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Salmon calcitonin in the treatment of post herpetic neuralgia.

SUMMARY

A 78-year-old man with severe chronic obstructive pulmonary disease presented to our pain medicine clinic for treatment of post herpetic neuralgia. Pharmacotherapy with tricyclic antidepressants, anticonvulsants, tramadol and traditional analgesics had failed, primarily due to adverse drug effects, particularly sedation, dizziness and nausea. Consequently, intravenous salmon calcitonin was administered, based on evidence of efficacy in the treatment of other neuropathic pain syndromes and its relatively benign side-effects profile. The patient reported immediate and sustained improvement in his post herpetic neuralgia for over two months, without adverse effects from the calcitonin therapy.

Key Words: salmon calcitonin, calcitonin, post herpetic neuralgia, neuropathic pain

Post herpetic neuralgia may be defined as pain that persists more than 30 days after the onset of acute herpes zoster rash or after cutaneous healing (1). In many treatment trials, the definition of post herpetic neuralgia is persisting pain for more than three months after resolution of the herpes zoster rash, although the time interval varies from one to six months (2). The pain is neuropathic in nature and may have a significant impact on the patient's quality of life and functional status, particularly in the elderly in whom post herpetic neuralgia is more prevalent (3).

During the acute phase of herpes zoster infection, preventive strategies such as the use of amitriptyline or possibly anti-viral drugs may reduce the risk of developing post herpetic neuralgia (4-6). Current treatments for post herpetic neuralgia include tricyclic antidepressants, anticonvulsants, opioid analgesics, tramadol, non-steroidal anti-inflammatory drugs, topical or systemic local anaesthetics, topical capsaicin and somatic or sympathetic neural blockade. Implantable spinal infusion devices, neural stimulators, neuro-ablative techniques and skin resection have also been used in the treatment of severe or intractable post herpetic neuralgia.

Adverse effects of drug therapy such as sedation, dizziness and nausea may limit the effective management of post herpetic neuralgia, particularly in the elderly.

Calcitonin is a peptide hormone that regulates calcium homeostasis in vertebrates. It may have other physiological effects including the modulation of pain. The analgesic effects of salmon calcitonin have been demonstrated in animal experiments and in the clinical treatment of acute vertebral fracture pain, complex regional pain syndrome and phantom limb pain.

We present the case of an elderly male patient with post herpetic neuralgia who responded to and tolerated salmon calcitonin therapy, where standard drug therapy with tricyclic antidepressants, anti convulsants and analgesics were ineffective, primarily due to adverse drug effects.

CASE HISTORY

A 78-year-old male presented to our pain medicine clinic seven weeks after developing severe, acute herpes zoster infection affecting the left neck and shoulder region. During the acute phase he was treated with anti-viral therapy (acyclovir) and amitriptyline and at various times with morphine, tramadol, paracetamol or codeine. Oral flucloxacillin was also prescribed to treat secondary infection of the herpetic vesicles.

Two weeks prior to his presentation at our clinic, his general practitioner commenced gabapentin 300 mg three times daily, tramadol slow-release 150 mg twice daily and amitriptyline 25 mg at night to manage his ongoing pain.

On presentation, the patient complained of pain in the left suprascapular region with radiation into the left lower neck. The pain was described as "burning" in quality with "knife-like" exacerbations. Pain intensity was rated as "severe" with a mean verbal numerical rating scale score of 8/10. The pain was constant and there were frequent exacerbations triggered by light touch, cold and movement in the affected region.

Examination demonstrated a resolving herpetiform rash over the left lateral neck, extending to the left suprascapular and shoulder regions and upper anterior chest wall, involving left-sided dermatomes from C2 to C4. There was marked tenderness to digital pressure over the left suprascapular region and decreased sensation to light touch and pinprick over the entire surface of the resolving rash.

The patient's past medical history included severe chronic obstructive pulmonary disease and depression. His exercise tolerance was limited by exertional dyspnoea and domiciliary oxygen was required for up to sixteen hours a day. There were no symptoms of an active psychiatric disorder. The patient still lived in his own home and maintained a degree of functional independence with the support of his wife.

A diagnosis of post herpetic neuralgia was confirmed and attempts to slowly increase doses of gabapentin, tramadol and amitriptyline were hampered by the development of significant sedation, dizziness and nausea. The patient was reluctant to use opioids, because of previous nausea and concerns regarding his respiratory disease.

