Interference with daily functioning by breakthrough pain in patients with cancer.

PURPOSE: To investigate the association between quality of life (QOL) and breakthrough cancer pain (BTCP) intensity in patients who met the commonly accepted definition of BTCP. METHODS: This study was a subset analysis of a South Korean multicenter, non-interventional, cross-sectional, nationwide survey. Participants were recruited from March 2016 to December 2017. BTCP was defined as a controlled background pain of less than a numeric rating scale (NRS) of 3 and any flare-up pain intensity. Pain intensity data were collected using the Brief Pain Inventory (BPI), which includes an interference assessment of the affective and physical domains. Patients were categorized by BTCP intensity into mild (NRS 1-3), moderate (4-6), and severe (7-10) groups. RESULTS: Of the 969 screened patients with cancer, 679 had ≤ NRS 3 background pain, of whom 438 completed the BPI. Of these 438 patients, 40, 204, and 194 were in the mild, moderate, and severe BTCP groups, respectively. The median NRS of BTCP was 6.0 (interquartile range = 5.0-8.0). Patients with moderate-severe BTCP had significantly higher interference with daily functioning (IDF) scores than did mild BTCP patients (3.3 vs. 5.7; p < 0.01). Both domains of IDF were significantly hampered proportionally by increased BTCP intensity (p < 0.001). The median total IDF scores of the no, moderate, and severe BTCP groups were 3.3, 5.0, and 6.9, respectively. Furthermore, IDF depended on BTCP intensity, duration, and frequency (p < 0.01) but not on pain type and cause. CONCLUSION: An increase in BTCP intensity is likely to result in IDF, regardless of the cause or type of BTCP.

Characteristics of Breakthrough Pain and Its Impact on Quality of Life in Terminally Ill Cancer Patients.

Purpose. This study aimed to characterize breakthrough pain (BTP) and investigate its impact on quality-of-life (QoL) in terminally-ill cancer patients. Similarities and differences between high and low predictable BTP were also tested. Methods. Secondary analysis of a multicenter longitudinal observational study included 92 patients at their end-of-life. BTP was assessed with a short form of the Italian version of the Alberta Breakthrough Pain Assessment Tool. QoL was assessed with the Palliative Outcome Scale (0-40). Patients were stratified by self-reported BTP predictability into unpredictable BTP (never or rarely able to predict BTP) and predictable BTP (sometimes to always able to predict BTP). Results. In all, 665 BTP episodes were recorded (median 0.86 episodes/day). A median duration of 30 minutes and a median peak intensity score of 7 out of 10 were reported. Time to peak was <10 minutes, 10 to 30 minutes, and ≥30 minutes in 267 (41.1%), 259 (39.9%), and 30 (4.6%) of the episodes, respectively. Onset of relief occurred after a median of 30 minutes. Time to peak (P < .001) and duration (P = .046) of BTP was shorter in patients with predictable pain (n = 31), who usually were younger than those with unpredictable pain (P = .03). The mean (SD) QoL score was 14.6 (4.6). No difference in QoL between patients with predictable and unpredictable BTP was found (P = .49). Conclusions. In terminally-ill cancer patients, BTP is a severe problem with a negative impact on QoL and has different characteristics according to its predictability.

Fentanyl citrate sublingual formulation (Vellofent®) for quick BTcP hindering.

The management of cancer pain presents manifold challenges: even though background pain is adequately controlled, patients frequently experience episodes of acute pain exacerbation known as breakthrough cancer pain (BTcP). The characteristics of BTcP are a rapid onset, a short duration, and a severe intensity. An innovative sublingual fentanyl citrate formulation (Vellofent®) has been developed to target BTcP. The new formulation allows to increase the solubility of fentanyl and to provide optimal oromucosal conditions for rapid drug absorption, thus featuring a shorter time to onset of pain relief (from 6 minutes post-administration).

Study of breakthrough cancer pain in an animal model induced by endothelin-1.

Cancer patients with bone metastases often suffer breakthrough pain. However, little progress has been made in the treatment of breakthrough pain and its associated mechanism(s) in the patient with cancer due to lacking of resembling and predictive animal models. We previously have demonstrated that endothelin-1 plays an important role in breakthrough cancer pain. In the present study, we have established an animal model of breakthrough cancer pain induced by endothelin-1. The animal model of breakthrough cancer pain is strictly followed the definition and meets the characteristics of breakthrough pain. The model is reliable, reproducible and easy to be produced. To our knowledge, this is the first report for establishing such an animal model. In addition, we also found that a selective ETA receptor antagonist BQ-123 could reverse endothelin-1 induced breakthrough pain. We further studied the characteristics of pain behaviors such as hind limb use score and voluntary wheel running as well as the electrophysiology of sciatic nerve fibers with the model. The murine model shows high resemblance compared to the breakthrough cancer pain in the patients with cancer clinically. It provides a platform for further study of the pathogenesis of breakthrough cancer pain and targeted intervention.

