ORIGINAL ARTICLE

A survey of Canadian cancer patients’ perspectiveson the characteristics and treatment of breakthrough pain

Gillian Bedard & Philippa Hawley & Liying Zhang &

Marissa Slaven & Pierre Gagnon & Stuart Bisland &

Margaret Bennett & Francois Tardif & Edward Chow

Received: 24 October 2012 /Accepted: 11 April 2013 /Published online: 2 May 2013# Springer-Verlag Berlin Heidelberg 2013

AbstractObjective Breakthrough pain is defined as a transient exac-erbation of pain that occurs spontaneously or in response toa trigger despite stable and controlled background pain. Thepurpose of this study was to explore Canadian patients’awareness of and experience with breakthrough pain incancer (BTPc).Methods Four Canadian cancer centers participated in anon-interventional survey recruiting cancer patients whoexperienced breakthrough pain. These patients were asked

about their pain, its impact on functioning, current manage-ment and interest in new treatments of BTPc.Results Ninety-four Canadian cancer patients participated inthis study, with 96 % stating that cancer pain impacted theirdaily living with over half unable to go to work or shopping.Fifty percent of patients said that an episode of BTPc lastedgreater than 60 minutes, with the pain score being on aver-age 7.8/10, impacting normal work (7.2/10) and generalactivity (7.1/10). Only 35 % of patients were very satisfiedwith the speed of relief of their medications. Those who didnot take their breakthrough pain medication for every epi-sode stated that was because the pain was not always severe(37 %), or they were afraid of becoming tolerant (23 %) oraddicted (12 %). Patients stated that the most importantfeatures of a new treatment for BTPc were the ability torelieve pain completely (47 %), and quickly (43 %). Patientsexpressed willingness to try transmucosal products (80 %)or nasal products (59 %).Conclusion Breakthrough cancer pain in Canadian cancerpatients greatly impacts their daily lives. There is room forimprovement in the management of BTPc, and the majorityof patients would be willing to try new treatments.

Keywords Breakthrough pain . Cancer . Patients’perspectives

Introduction

Cancer affects millions of patients worldwide, and with theimprovements in detection and treatment of cancer, patientstoday have improved life expectancy [1]. Unfortunatelymany consequences of cancer have not decreased. Pain isa common symptom experienced by many cancer patients,and it can manifest itself as continuous and/or episodic.Continuous or background pain is consistently felt by the

G. Bedard : L. Zhang :M. Bennett : E. ChowSunnybrook Health Sciences Centre, Odette Cancer Centre,University of Toronto, Toronto, ON, Canada

P. HawleyPalliative Medicine, BC Cancer Agency, University of BritishColumbia, Vancouver, BC, Canada

M. Slaven : S. BislandPalliative Care, Juravinski Cancer Center Hamilton Health ScienceCorporation, McMaster University, Hamilton, ON, Canada

P. Gagnon : F. TardifPsycho-oncologie, Centre Hospitalier Universitaire de Quebec,University of Quebec, Quebec City, QC, Canada

P. GagnonLaval University Cancer Research Center, Quebec City, QC,Canada

P. Gagnon : F. TardifMaison Michel-Sarrazin, Quebec City, QC, Canada

P. GagnonFaculty of Pharmacy, Laval University, Quebec City, QC, Canada

P. Hawley (*)Pain and Symptom Management/Palliative Care, VancouverCentre, BC Cancer Agency, 600 W 10th Ave,Vancouver, BC V5Z 4E6, Canadae-mail: phawley@bccancer.bc.ca

Support Care Cancer (2013) 21:2557–2563DOI 10.1007/s00520-013-1817-4

patient and often can be controlled with traditional pain med-ication, such as long-acting opioids along with adjuvant anal-gesics such as non-steroidal anti-inflammatory agents,tricyclics, and anticonvulsant medications [1]. Breakthroughpain has been defined as “a transient exacerbation of pain thatoccurs either spontaneously, or in relation to a specific andpredictable or unpredictable trigger, despite relatively stableand adequately controlled background pain” [2]. Break-through pain is often the cause of problems such as physicalimpairment, psychological distress, and decrease in socialwell-being, which severely dampen quality of life [3]. Break-through pain often manifests with inter- and intra-individualvariation, as it varies in timing and severity between patientsand between individual patient episodes [2].

