Contents lists available at ScienceDirect Critical Reviews in Oncology / Hematology journal homepage: www.elsevier.com/locate/critrevonc Non pharmacological interventions and non-fentanyl pharmacological treatments for breakthrough cancer pain: A systematic and critical review Sebastiano Mercadante a,b,c,d a Anesthesia & Intensive Care and Pain relief & Palliative Care Unit, La Maddalena Cancer Center, Via San Lorenzo 312, 90145, Italy b SAMO, Palermo, Italy c University of Texas, USA d University of Palermo, Italy ARTICLE INFO Keywords: Breakthrough cancer pain Opioids Fentanyl Morphine Methadone Ketamine Nitrous oxide Anti-inflammatory drugs ABSTRACT Background: Oral opioids or other pharmacological or non-pharmacological interventions are often suggested in the management of breakthrough cancer pain (BTcP). The aim of this systematic and critical review was to analyse and critically comment the evidence of any non-fentanyl therapies proposed for BTcP. Methods: A systematic literature search was carried out to find studies providing clinical data on any treatment excluding fentanyl products. Results: No data exist about the use of oral opioids. Some information is available on parenteral morphine in a large sample of patients and episodes of BTcP. For other treatments, including methadone, nitrous oxide, anti- inflammatory drugs, samarium, and gabapentin the existing data, observational and obtained in a small number of patients do not provide useful information to be generalized. Only ketamine, a drug difficult to use for many physicians, particularly in determined setting, provided some evidence according a randomized controlled double-blind study. Conclusions: Recommendations suggesting the use of oral opioids or other pharmacological and non-pharma- cologic interventions for BTcP, are not based on any, even minimal evidence. These treatments are worthwhile of further investigation, particularly in determined conditions that should fit the pharmacokinetics of oral opioids. 1. Introduction It has been recognized that cancer patients, despite having a well controlled background pain by an analgesic drug for most hours of the day, may experience acute painful episodes that are highly distressing. This phenomenon is commonly named breakthrough cancer pain (BTcP) (Mercadante and Portenoy, 2016). Non-pharmacological and pharmacological approaches have been invariably reported in litera- ture. The role of primary therapies, including hormonal manipulation, chemotherapy, the use of orthotic devices or surgical stabilization, radiotherapy, and the use of bisphosphonates have obvious implica- tions in preventing BTcP and may improve the quality of life, but they have never been investigated properly. Administration of analgesic drugs ‘as-needed’ is commonly suggested to manage episodes of BTcP. In particular, transmucosal fentanyl, that is a lipophilic drug, matches the characteristics to favour the passage through the mucosa and then across the blood-brain barrier to provide fast analgesia. All the studies performed with transmucosal fentanyl preparations, also named rapid onset opioids, suggest that this approach is more effective and rapid in comparison with oral opioids and placebo (Jandhyala et al., 2013; Mercadante, 2012). However, in many guidelines oral opioids or al- ternative non-pharmacological interventions are often reported (Anon, 2013; Daenick et al., 2006; NICE, 2017; Wengström et al., 2014). For example, the National Institute for Clinical Excellence (NICE) has issued a guideline indicating that oral morphine should be considered the first- line choice for BTcP (NICE, 2017). In United States, a prior treatment with oral opioids is required by much of the payer community before coverage for a transmucosal fentanyl preparation is provided (Mercadante and Portenoy, 2016). The aim of this systematic and cri- tical review was to analyse and critically comment the evidence of any non-fentanyl therapies proposed for BTcP. 2. Methods A systematic literature search on Pubmed, MedLine, and Embaseelectronic databases was carried out from each database text words and MeSH/EMTREE term was “breakthrough pain”. Studies were selected if prospective, if they were performed in adult patients with chronic cancer pain, containing data about methods used for the management of BTcP, and written in English language. Treatments that https://doi.org/10.1016/j.critrevonc.2017.12.016 Received 11 September 2017; Accepted 21 December 2017 E-mail address: terapiadeldolore@lamaddalenanet.it. Critical Reviews in Oncology / Hematology 122 (2018) 60–63 1040-8428/ © 2017 Elsevier B.V. All rights reserved. T