The Influence of Low Salivary Flow Rates on the Absorption of a Sublingual Fentanyl Citrate Formulation for Breakthrough Cancer Pain.

CONTEXT: Salivary gland hypofunction may affect the absorption of drugs through the oral mucosa, which in turn may affect their clinical efficacy (e.g., onset of action). OBJECTIVES: The aim of this study was to assess the pharmacokinetics of a sublingual fentanyl orally disintegrating tablet (Abstral, Prostrakan Inc.) in a group of cancer patients with salivary gland hypofunction. METHODS: Nine cancer patients with salivary gland hypofunction underwent a series of three pharmacokinetic studies with the sublingual fentanyl orally disintegrating tablet. In the first phase, the patients received no pretreatment; in the second phase, the patients were allowed to moisten the oral cavity before dosing; in the third phase, the patients were given pilocarpine hydrochloride (saliva stimulant) before dosing. Fentanyl concentrations were measured using a method of high-performance liquid chromatography with validated tandem mass spectrometric detection. RESULTS: The Tmax was longer, the Cmax was lower, the AUC0-30 lower, and the AUClast lower in the phase involving no pretreatment; the Tmax/Cmax/AUC0-30/AUClast were similar in the phase involving moistening of the oral cavity and the phase involving giving pilocarpine hydrochloride. CONCLUSION: The pharmacokinetics of the sublingual fentanyl orally disintegrating tablet appear to be negatively affected by the presence of salivary gland hypofunction, although the moistening of the oral cavity before dosing results in a pharmacokinetic profile similar to that seen with the giving of pilocarpine hydrochloride.

Breakthrough pain in cancer patients: prevalence, mechanisms and treatment options.

PURPOSE OF REVIEW: The aim of this article was to examine the definition, the characteristics, and the management of breakthrough cancer pain (BTP) in cancer patients by a critical review of recent literature. RECENT FINDINGS: BTP should be more correctly defined as an episode of severe intensity in patients receiving an adequate treatment with opioids able to provide at least mild analgesia. BTP is a heterogeneous condition as episodes vary between individuals. BTP can be classified into two big distinct pictures: spontaneous-type and incident-type pain. The principal pharmacological treatment of BTP is represented by the administration of opioids as needed. Recent reviews revealed that transmucosal preparation of fentanyl provided superior and more rapid pain relief as compared with placebo in the first 30 min after dosing. Few comparison studies among fentanyl products have been performed.Finally, although dose titration was recommended for years, a meaningful dosing according to the level of opioid tolerance may enhance the advantages of such products. SUMMARY: BTP represents a serious problem reported by many cancer patients despite receiving regular use of opioids. Subgroups of breakthrough pain have been identified. Different modalities of pharmacological interventions are available. Further studies are warranted to assess the net benefit of these drugs to assist decision-making by patients, clinicians, and payers according to individual clinical conditions.

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.

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 intensity-decrease of ≥33% and ≥50%-between 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.

An Observational Research Study to Evaluate the Impact of Breakthrough Cancer Pain on the Daily Lives and Functional Status of Patients.

Breakthrough cancer pain (BTcP) is common, resulting in significant physical and psychosocial morbidity. We assessed the impact of BTcP on 81 cancer patients attending Irish specialist palliative care services. BTcP occurred up to twice daily in 24 (30%) and 3-4 times daily in 57 (70%) of cases. Median scores for the 'worst' and 'least' pains in the previous 24 hours were 7 and 2/10 respectively. Pain lasted < 15 minutes in 19 (23.5%), 15-30 minutes in 25 (30.8%), 30-60 minutes in 18 (22.2%) and > 60 minutes in 19 (23.5%) of patients. BTcP had a negative impact on general activity, mood, walking ability, work, relations with others, sleep and overall enjoyment of life. BTcP increased anxiety, depression, anger, isolation, financial difficulties and an inability to undergo cancer treatments. Systematic assessment of BTcP should form an integral part of every oncology/palliative medicine assessment. Once identified, BTcP should be managed assiduously.

