Procedural pain in palliative care: is it breakthrough pain? A multicenter national prospective study to assess prevalence, intensity, and

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1 The Clinical Journal of Pain Publish Ahead of Print DOI: /AJP Procedural pain in palliative care: is it breakthrough pain? A multicenter national prospective study to assess prevalence, intensity, and treatment of procedure-related pain in patients with advanced disease ClinicalTrials.gov identifier: NCT Caterina Magnani M.D., Palliative Care Unit Antea, Rome Diana Giannarelli, Biostatistic Department Regina Elena National Cancer Institute, Rome Giuseppe Casale M.D., Palliative Care Unit Antea, Rome On behalf of the Procedural Pain in Palliative Care Study Group: Chiara Mastroianni R.N., Antea Palliative Care Unit, Rome; Alice Calvieri M.D., Palliative Care Unit Antea, Rome; Arianna Lombardi M.D., Antea Palliative Care Unit, Rome; Maria Consiglia Stefanelli R.N., Antea Palliative Care Unit, Rome; Paola Ruggeri R.N., Antea Palliative Care Unit, Rome; Laura Carbonara R.N., Antea Palliative Care Unit, Rome; Ana Dardeli, Antea Palliative Care Unit; Domenico Russo M.D., San Marco Palliative Care Unit, Latina; Michela Guarda R.N. San Marco Palliative Care Unit, Latina; Francesca Bordin M.D. Palliative Care Unit INI, Grottaferrata, Rome; Roberto Rossi M.D., San Raffaele Palliative Care Unit, Rocca di Papa, Rome; Maria Pietropaolo M.D., San Raffaele Palliative Care Centre, Montecompatri, Rome; Luigi

2 Galli M.D., Villa Rosa Palliative Care Unit, Viterbo; Patrizia Ginobbi M.D., Palliative Care Rome Foundation, Rome; Pierpaolo Carinci M.D., Albachiara Palliative Care Unit, Chieti; Nadia Peta, Teramo Psychologist Palliative Care Unit, Teramo; Barbara Rizzi M.D., Palliative Care Vidas Foundation, Milan; Alessandro Valle M.D., Palliative Care F.A.R.O., Turin; Azzurra Ottone M.D., Luce per la vita Palliative Care Unit, Rivoli, Turin; Eugenia Malinverni R.N, Luce per la vita Palliative Care Unit, Rivoli, Turin; Cinzia Possenti M.D., Seragnoli Fundation Bentivoglio Hospice, Bentivoglio, Bologna; Raffaella D Ambrosio M.D., Orsa Maggiore Palliative Care Unit, Biella; Girolamo Del Monte M.D., San Raffaele Palliative Care Unit, Cassino, Frosinone; Alessandro Marra M.D., Il Giardino dei Girasoli Palliative Care Unit, Eboli, Salerno; Patrizia Giardina M.D., Papardo Hospital Palliative Care Unit, Messina; Tania Gallo R.N., Niguarda Ca Granda Hospital, Palliative Care Department, Milan; Elisa Biscaldi M.D., Palliative Care Unit, Salvatore Maugeri Foundation, Pavia; Marcello Ricciuti M.D., San Carlo Hospital, Palliative Care Department, Potenza; and Rossella Ziliotto M.D., Fatebenefratelli Hospital, Palliative Care Department, Venice. Correspondence and requests for reprints should be addressed to Caterina Magnani, Piazza Santa Maria della Pietà, 5, Pad XXII, 00135, Rome, Italy. Fax Tel / c.magnani@antea.net / ricerca@antea.net The authors declare no conflict of interest. Funding: No grant was used to perform this work.

3 Abstract Objectives To assess the prevalence of breakthrough pain (BTP) provoked by 6 common procedures in patients with advanced disease. Methods A prospective, cross-sectional, multicenter, national study was performed in 23 palliative care units in Italy. Patients were recruited if they were undergoing one of the following procedures as part of normal care: turning, personal hygiene care, transfer from bed to chair, bladder catheterization, pressure ulcer care, and subcutaneous drug administration. The Numerical Rating Scale was used to measure pain intensity before, during, and after the procedure. Results One thousand seventy-nine eligible patients were enrolled; 49.7% were male and their mean age was 78.0 ± 11.2 years. Of all patients, 20.9% had experienced a BTP episode within the 24 hours prior to recruitment. The overall prevalence of procedureinduced BTP was 11.8%, and the mean intensity score (Numeric Rating Scale) was 4.72 ± Notably, patients experienced a significant increase in pain intensity during all procedures (P < ). A small proportion of patients (12.7%) received analgesics before undergoing any of the procedures, and almost none (1.7%) received analgesics during the procedures to alleviate acute pain. Discussion Our findings highlight that simple daily care procedures can lead to BTP among patients with advanced disease. Because such procedures are performed so often during palliative care, more individualized attention to procedural pain control is necessary. Further research on procedural pain in patients with advanced disease

