Multi-centre European study of breakthrough cancer pain: Pain characteristics and patient perceptions of current and potential management strategies

European Journal of Pain 15 (2011) 756–763

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Multi-centre European study of breakthrough cancer pain: Pain characteristics and patient perceptions of current and potential management strategies Andrew Davies a,⇑, Giovambattista Zeppetella b, Steen Andersen c, Anette Damkier d, Tove Vejlgaard e, Friedemann Nauck f, Lukas Radbruch g, Karl-Frederik Sjolund h, Mariann Stenberg i, Alison Buchanan j a

Palliative Medicine, St. Luke’s Cancer Centre, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, United Kingdom St. Clare Hospice, Hastingwood Road, Hastingwood, Essex CM17 9JX, United Kingdom Palliative Medicine, Roskilde Hospital, Kogevej 7-13, 4000 Roskilde, Denmark d Palliative Medicine, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark e Palliative Medicine, Sankt Maria Hospice Center, Blegbanken 3, 7100 Vejle, Denmark f Palliative Medicine, University Hospital Göttingen, Robert Koch Stasse 40, 37075 Gottingen, Germany g Palliative Medicine, University Hospital Bonn, Sigmund-Freud Strasse 25, 53127 Bonn, Germany h Pain Management, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden i Palliative Medicine, University Hospital Lund, SE-221 00 Lund, Sweden j Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom b c

a r t i c l e

i n f o

Article history: Received 23 August 2010 Received in revised form 8 November 2010 Accepted 19 December 2010 Available online 19 January 2011 Keywords: Pain Breakthrough pain Cancer Palliative care

a b s t r a c t 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. Fortytwo 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. Ó 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.

1. Introduction ⇑ Corresponding author. Tel.: +44 0208 6613182, fax: +44 0208 6613185. E-mail addresses: [email protected] (A. Davies), John.Zeppetella@ stclarehospice.org.uk (G. Zeppetella), [email protected] (S. Andersen), [email protected] (A. Damkier), tove.vejlgaard@slb. regionsyddanmark.dk (T. Vejlgaard), [email protected] (F. Nauck), [email protected] (L. Radbruch), karl-fredrik.sjolund@ karolinska.se (K.-F. Sjolund), [email protected] (M. Stenberg), alison. [email protected] (A. Buchanan).

Breakthrough pain has been defined as ‘‘a 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’’ (Davies et al., 2009). However, there is a lack of consistency in the use of the term breakthrough pain within the medical literature, and also within clinical practice. Indeed, the term is widely used to describe any

1090-3801/$36.00 Ó 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2010.12.004

A. Davies et al. / European Journal of Pain 15 (2011) 756–763

exacerbation of pain in patients with background pain, or even intermittent episodes of pain in patients without background pain. Breakthrough pain is common in patients with cancer pain (40– 80%) (Mercadante et al., 2002), and is a significant cause of morbidity in this group of patients (Portenoy et al., 1999; Hwang et al., 2003). The successful management of breakthrough pain depends on a combination of adequate assessment, appropriate treatment, and adequate re-assessment (Davies et al., 2009). Moreover, treatment includes a variety of strategies, including management of the underlying condition, modification of the background medication, utilisation of non-pharmacological interventions, and utilisation of ‘‘rescue’’ medication (Davies et al., 2009). The main objective of this unique study was to characterize breakthrough pain in a diverse population of cancer patients (nine sites, four countries), using a recommended diagnostic algorithm (Davies et al., 2009) and a specifically developed questionnaire. It should be noted that most published studies are single centre studies, and that most published studies do not report the diagnostic criteria adopted. Moreover, it appears that at least some published studies included patients with inadequately controlled background pain. A secondary objective of this study was to determine patient opinions about their current treatment for breakthrough pain, and potential treatments for breakthrough pain (e.g. oral transmucosal opioid formulations, intranasal opioid formulations).

