The effect of breakthrough pain on heart and lung function during the cancer pain treatment in palliative care

Introduction: The aim of the research was to determine the effect of breakthrough pain (BTP) on heart and lung function in patients whose cancer pain had been treated with strong opiates. Methods: A prospective study was conducted on 80 patients who were treated in recumbent patients’ hospice of Palliative Care Centre (hospice) University Clinical Centre Tuzla. The effect of pain breakthrough on heart function was monitored by blood pressure and pulse measuring outside. The effect on respiratory function was monitored by measuring the respiration number with SpO2 and pCO2 and pO2 capillary blood values outside, during and after relieving pain breakthrough. Results: Mean value for Karnofsky score for patients upon admission was 47.13 ± 11.05 and on discharge 51.25 ± 11.73. The total number of pain breakthroughs for patients within the 10 days of the treatment was 1396. During the pain breakthrough the mean of systolic pressure was 133.1 mmHg and it was statistically signifi cantly higher than the mean of systolic pressure measured after BTP relief with oral morphine. The mean of diastolic pressure measured outside of pain breakthrough was 75.9 mmHg and after the BTP relief it was 72.9 mmHg. The mean pulse outside of pain breakthrough was 92.7 heartbeats per minute and after the BTP relief 8 9.1 heartbeats per minute. Conclusion: Pain breakthrough leads to pulse acceleration, increased systolic and diastolic blood pressure and it also affects respiratory function by accelerating the respiration. © 2011 All rights reserved


Introduction
International Association for the Study of Pain -IASP, defi nes pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.Pain is the most frequent and the most severe symptom of in cancer patients and 75-90% of patients in terminal stage endure pain, the cause of cancer pain can be the cancer itself, cancer therapy or the accompanying disorders related to cancer pain.Tumour cells release endothelin, prostaglandins, alpha tumour necrosis factor (TNF), proteolytic enzymes prostaglandins (E 1 and E 2 ), proinfl ammatory cytokines (TNF, IL-1, IL-6), substance P, tumour growth factor and they also activate nociceptors that fi re spontaneously and create peripheral sensitization and fast tumour growth of diff erent types of tumours can lead to compression and nerve damage which causes ischemia and direct proteolysis (1).Tumour surgery can lead to nerve damage and neuropathic pain.Chemotherapy induces the release of algogenic cytokines, radiotherapy leads to tissue fi brosis with nerve compression and painful mucositis can be caused both by radio and chemotherapy (2).Breakthrough pain (BTP) is a temporary sudden pain, a subtype of incidental pain that occurs over the "basic" pain during the opiate treatment.It should be diff erentiated from the weakly controlled basic pain, which is also oft en a cause of the occurrence of pain breakthrough, also from emergency pain and "crescendo pain".When BTP occurs, basal pain is by defi nition relatively stable and under control (3).Th e governing committee of European Association for Palliative Care suggested the use of term "episodic pain" which they divided into two groups -with and without signifi cant basal pain (4).BTP by its intensity has to be severe to unbearable on basis of weak or medium severe pain.Portenoy and Hagen (5) described several characteristics that are important for understanding the BTP: ratio of BTP with fi xed dose of opiates, temporal characteristics of BTP (duration period, time of occurrence), the cause of occurrence of BTP, possible predictability of the occurrence and pathophysiology and etiology of BTP (Table 1).BTP occurs in 70-95% of the cases in patients in advanced stage of cancer disease (6).Th e intensity of BTP is oft en described as very severe and intensive pain (from 7-10 according to NRS (Numerical Rating Scale) with fast paroxysmal onset (<3 minutes) and the mean of reaching the "pain peak" in less than 10 minutes.In 80-90% of the cases the duration is from 15 to 30 minutes and the mean frequency in patients in terminal stage of the cancer illness is 4-7 painful episodes a day (7).In 27% of the cases it occurs spontaneously, while the occurrence of the BTP can be accelerated by activities such as movements, laughter, sneezing, coughing, sitting, touch, distension of hollow organs (bowels, urethra) or psychosocial stimuli (8).Th e cause of the BTP is most oft en related to bone pain (27%), local soft tissue tumour invasion (21%) and brachial plexus syndrome (9%) , and it can be classifi ed as nociceptive, visceral nociceptive or neuropathic (9).Two key components in treating BTP are: the size of individual salvage dose and tome interval of administering the drug.Most authors agree that the average "salvage dose" should be 10 to 20% of total daily dose of fast-acting strong opiate (10).In 17-30% of the cases, BTP is related to inadequate analgesic treatment, whether it is subdosing analgesics or too long time interval between the doses, which leads to reduction of concentration in the plasma e.g.opiate in the end of dose interval which causes the increase of pain intensity so called end dose insuffi ciency.At the same time the patients endure BTP not wanting to take fastacting opiate out of fear of side eff ects or developing resistance and addiction.Th e most frequently used drugs in BTP treatment are fast-acting oral opiates with the onset of 20 to 30 minutes aft er the administration, with maximal eff ect aft er 45 to 60 minutes (11).Much better eff ects in relieving the BTP, because of its fast acting onset, are achieved with transmucosal fentanyl citrate, which passes through the blood brain barrier within 3-5 minutes, with its peak eff ect within 20-40 minutes with its overall duration from 2-3 hours aft er the administering the drug (12).Intranasally applied fentanyl citrate spray, relieves the episodic pain signifi cantly faster (within 5-10 minutes) in regard to oral morphine, with safe way of application, without side-eff ects and good patient tolerance (13).Th e aim of the research was to establish the effect of BTP on heart and lung function in patients whose cancer pain was treated with strong opiates.

