Original Paper Oncology 1992:49:180-182
3 National Institute of Oncology and b Research Instituted'A gricultural Economy, Budapest. Hungary
Keywords Miacalcic nasal spray Analgetic Osteolytic métastasés Quality of life
Pain Killing with Calcitonin Nasal Spray in Patients with Malignant Tumors
Abstract The physiological role of calcitonin is the preservation of osseal integrity by reducing the osteoclast activity. On the other hand, this 32 amino acid peptide acts as an analgetic drug in cancer caused by osteolytic métastasés. In previous studies using injection form the pain killing activity was observed in 65% of the patients. As medical assistance is required for this treatment form, it was decid ed to compare the pain reducing activity of nasal spray with the ampule form. It was found that 300 M RC units of nasal spray equalled 100 M RC units injec tion. The pain killing activity was observed in 53.8% of the patients. The reduc tion in quantity of other analgetics used daily was 48.5%. The average decrease of the pain duration (in h) was 42.5%. The pain intensity measured by visual analogue scale dropped to 2.13 from 3.00. The results are similar to the analget ic effect observed in the injection form. Taking this into consideration, cal citonin nasal spray is highly recommended instead of ampules.
Introduction M ultimodality cancer treatment has brought about sig nificant improvement in the overall survival for many ma lignant diseases. However, the prolongation of life expec tancy does not mean in many cases a symptom-free period. More than 60% o f patients with advanced malignant tu mors report having pain, which is sometimes unbearable [I]. A novel possibility of pain relief is to give in pharm a cological dosage the physiologically present hormone, cal citonin (CT). which inhibits the osteoclast activity and also increases the beta endorphin level [2-4], Due to the former property of CT the pain killing effect can be understood in osteolytic bone destruction, while, on the other hand, the mechanism of other pain can be better explained through
beta endorphin [4, 5]. Theanalgesic and quality of life im proving activity of CT was investigated by us in our previous study [6]. According to our assumptions, a furth er increase could be developed in quality of life if the drug is delivered in a noninjection mode. The preliminary results of CT administration by nasal spray are discussed in the paper.
Material and Methods In our nonrandomized pilot study, which started in December 1990.26 patients with far advanced malignant tumors were enrolled. Two months prior to inclusion.the standard cytostatic treatment was not altered. No further therapy was given to 82% of the patients. However, their suspected life expectancy was a minimum of 3
Dr. Janos Szântô National Institute o f Oncology II 1122 Budapest ( Hungary)
< 1992 S. Karger AG. Basel 0030 2414/92/ 0493-0180 S 2.75/0
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.211.4.224 - 12/17/2017 1:17:17 AM
J. Szantoa N .Adya S. Jozsefh
Table 1 . Patient characteristics and main result
Mean age Range
26 22 54.1 37 80
Sex. F M
25/1
Diagnosis (type of malignancy) Breast Myeloma GI tract Thyroid Melanoma
17 5 2 1 1
Analgetic activity. % Reduction in pain duration. % Reduction in other analgetics, %
53.8 42.5 48.5
months. The investigated group consisted of 1 man and 25 women. Due to early death (2 patients), refusal (I patient) and bad compli ance (1 patient), only 22 cases were evaluable. The mean age was 54.1 years (37-80 years). 17 patients had breast cancer. 5 multiple myelo ma. 2 colon cancer. 1 thyroid neoplasia and 1 malignant melanoma. The patients received 3 x 1 puffeveryday into the nostrils from a 100 MRC units ampule (Miacalcic, salmon calcitonin, Sandoz). Two puffs were delivered to each nostril at 8 a.m. then 1 into one nostril 30 min later for the first 2 weeks, then 100 MRCU only once daily. The minimum duration of treatment was 4 weeks, the maximum period was 5 -I- months. The most important characteristics are shown in table 1. For an objective evaluation of the fairly subjective pain sensation, the patients recorded the changes in the consumption of standard mi nor or major pain killers, as well as the duration and intensity of pain. Patient mobility, representing one of the im portant quality of life fea tures. was bi-weekly controlled at our department. Changes in the duration of pain were determined by a score sys tem recommended by Sandoz Pharmaceutical Works: 0 = painless: 1 = pain lasting for 1 6 h; 2 = 7 12 h; 3 = 13 16 h: 4 = 19 24 h. Changes in the density o f pain were determined by the patients using a visual analogue scale once a week. Changes in the quality o f life were calculated on the basis of the Eastern Cooperative Oncology Group (ECOG) score system: 0 = fully active: I = capable of light work; 2 = in bed less than 50% o f time: 3 = in bed more than 50% o f time: 4 = completely bedridden [7]. As according to our previous studies [6. Szanto. unpubl. data], no laboratory changes could be observed, no check-ups were done on this item. The significance of the changes between initial and final mean values of visual analogue scales was statistically examined (t and F test). The relief of pain is demonstrated by empirical distribu tion curves (prior to therapy and on day 28 o f treatment). The hy pothesis of decrease was tested with u probes.
