Volume 38, Issue 4 , Pages 554-560, October 2009
Breakthrough Pain in Advanced Cancer Patients Followed at Home: A Longitudinal Study
Article Outline
Abstract
The aim of this study was to longitudinally assess breakthrough pain (BP) in advanced cancer patients who were admitted to home palliative care. One hundred and one consecutive patients who were admitted to one of the two home care programs and were representative of the cancer population followed at home in Italy were included. Patients were excluded only if at admission they were cognitively impaired or too unwell to provide reliable answers to questions regarding data collection. At admission (T0), and one month later (T1), data were recorded about the pharmacological treatment of background pain and its effectiveness; the presence of BP and its intensity, duration, and number of episodes; the occurrence of BP induced by movement; spontaneous relief after stopping activity and limitation of physical activity because of pain on movement; the analgesic drugs prescribed for BP; and the effectiveness of BP medication. After the initial assessment, patients received analgesics for background pain and BP, as well as symptomatic treatment usually provided at home, according to local policies and protocols. At T0, 70.2% of patients were receiving analgesic drugs, and 52% of them had uncontrolled pain. BP was reported by 49.2% of these patients and had a mean duration and number of episodes per day of 35.1 minutes (±35.0) and 2.4 (±1.5), respectively. Of patients with BP, 65.7% had pain on movement, which decreased spontaneously after stopping activity in 73.9%. Physical activity was strongly limited in 78.2% of these patients. Most patients did not have a BP medication prescription. At T1, a larger number of patients were receiving analgesics (P
<0.002), and the number of patients with BP medication significantly increased (P<0.001). The incidence of BP and pain on movement decreased (33% and 38.5%, respectively). This longitudinal study suggests that BP is a dynamic entity dependent on several factors, including analgesic treatment and the course of disease. This helps explain the different incidences reported in previous studies performed in different settings and conditions.
Key Words: Cancer pain, breakthrough pain, epidemiology
Introduction
In the cancer population, breakthrough pain (BP) is a transitory flare of pain superimposed on an otherwise stable pain pattern in patients treated with opioids.1 BP is still a difficult entity to recognize. Several cross-sectional studies have reported a variable incidence, dependent on the setting, such as hospice admissions, oncology inpatients, pain clinic patients, and patients followed at home, and the type of evaluation.2 At admission to four specialist palliative care inpatient units in the United Kingdom, 93% of patients had BP. Of those with BP, movement-precipitated BP occurred in 53%, and one-third reported BP as completely incapacitating.3 Similarly, 89% of patients admitted to a hospice reported a mean of seven episodes of BP of different intensities per day.4 In a home care setting, 86% of patients with persistent pain reported experiencing BP, half of them in association with a specific activity.5 A lower prevalence of BP was found in other studies. In a large survey performed on a predetermined day in different palliative care programs, including hospices and home care, in Catalonia, Spain, BP was reported by 41% of patients, with a mean 1.5 episodes per day.6 In patients admitted to inpatient units with a mean Karnofsky status of 60, the incidence of BP was 51.2%.7 At admission to a pain clinic, BP was reported by 39% of patients,8 whereas oncology outpatients and inpatients admitted with uncontrolled pain presented a global incidence of 70%.9 Finally, in an international survey performed in a wide range of patients with pain severe enough to be treated with opioids, a BP incidence of about 65% was found, which was associated with poor pain control and functional impairment.10
Other than examining different settings and populations, all these surveys had a cross-sectional design. No study has assessed changes over time in reported BP, either in relation to the course of disease or the analgesic treatment. For example, a type of BP—incident pain because of movement in patients with bone metastases—may be influenced by physical activity, which is dependent on the stage of disease. Moreover, patients often receive an analgesic treatment, which frequently can be effective or not sufficient, the outcome strongly influencing the feature of BP.
Patients with cancer pain can be placed in two extremes, with a large variability between these points: patients receiving oncologic treatment are quite different from advanced cancer patients with a short survival followed at home. Because of the dynamic course of cancer disease and analgesic regimen, it is likely that changes of these components influence BP.