4 should be encouraged to provide further evidence-based guidance on the use of the available medication for predictable pain flares. Key words: Breakthrough pain, palliative care, procedure, palliative care nursing, rapid-onset opioids. Introduction Many patients with advanced disease undergo daily treatment and care-related procedures, and any such procedure that causes actual or potential tissue damage can cause pain (often termed procedural pain ). As such, potentially painful procedures can range from simple nursing care procedures, such as wound dressing or turning in bed, to more invasive procedures such as tracheal suctioning. 1 In palliative care, invasive procedures are infrequent because the main aim of such care is to improve quality of life while minimizing the use of unhelpful invasive maneuvers and treatments. 2,3 However, minimally invasive care-related procedures such as turning, personal hygiene care, and pressure ulcer dressing might be performed many times per day to ensure symptom relief and improve quality of life. Just as patients respond individually to pain and its treatment, they might respond differently to the same procedure, regardless of its complexity. 4 Moreover, regardless of the procedure or setting, if pain is not prevented or managed appropriately, patients might experience harmful effects, and can come to refuse any subsequent procedures and lose faith in the health care professionals (HCPs). 1 The American Society for Pain Management Nursing (ASPMN) has published a position statement with clinical practice recommendations on procedural pain management. 1 Although there is a considerable amount of research into procedural pain among children, 5 few studies have been carried out on procedural pain management in

5 adults. The focus on the pediatric or neonatal populations may be due to the fact that these groups cannot communicate their pain in the same way as adults. 6 To date, the largest studies on procedural pain in adults within the intensive care unit (ICU) are the Thunder Project II, 7 reported in 2001, and the The Europain Study, 8 reported in In the Thunder Project II, 7 procedural pain was defined as the unpleasant sensory and emotional experience that arises from actual or potential tissue damage associated with procedures, regardless of the intensity of the induced and background pain. There is a particular lack of literature on procedural pain in palliative care, as well as how often patients undergo treatment and daily care nursing procedures. A controversial point is whether procedural pain should be included in the definition of breakthrough cancer pain (BTcP). According to Davies et al. 9 BTcP is defined as transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain ; this definition covers both spontaneous and incident pain as well as pain provoked, whether accidentally or not, by diagnostic and treatment procedures. 10 However, more recent studies have disagreed with this definition of BTcP, 11 and the debate remains open as to what can be defined as BTcP among patients exhibiting painful flares. 12 An extensive survey of clinicians working in selected Italian palliative care and pain therapy centers led to a reformulation of the recommendations for best practice regarding BTcP diagnosis and treatment. 13,14 The consensus was to specify the level of pain necessary for a BTcP diagnosis specifically, BTcP pain should have a difference of at least 3 points on the Numeric Rating Scale (NRS) of pain from the level of background pain. Although this definition was reached by a national panel

6 of experts in Italy, and has not yet been validated within an international context, it might be useful in recognizing BTcP. It must be noted that breakthrough pain (BTP) has been widely described among patients with chronic non-cancer-related pain Although very little is known about BTP among patients with chronic non-cancer pain, it has been reported to have an overall prevalence of >55% in a sample of 939 Italian patients. Drawing on the above definition of BTP, we defined procedural BTP in the present study as a transient episode of moderate or severe pain with rapid onset and short duration that occurs during a procedure, despite adequately controlled background pain (NRS <4), with a pain intensity difference (PID) of at least 3 points compared to baseline pain, in cancer and non-cancer patients with a fixed around-the-clock (ATC) opioid dose. 9,10 The primary objective of this study was to assess the prevalence of BTP provoked by six procedures commonly performed in the care of cancer and noncancer patients in palliative care units (PCUs). The secondary objective of this study was to assess the prevalence and intensity of procedural pain according to the definition proposed by Puntillo et al. in the Thunder Project II 7 ; procedural distress intensity; the frequency and characteristics of pharmacological treatment for procedural pain; self-perceived treatment efficacy; and patients compliance with the prescribed drug for procedural pain. Methods Subjects This was a prospective, cross-sectional, multicenter, national study involving 1239 patients from 23 specialist PCUs in 9 regions of Italy. The subjects included in