Fig. 1. Study o f pain intensity. Empirical distribution curve of pain intensity (x) prior loand on day 2 1o f treatment (Pl(.x)and Pll(x) respectively). P = P r(X < x ) = proportion o f patients with pain intensity less than x%. A naverage decrease of 22.3% wasobserved. Significance study: H„: E(X,) = E(XM); H,: E(X,)> E(X„). Result o lu test: 3.48 > 2.58 = u (99.5%). The hypothesis o f equality o f the mean values of pain intensity can be rejected in 99.5% because of the antihypothesis of decrease.
Results Relief of pain as a consequence of CT nasal spray was observed in 14 (53.8%) patients. The duration of pain sen sation dropped on average from 11.3 to 4.8 h (42.48%). (The most greatest decrease in length of time was 17 h). This time reduction on the score system is as follows; from 2.36 to 1.72. The quanity of minor and/or major analgetics used prior to CT treatment decreased by 48.5% (from an average of 3.36-1.63). Data of the mathematical analysis dealing with the visual analogue scales are shown in fig ure I. Figures of the performance status, representing an important component of quality of life, diminished from the initial mean of 3.00 to 2.13. The main results of the treatment are shown in table I. No side effects could be observed. Radiomorphologic improvement, i.e. calcium incorporation into the lytic bone areas and the alteration of their density, could not be visualized. Lifespan, despite the decreased pain and improved life quality, was un changed.
I81
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.211.4.224 - 12/17/2017 1:17:17 AM
Patients, n Evaluable
Discussion The most essential role of calcitonin is the preservation of osseal integrity [8]. The pain killing effect of this 32 ami no acid containing hormone is well known [9]. It is gener ally accepted that this hormone improves the quality of life, however, it can not prolong the total survival. The quality of life of the patients is more pronounced if they are independent o f any assistance delivering the drug. Giving injections to them for killing pain means that they are strictly bound to medical personnel. However, when other devices as. e.g., nasal spray as in our case, are used, the aforementioned problem no longer exists. Our unpub lished trial on dosage determination has clearly shown that only 300 M RCU nasal spray was equivalent to 100 MRCU Miacalcic injection. In other trials the ratio was 2:1 [10J.
With a recommended daily dose of 300 M RCU CT na sal spray was effective in 53.8% ofcancer patients, which is equal to our previous study using the injection form [6]. Concerning its effect, CT nasal spray cannot be ranged amongst any classical group of analgetics since it shows an effect in some patients where major analgetics failed (e.g. petidin). It should be stressed, however, that it exerts its pain reducing activity within 8-10 days after starting the treatment. 11has been show n that, in contrast to any other analget ic, CT nasal spray is a compound which reduces pain and thus improves quality of life. Our preliminary observa tions show that CT nasal spray may be used as an impor tant agent for pain treatment in cancer patients, however, more data are needed to form definitive conclusions.
