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Oral normal-release morphine has long been considered the gold-standard treatment for cancer breakthrough pain. However, its relatively long time to analgesic onset, delay in maximal analgesic effect and prolonged duration of action make it unsuitable for the management of breakthrough pain episodes. These limitations led to the development of an oral transmucosal formulation of the fast-acting opioid fentanyl (oral transmucosal fentanyl citrate [OTFC] lozenge on a plastic handle; Actiq®), which has been shown to produce more rapid and effective pain relief than oral morphine. However, the formulation itself has some limitations. Consequently, investigators have continued to develop other, newer generation, transmucosal formulations of fentanyl to further improve the management of breakthrough pain. Recently, five such compounds (Effentora®/Fentora®, Abstral®, Instanyl®, Breakyl®/Onsolis™ and PecFent®) have been concurrently approved in Europe and/or the US, and have documented efficacy in quickly relieving breakthrough pain episodes. All of the available pivotal efficacy trials of these agents are randomized, double-blind comparisons with placebo. There are no head-to-head trials comparing any of the newer transmucosal formulations with each other. Only one non-pivotal study of intranasai fentanyl spray used a transmucosal preparation as an active comparator. However, that comparator was OTFC, not one of the newer transmucosal products. Close examination of the existing trials assessing these newer transmucosal preparations reveals significant variation in many study parameters, such as patient selection criteria, severity of breakthrough pain episodes, proportions of patients with a neuropathic pain component, titration protocols, choice of the primary endpoints, protocols for repeat dosing and rescue medication, the separation of treated episodes and the extent of the placebo response, all of which may have affected efficacy results. It is therefore difficult to evaluate the relative efficacies of these treatments on the basis of the available trials. Furthermore, given the differences in design between studies, the value of any potential meta-analyses including these trials would likely be limited. Blinded head-to-head comparisons of new transmucosal fentanyl preparations would be the only way to conclusively determine comparative effectiveness, but given the impracticalities of conducting such studies, these are unlikely. [ABSTRACT FROM AUTHOR]

The usual management of cancer related breakthrough pain is with supplemental doses of analgesics (commonly opioids) at a dose proportional to the total around-the-clock opioid dose. The aim of this review, undertaken as part of a European Palliative Care Research Collaborative (EPCRC) project, to update the EAPC guidelines on opioid analgesics in cancer pain was to determine the evidence for the utility of opioids in the management of breakthrough pain in patients with cancer. Randomized controlled trials of opioids used as rescue medication were identified using electronic search strategies. Outcome measures sought were reduction in pain intensity measured by an appropriate scale, adverse effects, attrition, and patient satisfaction. The date of the final search was 31 July 2009. Eight studies (790 patients) met the inclusion criteria. Most studies investigated rescue medication delivery via the buccal or nasal transmucosal routes. Intravenous morphine has been compared with the transmucosal route and the two found to be effective. The oral route has not been formally tested although found to be an inferior comparator in one study. Most studies showed no meaningful relationship between the effective dose of transmucosal opioid and the around-the-clock scheduled medication or the previous rescue medication, although one study found a fixed proportion of either intravenous morphine or transmucosal fentanyl to be efficacious. [ABSTRACT FROM AUTHOR]

Breakthrough pain is a transient exacerbation of pain that occurs either spontaneously or in relation to a specific predictable or unpredictable trigger despite relative stable and adequately controlled background pain. Breakthrough pain is a common and distinct component of cancer pain and is typically of rapid onset, severe in intensity, and generally self-limiting with an average duration of 30-60 minutes. Despite the self-limiting nature of breakthrough pain, it can place significant physical, psychological, and economic burdens on both patients and their carers. Patients with breakthrough pain are often less satisfied with their analgesic therapy, they have decreased functioning because of their pain, and may also experience social and psychosocial consequences, such as increased levels of anxiety and depression. Successful management of breakthrough pain is best achieved by a thorough assessment which includes determining the severity, pathophysiology, and aetiology of the pain and takes into account both background and breakthrough pains while considering whether the underlying disease, co-morbidities or precipitating events are amenable to interventions. The features of breakthrough pain and the challenges it presents to patients, their carers, and health professionals are illustrated with a case study. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: The discovery of peripheral opioid receptors has become the scientific basis for topical use of opioids in malignant and nonmalignant ulcers and oropharyngeal mucositis. This systematic review aimed to assess the quality of published literature and to examine whether topical opioids are effective in controlling pain in palliative care settings. After a systematic literature review, 19 studies (six randomized controlled trials [RCTs] and 13 case reports) met the inclusion criteria for the review. Eighteen studies favored topical opioids in pain relief, as evidenced by reductions in post-treatment pain scores, but time to onset and duration of analgesia varied widely. Because of the heterogeneity of the studies, meta-analysis was not possible. Despite clear clinical benefits described in small RCTs, there is a deficiency of higher-quality evidence on the role of topical opioids, and more robust primary studies are required to inform practice recommendations. N-of-1 trials should be encouraged for specific clinical circumstances. [Copyright &y& Elsevier]