There are currently no nationally accepted guidelinesspecifically directed at breakthrough cancer pain in Canada,so patterns of practice vary from place to place and fromphysician to physician. A number of analgesics are used“off-label” for breakthrough pain and some new prepara-tions already available in other countries are expected tobecome available in Canada over the next few years. Thesuccessful management of breakthrough cancer pain re-quires thorough assessment of the patient and an individu-alized treatment plan [2]. In order for this to take place, theremust be effective communication between health care pro-fessionals and patients. In a study by Webber et al., it wasfound that patients often had difficulty in describing theirpain to their physician, as they were unable to find the rightwords to accurately describe it. It has been suggested thatthe word “Breakthrough” may not be well-understood bysome patients, and “Episodic” has been proposed as analternative term which may be better understood and moreamenable to accurate translation to languages other thanEnglish. This term is not however yet in common usage inCanada [3].

Oral formulations of opioids such as morphine, oxyco-done, and hydromorphone are the most common treatmentfor cancer pain, with rapid-release preparations of the back-ground pain medication being the most commonly useddrugs for breakthrough pain [2]. However, pharmacokineticstudies have demonstrated that these oral opioids can have adelayed onset of effect, and long duration of action, whereasthe onset of a typical breakthrough pain episode is rapid, andthe duration is short [4, 5]. Transmucosal administration offentanyl may be a better alternative as it takes only 10–15 min after administration to provide pain relief [5], and insome studies transmucosal fentanyl products have beenshown to be more effective than immediate-release mor-phine to relieve breakthrough pain [6].

Although studies have evaluated the safety and efficacy ofvarious medications for the treatment of breakthrough pain incancer patients, there have been relatively few studies deter-mining the patient’s perspective and their receptiveness to new

medications/administration routes. The purpose of this studywas to explore the experience of BTPc in Canadian cancerpatients.

Methods

This was a non-interventional survey conducted in the pal-liative care programs at four Canadian Oncology centers.The centers were the BC Cancer Agency (BCCA), CentreHospitalier Universitaire de Quebec–Hotel-Dieu de Quebec(CHUQ), Juravinski Cancer Centre (JCC), and the OdetteCancer Centre (OCC). Investigators identified patients usinga screening questionnaire. Patients were required to be over18 years of age, with a diagnosis of cancer, using prescribedmedication for background pain, and having BTPc, whichwas defined in the consent form. Stage of cancer was notassessed. The study received approval from each center’sinstitutional review board, and informed consent wasobtained before the patient completed the survey. Consentforms and surveys were available in both French andEnglish.

The survey questionnaire included 8 open-ended and 34close-ended questions for a total of 42 questions. The ques-tionnaire was adapted with permission from that used in amulti-center European Survey of BTPc, the results of whichhave been published previously [7].

It was administered during routine doctor visits and tookapproximately half an hour to complete. Eligible patientsprovided demographic information and answered questionson background and breakthrough pain characteristics andmanagement, including quality of life using a modifiedBrief Pain Inventory [8], the management of breakthroughpain and attitudes towards alternative routes of analgesiaadministration, along with the important features patientsthink a new treatment should encompass.

Data was analyzed using validated software (SAS version9.2 for Windows). Descriptive analysis included allconsenting eligible patients from all 4 centers. To test theassumption of item homogeneity, a cross-center analysiswas performed using Fisher exact test or Chi-square test asappropriate for categorical variables, or Kruskal–Wallis testfor continuous items, respectively. To account for multiplecomparisons of 40 questions (excluding province and diag-nosis date), a Boneferroni adjusted p value <0.001 (0.05/40)was considered as statistically significant.

Results

There were 94 patients accrued to this study. Fifty sevenpercent were female and half of the patients were betweenthe ages of 50–69 years old. Primary cancer sites included

2558 Support Care Cancer (2013) 21:2557–2563

the lung (21 %), breast (20 %), gastrointestinal (12 %),prostate (11 %), and others (36 %) (Table 1).

