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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]

Abstract: This study involved 320 cancer patients from four Northern European countries. Patients with breakthrough pain were questioned about the characteristics of their pain, the current management of their pain, and the acceptability/utility of alternative routes of administration. The median number of episodes was 3/day. Forty-four percent patients reported incident-type pain, 39% spontaneous-type pain, and 17% a combination of these pains. The median duration was 60min, and the median time to peak intensity was 15min. Three percent patients reported “mild” pain, 37% “moderate” pain, and 60% “severe” pain. Ninety percent patients stated that the pain interfered with their daily activities. All patients were using opioids as rescue medication (mainly oral morphine/oxycodone), whilst 28% patients were using non-opioids, and 50% patients were using non-pharmacological interventions. Only 55% patients took rescue medication every time they experienced breakthrough pain. Sixty-five percent patients would definitely consider using an oral transmucosal product; patients from Denmark were less likely to answer positively, and a positive response was associated with previous use of the route for breakthrough pain. Seventy-three percent patients reported regular oral problems. Forty-two percent patients would definitely consider using an intranasal product, with 26% patients stating they would definitely not use such a preparation; patients from Denmark and Sweden were less likely to answer positively, and a positive response was associated with male gender, and previous use of the route. Forty-four percent patients reported regular nasal problems. Sixty percent patients would definitely consider using a subcutaneous product, and 44% patients would definitely consider using an intrapulmonary product. [Copyright &y& Elsevier]

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]

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]

The article reviews the effect of breakthrough pain, how to manage it and new treatments for cancer patients. The study defines breakthrough pain as that which is felt by patients with cancer in connection with other pains. It is noted that there are several steps to manage breakthrough pain which includes the assessment of pain, changes in lifestyle and the causes of pain. It is also noted that analgesic is the treatment used for breakthrough pain which includes opioids, nonopioids and oral opioids.

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]