULTS: Twenty-five patients treated by PCIA with low-dose esketamine were included finally. Compared with T0, the NRS-11 scores of RP at T2, T3, T4, T5, and T6 decreased significantly (P < 0.05). The NRS-11 score of RP at T4 was significantly lower than that of T3 (P < 0.001), but there was no statistical difference between T5 and T4 (P > 0.05), the efficacy of esketamine in the treatment of RP was stable at one month after treatment. Likewise, compared with T0, the NRS-11 scores of BTP, frequency of BTP, and PSQI score decreased significantly at each time point after treatment (P < 0.05). These at T5 were significantly lower than T4 (P < 0.05), but there was no statistical difference between T6 and T5 (P > 0.05), the efficacy of esketamine was stable at 3 months after treatment. FBG also decreased significantly at each time point after treatment (P < 0.05), it tended to be normal and stable one month after treatment. All patients had mild symptoms of dizziness during treatment, and though a slight increase in noninvasive blood pressure (BP) was noted in all, the elevated BP did not exceed 30% of the baseline value. Four patients (16%) developed nausea without vomiting. There were no serious adverse reactions, such as respiratory depression. LIMITATIONS: The nonrandomized, single-center, small sample size, retrospective design is a major limitation of this study. CONCLUSIONS: PCIA with low-dose esketamine has a significant and long-term effect in the treatment of HZ associated with BTP. The RP was controlled, and the degree and frequency of BTP were significantly reduced after treatment, leading to improved quality of life. There were no serious adverse reactions worthy of clinical promotion.

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.

Breakthrough cancer pain in the radiotherapy setting: a systematic and critical review.

INTRODUCTION: Breakthrough pain (BP) is a complex phenomenon that has been reported to have a relevant role in the global management of cancer pain. Radiotherapy (RT) has a fundamental part in the treatment of many pain conditions, particularly oral mucositis and painful bone metastases. AREAS COVERED: The literature regarding the phenomenon of BP in the radiotherapy setting was reviewed. Three areas were assessed, including epidemiology, pharmacokinetics, and clinical data. EXPERT OPINION: Qualitative and quantitative data regarding BP in the RT setting are poor in terms of scientific evidence. Most papers assessed fentanyl products, particularly fentanyl pectin nasal spray, to resolve possible problems with transmucosal absorption of fentanyl due to mucositis of the oral cavity in patients with head and neck cancer or to prevent and treat procedural pain during RT sessions. According to the lack of clinical studies with large number of patients, BP should be included in the agenda of radiation oncologists.

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.

Retrospective Observational Study on the Characteristics of Pain and Associated Factors of Breakthrough Pain in Advanced Cancer Patients.

Objective: This study aimed to conduct a retrospective observational study to understand the status of characteristics of pain and identify potential variables influencing the clinical presentation of breakthrough cancer pain (BTP) in advanced cancer patients. Methods: Advanced cancer patients over 18 years of age; diagnosed with cancer of any type and stage III or IV in the palliative care ward with available data were enrolled between 2018 and 2020. Demographic data and pain-related information were collected by using structured electronic extraction form from Hospital Information System (HIS). Patients who had well-controlled background pain with an intensity ≤4 on a 0-10 numerical scale for >12 hours/day, the presence of transient exacerbations of pain with moderate-severe intensity (≧5), and clearly distinguish from background pain were regarded to have suffered BTP. Spearman correlation was conducted to explore the relationship between pain score and demographics characteristics. Factors significant in univariate analysis were included in the multiple regression model to explore independent predictive factors associated with the BTP. Results: Of 798 advanced cancer patients, the mean age was 56.7 (SD = 11.84) years. Lung cancer (29.95%) was the most common cancer, and pain (93%) was the most common symptom. More than half (n = 428, 53.6%) of the patients experienced BTP. The median number of BTP episodes was 4 (IQR = 2, 7, range: 1-42). The median intensity of BTP was 6 (IQR = 6, 7, range 5-10). Patients with severe background pain or BTP had longer hospital stay and more symptoms. Besides, more severe background pain was related to higher activity of daily living. Intramuscular injection of hydromorphone hydrochloride was the main medication for BTP onset. Younger age, background pain, anorexia, and constipation were independently associated with the presentation of BTP. BTP pain intensity was independently associated with bloating. Symptom numbers were an independent factor and positively associated with BTP episodes. Conclusions: BTP resulted in poor prognosis, which has a variable presentation depending on interdependent relationships among different characteristics. Good controlling of background pain and assessment of pain-related symptoms are essential for BTP management. BTP should be managed individually, especially the invisible pain among aged patients. Furthermore, BTP-related education and training were still needed.

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.

The combined analgesic effect of pregabalin and morphine in the treatment of pancreatic cancer pain, a retrospective study.