Patients from each center were analyzed individually todetermine if there was a difference between patient groups.Statistically significant variation between the centers wasnoticed in only three items on the questionnaire. When asked“how you would describe your current level of activity on anaverage day”, the largest group of patients from each centerhad differing responses; 44 % of BCCA patients respondedthat they were in bed or a chair more than half the day andcould perform only limited self-care activities, while the larg-est group of CHUQ patients (39 %) responded that they werein bed or chair for all hours of the day and were unable toperform any self-care activities. The largest group of JCCpatients (39 %) said that they were able to walk and capableof all self-care, but not able to carry out work activities, andthe largest group of OCC patients (35 %) were restricted fromphysically strenuous activity, but able to walk and do lightwork (p<0.0001). Statistically significant variation was alsoseen in the question of “what brings about your BTPc”. Re-sponses indicate that 38 % of BCCA patients, 0 % of CHUQpatients, 16 % of JCC patients and 3 % of OCC patients didnot know what brought on their BTPc (p=0.0001). The lastitem that demonstrated statistically significant difference be-tween the centers was the item of “how long does an episodeof BTPc last”. Seventy percent of BCCA patients, 82 % ofCHUQ patients and 47 % of JCC patients stated that anepisode lasted over 60min, while 56% of OCC patients statedthat an episode lasted less than 10 min (p<0.0001). There wasno significant difference on all other items. We therefore wereable to combine patients from the four centers for analysis.

From the responses, 96 % of all patients indicated cancerpain had impacted their day-to-day life, and 38 % indicatedthat they experienced an episode of BTPc “months” aftertheir initial diagnosis, with the mean being 2.6 months afterdiagnosis. Cancer pain had a large impact on almost allpatients, with 50 % of patients unable to shop, 45 % unableto prepare meals or drive, and 59 % unable to go to work.The majority of patients (83 %) required the assistance offamily or friends to do their daily activities because ofcancer pain. To cope with background cancer pain, 26 %of patients took hydromorphone, 19 % took oxycodone,14 % took fentanyl, 14 % took morphine, and 5 % tookmethadone. Thirty-seven percent of patients stated that theirfamily doctor was the one to first prescribe them medicationto control background pain, while 19 % reported that thiswas done by their medical oncologist, and 11 % by theirradiation oncologist. However, when patients needed achange in medication, they were most likely to call theironcology nurse (22 %) or oncologist (17 %), tell their familydoctor at the next appointment (14 %), or tell their palliativecare doctor (13 %). In the 2 months prior to taking thesurvey, 71 % of patients had their medications adjusted.

When asked about breakthrough pain, 44 % of patientsreported these episodes were brought on by walking, 43 %

Table 1 Patient demographics

All patients (n=94)

Gender

Female 54 (57.45 %)

Male 40 (42.55 %)

Age (years)

18–39 6 (6.38 %)

40–49 13 (13.83 %)

50–59 23 (24.47 %)

60–69 24 (25.53 %)

70–79 15 (15.96 %)

80+ 13 (13.83 %)

Province

British Columbia 32 (34.04 %)

Ontario 49 (52.13 %)

Quebec 13 (13.83 %)

Primary cancer site

Lung 20 (21.28 %)

Breast 19 (20.21 %)

Gastrointestinal 11 (11.70 %)

Prostate 10 (10.64 %)

Others 34 (36.17 %)

First episode of BTPc

Before diagnosis 19 (21.35 %)

Immediately 2 (2.25 %)

Months after diagnosis 34 (38.20 %)

Years after diagnosis 18 (20.22 %)

Do not know 16 (17.98 %)

Require assistance with daily activities because of pain

No 13 (16.67 %)

Yes 65 (83.33 %)

Require home care services

No 57 (74.03 %)

Yes 20 (25.97 %)

Residence

Home 82 (87.23 %)

Hospice 5 (5.32 %)

Home of a family member 4 (4.26 %)

Long-term care 3 (3.19 %)

Employment status

Not employed 13 (13.83 %)