Topical application of eutectic mixture of local anaesthetics cream failed to provide analgesia. Left-sided cervical plexus or stellate ganglion blockade was relatively contraindicated, given the risks of phrenic nerve block or pneumothorax in the presence of severe respiratory disease.

The patient was treated with 100 IU of salmon calcitonin (Miacalcic[R], Novartis), diluted in 100 ml of normal saline, infused intravenously over one hour on three consecutive days. Each infusion was preceded by metoclopramide 10 mg intravenously for nausea and vomiting prophylaxis. During the infusion, the patient was closely monitored for adverse effects by nursing staff.

The patient reported dramatic and immediate improvement in his pain within 24 hours of the first infusion. His mean verbal numerical rating scale score decreased from 8/10 to 2/10. He also reported a significant decrease in the frequency and intensity of stabbing pains in the left neck and shoulder region. There was further reduction in intensity and frequency of pain following two subsequent calcitonin infusions. No adverse effects related to the calcitonin infusions were reported.

The patient's analgesic requirements were subsequently reduced. Gabapentin, amitriptyline and tramadol were ceased after three weeks. Two months after completing the calcitonin therapy, he reported only minimal residual discomfort in the left shoulder region, requiring occasional doses of immediate-release tramadol. His quality of life had much improved and he no longer experienced side-effects such as sedation, dizziness or nausea associated with his previous drug therapy.

DISCUSSION

The onset of acute herpes zoster and post herpetic neuralgia is age-related, with an annual incidence for post herpetic neuralgia of 4.5 to 11 per 1000 for those over 80 years of age (1). Approximately 50% of patients over the age of 70 who develop post herpetic neuralgia have persistent pain lasting more than one year (6).

The treatment of post herpetic neuralgia is difficult, because 40% of patients fail to respond to routine drug therapies (7). Furthermore, preventive strategies using anti-viral agents have yielded mixed results although amitriptyline may be effective (1,4).

Pharmacological therapies such as amitriptyline, gabapentin, tramadol and oxycodone are effective in the treatment of post herpetic neuralgia (8-12). However, lack of tolerability due to adverse drug effects are a major drawback, particularly in the elderly, leading to dose reduction or cessation of treatment in some cases.

In a randomized controlled trial, 75.0% of patients treated for post herpetic neuralgia with gabapentin (2400 mg per day) reported adverse effects, particularly dizziness (33.0%) and somnolence (20.4%), compared with 49.5% in the placebo group (9). The number-needed-to-harm (NNH) for 'minor' side-effects with gabapentin in the treatment of acute and chronic pain was 2.5 (2.0-3.2) (13).

Seventy-six percent of post herpetic neuralgia patients treated with controlled-release oxycodone (mean dose up to 45 mg per day) reported adverse effects, principally constipation, nausea and sedation, however the rate was lower with tramadol (mean dose of 275.5 mg per day) at 29.7%, which did not differ significantly from placebo (11,12). Tricyclic antidepressants such as amitriptyline are frequently associated with 'minor' side-effects in the treatment of neuropathic pain with a NNH of 4.6 (3.3-6.7) (14).

The 'drop-out' rate due to adverse drug effects in the treatment of post herpetic neuralgia was between 13.3% and 17.6% for gabapentin and 9.4% for tramadol with no clear data for oxycodone or amitriptylines (8-10,12). The NNH for cessation of treatment due to adverse drug effects in post herpetic neuralgia was 11.2 (6.5-41.6) for gabapentin, 10.7 (6.1-44.8) for tramadol and 9.9 (5.3-84.6) for nortriptyline (8). The NNH for cessation of treatment in neuropathic pain was 17.1 (10-66) for opioids and 14.7(10-25) for tricyclic antidepressants (8). There are no clear data for the incidence of adverse drug effects when combining treatments for post herpetic neuralgia.

In summary, approximately three fourths of post herpetic neuralgia patients treated with gabapentin or controlled-release oxycodone and one third treated with tramadol reported adverse drug effects, with around one in ten patients withdrawing from treatment as a result. In our patient, intolerable sedation, dizziness and nausea due to drug therapy were the primary limiting factors in the treatment of his post herpetic neuralgia.

Several clinical trials have investigated the effects of salmon calcitonin in pain management. There is National Health and Medical Research Council (NHMRC) level 1 evidence for analgesia with salmon calcitonin in the treatment of complex regional pain syndrome and acute osteoporotic vertebral fractures (15-17). A randomized, placebo-controlled, crossover trial demonstrated that salmon calcitonin, administered in the immediate postoperative period, was highly effective in the treatment of phantom limb pain (18). There is also NHMRC level 4 evidence for analgesia with salmon calcitonin in phantom limb pain and painful diabetic neuropathy (19-21).

