Bone Vol. 30, No.

5, Supplement May 2002:71S74S

Analgesic Effects of Calcitonin

G. P. LYRITIS and G. TROVAS
Laboratory for the Research of Musculoskeletal System, KAT Hospital, Kifissia, Greece

The analgesic activity of salmon calcitonin (subcutaneous or intranasal) has been demonstrated in several prospective clinical trials, in patients suffering different painful skeletal conditions, including recent nontraumatic osteoporotic vertebral fractures. The mechanism of the analgesic effect of calcitonin is not clear. It is possible that specific binding sites for salmon calcitonin exist in the brain. Another explanation is that changes in descending serotonergic modification on the sensory transmission mediated by C afferents contribute to the analgesic effects of calcitonin on pain in osteoporotic patients. From the clinical point of use, the analgesic effect of calcitonin is beneficial throughout the whole period of medical treatment of osteoporotic patients. Salmon calcitonin in a daily dose of 100 IU subcutaneously or 200 IU intranasally reduces dramatically the back pain (p < 0.0005) after a recent osteoporotic vertebral fracture, and promotes the early mobility of patients. The finding that injectable or intranasally administered salmon calcitonin effectively controls severe pain in osteoporotic patients with a recent vertebral fracture, allowing them earlier mobility in combination with a reduction of the urinary hydroxyproline excretion, and a limitation of the considerable bone loss that may occur during prolonged bed rest, make this therapeutic scheme attractive. (Bone 30:71S74S; 2002) 2002 by Elsevier Science Inc. All rights reserved. Key Words: Salmon calcitonin; Analgesia; Skeletal pain; Acute vertebral fractures; Osteoporosis. Introduction Salmon calcitonin has been studied extensively in a variety of clinical trials employing both parenteral and intranasal routes of administration for the treatment of osteoporosis. Calcitonin has a variety of actions, which include inhibition of bone resorption, resulting in decreased plasma calcium levels, and also exerts a direct receptor-mediation action on osteoclasts. A number of reviews have concluded that salmon calcitonin is safe and effective in the treatment of osteoporosis.16,35,42 Salmon intranasal calcitonin in a daily dose of 200 IU results in a decrease in the incidence of vertebral fractures.6,16 Additionally, treatment with salmon calcitonin has been shown in controlled prospective double-blind studies to improve pain.15 Musculoskeletal pain, common in osteoporosis, is one of the most frequent symptoms for which medical
Address for correspondence and reprints: G. P. Lyritis, Laboratory for the Research of Musculoskeletal System, KAT Hospital, Kifissia, 145 61, Greece. E-mail: lyritis@ismni.org
2002 by Elsevier Science Inc. All rights reserved.

assistance is sought. Osteoporosis represents one of the main causes of back pain in postmenopausal women.11 On the other hand, in the same population, nonosteoporotic vertebral deformities are seen as often as osteoporotic ones, and they are also main causes of back pain. In women up to 60 years of age, back pain was found mostly due to degenerative disorders of the spine.28 The management of musculoskeletal pain with calcitonin in these patients, especially in the osteoporotic ones, combines the antiresorptive effect of calcitonin with analgesia, thus increasing the compliance of the osteoporotic patient to a long-term treatment and preventing disuse due to painful attacks, especially of the spine.3,42 Analgesic Mechanism of Calcitonin In humans, calcitonin alleviates pain associated with bone disorders.3 The analgesic effect of calcitonin has been obtained in animal experiments in different studies. Intracerebroventricular administration of 8 IU/kg salmon calcitonin raised the pain threshold in rabbits subjected to electrical stimulation of the dental pulp.5,10 This analgesic effect of salmon calcitonin reaches a peak at 90 min and appears to be sustained on repeated dosing,7 whereas the effect of equipotent doses of morphine (10 mg/kg) tends to decline with repeated administration. The effects of calcitonin and morphine together are additive, although they have been shown in vitro to act at different receptors.4 In patients with intolerable chronic pain, a single injection of salmon calcitonin via the subarachnoid route achieved pain control within few minutes.10 The explanation of the analgesic effect of calcitonin is still not clear. An old observation is that plasma levels of -endorphin, which is considered a potent analgesic,41 rise after intravenous administration of at least 50 IU salmon calcitonin in humans.12,19,31,32 These observations are supported by experimental findings of potent analgesic effect after intracerebral administration of -endorphin in rats.19 Inhibition of prostoglandin E2 synthesis as a result of an antiinflammatory activity of calcitonin was also proposed as an explanation of its analgesic effect.4,32 Another hypothesis is that movement of ionic calcium in neuronal membranes, particularly in the brain, is the main mechanism of the analgesic effect of calcitonin.4 The possibility of a direct action on calcitonin receptors in the central neural system seems to be an attractive hypothesis.9 Exogenous calcitonin is thought to cross the blood-brain barrier and to accumulate slowly in the brain, inducing analgesia once sufficient receptors are occupied.10,32 In a recently published study, Sibilia et al.38 reported that specific binding sites for amylin and salmon calcitonin are present in the pons-medulla of rat brain rats. The functional significance of the presence of these binding sites was evaluated in two different nociceptive tests, hot plate and tail flick.
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Bone Vol. 30, No. 5, Supplement May 2002:71S74S