Retired 39 (41.49 %)

Full-time employment 3 (3.19 %)

Part-time employment 1 (1.06 %)

Self-employed 4 (4.26 %)

Homemaker 2 (2.13 %)

On disability leave 32 (34.04 %)

Support Care Cancer (2013) 21:2557–2563 2559

stated they were spontaneous, 43 % by standing for longperiods of time, and 40 % by household activities. Onaverage, 37 % of patients experienced an episode of BTPcmore than three times a day, and 51 % of patients reportedthat the pain takes “minutes” to reach its peak. Eighty threepercent of patients subsequently had treatment for theirBTPc. When asked how long an episode lasted if they didnot take any extra medication, half of patients indicated thatthe pain would last over an hour (Fig. 1), with the meanseverity of this pain being 7.8/10. Patients also indicatedthat their breakthrough pain interfered with their everydayactivities. On a 0–10 scale, the mean interference scoreswere: 7.1 for general activity, 6.2 for mood, 6.1 for walkingability, 7.2 for normal work, 5.0 for relations with otherpeople, 5.6 for sleep, and 6.4 for enjoyment of life(Fig. 2). Patients often described their BTPc as “sharp”,“burning”, or “stabbing”.

To manage BTPc, 37 % of patients took hydromorphone,22 % took morphine, and 17 % took oxycodone (Table 2).Patients often felt that their pain was not completely relievedwith medication; 24 % experienced no or only slight relief,while 51 % experienced good relief and 19 % of patientshad very good relief. Patients also indicated that their med-ication took 20–30 min to begin working (24 %) or over30 min (24 %). Seventy-five percent of patients responding

very or slightly satisfied with the speed at which their painmedications provided them with relief, while 18 % of pa-tients were dissatisfied and approximately 8 % neutral to thetime of relief.

Only 33 % of patients indicated that they took theirbreakthrough pain medications every time they had an epi-sode. For those patients who did not take their medication,they reported the pain was not always severe enough (37 %),they were worried of becoming tolerant to the medication(23 %), the pain was not long-lasting enough to make takingmedication worthwhile (17 %), or they were worried aboutbecoming addicted (12 %) (Table 3).

When asked to rate the features a new treatment for BTPcshould encompass, the ability to relieve the pain completely,the ability to relieve pain quickly, and causing few sideeffects were the most important as rated by 47, 43, and11 % of patients, respectively.

When considering routes of administration, 37 % ofpatients indicated that they had used a transmucosal prepa-ration to treat breakthrough pain, while 24 % of patients hadused a nasal product for an unrelated medical condition inthe past. Patients who had used a transmucosal preparationliked the fact that it was quick acting (33 %), and easy to use(23 %). Other comments from patients indicated that theydisliked the taste (14 %), or had other undesirable

BTPc Frequency (N=92 available patients; DK = don’t know) Fig. 1 BTPc Frequency (N=92available patients; DK don’tknow)

Degree of Interference with Life due to Breakthrough Pain (N=94 patients)

*ranked 0 – 10 with 0 being no interference and 10 being the most interference

Fig. 2 Degree of interferencewith life due to breakthroughpain (N=94 patients). *Ranked0–10 with 0 being nointerference and 10 being themost interference

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characteristics, such as being hard to remove from package,needing a moist mouth, or not lasting long enough. Forpatients who were not currently using a transmucosal prepa-ration, 80 % indicated that would consider using one to treatbreakthrough pain in the future (Table 4). For patients whostated they would not try the product, the most prevalentreason was that they had a dry mouth (19 %) (Table 5).Patients who had used nasal products for other conditionsindicated they liked the ease of use (26 %). Patients dislikedthe fact that the nose burned and the product was not alwayseffective in alleviating their symptoms. When patients wereasked if they would consider the use of a nasal product to treatbreakthrough pain, 59 % indicated that they would (Table 4).

Discussion

This study is the first of its kind to be undertaken in cancerpatients in Canada, and provides insight into patients’ expe-riences of BTPc and its management. Results of this studysupport the published data on the characteristics of break-through cancer pain and its debilitating impact on patients[1–3, 8–11].