Accuracy of a Diagnostic Algorithm to Diagnose Breakthrough Cancer Pain as Compared With Clinical Assessment.

CONTEXT: Breakthrough cancer pain (BTCP) is a heterogeneous condition, and there are no internationally agreed standardized criteria to diagnose it. There are published algorithms to assist with diagnosis, but these differ in content. There are no comparative data to support use. OBJECTIVES: To compare the diagnostic ability of a simple algorithm against a comprehensive clinical assessment to diagnose BTCP and to assess if verbal rating descriptors can adequately discriminate controlled background pain. METHODS: Patients with cancer pain completed a three-step algorithm with a researcher to determine if they had controlled background pain and BTCP. This was followed by a detailed pain consultation with a clinical specialist who was blinded to the algorithm results and determined an independent pain diagnosis. The sensitivity, specificity, and positive and negative predictive values were calculated for the condition of BTCP. Further analysis determined which verbal pain severity descriptors corresponded with the condition of controlled background pain. RESULTS: The algorithm had a sensitivity of 0.54 and a specificity of 0.76 in the identification of BTCP. The positive predictive value was 0.7, and the negative predictive value was 0.62. The sensitivity of a background pain severity rating of mild or less to accurately categorize controlled background pain was 0.69 compared with 0.97 for severity of moderate or less; however, this was balanced by a higher specificity rating for mild or less, 0.78 compared with 0.2. CONCLUSION: The diagnostic breakthrough pain algorithm had a good positive predictive value but limited sensitivity using a cutoff score of "mild" to define controlled background pain. When the cutoff level was changed to moderate, the sensitivity increased, but specificity reduced. A comprehensive clinical assessment remains the preferred method to diagnose BTCP.

Pain management of the cancer patient.

INTRODUCTION: Cancer pain is one of the most important symptoms of malignant disease, which has a major impact on the quality of life of cancer patients. Therefore, it needs to be treated appropriately after a careful assessment of the types and causes of pain. AREAS COVERED: The mainstay of cancer pain management is systemic pharmacotherapy. This is, in principle, still based on the WHO guidelines initially published in 1986. Although these have been validated, they are not evidence-based. The principles are a stepladder approach using non-opioids, weak and then strong opioids. In addition, adjuvants can be added at any step to address specific situations such as bone or neuropathic pain. Patients, even if they are on long-acting opioids, need to be provided with immediate-release opioids for breakthrough pain. In case of inefficacy or severe adverse effects of one opioid, rotation to another opioid is recommended. EXPERT OPINION: There is a major need for more and better randomized controlled trials in the setting of cancer pain as the lack of evidence is hampering the improvement of current treatment guidelines.

Breakthrough cancer pain (BTcP): a synthesis of taxonomy, pathogenesis, therapy, and good clinical practice in adult patients in Italy.

Pain presents in 80% of patients with advanced cancer, and 30% have periods of increased pain due to fluctuating intensity, known as breakthrough cancer pain (BTcP). BTcP is high-intensity, short-duration pain occurring in several episodes per day and is non-responsive to treatment. The clinical approach to BTcP is variable. A review of the literature was performed to provide clinicians and practitioners with a rational synthesis of the ongoing scientific debate on BTcP and to provide a basis for optimal clinical approach to BTcP in adult Italian patients. Data show that circadian exacerbations of pain should be carefully monitored, differentiating, if possible, between fluctuations of background pain (BP), end-of-dose effect, and BTcP. BTcP should be monitored in all care contexts in clinical practice and each care facility must have all the medications and products approved for use in BTcP at their disposal. Data show that knowledge about medications for BTcP is lacking: medications for BTcP treatment are not interchangeable, although containing the same active substance; each physician must know the specific characteristics of each medication, its pharmacological properties, limitations in clinical practice, specifics relating to titration and repeatability of administration, and technical specifics relating to the accessibility and delivery. Importantly, before choosing a rapid-onset opioid (ROO), it is essential to deeply understand the status of patient and the characteristics of their family unit/caregivers, taking into account the patient's progressive loss of autonomy and/or cognitive-relational functionality. When BTcP therapy is initiated or changed, special attention must be paid to training the patient and family members/caregivers, providing clear instructions regarding the timing of drug administration. The patient must already be treated effectively with opioids before introducing ROOs for control of BTcP.

Managing difficult pain conditions in the cancer patient.