2. Methods The study was a multi-centre study, which involved 320 patients, nine specialist palliative care/pain units (see Acknowledgements), and four Northern European countries (Denmark, Germany, Sweden, United Kingdom). The study was approved by the relevant local research ethics committees, and was conducted in accordance with the relevant international, European, and national standards for clinical research (e.g. ICH Good Clinical Practice principles). Patients were given an information sheet in their native language, given the opportunity to ask questions about the study, and then asked to sign a consent form in their native language. Subjects were recruited from patients already receiving treatment in the nine palliative care/pain units. Subjects were recruited from both the inpatient population and the outpatient population. The inclusion criteria for the study were: (1) age > 18 yr; (2) cancer diagnosis; (3) cancer-related pain; (4) cancer-related breakthrough pain; and (5) regular use of opioid for moderate to severe pain (‘‘strong’’ opioid). Fig. 1 shows the diagnostic algorithm used to identify patients with breakthrough pain (Davies et al., 2009). The exclusion criteria for the study were: (1) cognitive impairment and (2) limited comprehension of native language. The questionnaire was specifically developed for the purposes of the current study. The Section 1 consisted of the screening questions to identify patients with breakthrough pain (Fig. 1): patients that ‘‘failed’’ the screening questions did not complete the remainder of the questionnaire. The Section 2 asked questions about the characteristics of the breakthrough pain, including interference with various daily activities (i.e. general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life). The interference with daily activities was assessed using a 0–10 numerical rating scale, where 0 represented ‘‘does not interfere’’ and 10 represented ‘‘completely interferes’’. The Section 3 asked questions about the current treatment of the breakthrough pain. Patients were also asked about their adherence with rescue medication for breakthrough pain (and reasons for non-adherence). The Section 4 asked about the most important features for a new treatment for breakthrough pain, the experience of alternative routes of administration (oral transmucosal,

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intranasal, intrapulmonary, subcutaneous), the acceptability of these alternative routes of administration for breakthrough pain, and factors that could affect the utilisation of these alternative routes of administration. In terms of acceptability of the route of administration, patients were asked to respond to the question (‘‘Would you consider using such a product to treat exacerbations of your pain?’’) with one of three options (‘‘yes’’; ‘‘no’’; ‘‘possibly’’). Patients that responded ‘‘no’’ were asked to state the reasons for not wanting to use this route of administration. Unfortunately, a translation inaccuracy meant that German patients were actually asked ‘‘Have you considered using such a product to treat exacerbations of your pain?’’. As a result, some German patients answered ‘‘no’’, and gave the reason as being unfamiliar with the route of administration (i.e. they had not considered using such a product in the past, but they may/may not consider using such a product in the future). The data were translated into English (where necessary), then were entered onto a secure data management system (at the Royal Marsden Hospital), and subsequently were analysed using IBM SPSS Statistics 18. The proportion of patients that would consider using each route of administration was calculated with 95% confidence intervals. Stepwise binary logistic regression was then used to determine the influence of specific factors on giving a ‘‘yes’’ answer to the questions about the acceptability of the routes of administration. The factors tested were age, gender, country of treatment, severity of pain, previous use of route for breakthrough pain, and previous use of route for any indication. Factors with a p-value less than 5% were considered significant.

3. Results 320. patients were recruited to the study, with 80 patients being recruited from each of the four countries. The median age of the subjects was 61 yr (range 23–91 yr), and there was a slight preponderance of female subjects (52% of total). The data on ECOG performance status and cancer diagnosis are summarized in Table 1. One hundred and forty-one patients (44%) reported incidenttype breakthrough pain (i.e. the episodes were related to an identifiable precipitant), 124 (39%) reported spontaneous-type breakthrough pain (i.e. the episodes were not related to an identifiable precipitant), 54 (17%) reported a combination of incident- and spontaneous-type breakthrough pain, and there was no information for one patient. The incident-type breakthrough pains were volitional in 106 patients (i.e. brought on by a voluntary act), non-volitional in 19 patients (i.e. brought on by an involuntary act), a combination of volitional and non-volitional in 11 patients, procedural in one patient and not specified in four patients. The median number of episodes of breakthrough pain was 3/ day (range 2/week–24/day). The median duration of untreated episodes was 60 min (range <1 min to 8 h), whilst the median time to reach peak intensity was 15 min (range <1–240 min) for all breakthrough pain episodes, 10 min (range <1–240 min) for incident-type pain episodes, and 20 min (range <1–240 min) for spontaneous-type episodes. The intensity of the breakthrough pain was rated as ‘‘mild’’ in 10 cases, ‘‘moderate’’ in 118 cases, and ‘‘severe’’ in 191 cases (with no specific information for one patient). It should be noted that the intensity of the background pain was rated as ‘‘mild’’ at worse in all cases (inclusion criterion). Unsurprisingly, 261 patients stated that the pain stopped them doing something, 26 that the pain ‘‘sometimes’’ stopped them doing something, and only 33 that the pain did not interfere with their daily activities. The median interference scores were: (a) ‘‘General activity’’ – 7 (range 0–10); (b) ‘‘Mood’’ – 5.5 (range 0–10); (c) ‘‘Walking ability’’ – 5 (range 0–10); (d) ‘‘Normal work (includes both work outside the home and housework)’’ – 7 (range