Breakthrough pain is a devastating side-effect of cancer.Ninety-six percent of our patients reported that cancer painaffected their daily lives and as a result they were unable towork, shop, prepare meals or care for their families. Whenrating interference of BTPc with daily activities from 0–10, no

item was rated below 5. On average, Canadian patients ratedthe interference with their life higher than European patientswho took part in a similar study by Davies et al. [2, 7].

These Canadian cancer patients experienced more thanthree episodes of breakthrough pain a day that lasted, onaverage, over 60 min to resolve if no pain medications weretaken, also corroborating the findings of Davies et al.; theaverage European patient experienced three episodes ofbreakthrough pain a day, each lasting 60 min [7]. Mean timeto peak onset of pain for Canadian patients was reported as18 min. It is interesting to note that some studies of ad-vanced cancer outpatients have reported only a few minutesto peak onset [11, 12]; however, the study undertaken in theEuropean population by Davies et al. found that it took15 min to reach peak onset, which is much closer to ourpatients’ experience [7].

The majority of patients were prescribed immediate-release opioids to swallow for their BTPc. The most com-mon opioids were hydromorphone or morphine (Table 2).Patients often found that the onset of relief took at least20 min for these medications, consistent with the pharma-cokinetics of oral opioids [5]. However, as breakthroughpain is usually brief, some patients found that their medica-tions were unsuccessful at relieving their episode of BTPc.Patients in the European study also perceived swallowedmedications to take 20 min to have an effect; Davies et al.noted that oral opioids do not reach their peak blood leveluntil 60–120 min after ingestion [7]. Because the swallowedoral opioids take so long to have an effect, almost 60 % ofour Canadian patients were dissatisfied or only slightlysatisfied with the speed of relief. It has been suggestedtherefore that swallowed oral opioids may not be suitablefor treatment of breakthrough pain [4], supported by 47 and43 % of our patients expressing desire for new BTPc treat-ments to relieve pain completely and quickly respectively,again consistent with the results from the European Survey[7]. Relatively few of our patients had been prescribedtransmucosal preparations because of limited availability ofapproved transmucosally delivered opioids in Canada. Sub-lingual fentanyl tablets (Abstral) have recently been approvedby Health Canada but are expensive and not covered by

Table 2 Primary prescription for breakthrough cancer pain (N=78available patients)

Drug name

Hydromorphone 29 (37.18 %)

Morphine 17 (21.79 %)

Oxycodone 13 (16.67 %)

Fentanyl 7 (8.97 %)

Methadone 4 (5.13 %)

Acetaminophen 4 (5.13 %)

Others 4 (5.06 %)

Table 3 Reasons for non-adherence with breakthroughmedication (N=60 availablepatients)

Note: patients were allowed toselect more than 1 answer

The pain is not always severe enough 22 (36.67 %)

I am worried about becoming tolerant (used to) the medication 14 (23.33 %)

The pain is not always long-lasting 10 (16.67 %)

I am worried about becoming addicted to the medication 7 (11.67 %)

The medication does not relieve the pain 6 (10.00 %)

The medication does not act fast enough 5 (8.33 %)

The medication causes unacceptable side effects 4 (6.67 %)

My doctor/nurse has set limits on the use of the medication 1 (1.67 %)

I cannot afford the medication 0 (0 %)

Support Care Cancer (2013) 21:2557–2563 2561

publicly funded health care plans. Fentanyl buccal films wereavailable for a brief period but were similarly expensive, notcovered, and were withdrawn from sale after only a fewmonths. Off-label use of lipophilic injectable opioids (mainlysufentanil) is relatively infrequent in Canada, used mainly bypalliative care specialists, with marked variation betweencenters. The numbers of participants using sublingual fentanylor sufentanil in this study were not sufficient to allow exam-ination of any link with satisfaction.

