Intranasal Fentanyl Versus Fentanyl Pectin Nasal Spray for the Management of Breakthrough Cancer Pain in Doses Proportional to Basal Opioid Regimen

The aim of this randomized, crossover, comparison study was to assess the analgesic and adverse effects of 2 nasal preparations, intranasal fentanyl (INFS) and fentanyl pectin nasal spray (FPNS), for breakthrough pain, given in doses proportional to opioid basal regimen. Each patient randomly received INFS or FPNS in doses proportional to opioid dosages used for background analgesia for 2 pairs of episodes. For each episode of breakthrough pain, pain intensity and adverse effects intensity were recorded just before starting the INFS or FPNS (T0) and 5 minutes (T5), 10 minutes (T10), and 20 minutes (T20) after the administration of the nasal drugs. Sixty-nine patients were studied. The mean age was 63.4 years, and 37 patients were males. For the present analysis, 188 episodes were considered. A statistical decrease in pain intensity was observed with both nasal drugs after 5, 10, and 20 minutes. A decrease in pain intensity of >33% was observed in 16, 102, and 159 treated episodes at T5, T10, and T20, respectively. Adverse effects were of mild nature in most cases or were preexistent because of basal opioid therapy. No differences were found in summed pain intensity difference 20 minutes after dosing. Most of patients did not find substantial preferences. INFS and FPNS were effective and well-tolerated treatments for breakthrough pain management. Both delivery systems, in doses proportional to the basal opioid regimen, provided significant analgesia within 10 minutes, without producing relevant adverse effects.PerspectiveThis article showed that INFS and FPNS in doses proportional to basal opioid regimen are equally safe and effective for the management of breakthrough pain in cancer patients. These data provide new insights on the use of nasal preparations of fentanyl.     

Transmucosal Immediate-Release Fentanyl for Breakthrough Cancer Pain: Opportunities and Challenges for Use in Palliative Care

Opioids are used to treat breakthrough cancer pain (BTCP) and can be classified by relative duration and onset of action. Regulatory approvals of numerous transmucosal immediate-release fentanyl (TIRF) formulations provide alternative options to palliative care–trained providers in the management of BTCP. TIRFs have been formulated as a sublingual tablet, sublingual spray, intranasal spray, pectin-based nasal spray, buccal tablet, and buccal soluble film. Differences exist between TIRFs regarding formulation design and dosing to treat BTCP. Opportunities for use include palliation of BTCP in head and neck cancer and/or radiation-induced mucositis. The purpose of this review is to discuss TIRF formulation and dosing, pharmacokinetics, clinical efficacy, patient acceptability, and safety/tolerability. In addition, barriers to TIRF utilization will be discussed.     

Breakthrough Cancer Pain in Patients With Abdominal Visceral Cancer Pain

Objective

The objective of this study was to assess the characteristics of breakthrough cancer pain (BTcP) in patients with abdominal cancer pain, and the eventual factors associated with its presentation.

Population Pharmacokinetics of Transdermal Fentanyl in Patients With Cancer-Related Pain

ABSTRACT

Determining the appropriate dose of transdermal fentanyl (TDF) for the alleviation of cancer pain requires determining the factors causing variations in serum fentanyl concentration after TDF treatment. The objective of this study was to identify these factors and incorporate them into a formula that can be used to predict serum fentanyl concentration after application of a TDF patch. Blood samples of cancer patients treated with a TDF patch for the alleviation of pain were collected at 24, 48, and 72 hours after application to evaluate population pharmacokinetics using the nonlinear mixed-effect model (NONMEM). Based upon this evaluation, Child-Pugh Score and use of a cytochrome P450 3A4 (CYP3A4) inducer were identified as the most significant factors in variations in serum fentanyl concentration and incorporated into the following Final Model formula: CL_fenta (L/h) = 3.53 × (15 ? Child-Pugh Score) × (1 + 1.38 × use or no use of CYP3A4 inducer). Bootstrap evaluation of the Final Model revealed a high convergence rate, suggesting that the model formula is a reliable and useful tool for determining TDF dose for the alleviation of cancer pain.     