The aim of this study was to longitudinally assess BP in different settings according to the different stages of disease and treatments. The present study focuses on advanced cancer patients who were followed at home in two representative palliative care programs existing in Italy. Data regarding patients assessed in oncology units longitudinally followed over a period of six months during the course of disease will be the subject of a concomitant study with a similar design.
Patients and Methods
This survey was a prospective observational cohort study. A consecutive sample of patients admitted to one of two home care programs in health care districts existing in Genoa and Catania, two large cities based in northern and southern Italy, respectively, who were representative of cancer populations followed at home in Italy, was surveyed over a period of three months. Patients were eligible regardless of their expected survival. Patients were excluded only if cognitively impaired or too unwell to provide reliable answers to questions during data collection. Informed consent and ethical committee approval were obtained.
At admission to the program, in addition to common demographic and disease-related data, data about the background pain, including pharmacological treatment and its effectiveness (if pain was moderate-severe in intensity, i.e., four out of 10 or more on a numerical scale from 0 to 10), were collected. The presence of BP was noted, and if present, information was obtained about its intensity, duration, number of episodes, presence induced by movement, spontaneous relief after stopping activity, and limitation of physical activity because of pain on movement were recorded. Analgesic drugs prescribed for BP and the effectiveness of these medications also were noted. For the purposes of this study, the definition of BP was a transitory flare of pain superimposed on an otherwise stable pain pattern in patients treated with opioids, with only pain of greater than moderate intensity being considered a BP. Parameters relative to background pain and BP in the previous 24 hours were measured using the patient's self-report. Data were recorded by home physicians on the first visit. After the initial assessment, patients received analgesics for background pain and BP, as well as symptomatic treatment usually provided at home, according to local policies and protocols, without changing routine activity. At a one-month interval, the same data collected at admission were recorded, again by interview conducted by the home care physician.
Statistics
Data were collected and analyzed using SPSS Software 14.0 version (SPSS, Inc., Chicago, IL). Statistical analysis of quantitative data, which included descriptive statistics, was performed for all the items. The paired Wilcoxon signed-rank test and the paired samples Student's t-test were used to compare the differences in pain intensity scores and other parameters in the time intervals. All P values were two-sided and P values less than 0.05 were considered to indicate statistical significance.
Results
One hundred and one consecutive patients were admitted to home care programs in Genoa and Catania. The characteristics of the patients are described in Table 1. Mean (standard deviation [SD]) Eastern Cooperative Oncology Group performance status score at study entry was 2.7 (1.1). The median survival time was 22 days (range: 3–91).
Table 1. Epidemiological Data of Patients Admitted to Home Care
| Age (years) | 71.9 (12.2) |
| Gender (M/F) | 54/47 |
| Mean survival (days) | 22 |
| Primary tumor | |
| Lung | 21 |
| Breast | 10 |
| Urogenital | 9 |
| Colon-rectum | 8 |
| Stomach | 7 |
| Pleura | 6 |
| Others | 40 |
At admission (T0), 73 patients (70.2%) were receiving analgesic drugs for their pain. More than half of the patients had uncontrolled pain, as 39 patients reported moderate-severe pain (exactly 39% of the entire sample, 52% of patients receiving analgesics). Of the 73 patients receiving analgesics, analgesic therapy was considered very effective, acceptable, poorly effective, and ineffective by 27, 26, 15, and 5 patients, respectively. Five patients were receiving nonopioid drugs, including paracetamol (acetaminophen) or ketorolac, 33 patients were receiving so-called “weak” opioids or low doses of “strong” opioids (less than that equivalent to 60mg of oral morphine/day), and 33 patients were receiving strong opioids in doses equal to or greater than 60mg of oral morphine or its equivalent per day. In two patients, data regarding analgesic consumption for basal pain were not obtained (Table 2).