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Q1. Do you have pain related to your cancer? Yes / No

If no, do not proceed with remainder of questionnaire

Q2. Is the pain present most of the time*, or would be present if not taking painkillers? (* pain present for ≥12 hr/day during the last week) Yes / No

If no, do not proceed with remainder of questionnaire

Q3. Is the pain well controlled for most of the time*? (* pain rated as ‘none’ or ‘mild’ but not as ‘moderate’ or ‘severe’, for ≥12 hr/day during the last week) Yes / No

If no, do not proceed with remainder of questionnaire

Q4. Do you have short - lived exacerbations of the pain (‘breakthrough pain’)? Yes / No

If no, do not proceed with remainder of questionnaire

Q5. Are you taking a strong painkiller* for the constant pain (‘background pain’)? (* e.g. morphine, fentanyl, hydromorphone, methadone, oxycodone) Yes / No

If no, do not proceed with remainder of questionnaire Fig. 1. Diagnostic algorithm used to identify patients with breakthrough pain (adapted from Davies et al., 2009).

Table 1 ECOG performance status and cancer diagnosis of subjects. ECOG performance status

Number of patients (n = 320)

ECOG 0 ECOG 1 ECOG 2 ECOG 3 ECOG 4 Not stated

5 (1.5%) 93 (29.0%) 107 (33.5%) 101 (31.5%) 12 (4.0%) 2 (0.5%)

Cancer diagnosis Breast Gastrointestinal Gynaecological Haematological Head and neck Lung Melanoma Sarcoma Urological Unknown

Number of patients (n = 320) 40 (12.5%) 87 (27.5%) 27 (8.5%) 13 (4.0%) 17 (5.5%) 43 (13.5%) 8 (2.5%) 12 (4.0%) 55 (17.0%) 16 (5.0%)

0–10); (e) ‘‘Relations with other people’’ – 6 (range 0–10); (f) ‘‘Sleep’’ – 4 (range 0–10); and (g) ‘‘Enjoyment of life’’ – 5.5 (range 0–10).

Most (76%) patients could identify an intervention that usually improved the breakthrough pain, although another 12% patients could identify an intervention that sometimes improved the breakthrough pain. In other words, 12% patients had found nothing that relieved their breakthrough pain. The interventions that were successful were pharmacological in 132 patients, non-pharmacological in 95 patients, a combination of pharmacological and nonpharmacological in 51 patients, and unspecified in four patients (totals include interventions that usually and sometimes improved the breakthrough pain). Ninety-three patients with isolated spontaneous-type breakthrough pain could identify an intervention that usually improved the breakthrough pain; the intervention was non-pharmacological in 23 (25%) patients, pharmacological in 58 (62%) patients, a combination of non-pharmacological and pharmacological in 11 (12%) patients, and not stated in 1 (1%) patient. Similarly, 115 patients with isolated incident-type breakthrough pain could identify an intervention that usually improved the breakthrough pain; the intervention was non-pharmacological in 45 (39%) patients, pharmacological in 47 (41%) patients, and a combination of nonpharmacological and pharmacological in 23 (20%) patients. All patients were using opioid analgesics as rescue medication/ ‘‘breakthrough medication’’ (Table 2), whilst 90 (28%) patients

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were also using non-opioid analgesics to manage the breakthrough pain episodes (Table 3). In addition, 159 (50%) patients were using non-pharmacological interventions to manage the breakthrough pain episodes (Table 4). A variety of different non-pharmacological interventions were being used, and in some cases patients would use more than one type of intervention. The most common strategy was the use of heat (e.g. heat pad, hot water bottle). As stated all patients were receiving an opioid to treat their breakthrough pain, although only 29 (9%) patients were receiving one of the transmucosal fentanyl products licensed for the management of breakthrough pain (Table 2). Ninety-six percent