Inadequate control of breakthrough pain in cancer pa-tients is a consistent finding; not surprising given the dis-connection between the characteristics of a typical event andthe pharmacokinetic profile of the swallowed oral opioidsmost commonly used to control it [9, 13, 14]. An alternative tothese is fentanyl; a synthetic opioid that is highly lipophilic,making it capable of rapid diffusion across the blood–brainbarrier. It has a high first-pass hepatic metabolism to inactivemetabolites, which are later excreted through the urine [15].These properties make fentanyl an ideal candidate fortransmucosal delivery, and numerous studies have exploredthe safety and efficacy of nasal as well as buccal/sublingualadministration of fentanyl [4, 16, 17]. These have demonstrat-ed that oral transmucosal administration of fentanyl results inrapid pain relief, and the onset of analgesia following intrana-sal administration has been reported to occur even faster, inless than 10 min [4, 16, 17]. The majority of our patients and

those surveyed in a similar European study indicated that theywould be open to trying one of these products [7]. Althoughpatients expressed willingness to try the sublingual/buccalroute, 72 % of patients stated they experienced dry mouth inthe 2 months prior to completing the survey, a problem thatcould potentially cause difficulties with the administration ofthe drug.

Nasal administration was also a route the majority ofthose surveyed would consider using. This route is lessutilized in clinical practice, as is evident by the fact thatonly 24 % of patients had previously used this route incomparison to 37 % of patients having previously used anoral transmucosally delivered drug (such as lorazepam), andmay require more comprehensive patient education to opti-mize adherence.

Approximately 23 % of patients had a fear of toleranceof their medications, and as a result did not take theirmedication when they had pain. It is apparent through thisstudy that patients need further education and more effec-tive dialogue with their healthcare professional to avoidreluctance to take appropriate medications. Breakthroughcancer pain is very heterogeneous and there is large vari-ation between and even within patients. Patients must beassessed and treated individually, with the most appropri-ate prescription being provided, given their individual cir-cumstances [2].

Limitations

This study relied solely on patients’ self-report, which canoften be inaccurate as patients are not always accurate inreporting their pain. For a variety of well-documented rea-sons patients are often reluctant to report pain and their

Table 5 Reasons for notwanting to use a new route ofadministration

Route of administration Reasons for not wanting to use route Number (%) of patients

Oral (N=54) Dry mouth 10 (18.52 %)

Don’t like the idea 7 (12.96 %)

Concerned about taste 5 (9.26 %)

Concerned about side effects 4 (7.41 %)

Concerned about effectiveness 3 (5.56 %)

Problems with mouth 1 (1.85 %)

Previous bad experience with product 0 (0 %)

Others 6 (11.11 %)

Nasal (N=59) Don’t like the idea 23 (38.98 %)

Concerned about effectiveness 8 (13.56 %)

Concerned about side effect 6 (10.17 %)

Problem with nose 2 (3.39 %)

Previous bad experience with product 1 (1.69 %)

Others 15 (25.42 %)

Table 4 Response to question: “Would you use such a product to treatepisodes of breakthrough cancer pain?” (N=90 available patients)

Oral product Yes 72 (80.00 %)

No 18 (20.00 %)

Nasal product Yes 53 (58.89 %)

No 37 (41.11 %)

2562 Support Care Cancer (2013) 21:2557–2563

concern about medication side-effects [18]. In addition tothis limitation, our study had also a relatively small samplesize. While the questionnaire was administered across Can-ada, including a Francophone region, only four sites partic-ipated, and patients were all under the care of specializedclinics, so likely to be more complex than those not receiv-ing specialist care. Further studies could include more pa-tients from a larger number of centers and different caresettings across Canada.

Conclusion

This is the first study of BTPc to be undertaken in theCanadian cancer population. Results of this study provideinsight into the current management of breakthrough cancerpain and the patients’ experience. It is well known thatbreakthrough cancer pain has a significant impact on pa-tients’ quality of life, and it is evident that there is largeroom for improvement in the management of BTPc; medi-cations did not always work and many often chose not totake them. In the future, patients along with healthcare pro-fessionals need to be further educated about BTPc and newtreatments available.

Acknowledgments This study was funded by Takeda Canada Inc.We thank all survey participants and research assistants.

Conflict of interest This study was funded by Takeda Canada Inc.The authors have full control of all primary data and agree to allow thejournal to review their data if requested.

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