Efficacy and Safety of Oral or Nasal Fentanyl for Treatment of Breakthrough Pain in Cancer Patients: A Systematic Review

Formulations of fentanyl that use buccal, sublingual, or nasal transmucosal routes of administration have been developed for the treatment of BTP in opioid-tolerant patients with cancer. The purposes of this analysis were to identify and review published data describing the efficacy and safety of different oral or nasal transmucosal fentanyl formulations for treatment of cancer-related BTP, based on a critical analysis of scientific literature. Oral transmucosal or intranasal fentanyl is an effective treatment for management of BTP episodes due to a potent analgesic effect, rapid onset of action, and sustained effect. Furthermore, it is a reasonably safe treatment, causing generally mild adverse events not leading to treatment discontinuation. Nevertheless, further progress in standardizing methodology, definitions, and criteria used both in research and in clinical practice is needed in order to generate quality information allowing a better understanding of the comparable efficacy of available formulations of fentanyl. A more rigorous assessment of long-term safety is also needed to establish a balance between benefits and risks of the available options.     

Validation of the Dutch Version of the Breakthrough Pain Assessment Tool in Patients With Cancer

ContextEssential for adequate management of breakthrough cancer pain is a combination of accurate (re-)assessment and a personalized treatment plan. The Breakthrough Pain Assessment Tool (BAT) has been proven to be a brief, multidimensional, reliable, and valid questionnaire for the assessment of breakthrough cancer pain.ObjectivesThe aim of this study was to examine the validity and reliability of the Dutch Language version of the BAT (BAT-DL) in patients with cancer.MethodsThe BAT was forward-backward translated into the Dutch language. Thereafter, the psychometric properties of the BAT-DL were tested, that is factor structure, reliability (internal consistency and test-retest reliability), validity (content validity and construct validity), and the responsiveness to change.ResultsThe BAT-DL confirmed the two-factor structure in 170 patients with cancer: pain severity/impact factor and pain duration/medication efficacy factor. The Cronbach's alpha coefficient was 0.72, and the intraclass correlation for the test-retest reliability was 0.81. The BAT-DL showed to be able to differentiate between different group of patients and correlated significantly with the Brief Pain Inventory. In addition, the BAT-DL was capable to detect clinically important changes over time.ConclusionThe BAT-DL is a valid and reliable questionnaire to assess breakthrough pain in Dutch patients with cancer and is a relevant questionnaire for daily practice.     

A multicenter, placebo-controlled, double-blind, multiple-crossover study of Fentanyl Pectin Nasal Spray (FPNS) in the treatment of breakthrough cancer pain

This randomized, double-blind, crossover study assessed the efficacy and tolerability of a new rapid onset nasal fentanyl formulation (Fentanyl Pectin Nasal Spray; FPNS) for breakthrough cancer pain (BTCP). Eighty-three of 114 patients experiencing one to four BTCP episodes/day while taking ?60 mg/day of oral morphine or equivalent successfully identified an effective dose of FPNS during a titration phase and entered a double-blind phase in which 10 BTCP episodes were treated with this effective dose (7) or placebo (3). Compared with placebo, FPNS significantly improved mean summed pain intensity difference (SPID) from 10 min (P < 0.05) until 60 min (P < 0.0001), including the primary endpoint at 30 min (P < 0.0001). FPNS significantly improved pain intensity (PI) scores as early as 5 min (P < 0.05); pain intensity difference (PID) from 10 min (P < 0.01); and pain relief (PR) scores from 10 min (P < 0.001). More patients showed a clinically meaningful (?2-point reduction in PI) pain reduction from 10 min onward (P ? 0.01) and 90.6% of the FPNS-treated versus 80.0% of placebo-treated BTCP episodes did not require rescue medication (P < 0.001). Approximately 70% of patients were satisfied or very satisfied with the convenience and ease of use of FPNS. Only 5.3% of patients withdrew from treatment due to adverse events, no significant nasal effects were reported, and 87% of patients elected to continue open-label treatment post-study. In this short-term study, FPNS was safe, well tolerated, and rapidly efficacious for BTCP.     

A Randomized,Double-Blind,Placebo-Controlled Study of Fentanyl Buccal Tablets for Breakthrough Pain: Efficacy and Safety in Japanese Cancer Patients

ContextRapid-onset opioids for treating breakthrough pain (BTP) in patients with cancer are needed in the Japanese care setting.ObjectivesTo examine the efficacy and safety of fentanyl buccal tablets (FBTs) for treating BTP in Japanese cancer patients.MethodsThis 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.ResultsA 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.ConclusionThe 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.     