Table 2 Opioids used by patients to manage breakthrough pain episodes.

a b

Opioid analgesica

Number of patients (n = 320)

Morphine Oxycodone Fentanyl Hydromorphone Ketobemidone Methadone Tramadol Diamorphine Buprenorphine Nicomorphine Not stated

138 (43.0%) 128 (40.0%) 30b (9.5%) 30 (9.5%) 6 (2.0%) 4 (1.0%) 3 (1.0%) 2 (0.5%) 1 (0.5%) 1 (0.5%) 5 (1.5%)

Patient could be using more than one medication. Twenty-nine transmucosal fentanyl; one parenteral fentanyl.

Table 3 Non-opioids used by patients to manage breakthrough pain episodes.

a

Non-opioid analgesica

Number of patients (n = 320)

None Paracetamol Systemic non-steroidal anti-inflammatory drug (NSAID) Topical non-steroidal anti-inflammatory drug (NSAID) Benzodiazepine Antispasmodic (smooth muscle relaxant) Anticonvulsant Antipsychotic Local anaesthetic Oxygen

230 (72.0%) 57 (18.0%) 21 (6.5%) 8 (2.5%) 8 5 2 1 1 1

(2.5%) (1.5%) (0.5%) (0.5%) (0.5%) (0.5%)

Patient could be using more than one medication.

Table 4 Non-pharmacological interventions used by patients to manage breakthrough pain episodes.

a

Interventiona

Number of patients (n = 320)

None Change of position Physical support Rest/sleep Movement/exercise Heat Cold Rubbing/massage Transcutaneous electrical nerve stimulation (TENS) Relaxation/visualization Distraction Miscellaneous other interventions

159 (49.5%) 28 (8.5%) 7 (2.0%) 41 (13.0%) 16 (5.0%) 72 (22.5%) 3 (1.0%) 11 (3.5%) 12 (3.5%) 10 (3%) 8 (2.5%) 8 (2.5%)

Patient could be using more than one intervention.

patients receiving morphine alone for background pain were prescribed morphine for breakthrough pain; the modal dose of rescue medication was 1/6th total daily dose of background morphine (range 1/32–1/2). Similarly, 96% patients receiving oxycodone alone for background pain were prescribed oxycodone for breakthrough pain; the modal dose of rescue medication was 1/8th total daily dose of background oxycodone (range 1/18–1/2). The amount of relief provided by the rescue medication was ‘‘complete’’ in 52 patients, ‘‘good’’ in 195 patients, ‘‘slight’’ in 57 patients, ‘‘none’’ in five patients, and not stated in 11 patients. Two hundred and forty-four patients were ‘‘satisfied’’ with their rescue medication, 71 patients were not satisfied, and 4 patients did not provide an answer to the question. In spite of the above, patients reported a relatively slow onset of action, and a slow time to peak effect for their rescue medication. Thus, the perceived median onset of action of oral morphine was 20 min, and the perceived median time to peak effect was 30 min. Similarly, the perceived median onset of action of oral oxycodone was 30 min, and the perceived median time to peak effect was 45 min. (The perceived median onset of action of transmucosal fentanyl products was 10 min, and the perceived median time to peak effect was also 10 min). Moreover, 177 (55%) patients reported that their rescue medication caused adverse effects, predominantly opioid-related side effects, and especially sedation (‘‘drowsiness’’). Interestingly, only 176 (55%) patients took their rescue medication every time they experienced breakthrough pain, although the reasons for non-adherence were many and varied (Table 5). The so-called ‘‘other’’ reasons for non-adherence related to factors such as access to rescue medication, ease of use of rescue medication, dislike of rescue medication, family concerns about rescue medication, and preference/efficacy of non-pharmacological interventions. The patient ratings of ‘‘important features’’ of a new rescue medication for breakthrough cancer pain are shown in Table 6. Overall, the most important feature was ‘‘relieves pain completely’’, although patients from Denmark and Sweden rated ‘‘relieves pain quickly’’ as the most important feature (and rated ‘‘relieves pain completely’’ as the second most important feature). Other factors that patients mentioned as being important included availability of medication (n = 3), type of formulation (n = 3), route of administration (n = 2), size/portability of medication (n = 4), unobtrusiveness of medication (n = 2), duration of effect (n = 4), and rigorous testing of medication (n = 2). Sixty-five percent (208) patients stated that they would definitely consider using an oral transmucosal product to manage their breakthrough pain (95% confidence intervals: 59.6–70.0%), with only 9% (29) patients stating that they would definitely not use such a preparation (Fig. 2). The individual country responses are shown in Table 7; patients from Denmark [Odds ratio 0.43 (95%