Table 2. Parameters Recorded at Admission (T0) and One Month Later (T1)
| Parameters | T0 (n=101) | T1 (n=41) | P |
|---|---|---|---|
| Uncontrolled pain | 39/101 (39%) | 9/41 (22%) | 0.057 |
| Background pain medication | 73/101 (72%) | 39/41 (95%) | 0.002 |
| Nonopioids | 5/73 (7%) | 3/39 (8%) | 0.868 |
| Low-dose opioids | 33/73 (45%) | 10/39 (26%) | 0.042 |
| Strong opioids | 33/73 (45%) | 13/39 (33%) | 0.223 |
| Unavailable data | 2/73 (3%) | 13/39 (33%) | 0.001 |
| Breakthrough pain | 35/73 (48%) | 13/39 (33%) | 0.136 |
| Pain on movement | 23/35 (66%) | 5/13 (38%) | 0.088 |
| BP medication | |||
| Available data | 93/101 (92%) | 30/41 (73%) | 0.002 |
| No prescription | 63/93 (68%) | 10/30 (33%) | 0.001 |
| BP medication | 30/93 (32%) | 20/30 (67%) | 0.001 |
| OTFC | 7/30 (23%) | 7/20 (35%) | 0.368 |
| Oral morphine | 8/30 (27%) | 7/20 (35%) | 0.528 |
| Subcutaneous morphine | 0/30 (0%) | 1/20 (5%) | 0.400 |
| Tramadol-codeine | 6/30 (20%) | 0/20 (0%) | 0.037 |
| Oxycodone | 0/30 (0%) | 4/20 (20%) | 0.021 |
| Nonopioids | 9/30 (30%) | 1/20 (5%) | 0.030 |
Of 73 patients receiving analgesics for their pain at admission, 35 patients (49.2%) had BP, with a mean (SD) pain intensity of 8.0 (±1.2) on a 0–10 scale. The mean (SD) duration of BP and the mean (SD) number of episodes per day were 35.1 minutes (35.0) and 2.4 (1.5), respectively. Of the 35 patients with BP, 23 (65.7%) had pain on movement, with a mean (SD) pain intensity of 7.0 (2.2). In 17 of these patients (73.9%), pain decreased spontaneously after stopping activity. The mean duration of this kind of episode was less than 30 minutes in six patients, 30–60 minutes in five patients, and undefined or dependent on the type of movement in the remaining patients. Physical activity was strongly limited in 18 of these 23 patients (78.2%).
Data regarding the treatment of BP pain were available in 93 patients. Of these, 63 patients had no prescription of BP medication. Seven patients were prescribed transmucosal fentanyl, eight patients oral morphine, six patients tramadol or codeine, and the remaining, nonopioid analgesics (Table 2). The treatment was considered very effective, acceptable, poorly effective, and ineffective, by 14, seven, eight, and one patients, respectively.
One month later (T1), 41 patients were still alive. The number of patients receiving analgesic drugs for their pain significantly increased (39 patients [95.1%], P<0.002). Only nine patients (22%) reported moderate-severe pain (P=0.057 compared with T0 [Table 2]). When specifically considering the 41 patients who followed up at T1, the number of patients with uncontrolled background pain decreased from 13 patients (at T0) to nine patients (at T1). The difference was not significant, possibly because of the low number of patients (P<0.318). For the same reasons, the intensity of background pain decreased from 5.8±1.9 to 4.6±1.9, but was not significant (P<0.172).
Three patients were receiving nonopioid drugs; 10 patients were receiving tramadol, codeine, or oral morphine or equivalent of less than 60mg per day; and 13 patients were receiving oral morphine or equivalent equal to or more than 60mg per day. Data regarding analgesic consumption for background pain for the remaining patients were not obtained. Data regarding the effectiveness of analgesic therapy were available in 30 of 39 patients receiving analgesics. Analgesic treatment was considered highly effective in 26 patients, acceptable in three patients, and poorly effective in one patient.