Patients
A prospective study has been conducted on 80 patients who were treated in recumbent patients' hospice at Palliative Care Centre of Clinical Centre Tuzla in the period of September 2010 to March 2011.Basal Cancer pain (with 7-10 intensity according to NRS) was treated with strong opiates (oral morphine and transdermal fentanyl) whose doses were increased every third day of the treatment by 50%, unless more than two pain breakthrough occurred the previous day, in which case a salvage dose of 8 mg of oral morphine was  patient/a day).On the fourth day of the treatment the total of 160 BTP were noted (2.0 breakthroughs/per patient/a day) which is statistically signifi cantly less compared to the fi rst day (p= 0.008).Also, in the following days, the BTP kept reducing and on the tenth day total of 53 BTP was registered (0.66 breakthroughs/per patient/a day), which is statistically signifi cantly less compared to the day of the admission (p< 0.0001) (Figure 1).

Th e eff ect of BTP on cardiovascular system
During the BTP, mean value of systolic pressure in all 80 examinees (in 1396 measurements) was 133.1 mm Hg (from 115 do 165 mm Hg) and was statistically signifi cantly greater (p< 0.0001) than systolic pressure mean measured in a state of stabile, controlled pain (outside BTP) when the mean was 120.4 mm Hg (from 100 to 140 mm Hg).Aft er relieving BTP by salvage dose of oral morphine the mean of systolic pressure was 114.5 mm Hg (from 80 to 140 mm Hg) and was statistically signifi cantly lower (p<0.0001)compared to the systolic pressure during the BTP (Figure 2).Th e mean of diastolic pressure in all 80 examinees, monitored outside BTP was 75.9 mm Hg (from 60 to 95 mm Hg).During the BTP the mean of diastolic pressure (in 1396 measurements) was 84.7 mm Hg (from 70 to 130 mm Hg) and was statistically signifi cantly higher (p<0.0001)compared to measuring outside BTP.Th e value of diastolic pressure aft er relieving the BTP with salvage dose of oral morphine was 72.3 mm Hg (from 50 to 95 mm Hg) and was statistically signifi cantly lower (p< 0.0001) compared to diastolic pressure during the BTP (Figure 2).Measured outside BTP, mean pulse in for all 80 patients was 92.7 heartbeats per minute (From 78 to 110 heartbeats per minute).
During the BTP statistically signifi cant pulse acceleration occurs (p< 0.0001) so the mean rises to 102.2 heartbeats per minute (from 83 to 120 heartbeats/min), followed by signifi cant pulse slow down aft er relieving the BTP with oral morphine (p< 0.0001), so the mean shows 89.1 heartbeats per minute (from 64 to 107 heartbeats/min) (Figure 2).