7 the study underwent one of the six selected procedures. Procedures were selected in a previous study phase, using a quali-quantitive technique 8,20,21 : namely, a focus group involving 12 HCPs who were experts in palliative care, and a questionnaire survey delivered via interviews with a convenience sample of 100 patients and 100 caregivers admitted to hospice. 21 According to the results of this previous phase, the most common, distressing, and potentially painful procedures performed in palliative care were turning, personal hygiene care (or bed-bathing), transfer from the bed to an armchair or wheelchair, bladder catheterization, pressure ulcer care, and subcutaneous drug administration. As such, these procedures were included in the design of the present study. The study protocol was approved by the local research ethics committees and has been conducted in accordance with the international standards for clinical research. Patients were given an information sheet, after which they had the opportunity to ask questions about the study. Then, they were asked to sign a consent form. There was no planned sampling method we recruited patients who fulfilled the selection criteria consecutively. We did, however, plan for at least 120 patients, assuming an equal distribution of opioids. According to a power analysis, a sample size of 30 patients allowed us to identify an effect size of about 0.5 at a significance level of 5% with a power of 80% using the paired Student's t-test. The subjects were recruited from among those already receiving care in the 23 specialist PCUs between October and December 2015, from both inpatient and outpatient populations. The inclusion criteria were as follows: (1) older than 18 years of age; (2) undergoing at least one of the six study procedures defined as among the most painful as part of their standard care; and (3) controlled background pain (NRS 4) within the last 24 hours. In

8 contrast, the exclusion criteria were as follows: (1) cognitive impairment; (2) any condition associated with altered pain perception; (3) Karnofsky Performance Status score (KPS) < 20; and (4) procedures performed during emergency situations or at night (8:00 pm to 8:00 am), to ensure that we avoided adding additional burden to HCPs. Each PCU had a site coordinator, who was a medical doctor or nurse with research experience or who had access to personnel with such experience. PCU coordinators sent all completed data collection packets to the coordinating center in Rome, where the data were entered into an electronic database. Protocol (Figure 1) At recruitment, we collected some of subjects data in a case report form (CRF): age, underlying disease, KPS score, background pain (mean pain score on the NRS in the last 24 hours), BTP episodes in the last 24 hours, and current pain treatment. One data collector assisted with administration of each procedure, but the person who actually performed the procedure was not the data collector. Before each procedure was performed, patients were asked by the research nurse or medical doctor to indicate the level of pain that they were experiencing at that time, using a 0 10 NRS (with higher values indicating greater pain intensity). 22 Immediately after the procedure was performed, a nurse or medical doctor (who differed from those who performed the procedure) asked the patient to rate the pain experienced during the procedure. Ten minutes after the procedure, pain intensity and procedural distress were measured and recorded in the CRF. Procedural distress was defined as any negative emotional response to the procedure, and was measured on a scale from 0 to 10, where 0 indicates no distress and 10 indicates the worst possible distress. 7

9 Data on the analgesics administered within the 30-minute period preceding the procedure as well as during the procedure were recorded in the CRF. The duration of the procedure was also recorded. For all patients who had received analgesics to treat procedural pain, we also measured patients perceived efficacy of the administered analgesic. Patients were asked, Do you think that your analgesic treatment provided effective relief for your procedure-related pain? A 5-point Likert-type scale ranging from 1 (not effective at all) to 5 (very effective) was used to answer. We also assessed patients compliance with procedural pain treatment. Because there are currently no specific adherence monitoring tools for BTP, patients were asked, Do you usually take the prescribed drug for procedural pain prevention or treatment? If patients said that they did not, they were asked to indicate the main reason by choosing it from a list of possible reasons for poor compliance with BTP treatment from the results of the European multicenter study conducted by Davies et al. 23 Data analysis The data from this prospective observational study were described as absolute frequencies and percentages for categorical variables and means with standard deviation (SDs) for continuous variables. The associations between categorical variables were evaluated with the chisquare test, while differences in continuous variables were determined with Student s t-test, paired or unpaired, as appropriate. IBM SPSS Statistics 21 (IBM Corp., Armonk, NY) was used for all analyses. A P-value of <0.05 was considered as statistically significant. Procedure-induced pain was considered as procedural BTP if the PID between during the procedure and 10 minutes before it was 3. When the PID was >0 but <3, procedure-induced pain was considered as simple procedural pain. 7