In the 41 patients who had a follow-up, BP was present in 15 (36.5%) and 13 patients (31.7%) at T0 and T1, respectively, and the mean (SD) BP intensity did not change (8.2±1.3 and 8.2±1.4, at T0 and T1, respectively). The number of patients with pain on movement decreased from eight to five (P<0.364). Mean (SD) intensity of pain on movement was 6.9 (2.3) and 7.8 (1.6) at T0 and T1, respectively (P<0.391). These changes were not significant, possibly because of the low number of patients.
Of 13 patients who were receiving analgesic drugs and had episodes of BP (33%), five patients (38.5%) had pain on movement, with a mean (SD) pain intensity of 7.8 (1.64), and four patients (30.8%) had pain which decreased spontaneously after stopping activity. The mean duration of this kind of episode was less than 30 minutes in 11 patients, and mostly, only one episode per day was recorded (nine patients). Physical activity was strongly limited in three patients.
Data regarding the treatment of BP at T1 were available in 30 patients. Of these, only 10 patients had no prescription of BP medication (33%, P<0.001). Seven patients were prescribed transmucosal fentanyl, seven patients were prescribed oral morphine, four patients oxycodone, and one patient parenteral morphine. The treatment was considered satisfactory in most patients, very effective and acceptable in 10 and three patients, respectively.
Discussion
This survey was performed in two standard home care programs existing in Italy, which follow advanced cancer patients with a limited survival time of about three weeks. About two-thirds of patients were receiving analgesics for background pain, which was uncontrolled in about half of the cases, possibly because patients were undertreated before admission to the home care program in terms of type and doses of analgesics, as confirmed by the relatively high number of patients who were dissatisfied. It is likely that dissatisfied patients having uncontrolled background pain have significantly more occurrences of BP.1, 4, 9 In other studies, a high intensity of background pain has been associated with BP.1 The intensity of baseline pain also was higher in outpatients and inpatients without BP referred to a pain clinic, where neuropathic pain prevailed as a cause of BP.8 These data confirm that different types of referral, setting, and assessment may provide different information.
About half of these patients had episodes of BP clearly distinguishable from background pain, usually pain because of movement, which strongly influenced physical activity. This approximates a previous observation where only pain of greater than moderate intensity on an otherwise controlled background pain was considered as a BP, with an incidence of 51.2%.1 It is similar to the findings in a hospice and home care population in Spain.6 This contrasts with previous experiences in other settings reporting higher rates of BP.3, 4 These differences can be explained by different pain intensities across studies or the lack of background pain in a large number of patients. In another study reporting an 86% incidence of BP, the timing of the interview is unclear; 5 data recorded by the same group report large differences in prevalence, ranging from 39% to 68%.8 In patients admitted with uncontrolled background pain, BP incidence was 70%.9
The number of episodes per day of BP is highly variable in the literature, and may be related to the adequacy of pharmacological therapy, or, given the origin often because of movement-induced pain, may be dependent on the balancing of physical activity and incident pain. Mobilization may be the most frequent trigger for BP.6 Physical activity was strongly limited by incident pain in a large number of patients, possibly explaining the low number of BP episodes recorded in this population. In a hospice study, over a third of patients were reported as completely incapacitated, but this finding was not specifically associated with movement-induced pain.3 In contrast to this low rate of BP, undertreated neuropathic pain may produce even hundreds of episodes of BP per day,8 again demonstrating that the number of episodes of BP per day cannot be easily predicted.
The mean duration of BP at admission was about 30 minutes, in accordance with previous figures reported in different settings.3, 4, 5, 6, 8 It is unclear whether the duration of BP reported in most epidemiological studies of BP is spontaneous, because of stopping activity, or the consequence of a medical intervention. This issue should be better defined and appropriately debated.