Table 5 Reasons for non-adherence with rescue medication.

a b

Potential reason for not taking rescue medication

Number positive responsesa

Number ‘‘main reason’’ responses (n = 144)

Pain is not always severe Pain is not always long lasting Painkiller is not effective Painkiller causes side effects Worried about addiction Worried about tolerance Limits on use of painkiller Other reasons Not stated

65 60

31 (21.5%) 27 (18.5%)

22 31 42 33 7 26 n/a

17 (12.0%) 15 (10.5%) 16 (11.0%) 8 (5.5%) 5 (3.5%) 17b (12.0%) 8 (5.5%)

Patient could give any/all reasons. See text.

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Table 6 Rankings of important features of rescue medication for breakthrough cancer pain. Most important feature (n = 320) Relieves pain completely Relieves pain quickly Causes few side effects Easy to use Can be given by relative/carer Not expensive Unknown

Second most important feature (n = 320)

Third most important feature (n = 320)

Forth most important feature (n = 320)

Fifth most important feature (n = 320)

Sixth most important feature (n = 320)

150 (47.0%)

96

36

24

9

0

141 (44.0%)

127

35

10

2

0

13 (4.0%)

53

143

68

35

3

8 (2.5%) 3 (1.0%)

25 12

82 12

167 39

29 203

4 46

0 (0.0%) 5 (1.5%)

2 5

7 5

7 5

37 5

262 5

250

Number of patients

208 193

200

150

135

142

100

82

77 77

70 58

67 55

50

26 31

29 16

14

0 Yes

Oral transmucosal route

No

Possibly

Intranasal route

Intrapulmonary route

Unfamiliar with concept

Subcutaneous route

Fig. 2. Responses to questions about potential use of different routes of administration (‘‘would you consider using such a product?’’).

Table 7 Responses to questions about potential use of different routes of administration by country (‘‘would you consider using such a product?’’).

a

Routes of delivery

Response to question

All countries (n = 320)

Denmark (n = 80)

Germany (n = 80)

Sweden (n = 80)

United Kingdom (n = 80)

Oral transmucosal

Yes No Possibly Unfamiliar with concepta

208 (65.0%) 29 (9.0%) 67 (21.0%) 16 (5.0%)

45 12 23 n/a

41 11 12 16

60 5 15 n/a

62 1 17 n/a

Intranasal

Yes No Possibly Unfamiliar with concepta

135 (42.0%) 82 (26.0%) 77 (24.0%) 26 (8.0%)

38 16 26 n/a

7 38 9 26

37 15 28 n/a

53 13 14 n/a

Intrapulmonary

Yes No Possibly Unfamiliar with concepta

142 (44.5%) 70 (22.0%) 77 (24.0%) 31 (9.5%)

45 9 26 n/a

9 33 7 31

30 21 29 n/a

58 7 15 n/a

Subcutaneous

Yes No Possibly Unfamiliar with concepta

193 (60.0%) 58 (18.0%) 55 (17.0%) 14 (5.0%)

64 2 14 n/a

44 17 5 14

38 20 22 n/a

47 19 14 n/a

See text for discussion.

CI: 0.22–0.87); p = 0.019] were less likely to answer the question ‘‘yes’’ than those from the United Kingdom (the reference country for the logistic regression), with the results for Germany being influenced by the translation inaccuracy. The only other factor that

was associated with a positive response was previous use of the route to manage breakthrough pain (p = 0.001). Of note, 129 patients had previously used the oral transmucosal route, with 71 patients having used it to manage breakthrough pain. Table 8

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A. Davies et al. / European Journal of Pain 15 (2011) 756–763 Table 8 Reasons for not wanting to use different routes of administration. Route of delivery

Reasons for not wanting to use route of delivery

Oral transmucosal (n = 29)