10 Results Patients were recruited from 23 Italian PCUs that provided daily assistance to 1550 patients during the study period (35% inpatients and 65% outpatients). Of these patients, a total of 1239 participated in the study. We included all 1239 patients and then assessed them according to the inclusion/exclusion criteria. Data from 1079 patients were usable (160 case report forms lacked pain intensity data); each case report form represented one patient. Most of the subjects (96%) were cancer patients, with the remaining 4% having end-stage organ failure. The proportions of inpatients and outpatients were 34.4% and 65.6%, respectively. Table 1 lists the main patient characteristics. The mean background pain intensity was 0.98 ± 1.29 on the NRS. We observed that 63.7% of patients were undergoing fixed ATC opioid therapy. Most participants were taking transdermal fentanyl (24.7%) and oral oxycodone (14.4%). The prevalence of BTP episodes (unprovoked by procedures) within the 24 hours before patients recruitment to the study was 20.9%. One hundred eighty-three of patients who exhibited BTP (81%) used drugs for its treatment. The drugs used for BTP treatment were as follows, in descending order of frequency: oral immediaterelease (IR) morphine (n = 76, 41.3%), transmucosal immediate-release fentanyl (TIRF; n = 43, 23.2%), and intravenous or subcutaneous morphine (n = 17, 9.2%). The remaining patients used non-steroidal anti-inflammatory drugs (NSAIDs) for BTP treatment. Table 2 shows the results for background pain and BTP treatment. The prevalence of procedural BTP (PID 3) was 11.8%. The mean intensity of procedural BTP according to the NRS was 4.72 ± The 19% of patients with a previous episode of BTP also experienced procedural BTP ( 2 = 12.64, P < ). The prevalence of simple procedural pain (with a PID > 0 but <3) was

11 27.8% (mean intensity score NRS 1.95 ± 1.10). The baseline pain 10 minutes before the procedure was found to be unrelated to pain intensity during the procedure (t(1077) = 1.45, P = 0.15). Table 3 shows the frequencies of procedures and mean pain intensity scores for each procedure. In general, patients reported mild pre-procedural pain intensity (0.63 ± 1.2 according to the NRS), which significantly increased during all of the procedures (P < ). The most frequently reported procedure was transfer and the most painful was pressure ulcer care (Table 3). Patients reported mild post-procedural pain intensity (0.64 ± 1.17), and experienced a significant decrease in pain intensity after all procedures (P < ) compared to during them. The mean overall procedural distress score was 1.07 ± Among the 1079 patients who participated, 137 (12.7%) received analgesics before undergoing any of the procedures. The distribution of administered analgesic drugs by procedure is reported in Table 4. Most of these patients were undergoing pressure ulcer care or personal hygiene care. Notably, TIRF was the most frequently administered drug for procedural BTP prevention. TIRF was never administered to non-cancer patients, who typically received oral IR morphine for procedural BTP prevention. Among the 1079 subjects, 18 (1.7%) received analgesics during any of the procedures because of acute pain arising therein. Only 4 of these patients received opioids, while the others received NSAIDs. Patients assessments of the efficacy of the analgesics for procedural pain treatment are reported in Table 5. In contrast, the administration time (minutes before the procedural performance) is reported in Table 6.

12 Finally, 426 (39.6%) of all of the patients were prescribed opioids as a preventative measure for procedural pain. Of these, 78.6% were declared to be noncompliant. The barriers to compliance are reported in Table 7. Discussion Nursing-care-related procedures such as turning in bed, bathing, and pressure ulcer dressing are routine activities during palliative care aimed at providing quality of life improvement and symptom palliation. Physicians do not always think of such activities as procedures that can cause pain and distress, and therefore could overlook the need to provide preemptive analgesia measures. 1 Nevertheless, these nursing activities are commonly described as procedures in the literature. 1,7,8 As noted above, the definition of procedure-related pain is controversial: some researchers have described it as either a form of incident BTP or the unpleasant sensory and emotional experience that arises from actual or potential tissue damage associated with procedures. 7 Despite this lack of consensus regarding the definition of procedural pain definition and unavailability of specific studies supporting a given definition, it clearly has a significant impact on patients quality of life. 9 It is therefore essential that procedure-related pain is adequately assessed and treated. A plan for providing procedural comfort should include nonpharmacological and pharmacological interventions based on each patient s unique characteristics, the care setting, and the procedure being performed. 1 Thus far, this is the first national prospective study documenting the prevalence, intensity, and treatment characteristics of procedural pain experienced by adult patients with both cancer and non-cancer illness in palliative care. We found that the prevalence of procedural BTP was 11.8%. Furthermore, patients were more likely to experience procedural BTP if they had had a previous episode of BTP. When