Only a smaller number of patients (32%) were prescribed medications for BP at admission. Similar figures were reported in previous studies at hospice admission, where 43% of patients were prescribed no rescue medication.4 In contrast, the rate of BP medication, mainly oral morphine, was very high in patients surveyed in Catalonia.6
After one month, only about 40% of patients were still living. Most patients had controlled pain and were satisfied with the analgesic treatment, possibly because the pattern and the efficacy of background pain medication and BP medication changed. In particular, the number of patients with a BP prescription increased. Moreover, the pattern of BP medication changed, with oral transmucosal fentanyl, oral morphine, and oral oxycodone prevailing over nonopioids, or opioids for moderate pain, which were significantly less frequently used. Of interest, the incidence of BP decreased, although it did not attain significance because of the low number of patients living at the time of the second assessment performed one month later. This finding can be explained by the better analgesic regimen, the reduced physical activity in patients close to death, or both.
Data regarding BP remains quite controversial in the literature, mainly because of the influence of different settings, treatments, and the lack of a longitudinal perspective in assessing cancer patients. This study showed that BP characteristics may change over time. For example, one can assume that the incidence of BP, particularly movement-related pain, may decrease with the worsening of disease, as a consequence of a reduced level of activity, or because patients stop even minimal activity after feeling an increase in pain intensity. Alternatively, a better analgesic approach may limit the occurrence of BP episodes. The duration of BP episodes is evidently limited by a better BP medication prescribed after admission. Thus, the changes in physical activity as well as analgesic regimen may modify conclusions about BP when it is longitudinally examined.
This underscores the need for a longitudinal assessment of a phenomenon that is invariably dependent on stage of disease, patient, and therapeutic factors. In other words, this phenomenon is impossible to assess as a pure event, because it is strongly influenced by activity or analgesic regimen. This approach better reflects what happens in clinical practice, rather than providing just a photograph of a phenomenon that is dynamic and influenced by several factors. As any photograph taken when a subject is moving, the development of such a photograph could be out of focus.
The findings of this study contradict some of the information drawn from previous cross-sectional studies, which have suggested that a large number of patients may experience BP.4, 5 These data are probably dictated by previous undertreatment, rather than by real incidence of the phenomenon. Paradoxically, the “pure” entity of BP should be studied in patients receiving no analgesic treatment, which is ethically unacceptable and unrealistic, and would contradict the original definition of BP, or in different conditions where patients receive analgesics with no, partial, or adequate pain relief.
Thus, it is difficult to have a clear idea about a complex phenomenon, and a prospective evaluation may help understand what happens in individual patients. For example, in a survey performed in selected patients seen in an oncologic setting with predetermined uncontrolled background pain, data were reviewed one week after a visit. Of 70% of patients initially reporting BP, only half (36%) still had BP after pain management began, suggesting that medical intervention may decrease the occurrence of BP, which is unmasked by a poor efficacy of background medication. Of interest, the duration of BP, a median of 15 minutes, did not change despite prescription of rescue medication, presumably based on oral morphine, which was otherwise considered effective by 83% of patients;9 however, the selection criteria applied in this latter study, where patients with uncontrolled pain were admitted, cannot allow any comparison with data from the present study.
Limitations of this study include the relatively high number of missing data, mainly because of the inability to answer specific questions in severely ill patients, and the low number of patients living after one month of home care. However, this finding exactly reflects the clinical setting of home care programs in Italy, with a survival time of about three weeks on average because of a regrettable bias toward late referral to home care programs, often just close to death.11 The same reasons strongly influence collecting data in patients with physical exhaustion, with large attrition rates typical of any longitudinal palliative care study with different collection points.12
The fact that BP is highly prevalent among patients with cancer pain and predicts more severe pain7, 10 may reflect that patients with uncontrolled pain are more likely to unmask BP episodes.13 If patients with BP have scores indicative of greater functional impairment,6 paradoxically, changes in physical activity because of progression of disease in severely ill patients and an improvement of an analgesic regimen may reduce the occurrence of BP. A survey of the course of BP over a six-month observation in patients admitted to an oncology ward, concomitantly planned with the present study, should provide further data about a complex phenomenon such as BP.
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PII: S0885-3924(09)00627-7
doi:10.1016/j.jpainsymman.2008.12.008
© 2009 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
Volume 38, Issue 4 , Pages 554-560, October 2009