Current/previous problems with mouth

a

Number ‘‘main reason’’ responses

9

9

‘‘I don’t like idea of such a product’’ Previous bad experience Concerns about effectiveness Concerns about side effects Concerns about addiction Other reasonsb Not stated

11 1 3 2 1 5 1

8 0 3 1 1 4 3

Intranasal (n = 82)

Current/previous problems with nose ‘‘I don’t like idea of such a product’’ Previous bad experience Concerns about effectiveness Concerns about side effects Concerns about addiction Other reasonsb Not stated

20 52 5 11 8 7 6 6

13 38 4 5 2 4 5 11

Intrapulmonary (n = 70)

Current/previous problems with lungs

17

12

‘‘I don’t like idea of such a product’’ Previous bad experience Concerns about effectiveness Concerns about side effects Concerns about addiction Other reasons Not stated

44 2 14 8 4 7 3

33 0 8 4 1 7 5

Current/previous problems with skin ‘‘I don’t like idea of such a product’’ Previous bad experience Concerns about effectiveness Concerns about side effects Concerns about addiction Other reasons Not stated

9 36 5 4 6 2 11 7

5 28 2 0 1 2 11 9

Subcutaneous (n = 58)

b

Number positive responsesa

Patient could give any/all reasons. See text.

shows the reasons given for not wanting to use this route of administration; the main ‘‘other’’ reasons included preference for alternative route (three patients), and contentment with current treatment (one patient). Seventy-three percent (234) patients reported the existence of at least one regular oral problem, including 212 patients with xerostomia, 60 patients with oral discomfort, and 33 patients with difficulty opening mouth. Forty-two percent (135) patients stated that they would definitely consider using an intranasal product to manage their breakthrough pain (95% confidence intervals: 36.9–47.6%), with 26% (82) patients stating that they would definitely not use such a preparation (Fig. 1). The individual country responses are shown in Table 7; patients from Denmark [Odds ratio 0.30 (95% CI: 0.15–0.60); p = 0.019] and Sweden [Odds ratio 0.25 (95% CI: 0.12–0.51); p = 0.019] were less likely to answer the question ‘‘yes’’ than those from the United Kingdom, with the results for Germany being influenced by the translation inaccuracy. The other factors that were associated with a positive response were male gender (p = 0.017), and previous use of the route to manage any condition (p < 0.001). Of note, 135 patients had previously used the intranasal route, with seven patients having used it to manage breakthrough pain. Table 8 shows the reasons given for not wanting to use this route of administration; the main ‘‘other’’ reasons included preference for alternative route (three patients), contentment with current treatment (one patient), and perceived inconvenience of intranasal route (one patient). Forty-four percent (141) patients reported the existence of at least one regular nasal problem, including 60 patients with dry nose, 24 patients with nasal discomfort, 61 patients with ‘‘blocked nose’’ and 56 patients with rhinorrhoea.

Interestingly, 60.3% patients stated that they would definitely consider using a subcutaneous product to manage their breakthrough pain (95% confidence interval: 54.9–65.5%), and there was an association between a positive response and the previous use of this route to manage breakthrough pain (p < 0.001). However, there were significant differences between the countries, with more Danish patients giving a positive response [Odds ratio 2.29 (95% CI 1.09–4.85), and fewer Swedish patients giving a positive response [Odds ratio 0.51 (95% CI: 0.26–1.00); p = 0.050], than those from the United Kingdom. Similarly, 44.4% patients stated that they would definitely consider using an intrapulmonary product to manage their breakthrough pain (95% confidence interval: 39.0–49.9%), and there was an association between a positive response and the previous use of this route to manage any condition (p = 0.003). Again, there was a significant difference between the countries, with fewer Swedish patients giving a positive response [Odds ratio 0.23 (95% CI: 0.17–0.45); p < 0.001] than those from the United Kingdom. Other data relating to these routes of administration are shown in Tables 7 and 8.