13 compared with previous studies, where BTP prevalence ranged from 40 to 80%, 23,24 the overall BTP prevalence was rather low in our study, at 20.9%. In the present study, the prevalence of procedural pain that cannot be defined as BTP was 27.8%. Regardless of its lower intensity, patients suffering from such pain deserve correct assessment and treatment. The NRS scores were significantly higher during the procedure compared to before it for all procedures (P < 0.001). Pain at the time of the procedure was significantly higher than baseline pain even though the most frequent procedures were relatively simple, such as being transferred from a bed to a wheelchair, turning, or personal hygiene care. Although patients reported relatively mild mean pain intensity scores (NRS 2.3 ± 1.64) for the included procedures, these procedures may be performed many times a day; such repetitive pain in this way may have a cumulative negative impact on quality of life. 7 Therefore, all procedure-related pain must be assessed and adequately treated in each patient, as adequately controlled pain can improve functional status, such as greater mobility, and therefore represents an important outcome in palliative care. In the present study, the percentage of patients undergoing any of the procedures who received analgesics was 12.7%. Patients were more likely to receive analgesics before undergoing pressure ulcer care than before other procedures. Notably, despite the greater prevalence of analgesics before this procedure, it remained the most painful procedure. This may suggest that the pre-emptive analgesics administered for this procedure were not completely effective, perhaps due to an insufficient dose or inappropriate drug choice. However, most of the patients receiving analgesics before the procedure received TIRF, although oral immediate-release (IR) morphine and NSAIDs were

14 also often administered. However, overall, BTP was mainly treated with oral IR morphine; only 23.3% of patients with BTP received TIRF and more than 25% were treated with NSAIDs. The European Association for Palliative Care 25 hesitantly recommends the use of IR formulations of opioids with short half-lives for procedureinduced BTP. According to these guidelines, oral IR morphine should be restricted to those cases of predictable, procedure-related pain that persists beyond 60 minutes. 11 Nevertheless, some studies have pointed out that oral IR morphine has been considered inappropriate for BTP treatment, with TIRF being the more effective treatment option. 26 This is because of the pharmacokinetics of oral IR morphine: slow onset of analgesia (30 40 minutes), long half-life (2 hours), extensive first-pass metabolism, and poor bioavailability (20 40%). More specifically, these characteristics do not correlate with the typical BTP features, including sudden onset and short duration. 27 Instead, rapid-onset opioids (ROOs), which are fast-acting and have less persistent effects, may be the preferred choice when procedures are not predictable 12,28 and when procedure-induced pain does not persist beyond 30 minutes. The results from this study show that 10 minutes after a procedure, patients experienced pain relief. Among outpatients, nursing care procedures are often unpredictable. The risks of administering oral IR morphine too early or too late before a procedure are that it becomes inefficient or provokes worthless and persistent adverse effects such as drowsiness and opioid-induced constipation. For inpatients, such procedures are not always predictable. For instance, patients may have the immediate need for personal hygiene care or desire to be moved from the bed to a wheelchair for a specific time. Advanced disease can change the perception of time so that a routine simple activity may turn into a fundamental action that must be not delayed. Thus, in our opinion,

15 ROOs would be a valid option for procedural BTP and should therefore be considered when choosing the appropriate treatments. Still, oral IR morphine might be the preferred choice for when procedure-induced pain does not have the characteristics of a BTP or if patients are not tolerant. Furthermore, oral IR morphine is preferred for non-cancer BTP, where TIRF is still contraindicated for this population. Other drugs, such as NSAIDs, are often used as the first resort for procedural BTP treatment in routine clinical practice. However, none of these drugs seem to possess the pharmacokinetic properties required for treating unpredictable pain: indeed, the onset of analgesic action of oral NSAIDs is min, and this reaches its peak efficacy at min. 9 NSAIDs can be justified to treat particular forms of episodic pain, such as that triggered by bone metastases. 29 However, they can interfere with platelet aggregation and can induce lesions within the gastric mucosa if repeatedly used. This potential must be considered when determining the appropriateness of their administration, especially for the treatment or prevention of pain induced by daily care procedures. In this study, 74% of patients who received TIRF for procedural BTP reported the analgesic to be highly or completely effective, in contrast to the 52% of patients who received oral IR morphine and 27% who received oral NSAIDs. Thanks to its short half-life, TIRF provokes minor adverse effects due to the summation of effects with other ATC opioids. Furthermore, TIRF, in one of its varying formulations, can allow one to perform any procedure after 6 15 minutes. In the present study, TIRF for prevention of procedural BTP was administered a maximum of 15 minutes before the procedures in most of the cases. In contrast, oral IR morphine was administered between 5 and 30 minutes before. The findings might suggest that procedures are too often performed before the onset time of oral IR morphine; in fact, oral IR morphine

