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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 60 min, and the median time to peak intensity was 15 min. 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 © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

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 degrees 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.

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.

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.

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]

Seventeen terminally ill cancer patients with primary or secondary intra- thoracic malignancy complaining of breathlessness were treated with nebulized morphine in doses of 20 mg 4-hourly for 48 h. The effect on dyspnoea was evaluated using the Dyspnoea Assessment Questionnaire. Most patients felt less dyspnoeic after 24 h; the effect was maintained, but not improved upon, after 48 h. [ABSTRACT FROM PUBLISHER]

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]