References
182
6 Szanto J. Jozscf S. Rado J. Juhos E. Hindy 1. Eckhardt S: Pain killing with calcitonin in pa tients with malignant tumours. Oncology 1986:43:69-72. 7 Eastern Cooperative Oncology Group: Func tional assessment scale: in Rubin P (ed): Clini cal Oncology: A Functional Approach. New York. American Cancer Society. 1983. p 91. 8 Gcnnary C. Francini G. Civitelli R, Maioli E, Gonelli S. Bartalini P: Effects of calcitonin treatment on bone pain and bone turnover in Paget'sdisease of bone. M iner Mclab Res Italy 1981:2:109-113.
Szântô/Ady/Jôzsef
9 Welzel D: Analgesic potential of salmon cal citonin in postoperative pain: in Gennary C. Segre G (eds): The Effects of Calcitonin in Man. Milano. Masson. 1983. p 223. 10 Böhning W. Ringe JD. Welzel D. Bode V: In tranasales Lachscalcitonin zur Prophylaxe des Knochenmineralverlustes bei Stcroidbcdiirftigon. chronisch-obstruktiven Atemwegser krankungen. Arzneimittelforschung 1990:40: 1000-1003.
Calcitonin as Pain Killer
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.211.4.224 - 12/17/2017 1:17:17 AM
1 Hoffmann L: Behandlung von Tumorschmerzen. Onkologie 1984;7(suppl. 1):62—64. 2 Copp DH: Evolution of calcium regulation in vertebrates. Clin Endocrinol Metab 1972:1: 21-32. 3 Lucht U. Norgaard J O: Uptake of peroxidase by calcitonin inhibited osteoclasts. Histoche mistry 1977:54:143-148. 4 PecileA. Ferri S. Braga PC: Effect of intracerebrovascular calcitonin in concious rabbit. F.xperientia 1975:31:332-333. 5 Bonucci E: New knowledge on thcorigin. func tion and fate of osteoclasts. Clin Ortop 1981:158:252-269.
3 National Institute of Oncology and b Research Instituted'A gricultural Economy, Budapest. Hungary
Keywords Miacalcic nasal spray Analgetic Osteolytic métastasés Quality of life
Pain Killing with Calcitonin Nasal Spray in Patients with Malignant Tumors
Abstract The physiological role of calcitonin is the preservation of osseal integrity by reducing the osteoclast activity. On the other hand, this 32 amino acid peptide acts as an analgetic drug in cancer caused by osteolytic métastasés. In previous studies using injection form the pain killing activity was observed in 65% of the patients. As medical assistance is required for this treatment form, it was decid ed to compare the pain reducing activity of nasal spray with the ampule form. It was found that 300 M RC units of nasal spray equalled 100 M RC units injec tion. The pain killing activity was observed in 53.8% of the patients. The reduc tion in quantity of other analgetics used daily was 48.5%. The average decrease of the pain duration (in h) was 42.5%. The pain intensity measured by visual analogue scale dropped to 2.13 from 3.00. The results are similar to the analget ic effect observed in the injection form. Taking this into consideration, cal citonin nasal spray is highly recommended instead of ampules.
Introduction M ultimodality cancer treatment has brought about sig nificant improvement in the overall survival for many ma lignant diseases. However, the prolongation of life expec tancy does not mean in many cases a symptom-free period. More than 60% o f patients with advanced malignant tu mors report having pain, which is sometimes unbearable [I]. A novel possibility of pain relief is to give in pharm a cological dosage the physiologically present hormone, cal citonin (CT). which inhibits the osteoclast activity and also increases the beta endorphin level [2-4], Due to the former property of CT the pain killing effect can be understood in osteolytic bone destruction, while, on the other hand, the mechanism of other pain can be better explained through
beta endorphin [4, 5]. Theanalgesic and quality of life im proving activity of CT was investigated by us in our previous study [6]. According to our assumptions, a furth er increase could be developed in quality of life if the drug is delivered in a noninjection mode. The preliminary results of CT administration by nasal spray are discussed in the paper.