16 can take more than 30 min to take effect and its peak pharmacological effects may occur only after min. 30 A valid assessment of procedural pain intensity and treatment should not only be aimed at adjusting treatment if necessary, but also at assessing and promoting compliance. 10 In the present study, we investigated procedural pain treatment compliance. However, specific tools for monitoring cancer patients adherence to treatment do not exist 31 ; thus, it was monitored by self-assessment in the present study. We found that 78% of the sample declared to be not compliant with procedural pain treatment. This is in contrast to Davies et al., 23,27 who reported that adherence to BTP treatment was found in only 55% of a sample of 320 patients. The main barriers to compliance were related to personal will of enduring pain when it is short and mild and resistance to opioid use. 23 In order to avoid lack of adherence, HCPs should provide correct information on the properties and safety profile of analgesics given. Patients and their families should understand that pain must not be endured, due to its harmful effects on their quality of life. Study limitations First, the subjects in this study were a convenience sample of patients undergoing one of six procedures. Second, patients were ineligible if they were unable to communicate their pain with an NRS; these patients might have experienced pain and distress as well. Third, the six studied procedures were selected from the coordinating center using a quali-quantitative method; however, other daily, nursing, or palliative care procedures might be frequently provided to palliative care patients and thus deserve to be studied. Fourth, the generalizability of the study findings across cancer and non-cancer patients is limited because of the small number of noncancer patients in the sample. Finally, the descriptive design of the study precluded

17 testing of specific interventions for procedural pain. Nevertheless, this study is the first prospective multicenter study on procedure-induced pain in palliative care adult patients. Conclusion Procedural pain might be classified as BTP only if it is a transient exacerbation of pain that occurs in relation to a specific predictable diagnostic, treatment, or care-related daily procedure, despite adequately controlled background pain with fixed ATC opioids. Nevertheless, procedure-induced pain that does not have BTP characteristics must be recognized and adequately treated. Further research on procedural pain in patients with advanced disease should be encouraged to provide evidence-based guidance on the use of the available drugs for predictable pain flares. Furthermore, preemptive analgesia is recommended for patients who experienced previous procedure-related pain. Acknowledgments We would like to thank Veronica Fabiano, Clinical Trial Assistant, Fatebenefratelli San Giovanni Calibita Hospital, Rome; Laura Surdo, Antea Palliative Care Unit, Rome; Sabrina Castellana, Antea Palliative Care Unit, Rome; Filomena Spasiano, Biostatistical Unit, Regina Elena National Cancer Institute, Rome. Furthermore, we would like to thank Editage ( for English language editing.

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20 20. Stinson J, Yamada J, Dickson A et al. Review of systematic reviews on acute procedural pain in children in the hospital setting. Pain Res Manag. 2008;13(1): Magnani C, Mastroianni C, Giannarelli D et al. Procedural pain in palliative care: a multicenter prospective observational study. Eur J Palliat Care. In press. 22. Brunelli C, Zecca E, Martini C et al. Comparison of numerical and verbal rating scales to measure pain exacerbations in patients with chronic cancer pain. Health Qual Life Outcomes. 2010;8: Davies A, Zeppetella G, Andersen S et al. Multi-centre European study of breakthrough cancer pain: pain characteristics and patient perceptions of current and potential management strategies. Eur J Pain. 2011;15(7): Mercadante S, Lazzari M, Reale C et al. Italian Oncological Pain Survey (IOPS): A multicentre Italian study of breakthrough pain performed in different settings. Clin J Pain. 2015;31(3): Caraceni A, Hanks G, Kaasa S et al. Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol. 2012;13:e Velázquez Rivera I, Muñoz Garrido JC, García Velasco P et al. Efficacy of sublingual fentanyl vs. oral morphine for cancer-related breakthrough pain. Adv Ther. 2014;31(1): Davies A, Buchanan A, Zeppetella G et al. Breakthrough cancer pain: an observational study of 1000 European oncology patients. J Pain Symptom Manage. 2013;46(5): Zeppetella G. Impact and management of breakthrough pain in cancer. Curr Opin Support Palliat Care. 2009;3:1-6.