Th e eff ect of breakthrough pain on respiratory system
Th e mean number of respirations, measured in a state of stabile, controlled pain was 13.6 per minute (from 12 to 16), with statistically sig-nifi cant respiration acceleration (p<0.0001)during the BTP to the mean of 15.6 per minute (from 12 to 21 respirations per minute).Relieving BTP with salvage dose of oral morphine signifi cantly slows down the respiration speed (p<0.0001)so the mean number of respirations per minute is 12.8 (from 11 to 16) (Figure 3).Th e mean of partial pressure of carbon dioxide in capillary blood (pCO 2 ) in all 80 patients outside BTP was 40.2 mm Hg (from 29.6 to 51.1 mm Hg) while during the BTP statistically signifi cant (p< 0.0001) increase of pCO 2 to the mean of 44.2 mm Hg occurred (from 30.2 to 57.2 mm Hg), and relieving BTP with salvage dose of oral morphine signifi cantly reduces the mean of pCO 2 mm Hg (from 28.3 to 51.1 mm Hg) (Figure 4).Partial pressure of oxygen (pO2) in capillary blood in all patients outside BTP in mean was 75.9 mm Hg (from 62.7 to 91.6 mm Hg) and is statistically signifi cantly higher (p< 0.0001) than pO 2 mean during BTP, which was 71.9 mm Hg (from 55.7 to 88.4 mm Hg) on mean.By relieving the pain by salvage dose of oral morphine the ventilation improves so the mean of pO 2 was 77.7 mm Hg (63.1 to 92.7 mm Hg), which is statistically signifi cantly higher (p< 0.0001) than during BTP (Figure 4).Th e saturation mean (SpO 2 %) measured with pulse oximeter in all 80 patients, monitored outside BTP was 92.8 % (from 83 to 96%) only to be statistically signifi cantly smaller during the BTP (p<0.0001) when it was 89.1 % (from 79 to 96%) and aft er relieving BTP with oral morphine, the mean SpO 2 94.5% (from 84 to 98%) and it was statistically signifi cantly higher (p<0.0001)compared to the means of SpO 2 during BTP but also before the onset of BTP (Figure 4).