Abstract: Breakthrough pain is a common and distinct component of cancer pain that is usually managed with normal release opioids (also known as rescue medication) either before or soon after its onset. A prospective survey of hospice inpatients with breakthrough pain was undertaken to characterize their pain and then compare the time to onset of pain relief of their rescue medication. Patients presented with, on average, 1.7 different types of breakthrough pains (range, 1–4). The average number of breakthrough pains was four per day (range, 1–8), and the average duration of breakthrough pain was 35minutes (range, 15–60); most occurred suddenly and unpredictably. Patients used morphine, oxycodone, hydromorphone, methadone, or oral transmucosal fentanyl citrate as rescue medication and the average time to meaningful pain relief following their administration was 31minutes (range, 5–75). No difference was found between morphine, oxycodone, and hydromorphone. Methadone appeared to work faster than morphine (P <0.01) but no faster than oxycodone or hydromorphone, whereas oral transmucosal fentanyl citrate worked faster than morphine, oxycodone, hydromorphone, and methadone (P <0.001). [Copyright &y& Elsevier]

Several studies have reported that opioids applied topically to painful ulcers produce an analgesic effect. It is unknown whether these opioids (usually mixed with hydrogels) are stable and, if so, for how long. We investigated the stability of morphine sulphate and diamorphine hydrochloride, each mixed with intrasite gel at a concentration of 1.25 mg/mL. Samples were prepared in the laboratory and then stored in plastic containers in the dark, at room temperature, in conditions of normal day/night at room temperature, and at 4°C. Aliquots were collected from each container over a 28-day period and analysed using HPLC. No known degradation products were measured in the morphine–intrasite gel mixture stored for up to 28 days, irrespective of the temperature and whether or not samples were exposed to light, suggesting that morphine remains stable. Diamorphine, breaks down to morphine and no other degradation products are measurable. [ABSTRACT FROM AUTHOR]

The analgesic effects of morphine applied topically to painful ulcers was assessed in a randomized, double-blind, placebo-controlled, crossover pilot study of five patients with painful sacral sores. Patients were treated for two days with either 10 mg morphine sulfate or placebo (water for injection) applied topically to the ulcer. After a two-day wash-out period, patients were crossed over for a further two days of the alternative treatment. Patients were asked to rate analgesia using a visual analogue scale (VAS) and to document any local or systemic adverse effects. All patients reported lower VAS scores with morphine compared to placebo and no local or systemic adverse events attributable to morphine were noted by either patients or nursing staff. This pilot study suggests that morphine applied topically is an effective method of producing local analgesia, well tolerated by patients, and not associated with systemic adverse effects. [Copyright &y& Elsevier]

During COVID-19, it was critical that services adapted to meet the high demands of the pandemic. This qualitative study explores the experiences of several staff members of the community palliative care team, as they adapted the delivery of their services to such pressures. Semi-structured interviews via a virtual platform were conducted and four themes were identified: service development, communication, inter-professional relationships and support mechanisms. The participants supported the change in service delivery and use of technology to triage patients. The participants also reported improved collaboration and patient care-coordination, and enhanced support mechanisms used by the team helped sustain resilience and wellbeing. Although challenging, the team embraced the changes and described improved collaboration and coordination of patient care. [ABSTRACT FROM AUTHOR]

In this article the author discusses guidelines on the pharmacological management of cancer pain which were created and published by the World Health Organization. The author is supportive of the organization's original guidelines on the management of cancer pain but suggests that in 2011 they may have to be adapted since new drugs, formulations, and different methods of administration have changed the way in which cancer pain is managed.

Abstract: 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. [Copyright &y& Elsevier]

Breakthrough pain is a transient exacerbation of pain that occurs either spontaneously or in relation to a specific predictable or unpredictable trigger despite relative stable and adequately controlled background pain. Breakthrough pain is a common and distinct component of cancer pain and is typically of rapid onset, severe in intensity, and generally self-limiting with an average duration of 30-60 minutes. Despite the self-limiting nature of breakthrough pain, it can place significant physical, psychological, and economic burdens on both patients and their carers. Patients with breakthrough pain are often less satisfied with their analgesic therapy, they have decreased functioning because of their pain, and may also experience social and psychosocial consequences, such as increased levels of anxiety and depression. Successful management of breakthrough pain is best achieved by a thorough assessment which includes determining the severity, pathophysiology, and aetiology of the pain and takes into account both background and breakthrough pains while considering whether the underlying disease, co-morbidities or precipitating events are amenable to interventions. The features of breakthrough pain and the challenges it presents to patients, their carers, and health professionals are illustrated with a case study. [ABSTRACT FROM AUTHOR]

