Evaluation of the analgesic effect of salmon calcitonin in metastatic bone pain
Aim: To evaluate the efficacy of calcitonin in controlling metastatic bone pain. Materials and methods: Patients with bone metastases, with a numerical pain score greater than 4 wererandomized to receive calcitonin 200 IU subcutaneously 6 hourly for 48 hours (n= 10) or normal saline placebo (n = 10) . The parameters measured were the 11-point numerical pain score, ECOG functional capacity score, morphine consumption in 24 hours, duration of pain in 24 hours and subjective assessment of efficacy of treatment by a blinded investigator. Results: There was a statistically significant decrease in pain score at 48 hours (2 vs 6) and 7 days (3 vs 6) in the calcitonin arm as compared to the control arm. The reduction in duration of pain (3 vs 13) and improvement in ECOG (1.5 vs 2.5) score were also statistically significant. Adverse effects were nausea in 5 patients and vomiting in 3 patients on the day of calcitonin administration. This was controlled with antiemetics. There was no significant change in serum calcium level in either group.
Keywords: Metastatic bone pain, pain score, salmon calcitonin
Bone metastases are a major cause of morbidity in patients with cancer. Breast, prostate and lung cancers account 80% of patients with bone metastases (Nielson et al 1991). Not all patients respond to analgesics and radiotherapy. Calcitonin has been postulated to reduce bone resorption, increase circulating endogenous opioid, and to have endorphin receptor agonist activity. (Gennari, 1988; Spigset, 1993 and Mystakidou 1999).
The study was conducted at the Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi between June and December 2002.
Written informed consent was obtained from all participants. Patients receiving anticancer therapy during the period of study were excluded.
Group A (n= 10), received 200 IU of Salmon calcitonin subcutaneously (SC) 6 hourly for 48 hours.
Group B (n=10), received normal saline as placebo 6 hourly for 48 hrs.
All patients were hospitalized for two days. Complete blood count and serum calcium, creatinine and liver function tests were done at baseline, 7 and 45 days.
Patients continued to receive their analgesic regimen which included a non steroidal, paracetamol and oral morphine. They were instructed to take extra doses of oral morphine for breakthrough pain. On follow up visits the opioid dose was titrated upwards in patients who had inadequate analgesia
The following parameters were recorded at 48 hours, 7 days and 45 days:
All patients were observed for allergic reactions, nausea and vomiting, diarrhoea and hypocalcaemia.
Statistical Analysis: - The Wilcoxon rank-sum (Mann-Whitney) test was used to compare different parameters between the two groups at different time points.
A total of 20 patients were studied. The demographic details and primary sites are listed in [Table - 1]
[Table - 2] shows the pain score (NPS) in both the groups at different time points. From a baseline of 6.5, the median pain score in the calcitonin group decreased to 2 at 48 hours and 3 at 7 days.
Both groups had a poor baseline performance status of 3 [Table - 3]. There was significant improvement in the study group at 48 hours and 7 days. This improvement was not sustained upto 45 days.
The median duration of pain in both groups was 14 hours [Table - 4]. This had reduced to 3 hours in the study group in the week following calcitonin adminstration as compared to 13 hours in the placebo group.
[Table - 5] shows total morphine consumption per day in both study and control groups. There is a significant increase in morphine consumption in the control group at 45 days.
The intervention was assessed as useful in eight out of ten patients given calcitonin and one of ten controls [Table - 6].
Nausea and vomiting were noted in 5 and 3 patients respectively on the day of calcitonin administration. This was controlled with antiemetics. There was no clinically significant reduction in the serum calcium level [Table - 7].
The analgesic action of salmon calcitonin has been demonstrated in Sudeck's atrophy (Nuti et al, 1987) and Paget's disease of bone (Bijovet et al, 1967; Woodhouse et al, 1971; Woodhouse et al, 1972). Calcitonin is postulated to reduce bone resorption, increase circulating endogenous opioid, and act as an endorphin receptor agonist (Gennari, 1988; Spigset, 1993 and Mystakidou 1999).
Hindley et al (1982),found calcitonin 200 IU 6 hourly for 48 hours effective in relieving cancer pain. They analyzed three parameters: VAS, global pain score and analgesic ranking. 8 out of 13 patients in the calcitonin group had improvement in VAS at one week as compared to two out of twelve patients in the placebo group. However when the composite response of all the three parameters were calculated, only four patients in the calcitonin group had clinically significant improvement at one week as against none in the placebo group, and all 4 were patients with skeletal metastases.
Schiralidi et al (1987), observed a significant reduction in pain score from 3.2 to 0.8 at 5 days and 0.6 at 15 days following administration of 1200 units of calcitonin over 3 days.
In the present study at 48 hours the NPS remained stable in the control arm but decreased from 6.5 to 2 in the calcitonin arm. The calcitonin arm continued to have significantly lower pain scores at 7 days.
Analgesic consumption too was significantly lower in the calcitonin group. This difference was sustained at 45 days. Similarly Szanto et al (1986) and Roth & Kolaric (1986) found reduced analgesic consumption in patients who had been treated with calcitonin.
The analgesic efficacy of calcitonin was also reflected in other parameters. While both study and control groups experienced a reduction in the duration of pain and improved mobility after analgesic titration, the duration of pain and the ECOG performance status were significantly lower (better) in the calcitonin group at 48 hours and 7 days. This advantage was not sustained at 45 days.
Other authors have also reported reduction in pain duration (Szanto et al 1986, Roth & Kolaric 1986); and improved performance status (Szanto et al 1986). Blomqvist (1988) however did not find significantly greater improvement in performance status in those receiving calcitoinin as compared to controls. This may have been because the majority of cases and controls included in their study already had stable or regressing disease.
Salmon calcitonin therapy was rated as extremely or moderately useful in 8 out of 10 patients,by a blinded observer. In contrast it was judged to be 'not useful' in 9 of 10 controls. Although such subjective observer assessment has limited validity, it is consistent with the other results in the study.
We did not find significant reduction in serum calcium levels after calcitonin administration [Table - 7]. Similar findings have also been reported by other investigators (Gennari et al 1989; Blomqvist et al 1988; Roth and Kolaric 1986).
To conclude, we found salmon calcitonin effective in rapidly reducing pain due to skeletal metastases. The treatment was associated with minimal adverse effects.
Palliative radiotherapy and oral analgesics remain the mainstay of pain management in bone metastases. Bisphosphonates have been shown to reduce skeletal morbidity (Housten & Rubens, 1995; Hortobagyi et al, 1996). A proportion of patients may need anaesthetic or physiatric measures to relieve bone pain (Mellette & Blunk, 1994). Salmon calcitonin could be a useful option in patients whose bone pain is refractory to standard therapeutic modalities.
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6], [Table - 7]