4. Discussion This is a unique study in terms of the population studied and the methodology utilised. The results of the study confirm the impact of breakthrough cancer pain, not only in terms of the morbidity associated with the pain per se, but also in terms of the interference with the activities of daily living (Portenoy et al., 1999; Hwang et al., 2003). Thus, a ‘‘typical’’ patient in this study would experience

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three episodes each day, with each episode lasting 60 min, and each episode being at least moderate in intensity. However, it is clear from the data that breakthrough pain is a heterogeneous condition, and that episodes vary both between individuals and also within individuals (at the same time). Hence, the management of breakthrough pain must be individualised (Davies et al., 2009), and patients should be continuously re-assessed to determine any change in the nature of the breakthrough pain (Davies et al., 2009). The temporal characteristics of the breakthrough pain episodes in the current study were somewhat different from those reported in many published studies (i.e. longer duration, longer time to reach peak intensity) (Portenoy and Hagen, 1990; Portenoy et al., 1999; Zeppetella et al., 2000; Gomez-Batiste et al., 2002; Hwang et al., 2003). Nevertheless, the median duration of untreated episodes in the current study is consistent with the median duration of untreated episodes in other published studies (i.e. 60 min) (Fine and Busch, 1998; Portenoy et al., 2010). We cannot explain the disparity between the time to reach peak intensity in the current study (i.e. 15 min) and the time to reach peak intensity in other published studies (i.e. 1–3 min) (Portenoy et al., 1999, 2010). It should be noted, however, that in many instances the pain became intense shortly after the start of the episode, even if the pain did not peak in intensity until 15 min after the start of the episode. Eighty-eight percent of patients had identified an intervention that at least ‘‘sometimes’’ improved their breakthrough pain: in 34% of these patients the treatment was a non-pharmacological intervention, and in another 18% of these patients the treatment was a combination of a pharmacological and non-pharmacological intervention. A variety of different non-pharmacological interventions were utilised, and in some cases more than one non-pharmacological intervention was utilised at the same time. Interestingly, there is little data to support the use of such interventions in this situation (Christelis and Filshie, 2006). Nevertheless, patients appear convinced of their efficacy, and often use non-pharmacological interventions in preference to pharmacological interventions. Most patients were receiving oral opioids as rescue medication for their breakthrough pain. The majority of patients (76%) were satisfied with their rescue medication, with 52 patients reporting ‘‘complete’’ relief and 195 patients reporting ‘‘good’’ relief from their medication. However, the perceived median onset of action of the oral opioids was 20–30 min, and the perceived median time to peak effect was 30–45 min. (Clinical data suggest that the actual onset of action of oral opioids is 20–30 min, and that the actual time to peak effect is 60–120 min (Bailey and Farley, 2006)). Thus, there is a disparity between the pharmacodynamic profile of oral opioids and the temporal characteristics of breakthrough pain. Equally, it should be remembered that oral opioids have a relatively prolonged duration of action (i.e. 3–6 h) (Bailey and Farley, 2006), and this prolonged duration of action may be associated with ongoing/delayed adverse effects. The perceived median onset of action of the transmucosal fentanyl products was 10 min, and the perceived median time to peak effect was also 10 min. Non-adherence with rescue medication was an issue in this study, and has been previously reported in this group of patients (Davies et al., 2008; Zeppetella, 2008). The reasons for non-adherence were varied, and while some were clearly appropriate (e.g. pain is not always severe, pain is not always long lasting), others reflected actual problems with the use of rescue medication (e.g. lack of efficacy, lack of tolerability) or perceived problems with the use of rescue medication (e.g. risk of addiction, risk of tolerance). Not surprisingly, many of the concerns about rescue medication are similar to those about ‘‘around-the-clock’’ medication (background pain medication). In many cases, adherence could be improved by relatively simple interventions from the healthcare professional (e.g. one to one education about the risk of addiction/ risk of tolerance).