In the hot plate test, amylin significantly increased the response latencies, as did salmon calcitonin. These results demonstrated that a 40-fold greater dose of amylin is necessary to produce a comparable antinociceptive effect to that exerted by salmon calcitonin. The authors suggested that the central inhibitory effect of salmon calcitonin on pain is strong and interacts with amylin. Yoshimura44 studied the antinociceptive effect of eel calcitonin on prolonged hyperalgesia induced by ovariectomy, and suggested that beneficial effects in the behavioral and electrophysiological measurements may be caused by an alteration in the level of spinal seretonergic receptor expression. According to the author, changes in descending serotonergic modification on the sensory transmission mediated by C afferents contribute to the analgesic effects of calcitonin in osteoporotic patients suffering chronic pain. An extensive literature recently has appeared about the importance of calcitonin peptide, the calcitonin generelated peptide (CGRP), in painful conditions. It is well known that sympathetic, parasympathetic, and sensory nerves, which store a considerable number of neurotransmitters, innervate cerebral circulation. In patients with headaches, a clear association between head pain and the release of CGRP was demonstrated, mainly due to the potent vasodilator effect of CGRP.8 It is interesting that endogenous CGRP seems to play an important role also in the plastic neurogenic changes occurring in response to peripheral inflammatory events, such as inflammatory arthritis of the knee, including the development of nociceptive behaviors.45 Calcitonin Effects on Musculoskeletal Pain Osteopenia is frequently associated with skeletal pain. The differential diagnosis for osteopenia is extensive, but individualizing the patient workup begins with a careful clinical history, appropriate radiographic examination and possibly bone scan, computed tomography, and magnetic resonance imaging. Above the half of chronic pain related to muscleskeletal syndromes are located in the area of the head and back.17 Osteoporosis-related fractures have important health consequences for older individuals, including disability and increased mortality. Clinical or subclinical vertebral fractures are a common cause of acute back pain,21 which produces disability and seriously influences quality of life, but it is surprising that most of these patients do not receive an antiosteoporotic treatment. In fact, in a retrospective study, only 18% of medical records indicated that fracture patients had been prescribed antiosteoporotic medications.11 Back pain in the majority of these patients is treated with prolonged bed rest, local and systemic analgesia, and bracing.21 The elongation of bed rest in these patients results in increase of bone loss (identified by increase of hydroxyproline excretion40) and muscle weakness and joint stiffness. Another interesting aspect is that because most osteoporotic vertebral fractures happen in high bone-turnover patients22, in these patients, postfracture immobilization is an additional risk factor of an increased bone loss.24 The analgesic effect of salmon calcitonin in patients suffering an acute postfracture vertebral pain has been demonstrated in a series of double-blind, randomized prospective studies.2,14,16,20,2326,34 Nasal salmon calcitonin in a daily dose of 200 IU has an equivalent analgesic effect as 100 IU of injectable salmon calcitonin.7,20,33 The analgesic efficacy of nasal calcitonin was tested in 32 men and 68 postmenopausal women with a mean age of 76 and 71 years, respectively, who had sustained a nontraumatic vertebral fracture within the

Figure 1. Nasal salmon calcitonin reduced significantly pain (VAS) at the site of the vertebral osteoporotic fracture. Patients with a rating below 7 are able to perform almost all locomotor functions.

previous 5 days and were confirmed radiographically and clinically.24 The patients were hospitalized for a period of 28 days and were randomly assigned to receive either 200 IU of salmon nasal calcitonin or a matching placebo nasal spray. In addition, patients were permitted to take paracetamol as a rescue analgesic, up to 6 tablets of 500 mg daily. Treatment was initiated after baseline measurements on day 0. Pain evaluation was performed daily using a visual analogue (VAS) 10-degree scale (0 no pain, 10 agonizing pain). Pain was tested during different locomotor functions (e.g., bed rest, sitting, standing, and walking). In our experience,22,23 if a patient records a pain above 7 (in the VAS scale), he or she is not capable of attempting the recommended locomotor function. In turn, a rating of pain less than 7 suggests that patient does not require nursing and bed rest, and that he or she is able to begin physiotherapy. After the completion of 28 days of follow-up, it was found that pain was reduced dramatically in the group receiving calcitonin (p 0.001) (Figure 1). The analgesic effect of nasal calcitonin was negatively associated with the number of paracetamol tablets consumed. Pain rating on the VAS showed that the most patients gradually gained full mobility after the first week of calcitonin treatment. The number of patients who remained bedridden was significantly greater in the placebo group at all time points than in the calcitonin group (Figure 2).

Figure 2. Pain (VAS) in bedridden position. Almost all patients receiving nasal spray placebo stayed in bed during the whole period of observation, while calcitonin treated patients (pain score below 7) were mobilized a week after the initiation of treatment.

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Analgesic Effect of Calcitonin in Patients With Bone Metastases Skeletal metastases are the most serious cause of disabling pain in patients suffering cancer. Patients with breast or prostate cancer referred for bone scintigraphy report bone pain in a significant fraction (79% of breast and 78% of prostatic patients), but only half of them describe the painful region at the site of metastasis.27 These results indicate that pain is not a reliable indicator of the presence of location of metastatic bone disease. In cases where pain is definitely related to the metastatic region, radiotherapy is the main method for alleviating pain, but it is commonly associated with side effects and requires special equipment, dosimetry, and hospitalization.30 Calcitonin has been used as an analgesic medication in many prospective clinical trials in the management of skeletal pain,1,13,14,37,39 and it has been found to have a significant analgesic effect in patients with intractable pain associated with metastatic bone disease. In bone metastases from breast cancer, salmon calcitonin administered in a daily dose of 100 IU improved pain and quality of life.36 A number of other studies have confirmed that administration of salmon calcitonin has a significant analgesic effect in cancer patients with bone metastases, which can cause intractable pain.1,37 Other Analgesic Effects of Calcitonin Calcitonin has been reported to relieve pain in other conditions, except for musculoskeletal system pain. Phantom limb pain, a constant pain after leg amputation, has been relieved after injectable calcitonin treatment.18 Algodystrophy and Sudecks atrophy, a common postinjury painful condition, have been shown to improve after calcitonin treatment.29 References
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