Consistent and Clinically Relevant Effects with Fentanyl Buccal Tablet in the Treatment of Patients Receiving Maintenance Opioid Therapy and Experiencing Cancer‐Related Breakthrough Pain

Fentanyl buccal tablet (FBT) has shown efficacy and tolerability in patients with cancer‐related persistent pain treated with maintenance opioids. We conducted a combined analysis of two similarly designed, randomized, placebo‐controlled studies to further evaluate the consistency and clinical relevance of analgesia outcomes. Of the 252 patients enrolled, 150 fulfilled the criteria for efficacy analysis and experienced 1,417 breakthrough pain episodes. A consistently greater effect was noted with FBT vs. placebo on the following measures: improvements from baseline of ≥33% and ≥50% in pain intensity (PI), a ≥2‐point reduction in PI, and a score of ≥2 for pain relief. Improvements in these clinically meaningful efficacy measures were seen with FBT at 15 minutes (earliest common evaluation) and remained evident at 60 minutes (final common evaluation). They were also reflected in a more favorable global medication performance assessment for FBT over placebo. FBT was generally well tolerated; most adverse events were typical of potent opioid use in a cancer population. Application‐site (buccal) abnormalities were infrequent and led to withdrawal of three patients. There were no serious adverse events or deaths attributable to FBT. This analysis suggests that FBT provides an analgesic effect that is consistent across multiple clinically relevant efficacy measures.     

Breakthrough Cancer Pain: Mending the Break in the Continuum of Care

ABSTRACT

On February 23, 2010, the American Pain Foundation (APF), a nonprofit organization that promotes pain research and increased investments in pain research, hosted a roundtable discussion at Beth Israel Medical Center on cancer-related pain, with a specific focus on breakthrough cancer pain. This report summarizes discussions from that meeting, including recommendations and areas of consensus.     

Intranasal Fentanyl Versus Placebo for Treatment of Episodic Breathlessness in Hospice Patients With Advanced Nonmalignant Diseases

ContextEpisodic breathlessness is a distressing and difficult to treat symptom because of its short duration. Fast actioned intranasal fentanyl (INF) is potentially more suitable than oral opioids.ObjectivesTo examine the feasibility, preliminary efficacy, and safety of INF for the treatment of episodic breathlessness from advanced nonmalignant conditions in hospice patients.MethodsPhase IIB, double-blind, randomized controlled, multisite, INF citrate solution vs. placebo crossover feasibility study. Opioid-tolerant patients were to treat six episodes of breathlessness using INF spray. The primary outcome was change in the Visual Analogue Scale for dyspnea (VAS-D) score from baseline to 15 minutes after study drug's administration (VAS-D₁₅). Other outcomes were to collect demographic data and determine the use of rescue medications, safety, and feasibility of the study design.ResultsTwenty-one of 49 eligible patients were enrolled, and 19 (90%) patients completed the study. The mean difference in VAS-D₁₅ between fentanyl and placebo was ?3.37 mm (95% CI = ?10.35 to 3.61 mm; P = 0.337). There was no statistically significant or clinically meaningful difference between INF and placebo in relieving the sensation of discomfort in episodic breathlessness. No significant drug-related adverse event or detrimental effect on vital signs was observed.ConclusionWe found no difference between INF and placebo in relieving episodic breathlessness in nonmalignant conditions. INF was well tolerated, and the study design proved to be feasible in hospice patients with advanced diseases. Future study using higher concentration of fentanyl solution may be warranted.     

Improved Pain Resolution in Hospitalized Patients through Targeting of Pain Mismanagement as Medical Error

Current strategies to reduce excess pain among hospitalized patients remain inadequate. New, effective approaches are urgently needed. In this prospective observational study of a performance-improvement intervention, we studied the effect of computer-generated, real-time alerts used by nurses on the rate of a medical error in pain management defined as lack of reassessment within 120 minutes from the last observation of severe pain. We also studied duration of severe pain events and frequency of treatment of opioid-related adverse effects. Analyses of 51,619 consecutive observations of severe pain were performed in monthly intervals. Significant decrease in error rate (delayed pain reassessment) was observed postintervention (mean ± standard error [SE]: 35.8% ± 0.7%) compared with preintervention rate (56.2% ± 1.4%, P < 0.0001). Among 6305 unique severe pain events examined during four months pre- and postintervention, time to resolution of severe pain decreased significantly (median time preintervention [January 2006] of 195 minutes compared with median time postintervention of 117, 106, and 101 minutes [January, April, and June 2007], P < 0.0001). Hospital-wide, unanticipated monthly naloxone administration decreased postintervention (mean ± SE: 1.48 ± 0.21 per month per 1000 inpatients) compared with preintervention (2.69 ± 0.35, P = 0.0130). Hospital-wide implementation of real-time, computer-generated alerts identifying instances of delayed pain reassessment resulted in sustained reduction of error rate and faster resolution of severe pain without oversedation.     