BACKGROUND: Pregabalin is commonly used to relieve neuropathic pain. However, data are lacking on its efficacy for the treatment of chronic cancer pain. The purpose of this study was to determine the analgesic efficacy of pregabalin combined with morphine in the management of pancreatic cancer pain. METHODS: This study reviewed patients who were prescribed morphine and 150 mg/d pregabalin between 1 January 2017 and 10 November 2018 in our institute. The primary outcomes of this study were the average pain score and dose of morphine. Secondary outcomes included characters of breakthrough cancer pain, functional interference related to pain, anxiety/depression status, and incidence of treatment-related adverse events during the study. RESULTS: A total of 240 patients with pain related to pancreatic cancer were included in the study. The results showed that patients of both combination therapy group (pregabalin+morphine) and monotherapy group (morphine) achieved similar analgesic efficacy, demonstrated by NRS (2.4 ± 0.9 vs. 2.6 ± 0.9; combination vs. monotherapy) at the end of the study. Mean daily dose of morphine used in the combination group was significant lower compared to monotherapy group (39.5 ± 16.0 mg vs. 61.5 ± 19.3 mg, net difference 23.5, 95% CI: 18.4-28.6, p < â€Š0.001). The change of functional interference score related to pain was significantly different between combination and monotherapy group (12.0 ± 0.4 vs. 9.8 ± 4.9; net difference, 2.3; 95% CI: 1.1-3.3; p < 0.001). Patients in combination therapy group had experienced shorter duration of breakthrough cancer pain than those in monotherapy group (X2 p < 0.001, Cramer's V:0.36). The incidence of somnolence, dizziness, and cognitive dysfunction were significantly higher in the combination group compared to monotherapy group. No serious treatment-related side effects were observed. CONCLUSIONS: The findings of this study supported the use of pregabalin with morphine to relieve pain in patients of pancreatic cancer.

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).

Study on dosage range evaluation opioid analgesic for breakthrough pain in cancer patients: a retrospective study.

BACKGROUND: Breakthrough pain is an exacerbation of pain occurring in patients with chronic pain who receive opioid therapy every day. Breakthrough pain has not been routinely recognized, evaluated and treated. This study aimed to analyze the utilization of opiates analgesics, including dose regimentation, frequency of use, and the actual adverse effects in cancer patients with breakthrough pain. METHODS: Data were collected by the retrospective method in the period from January to December 2017. Patients involved received opioids around the clock for treating background pain and rescue medication for treating breakthrough pain. The percentage of the rescue medication dose was calculated based on the total daily opioid dose to treat background pain. Descriptive analysis was used. RESULTS: From 335 visits, there were 334 of patient visit where the patient received immediate-release morphine as a rescue medication with a dose percentage between 6.67-60%, and 1 visit where the patient received codeine with a dose percentage of 16.67%. Of 335 visits, 233 patient visits received the right proportion of opioid rescue medication doses, while 102 patient visits received a greater dose proportion than the recommended dose of 5-20%. CONCLUSIONS: Immediate-release morphine is the most commonly prescribed analgesic to treat breakthrough pain and used at 6.67-60% of daily dose with the frequency of use between 2 to 6 times a day. There were 189 (56.42%) patient visits when the patient experienced the adverse effects of the opioid. The identified actual adverse effects are constipation, nausea, and vomiting.

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.

A randomized, double-blind, crossover, dose ranging study to determine the optimal dose of oral opioid to treat breakthrough pain for patients with advanced cancer already established on regular opioids.

BACKGROUND: Pain in people with advanced cancer is prevalent. When a stable dose of opioids is established, people still experience episodic breakthrough pain for which dosing of an immediate release opioid is usually a proportion of the total daily dose. METHODS: This multi-site, double blind, randomized trial tested three dose proportions (1/6, 1/8, 1/12 of total daily dose) in two blocks, each block with three dose proportions in random order (6 numbered bottles in total). When participants required opioid breakthrough doses and it was their first breakthrough dose for that study day, they took the next numbered bottle rather than their usual breakthrough dose. (Subsequent doses on that day reverted to their usual dose.) RESULTS: Eighty-five people were randomized in this study of whom 81 took at least one dose and 73 (90%) took at least block one (one of each dose proportion). No dose was found to be optimal at 30 min with approximately one-third of participants showing maximal reduction with each dose proportion. Median time to pain relief was 120 min. There were no differences in harms: drowsiness, confusion, nausea or vomiting at 30, 60 or 120 min. CONCLUSIONS: This adequately powered study did not show any difference with three dose proportions for reduction in pain intensity, time to pain relief, pain control on the subsequent day nor any difference in harms. From first principles, this suggests 1/12 the 24 hourly dose should be used as the lowest dose that delivers benefit. Future studies should include a placebo arm. SIGNIFICANCE: Despite the widespread use of immediate release morphine solution for breakthrough cancer pain, the ideal dose derived from background dose has not been determined in an adequately powered randomized, double-blind, crossover, dose ranging study. This study tested three dose levels in people with advanced cancer. Given no differences in time to onset, level of analgesia achieved, nor side effects, the lowest dose tested (1/12th of the daily dose) should be used.

Breakthrough cancer pain: review and calls to action to improve its management.

In this paper, we review the current state of breakthrough cancer pain (BTcP) management. BTcP is a heterogeneous condition and a global problem for cancer patients. It is often managed suboptimally, which results in a negative outcome for patients, healthcare providers, and healthcare systems. Several barriers to the appropriate management of BTcP have been identified. These include, among others, an incomplete definition of BTcP, poor training of healthcare providers and patients alike, a lack of a multidisciplinary approach and the absence of specific protocols and tools. We provide some actions to help physicians and patients improve their approach to BTcP, including specific training, the design of easy-to-use tools for BTcP identification and assessment (such as checklists and pocket-sized cards), individualized treatment, and the use of multidisciplinary teams.