The oral transmucosal route of administration is well established in the management of breakthrough pain (Zeppetella, 2009). Indeed, 22% patients had previously used this route to manage their breakthrough pain, although only 9% patients were still receiving a relevant product at the time of the study. The oral transmucosal route was the most acceptable route, with only 9% patients stating that they would definitely not use such a preparation to manage their breakthrough pain. However, 73% patients reported the existence of at least one regular oral problem, and some oral problems may influence the efficacy and/or tolerability of certain oral transmucosal products (e.g. xerostomia) (Davies and Vriens, 2005). The acceptability of the oral transmucosal route was positively influenced by the previous use of this route to manage breakthrough pain (but not to manage other indications). This result was not unexpected, since oral transmucosal opioids have been shown to be effective and well tolerated in this scenario (Zeppetella, 2009). Danish patients were less likely to answer ‘‘yes’’ to the question about acceptability of the oral transmucosal route (and also the intranasal route), which presumably reflects cultural differences between the populations. In contrast, Danish patients were more likely to answer ‘‘yes’’ to the question about acceptability of the subcutaneous route. Currently, the intranasal route of administration is not well established in the management of breakthrough pain. Indeed, only 2% patients had previously used this route to manage their breakthrough pain, and only one patient were still receiving a relevant product at the time of the study. (The study was undertaken at a time when there was no commercially available intranasal formulation). Nevertheless, emerging data suggest that intranasal formulations may have significant advantages over oral formulations, and also oral transmucosal formulations (Kress et al., 2009; Mercadante et al., 2009). The intranasal route was the least acceptable route, with 26% patients stating that they would definitely not use such a preparation to manage their breakthrough pain. The main reason given was ‘‘I don’t like the idea of such a product’’, although it should be noted that changes in patient’s opinions can occur as a result of changes in circumstances (e.g. increasing pain intensity) (Walker et al., 2003). The other reasons given may not be relevant in clinical practice (e.g. concerns about lack of efficacy in patients with nasal symptoms) (Nave et al., 2009a,b), or could be amenable to straightforward interventions (e.g. education to overcome concerns about development of addiction in patients using nasal opioids). The acceptability of the intranasal route was positively influenced by the previous use of this route to manage other indications. This result was again not unexpected, since other investigators have reported that the acceptability of different routes was affected by previous experience of the route of administration (Walker et al., 2003). Scandinavian patients were less likely to answer ‘‘yes’’ to the question about acceptability of the intranasal route, which presumably reflects cultural differences between the populations. Interestingly, male patients were more likely to answer ‘‘yes’’ to the question about acceptability of the intranasal route. A high acceptability of the subcutaneous route has previously been reported (Walker et al., 2003), and undoubtedly reflects the relatively fast onset of action of parenteral opioids (compared to oral opioids). Thus, the acceptability of the subcutaneous route was positively influenced by the previous use of this route to manage breakthrough pain (35% study patients). Walker et al. reported that the acceptability of different routes was affected by the severity of the breakthrough pain (Walker et al., 2003). For example, in the case of mild to moderate pain, 44% patients would say ‘‘yes’’ to the buccal route, 63% to the sublingual route, 50% to the intranasal route, 60% to the intrapulmonary

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route, and 52% to the subcutaneous route. However, in the case of severe pain, 63% patients would say ‘‘yes’’ to the buccal route, 75% to the sublingual route, 68% to the intranasal route, 75% to the intrapulmonary route, and 87% to the subcutaneous route. In the current study, the acceptability of different routes was not similarly affected by the severity of the breakthrough pain.

5. Conclusion Breakthrough pain is common in patients with cancer pain, and is a significant cause of morbidity in this group of patients. Many of the patients in the study were satisfied with their rescue medication (usually an oral opioid), although on further questioning there were often issues relating to the relative efficacy and/or tolerability of their rescue medication. The introduction of novel transmucosal opioid formulations may address some of these issues, although the study highlights further issues around the acceptability/practicalities of novel routes of administration. It should be emphasised that the utilisation of rescue medication is only one aspect of the management of breakthrough cancer pain. Thus, the successful management of breakthrough cancer pain depends on a combination of thorough assessment, appropriate/targeted treatment(s), and thorough re-assessment. Moreover, treatment involves a variety of strategies, including management of the underlying condition, modification of the background (‘‘around-the clock’’) medication, utilisation of nonpharmacological interventions, and utilisation of interventional techniques.

Acknowledgements The study was supported by an educational grant from Nycomed, who market InstanylÒ (intranasal fentanyl) for the management of breakthrough cancer pain. The authors would like to acknowledge the assistance of all of the staff at the research institutions: Roskilde Hospital (Denmark), Odense University Hospital (Denmark), Sankt Maria Hospice (Denmark), University Hospital Aachen (Germany), University Hospital Gottingen (Germany), Karolinska University Hospital (Sweden), University Hospital Lund (Sweden), Royal Marsden Hospital (UK), and St. Clare Hospice (UK). The authors would like to specifically acknowledge the assistance of Dr. Linda Bertram, Dr. Bernd Alt Epping, Yiva Liden, Hanne Schou Bredsdorff, Melanie Waghorn, Dr. Qamar Abbas and Beth Burton.

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