Context The successful management of breakthrough pain depends on a combination of adequate assessment, appropriate (individualized) treatment, and adequate re-assessment. Currently, there is no fully validated clinical assessment tool for breakthrough pain in cancer patients. Objectives The aim of this project was to develop and validate a breakthrough pain assessment tool (the BAT) for use in the clinical setting. Methods The content of the BAT was determined by reviewing the medical literature, conducting a Delphi process with experts in breakthrough pain and/or pain assessment and conducting semi-structured interviews with cancer patients with breakthrough pain. The tool was then subjected to a series of standard psychometric tests to assess its factor structure, validity (i.e., content validity, construct validity), reliability (i.e., internal consistency, test-retest reliability), and responsiveness to change. Results The BAT comprised two pages with 14 questions. Factor analysis confirmed the presence of two underlying factors. Psychometric testing confirmed that the tool is valid, reliable, and responsive to change. Conclusion This study provides initial evidence for the validity and reliability of the breakthrough pain assessment tool which may be used to facilitate the management of patients with breakthrough cancer pain in the clinical setting. [ABSTRACT FROM AUTHOR]

Abstract: Context: Breakthrough pain is common in patients with cancer and is a significant cause of morbidity in this group of patients. Objectives: The aim of this study was to characterize breakthrough pain in a diverse population of cancer patients. Methods: The study involved 1000 cancer patients from 13 European countries. Patients were screened for breakthrough pain using a recommended diagnostic algorithm and then questioned about the characteristics and management of their pain. Results: Of the 1000 patients, 44% reported incident pain, 41.5% spontaneous pain, and 14.5% a combination. The median number of episodes was three a day. The median time to peak intensity was 10 minutes, with the median for patients with incident pain being five minutes (P < 0.001). The median duration of untreated episodes was 60 minutes, with the median for patients with incident pain being 45 minutes (P = 0.001). Eight hundred six patients stated that pain stopped them doing something, 66 that it sometimes stopped them doing something, and only 107 that it did not interfere with their activities. Patients with incident pain reported more interference with walking ability and normal work, whereas patients with spontaneous pain reported more interference with mood and sleep. As well, 65.5% of patients could identify an intervention that improved their pain (29.5%, pharmacological; 23%, nonpharmacological; 12%, combination). Regarding medications, 980 patients were receiving an opioid to treat their pain, although only 191 patients were receiving a transmucosal fentanyl product licensed for the treatment of breakthrough pain. Conclusion: Breakthrough cancer pain is an extremely heterogeneous condition. [Copyright &y& Elsevier]

Breakthrough cancer pain is a significant problem for many patients with cancer because of the fast onset and often unpredictable nature of the pain episodes. The rapid onset opioids therefore have a central role to play in the management of breakthrough cancer pain. The rapid onset opioid fentanyl buccal tablet provides a fast analgesic effect and is easy to administer. However, titration of the medication is essential in order to optimize the management of pain. This is because individual patient characteristics, comorbidities, and other treatments may influence the absorption, pharmacokinetics, and pharmacodynamics of drugs. It is therefore important to individualize treatment by determining the effective dose for each patient, which is the dose that provides adequate analgesia and minimizes undesirable adverse effects. Data from clinical studies of fentanyl buccal tablet show that patients' effective doses ranged from 100 to 800 µg per episode, highlighting the need for the titration process. Following successful dose titration, treatment with fentanyl buccal tablet can achieve significant pain relief as early as 10 minutes after administration, resulting in a high level of patient satisfaction. [ABSTRACT FROM AUTHOR]

A number of studies have reported the analgesic effect of morphine when applied topically to painful skin ulcers. It has been suggested that morphine may exert a local action, as opioid receptors have been demonstrated on peripheral nerve terminals. In this study, we investigated the bioavailability of topically applied morphine to cutaneous ulcers. Six hospice inpatients with skin ulcers were given morphine sulfate 10 mg in Intrasite gel topically and morphine sulfate 10 mg subcutaneously over 4 hours, at least 48 hours apart, in randomized order. Morphine, morphine-6-glucuronide (M6G), and morphine-3-glucuronide (M3G) were determined in plasma using a specific HPLC method. In five patients morphine and its metabolites were undetectable when applied topically. In one patient (with the largest ulcer), morphine and M6G were detected. The calculated morphine and M6G bioavailability in this patient were 20% and 21%, respectively. M3G was also detected but was below the lower limit of quantitation. When applied topically to ulcers, morphine was not absorbed in the majority of patients, suggesting any analgesic effect would be mediated locally rather than systemically. However, in ulcers with a large surface area, systemic absorption may occur. [Copyright &y& Elsevier]

The analgesic effects of morphine applied topically to painful ulcers was assessed in a randomized, double-blind, placebo-controlled, crossover pilot study of five patients with painful sacral sores. Patients were treated for two days with either 10 mg morphine sulfate or placebo (water for injection) applied topically to the ulcer. After a two-day wash-out period, patients were crossed over for a further two days of the alternative treatment. Patients were asked to rate analgesia using a visual analogue scale (VAS) and to document any local or systemic adverse effects. All patients reported lower VAS scores with morphine compared to placebo and no local or systemic adverse events attributable to morphine were noted by either patients or nursing staff. This pilot study suggests that morphine applied topically is an effective method of producing local analgesia, well tolerated by patients, and not associated with systemic adverse effects. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Control of Pain in Adults with Cancer: Summary of SIGN Guidelines," by P.J. Cormie, M. Naim, and J. Welsh.