21 29. Sima L, Fang WX, Wu XM et al. Efficacy of oxycodone/paracetamol for patients with bone-cancer pain: a multicenter, randomized, double-blinded, placebo-controlled trial. J Clin Pharm Ther. 2012;37: Coluzzi PH, Schwartzberg L, Conroy JD et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain. 2001;91(1-2): Jacobsen R, Moldrup C, Christrup L et al. Patient-related barriers to cancer pain management: a systematic exploratory review. Scand J Caring Sci. 2009;23: Figure 1. Flow diagram of the study protocol

22 Table 1 Patient characteristics N (%) or mean (±SD) Mean age 78.0 (±11.2) Sex Male 536 (49.7) Female 543 (50.3) Setting Inpatients 371 (34.4) Outpatients 708 (65.6) Main disease Cancer 1035 (96.0) Non-cancer 43 (4.0) Missing data 1 Karnofsky Performance Status score > (12.4) (39.8) (47.8) (1.6) Cancer localization Lung cancer 231 (21.4) Colorectal cancer 124 (11.5) Breast cancer 117 (10.9) Prostate 81 (7.5) Other 482 Metastasis 1

23 Multiple 411 (38.1) Bone 116 (10.8) Lymph Nodes 70 (6.5) Lung 54 (5.0) Liver 33 (3.1) Other 104 (36.5) 1 Only applied to cancer patients Table 2 Background pain and BTP treatment characteristics Characteristic n (%) Fixed ATC opioid therapy Yes 687 (63.7) for background pain No 391 (36.3) Missing data 1 ATC opioids for background TD fentanyl 266 (24.7) pain Oral oxycodone 155 (14.4) IV/SC morphine 85 (7.9) Oral morphine 65 (6.0) Oral tramadol 40 (3.7) Tapentadol 16 (1.5) Oral hydromorphone 10 (0.9) IV/SC tramadol 7 (0.6) TD buprenorphine 6 (0.6) Oral codeine 38 (3.5)

24 BTP (24 h before Yes 226 (20.9) recruitment) No 853 (79.1) BTP treatments Yes 183 (81) No 43 (19) Drugs used for BTP Oral IR morphine 76 (41.5) treatment IV/SC morphine 17 (9.2) Transmucosal 36 (19.5) sublingual fentanyl Intranasal fentanyl 7 (3.7) NSAIDs 47 (26.1) Abbreviations: ATC, around-the-clock; TD, transdermal; BTP, breakthrough pain; IR, immediate-release; IV, intravenous; SC, subcutaneous; NSAIDs, non-steroidal antiinflammatory drug.

25 Table 3 Procedure frequency and pain intensity mean score according to procedure Procedures N (%) Preprocedural mean pain intensity (±SD) Turning 281 (26) Personal hygiene care Transfer from bed to armchair or wheelchair Pressure ulcer/wound care Bladder catheterization Subcutaneous drugs administration 176 (16.3) 310 (28.7) 152 (14.1) 29 (2.7) 131 (12.2) 0.64 (1.08) 0.74 (1.53) 0.64 (1.08) 0.64 (1.22) 0.31 (0.71) 0.23 (0.75) Mean pain intensity during the procedure (±SD) SD: Standard deviation Pain intensity was scored on a 0 10 numerical rating scale t = t-value df = degrees of freedom P value (pain intensity difference between before and during the procedure) 1.49 (1.76) < t = 8.6, df = (2.06) < t = 5.0, df = (1.95) < t = 8.5, df = (1.47) t = 3.3, df = (1.93) < t = 8.7, df = (1.18) < t = 6.4, df = 130 Mean pain intensity after the procedure (±SD) P value (pain intensity difference between during and after the procedure) 0.72 (1.08) < t = 9.4, df = (1.30) < t = 6.7, df = (1.27) < t = 8.9, df = (1.03) t = 1.8, df = (1.63) < t = 10.4, df = (0.77) < t = 6.4, df = 130