Material and Methods In our nonrandomized pilot study, which started in December 1990.26 patients with far advanced malignant tumors were enrolled. Two months prior to inclusion.the standard cytostatic treatment was not altered. No further therapy was given to 82% of the patients. However, their suspected life expectancy was a minimum of 3
Dr. Janos Szântô National Institute o f Oncology II 1122 Budapest ( Hungary)
< 1992 S. Karger AG. Basel 0030 2414/92/ 0493-0180 S 2.75/0
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.211.4.224 - 12/17/2017 1:17:17 AM
J. Szantoa N .Adya S. Jozsefh
Table 1 . Patient characteristics and main result
Mean age Range
26 22 54.1 37 80
Sex. F M
25/1
Diagnosis (type of malignancy) Breast Myeloma GI tract Thyroid Melanoma
17 5 2 1 1
Analgetic activity. % Reduction in pain duration. % Reduction in other analgetics, %
53.8 42.5 48.5
months. The investigated group consisted of 1 man and 25 women. Due to early death (2 patients), refusal (I patient) and bad compli ance (1 patient), only 22 cases were evaluable. The mean age was 54.1 years (37-80 years). 17 patients had breast cancer. 5 multiple myelo ma. 2 colon cancer. 1 thyroid neoplasia and 1 malignant melanoma. The patients received 3 x 1 puffeveryday into the nostrils from a 100 MRC units ampule (Miacalcic, salmon calcitonin, Sandoz). Two puffs were delivered to each nostril at 8 a.m. then 1 into one nostril 30 min later for the first 2 weeks, then 100 MRCU only once daily. The minimum duration of treatment was 4 weeks, the maximum period was 5 -I- months. The most important characteristics are shown in table 1. For an objective evaluation of the fairly subjective pain sensation, the patients recorded the changes in the consumption of standard mi nor or major pain killers, as well as the duration and intensity of pain. Patient mobility, representing one of the im portant quality of life fea tures. was bi-weekly controlled at our department. Changes in the duration of pain were determined by a score sys tem recommended by Sandoz Pharmaceutical Works: 0 = painless: 1 = pain lasting for 1 6 h; 2 = 7 12 h; 3 = 13 16 h: 4 = 19 24 h. Changes in the density o f pain were determined by the patients using a visual analogue scale once a week. Changes in the quality o f life were calculated on the basis of the Eastern Cooperative Oncology Group (ECOG) score system: 0 = fully active: I = capable of light work; 2 = in bed less than 50% o f time: 3 = in bed more than 50% o f time: 4 = completely bedridden [7]. As according to our previous studies [6. Szanto. unpubl. data], no laboratory changes could be observed, no check-ups were done on this item. The significance of the changes between initial and final mean values of visual analogue scales was statistically examined (t and F test). The relief of pain is demonstrated by empirical distribu tion curves (prior to therapy and on day 28 o f treatment). The hy pothesis of decrease was tested with u probes.
Fig. 1. Study o f pain intensity. Empirical distribution curve of pain intensity (x) prior loand on day 2 1o f treatment (Pl(.x)and Pll(x) respectively). P = P r(X < x ) = proportion o f patients with pain intensity less than x%. A naverage decrease of 22.3% wasobserved. Significance study: H„: E(X,) = E(XM); H,: E(X,)> E(X„). Result o lu test: 3.48 > 2.58 = u (99.5%). The hypothesis o f equality o f the mean values of pain intensity can be rejected in 99.5% because of the antihypothesis of decrease.