Whereas most pain due to cancer can be relieved with relatively simple methods using oral analgesics, as suggested by WHO guidelines, some patients may have difficult pain situations that require more complex approaches. It is estimated that 10-20 % of cancer patients suffer from pain that is not easily relieved. There are a number of factors that may reduce the efficacy of opioids in the management of cancer pain. Neuropathic pain (NP) and breakthrough pain (BP), especially of the incident subtype, have been identified as challenges for clinicians. In several prognostic studies, these two mechanisms were associated with limited positive outcomes compared with other syndromes. Opioid-induced hyperalgesia has recently been described as representing a challenge for physicians in the clinical setting. The global response to opioids, including the development of adverse effects, typically varies by individual and is likely genetically determined. Moreover, clinical evidence suggests that different opioids may produce different effect profiles, and so it is more appropriate to consider the response to each individual opioid rather than general opioid response. This paper will review both pharmacological and procedural mechanisms and treatments of these difficult pain syndromes.

Breakthrough cancer pain: the current situation.

Breakthrough pain is common in patients with cancer. This paper describes the clinical features of breakthrough cancer pain (BTcP) and its impact on activities of daily living. It also describes the principles of BTcP management, highlighting some of the current issues and problems. A follow-up paper will describe current approaches to managing BTcP.

Breakthrough pain in patients with abdominal cancer pain.

OBJECTIVE: Characterization of breakthrough cancer pain (BTcP) in patients with abdominal cancer is lacking. The aim of this study was to assess the characteristics of BTcP in patients with abdominal cancer pain. PATIENTS AND METHODS: In an observational cohort study, from a consecutive sample of patients admitted to a pain relief and supportive care unit for a period of 13 months, patients with abdominal disease due to cancer, including primary cancer or metastases, were assessed for the presence of chronic abdominal pain; its mechanism, intensity of background pain, and pain flares, which were distinguishable from the baseline pain, were recorded. Patients presenting with pain flares were assessed regarding the causes and the possible factors associated with it. Patients were reassessed when background pain control was considered optimal. RESULTS: From a sample of 522 patients admitted to an acute pain relief and palliative care unit in a period of 13 months, 100 patients with abdominal disease were available. The mean age was 65.3 years (SD±11.4); of the 100 patients, 45 (45%) were males. The mean Karnofsky status was 47.7 (SD±11.1). At admission (T0), 67 patients (67%) had background pain with mean pain intensity of 4.9 (SD±1.6). Sixty-one patients of those with background pain (91%) had superimposed and well-distinguished pain flares. After analgesic optimization (T1), the mean background pain intensity was 1.7 (SD±1.2), and 55.2% of patients had BTcP episodes. The difference with T0 was significant (P<0.0005). CONCLUSIONS: This preliminary study provides new insights on the characteristics of BTcP in a subclass of patients with abdominal disease. It has been estimated that about 55% of patients with well-controlled background pain will develop BTcP episodes. This percentage was higher (about 90%) in patients who presented with uncontrolled background pain, underlying the need to better characterize patients with BTcP, only after a careful optimization of basal pain, as considered by the definition of BTcP.

A randomized, double-blind, placebo-controlled study of fentanyl buccal tablets for breakthrough pain: efficacy and safety in Japanese cancer patients.

CONTEXT: Rapid-onset opioids for treating breakthrough pain (BTP) in patients with cancer are needed in the Japanese care setting. OBJECTIVES: To examine the efficacy and safety of fentanyl buccal tablets (FBTs) for treating BTP in Japanese cancer patients. METHODS: This was a randomized, double-blinded, placebo-controlled study. In subjects receiving around-the-clock (ATC) opioids at doses of 30 mg or more to less than 60 mg or 60-1000 mg of oral morphine equivalents (low and high ATC groups), dose titration was started from 50 to 100 µg FBT, respectively. Subjects whose effective dose was identified were randomly allocated to a prearranged administration order of nine tablets (six FBTs and three placebos), one tablet each for nine episodes of BTP (double blinded). Efficacy and safety of FBT were assessed for patients overall, and also for the low and high ATC groups. RESULTS: A significant difference was observed between FBT and placebo for the primary endpoint of pain intensity difference at 30 minutes. The analgesic onset of FBT was observed from 15 minutes in several secondary variables (e.g., pain relief). Adverse events were somnolence and other events associated with opioids were mostly mild or moderate. Of the low and high ATC group subjects, an effective FBT dose was identified in 72.2% and 73.1%, respectively. CONCLUSION: The safety of FBT and its analgesic effect on BTP were confirmed in Japanese cancer patients receiving opioids. Our findings suggest that analgesic onset may occur from 15 minutes after FBT, and that FBT can be administered to patients with low doses of ATC opioids.