26 Table 4 Distribution of analgesics according to procedure Procedures No. of patients receiving analgesics before the Oral IR Morphine IV/SC Morphine TIRF NSAIDs procedure Turning 22 6 (27.2) 4 (18.2) 7 (31.8) 5 (22.8) Personal hygiene care Transfer from bed to armchair or wheelchair Pressure ulcer/wound care 32 4 (12.5) 8 (25.0) 12 (37.5) 39 8 (20.5) 1 (2.5) 19 (48.7) (38.4) 5 (12.8) 8 (20.5) 8 (25.0) 11 (28.3) 11 (28.3) Bladder 4 2 (50.0) 2 (50.0) 0 (0) 0 (0) catheterization Subcutaneous drugs administration 1 0 (0) 0 0 (0) 1 (100.0) Note: All numbers are n (%), with percentages reflecting number out of the total receiving analgesics before a given procedure. Abbreviations: TIRF, transmucosal immediate-release fentanyl; NSAIDs, nonsteroidal anti-inflammatory drugs

27 Analgesics administered before the procedures (No. of patients) Table 5 Patients perceived efficacy of procedural pain treatment Self-assessed efficacy score N. of patients (%) Total Oral IR morphine (0) (5.7) (37.1) (54.4) (2.8) (100) IV/SC morphine (0) (0) (55) (30) (15) (100) Transmucosal oral fentanyl (0) (0) (23.7) (64.3) (12) (100) Transmucosal nasal fentanyl (0) (0) (50) (25) (25) (100) NSAIDs (5.5) (27.8) (38.9) (27.8) (0) (100) Abbreviations: IR, immediate-release; NSAIDs, non-steroidal anti-inflammatory; IV, intravenous; SC, subcutaneous 1 = no efficacy; 2 = low efficacy; 3 = moderate efficacy; 4 = high efficacy; 5 = complete efficacy

28 Opioids administered before the procedures (No. patients ) Table 6 Administration time of analgesics for procedural pain Administration time (minutes before the procedure) No. of patients (%) Total (<5) (5 15) (15 30) (30 40) (40 60) Oral IR morphine 2 (1.5) 9 (6.6) 16 (11.7) 1 (0.7) 7 (5.1) 35 (25.5) IV/SC morphine 0 (0) 7 (5.1) 13 (9.5) 0 (0) 0 (0) 20 (14.6) Transmucosal oral 0 (0) 24 (17.4) 10 (7.2) 8 (5.8) 0 (0) 42 (30.4) fentanyl Transmucosal nasal 1 (0.7) 3 (2.2) (2.9) fentanyl NSAIDs 1 (0.7) 0 (0) 12 (8.8) 7 (5.1) 16 (11.7) 36 (26.3) Abbreviations: IR, immediate-release; NSAIDs, non-steroidal anti-inflammatory; IV, intravenous; SC, subcutaneous

29 Table 7 Barriers to procedural pain treatment compliance Why do you usually don t take your prescribed drugs for procedural pain? No. of Patients (%) Pain is not always so severe 177 (52.8) Pain is tolerable because it lasts only a few 109 (32.5) minutes Analgesics are not effective 4 (1.2) Analgesics cause too many adverse effects 13 (3.9) I'm afraid of becoming addicted 10 (3) I'm not able to intake this drug easily 5 (1.5) No answer 17 (5.1) Total 335 (100)

30 Figure 1 Flow diagram of the study protocol Figure 1. Flow diagram of the study protocol Assessment for eligibility Informed written consent Enrollment Data collection: - Age - Primary disease - KPS score - Background pain (mean NRS in the last 24 hours) - Number of BTP episodes in the last 24 hours - Current pain treatment (medication, dosage) Inclusion criteria: 1. >18 years of age 2. Undergoing one of the six selected procedures as part of their standard care 3.Controlled background pain (NRS 4) within the last 24 hours Exclusion criteria: 1. Cognitive impairment 2. Any condition associated with altered pain perception 3. KPS < Procedures performed during emergency situations or at night (8:00 pm to 8:00 am) 10 minutes before the procedure Data collection: -Type of procedure -Pain intensity (NRS) before the procedure -Possible analgesics taken before the procedure (preventive analgesia) Immediately after the procedure Data collection: -Pain intensity (NRS) experienced during the procedure -Procedure duration -Possible procedure interruption for unbearable pain and analgesics administration 10 minutes after the procedure Data collection: -Pain intensity (NRS) after the procedure -Possible analgesics administration -Pain distress (NRS) experienced during the procedure For all patients who had received analgesics to treat procedural pain, patients perceived efficacy was also measured with the question: Do you think that your analgesic treatment provided effective relief for your procedure-related pain? (5-point Likert scale) Patients compliance with procedural pain treatment was assessed with the question: Do you usually take the prescribed drug for procedural pain prevention or treatment? (answered by choosing from a list of possible reasons for poor compliance with BTP treatment adapted from Davies et al. 23 )