Discussion
In the study that monitored the eff ects of cancer pain treatment with transdermal fentanyl within the period of 3 months, Karnofsky score was relatively constant during the treatment, with the mean of 69 ± 2 on the fi rst day, 68 ± 2 at the end of the second month and 69 ± 2 at the end of the study (14).In our study, mean value of Karnofsky score for all 80 patients upon admission was 47 ± 11.05 and upon release 51.25 ± 11.73, so aft er relieving the pain Karnofsky score was signifi cantly better (p=0.0005).Th e study of Marinangeli and associates on 48 patients in advanced stage of carcinoma showed, contrary from our study, that aft er the opiate treatment with the average duration of 76.66 ± 41.15 and signifi cant reduction of pain intensity (p = 0.04), statistically signifi cant reduction of Karnofsky performance status occurs (from 58.92 ± 5.56 upon admission, with the reduction of -24.04) and the degree of life quality, shows deterioration of general condition (15).In our study, aft er relieving the pain with strong opiates, dyspnea was statistically signifi cantly reduced (p< 0.0001; 4.41 ± 2.13 compared to 1.95 ± 1.43.BTP signifi cantly accelerates respiration, but no considerable diff erence was noted compared to the number of respirations before the BTP (13.6/min) and aft er relieving the pain with strong opiates (12.8/min).A study published for palliative care units in Japan states that dyspnea occurs in 29 to 74% of the patients, regardless of the type of carcinoma in terminal stage of the illness, in which respiratory depression treated by morphine is defi ned as deceleration of breathing by more than 10% and it reduces SpO 2 by more than 5. Th e mean dose of morphine used was 65 mg/per day/per patient (in our study 52.42 mg within all ten days of the treatment.)Also, in our study, there was no signifi cant diff erence in the number of respirations (p= 0.117) before and after the application of morphine.In this study the mean of oxygen saturation (SpO 2 %) measured by pulse oximeter was around 88% before, and up to 98% aft er the morphine treatment (p=0.125), and as well as in our study there was no statistically signifi cant diff erence.Th is study concurrently draws a conclusion that if the morphine is applied in the form of nebulizer (if it is inhaled) it relives the breakthrough pain or sudden onset of dyspnea signifi cantly faster and it has far less system side eff ects (constipation, drowsiness etc.) (16).
In random double-blind controlled study con-  2009) follows the impact of chronic pain treatment effi ciency on heart function.Th e research was conducted on 37 patients whose pain was determined by numerical scale (from 0 to 10), and the treatment, depending on pain intensity was conducted accordingly to the guidelines of tree level scale.Th e pain intensity during the fi rst check-up was on average 8 (from 6, 0 to 10, 0), during the fi rst control check-up 5 (from 2.7 to 6.5) and 4 (from 2.5 to 5.3) during the third examination which is statistically signifi cantly less (p<0.001).Th e mean of systolic pressure was, as in our study as well, signifi cantly reduced (p<0.001)aft er relieving the pain, at the control check-up compared to the fi rst examination [130 (from 120 to 148 mm Hg) compared to 150 (from 130 to 160 mm Hg) ].Th e mean of diastolic pressure was signifi cantly reduced (p<0.007)at the control check-up [90 (out of 80 to 98 mm Hg) compared to 80 (from 80 to 88 mm Hg)] which corresponds with the results of our study, while contrary to the results of our study, in this research there was no signifi cant diff erence in the heart function frequency [p = 0.821; 78 (72 to 83 per minute) compared to 78 (71 to 83 per minute)] (20).

Conclusion
Breakthrough pain, as an "acutization" of chronic cancer pain aff ects the cardiovascular system leading to pulse acceleration, increase of systolic and diastolic blood pressure.Breakthrough pain affects the respiratory function by leading to respiration acceleration, the increase of pCO 2 values, and the reduction of pO 2 and SpO 2 values, without statistically signifi cant diff erence in relation to mentioned parameters before the onset of breakthrough pain.By using modern fast-acting opiates such as transmucosal fentanyl citrate or internasal fentanyl citrate spray, the breakthrough pain is much more easily intercepted (within 5-10) minutes and by doing that the eff ect of BTP on cardiovascular and respiratory system is reduced.

Competing interests
Th e authors declare that they have no confl ict of interest.

FIGURE 1 .FIGURE 2 .FIGURE 3 .FIGURE 4 .
FIGURE 1. Number of BTP through days of treatment in all examinees FIGURE 2. The values of blood pressure and pulse depending on BTP

TABLE 1 .
Differentiation of basal cancer and breakthrough pain required.General condition of the patients was assessed using Karnofsky score upon admission and also aft er 10 days of treatment.Th e eff ect of pain breakthrough on heart function was monitored by measuring the blood pressure (systolic and diastolic) and pulse outside, during and aft er relieving the BTP with salvage dose of oral morphine.Th e eff ect on respiratory function was monitored by measuring the number of respirations, values of SpO 2 measured with pulse oksymeter pCO 2 and pO 2 -from ABS medical report, from capillary blood, outside, during and aft er relieving BTP by salvage dose of oral morphine.Th e study excluded the following patients; patients allergic to strong opiates, patients who have previously used strong opiates, patients with heavy vomiting that hindered the intake of oral morphine, patients with increased value of pCO 2 due to respiratory insuffi ciency or as a sign of renal and liver insuffi ciency.
.75 breakthroughs per patient a day).On the fi rst day of treatment, total number of pain breakthroughs was 208 (2.6 breakthroughs per patient a day), on the second day it was 184, and on the third day 186 BTP (2.3 breakthrough/per