Results Relief of pain as a consequence of CT nasal spray was observed in 14 (53.8%) patients. The duration of pain sen sation dropped on average from 11.3 to 4.8 h (42.48%). (The most greatest decrease in length of time was 17 h). This time reduction on the score system is as follows; from 2.36 to 1.72. The quanity of minor and/or major analgetics used prior to CT treatment decreased by 48.5% (from an average of 3.36-1.63). Data of the mathematical analysis dealing with the visual analogue scales are shown in fig ure I. Figures of the performance status, representing an important component of quality of life, diminished from the initial mean of 3.00 to 2.13. The main results of the treatment are shown in table I. No side effects could be observed. Radiomorphologic improvement, i.e. calcium incorporation into the lytic bone areas and the alteration of their density, could not be visualized. Lifespan, despite the decreased pain and improved life quality, was un changed.
I81
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.211.4.224 - 12/17/2017 1:17:17 AM
Patients, n Evaluable
Discussion The most essential role of calcitonin is the preservation of osseal integrity [8]. The pain killing effect of this 32 ami no acid containing hormone is well known [9]. It is gener ally accepted that this hormone improves the quality of life, however, it can not prolong the total survival. The quality of life of the patients is more pronounced if they are independent o f any assistance delivering the drug. Giving injections to them for killing pain means that they are strictly bound to medical personnel. However, when other devices as. e.g., nasal spray as in our case, are used, the aforementioned problem no longer exists. Our unpub lished trial on dosage determination has clearly shown that only 300 M RCU nasal spray was equivalent to 100 MRCU Miacalcic injection. In other trials the ratio was 2:1 [10J.
With a recommended daily dose of 300 M RCU CT na sal spray was effective in 53.8% ofcancer patients, which is equal to our previous study using the injection form [6]. Concerning its effect, CT nasal spray cannot be ranged amongst any classical group of analgetics since it shows an effect in some patients where major analgetics failed (e.g. petidin). It should be stressed, however, that it exerts its pain reducing activity within 8-10 days after starting the treatment. 11has been show n that, in contrast to any other analget ic, CT nasal spray is a compound which reduces pain and thus improves quality of life. Our preliminary observa tions show that CT nasal spray may be used as an impor tant agent for pain treatment in cancer patients, however, more data are needed to form definitive conclusions.
References
182
6 Szanto J. Jozscf S. Rado J. Juhos E. Hindy 1. Eckhardt S: Pain killing with calcitonin in pa tients with malignant tumours. Oncology 1986:43:69-72. 7 Eastern Cooperative Oncology Group: Func tional assessment scale: in Rubin P (ed): Clini cal Oncology: A Functional Approach. New York. American Cancer Society. 1983. p 91. 8 Gcnnary C. Francini G. Civitelli R, Maioli E, Gonelli S. Bartalini P: Effects of calcitonin treatment on bone pain and bone turnover in Paget'sdisease of bone. M iner Mclab Res Italy 1981:2:109-113.
Szântô/Ady/Jôzsef
9 Welzel D: Analgesic potential of salmon cal citonin in postoperative pain: in Gennary C. Segre G (eds): The Effects of Calcitonin in Man. Milano. Masson. 1983. p 223. 10 Böhning W. Ringe JD. Welzel D. Bode V: In tranasales Lachscalcitonin zur Prophylaxe des Knochenmineralverlustes bei Stcroidbcdiirftigon. chronisch-obstruktiven Atemwegser krankungen. Arzneimittelforschung 1990:40: 1000-1003.
Calcitonin as Pain Killer
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.211.4.224 - 12/17/2017 1:17:17 AM
1 Hoffmann L: Behandlung von Tumorschmerzen. Onkologie 1984;7(suppl. 1):62—64. 2 Copp DH: Evolution of calcium regulation in vertebrates. Clin Endocrinol Metab 1972:1: 21-32. 3 Lucht U. Norgaard J O: Uptake of peroxidase by calcitonin inhibited osteoclasts. Histoche mistry 1977:54:143-148. 4 PecileA. Ferri S. Braga PC: Effect of intracerebrovascular calcitonin in concious rabbit. F.xperientia 1975:31:332-333. 5 Bonucci E: New knowledge on thcorigin. func tion and fate of osteoclasts. Clin Ortop 1981:158:252-269.