Finding Peace Beyond the Pain: Sunder's Journey in the Hospice

Dame Cicely Saunders revolutionized the concept of pain by coining the term “total pain”, the sum of the physical, psychological, social, spiritual, emotional components that make up the total pain experience. Optimal pain relief may not be possible until all elements of the pain and suffering are addressed. This narrative describes the journey of Sunder in the hospice. A caring husband, and a doting father, he came to the hospice by force, in immense pain and suffering. He stayed on by choice and found the peace he was looking for beyond his pain and sufferings, ably supported by the dedicated hospice team. He was able to live the last few months of his life as comfortably as was possible, and left this world in peace, with dignity. The narrative reiterates the belief that hospice, with its philosophy of active “total care” is an ideal place for addressing the concept of “total pain.”     

Functional Status of Stroke Patients in Long-Term Care

Thirty persons who had remained in long-term care for one year or more post-stroke were assessed with respect to motor function, cognitive, perceptual, and communication ability and ADL capacity. Before the stroke they had lived an independent life, although 40% suffered from cardiovascular disease. At the follow-up, all patients had severe impairments due to the brain damage. None could walk or stand independently, ten could not call for help or attract attention in any way, and 13 could not take part in a conversation. Eleven patients had severe pain in spite of treatment with analgesics. Pain treatment and training methods that can reduce dependence and improve the quality of life for patients like these need to be developed. More appropriate assessment instruments for this patient group have to be constructed to make evaluation of training and care possible.     

Comparison of Fentanyl and Morphine in the Prehospital Treatment of Ischemic Type Chest Pain

In the treatment of acute coronary syndromes, reduction of sympathetic stress and catecholamine release is an important therapeutic goal. One method used to achieve this goal is pain reduction through the systemic administration of analgesia. Historically, morphine has been the analgesic of choice in ischemic cardiac pain. This randomized double-blind controlled trial seeks to prove the utility of fentanyl as an alternate first-line analgesic for ischemic-type chest pain in the prehospital setting. Successive patients who were treated for suspected ischemic chest pain in the emergency medical services system were considered eligible. Once chest pain was confirmed, patients received oxygen, aspirin, and nitroglycerin therapy. If the ischemic-type chest pain continued the patient was randomized in a double-blinded fashion to treatment with either morphine or fentanyl. Pain scale scores, necessity for additional dosing, and rate of adverse events between the groups were assessed every 5 minutes and were compared using t-testing, Fisher's Exact test, or Analysis of Variance (ANOVA) where appropriate. The primary outcome of the study was incidence of hypotension and the secondary outcome was pain reduction as measured by the visual analog score and numeric rating score. A total of 207 patients were randomized with 187 patients included in the final analysis. Of the 187 patients, 99 were in the morphine group and 88 in the fentanyl group. No statistically significant difference between the two groups with respect to hypotension was found (morphine 5.1% vs. fentanyl 0%, p = 0.06). Baseline characteristics, necessity for additional dosing, and other adverse events between the two groups were not statistically different. There were no significant differences between the changes in visual analog scores and numeric rating scale scores for pain between the two groups (p = 0.16 and p = 0.15, respectively). This study supports that fentanyl and morphine are comparable in providing analgesia for ischemic-type chest pain. Fentanyl appears to be a safe and effective alternative to morphine for the management of chest pain in the prehospital setting.     

Fentanyl Tolerance in the Treatment of Cancer Pain: A Case of Successful Opioid Switching From Fentanyl to Oxycodone at a Reduced Equivalent Dose

Opioids are not generally deemed to have an analgesic ceiling effect on cancer pain. However, there have been occasional reports of tolerance to opioid development induced by multiple doses of fentanyl. The authors report a case of suspected tolerance to the analgesic effect of opioid, in which an increasing dose of fentanyl failed to relieve the patient's cancer pain symptoms, but opioid switching to oxycodone injections enabled a dose reduction to below the equivalent dose conversion ratio. The patient was a 60-year-old man diagnosed with pancreatic body carcinoma with multiple metastases. The base dose consisted of 12 mg/day of transdermal fentanyl patches (equivalent to 3.6 mg/day, 150 μg/h fentanyl injection), and rescue therapy consisted of 10 mg immediate-release oxycodone powders. Despite the total daily dose of fentanyl reaching 5.6 mg (equivalent to 560 mg oral morphine), the analgesic effect was inadequate; thus, an urgent adjustment was necessary. Due to the moderate dose of fentanyl, the switch to oxycodone injection was done incrementally at a daily dose equivalent to 25% of the fentanyl injection. The total dose of oxycodone was replaced approximately 53.5% of the dose of fentanyl prior to opioid switching.