Prevalence of breakthrough cancer pain: a systematic review and a pooled analysis of published literature.

CONTEXT: Despite the large body of literature on breakthrough cancer pain (BTcP), an accurate estimate of BTcP prevalence is still not available. OBJECTIVES: To provide an estimate of BTcP prevalence and investigate the association between different prevalence rates and possible determinants. METHODS: We conducted MEDLINE and EMBASE searches for studies published from 1990 to 2012 reporting data on BTcP prevalence in adult cancer populations. Pooled prevalence rates from observational studies with an acceptable methodological quality were computed. The association between BTcP prevalence and possible predictors was investigated using subgroup analyses and meta-regression. RESULTS: Twenty-seven observational studies were identified. When quality criteria were applied, only 19 studies were included in the pooled analysis. The overall pooled prevalence was 59.2%, with high heterogeneity. The lowest prevalence rates were detected in studies conducted in outpatient clinics (39.9%), and the highest prevalence was reported in studies conducted in hospice (80.5%). The association between BTcP prevalence and other determinants such as publication year, age, gender, metastatic disease prevalence, or baseline pain intensity did not reach statistical significance. CONCLUSION: In the context of a large between-studies heterogeneity, more than one in two patients with cancer pain also experiences BTcP, with some variability according to clinical and organizational variables.

A network meta-analysis of the efficacy of opioid analgesics for the management of breakthrough cancer pain episodes.

CONTEXT: With many medications available for the management of breakthrough cancer pain (BTCP), physicians may require additional guidance in selecting an appropriate medication to suit an individual patient's needs. OBJECTIVES: To identify all the evidence and assess the relative clinical value of currently approved BTCP medications. METHODS: Following a systematic literature search (2007-2010), the results of 10 randomized controlled trials investigating the effects of BTCP medications (intranasal fentanyl spray [INFS], fentanyl pectin nasal spray, fentanyl sublingual tablets, fentanyl buccal soluble film, fentanyl buccal tablets, oral transmucosal fentanyl citrate, and morphine sulfate immediate release) were synthesized using a network meta-analysis. The main outcome was pain intensity difference (PID) relative to placebo up to 60 minutes after the intake of medication. RESULTS: INFS, fentanyl pectin nasal spray, fentanyl buccal tablet, and oral transmucosal fentanyl citrate showed greater PIDs relative to placebo than other BTCP medications 15 minutes after intake. All other medications showed greater PIDs relative to placebo at 30 minutes, except morphine sulfate immediate release, which did not show efficacy over placebo until 45 minutes. Only INFS produced clinically meaningful pain relief (absolute PID ≥2) at 15 minutes. CONCLUSION: From current evidence, although all BTCP medications provided pain relief within the time frames assessed, transmucosal fentanyl medications achieved a greater level of pain relief in a shorter time frame than placebo or oral morphine.

A report on the long-term use of fentanyl pectin nasal spray in patients with recurrent breakthrough pain.

CONTEXT: As patients with cancer are living longer, there is a need to ensure that treatments used for palliative care are well tolerated and effective during long-term use. OBJECTIVES: To investigate the long-term use of fentanyl pectin nasal spray (FPNS) for the treatment of breakthrough pain in cancer (BTPc) in patients receiving regular opioid therapy. METHODS: Adult patients (N = 401) taking at least 60 mg/day oral morphine or equivalent, experiencing one to four episodes of BTPc a day, entered an open-label long-term study (NCT00458510). Patients had either completed an FPNS randomized controlled trial or were newly identified. Of these, 171 patients continued into an extension study. Up to four episodes of BTPc a day were treated with FPNS at 100-800 µg titrated doses. During the extension study, patients visited the clinic every four weeks for assessment and reporting of adverse events (AEs). RESULTS: There were 163 patients with documented FPNS use. The mean duration of use was 325 days; 46 patients used FPNS for ≥360 days; the maximum duration was 44 months. Seventy percent of patients did not change their FPNS dose; 2% of patients withdrew from the study because of the lack of efficacy. The most common AEs, aside from disease progression, were insomnia, 9.9%; nausea, 9.4%; vomiting, 9.4%; and peripheral edema, 9.4%. The overall incidence of FPNS-related AEs was 11.1%, the most common being constipation (4.1%), with no apparent dose relationship. Ten patients (5.8%) experienced nasal AEs, most of which were mild or moderate. CONCLUSION: FPNS appeared to provide sustained benefit and was well tolerated during long-term treatment of BTPc.