Adverse effects with salmon calcitonin therapy, although common, are usually minor and transitory in nature. In a randomized controlled trial of calcitonin for the treatment of phantom limb pain, 57% of patients reported minor adverse effects including nausea (28%), vomiting (24%), flushing (19%), dizziness (9.5%) and drowsiness (9.5%) (18).

Therefore, the decision to administer salmon calcitonin in our patient was based on evidence of efficacy in the treatment of other neuropathic pain syndromes and the drug's relatively benign adverse effects profile.

Although pain control improved immediately after the salmon calcitonin therapy, other factors may have contributed to the reduction in pain including spontaneous disease regression and placebo effect. However the time course of response to the calcitonin infusions suggests a causal relationship. In addition, pain relief persisted far beyond the pharmacological duration of action of the drug, a phenomenon frequently noted in the treatment of phantom limb pain, although the 'mechanism' responsible for this effect is unknown.

Calcitonin

Calcitonin is a 32-aminoacid peptide hormone produced by the para-follicular cells of the thyroid gland in mammals and the ultimo-branchial glands of birds and fish. Salmon calcitonin has a greater physiological and analgesic potency than mammalian forms of the hormone and is reproduced as a synthetic drug for clinical use.

Calcitonin binds to a 7-membrane-spanning-array, G protein-coupled receptor (similar in structure to an opioid receptor) with cyclic-adenosine monophosphate and calcium acting as secondary messengers. Calcitonin receptors are most prevalent in bone (osteoclasts), kidney (renal tubular cells), the central nervous system and the gastrointestinal tract, but are also expressed by macrophages and some breast and lung cancer cells.

In vertebrates, the primary physiological role of calcitonin is the regulation of systemic calcium flux. It is likely that calcitonin produces its primary analgesic effect through receptor-mediated modulation of serotonergic neuronal activity in pain pathways of the central nervous system, although anti-inflammatory (prostaglandin) and endorphin-mediated mechanisms have also been proposed (22-25). The adverse effects of calcitonin therapy such as sedation, nausea, skin flushing and diarrhoea may reflect increased serotonergic activity.

Synthetic salmon calcitonin (as a polyacetate polyhydrate) is most commonly available as an injection in concentrations of 100 or 50 IU per millilitre. One IU is equivalent to 0.2 [mu]g of the pure peptide. Administration of salmon calcitonin for treatment of post herpetic neuralgia is an 'off-licence' indication with the drug being registered in Australia for the treatment of Paget's disease of bone and hypercalcaemia. (26).

The bioavailability of salmon calcitonin administered via subcutaneous or intramuscular injection is approximately 70%. Metabolism and subsequent elimination of calcitonin is primarily renal, with an elimination half-life of between 60 and 90 minutes. The development of clinically significant hypocalcaemia has not been reported in pharmacodynamic studies and there are no known drug interactions with salmon calcitonin. Contraindications include known allergy, pregnancy and lactation (26). According to MIMS Australia, in April 2005 the cost of a 100 IU ampoule of salmon calcitonin for injection was approximately A$33.00 via the Australian Pharmaceutical Benefits Scheme.

In conclusion, this case report suggests that salmon calcitonin may be beneficial in the treatment of post herpetic neuralgia. However, further clinical research is required to establish the efficacy and tolerability of salmon calcitonin compared with current therapies.

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(22.) Nakamoto H, Soeda Y, Takami S, Minami, M, Satoh M. Localization of calcitonin receptor mRNA in the mouse brain: coexistence with serotonin transporter mRNA. Brain Res Mol Brian Res 2000; 76:93-102.

(23.) Ormazabal MJ, Goicoechea C, Sanchez E, Martin MI. Study of mechanisms of calcitonin analgesia in mice. Involvement of 5HT3 receptors. Brain Res 1999; 845:130-138.

(24.) Ceserani R, Colombo M, Olgiati V, Pecile A. Calcitonin and the prostaglandin system. Life Sci 1979; 25:1851-1886.

(25.) Laurian L, Oberman Z, Graf E, Gilad S, Hoerer E, Simantov R. Calcitonin induces increase in ACTH, beta-endorphin and cortisol secretion. Horm Metab Res 1986; 18:268-271.

(26.) Miacalcic[TM] and Miacalcin[TM] product information. Novartis Pharmaceuticals Australia Pty Ltd, 1999.

E.J. VISSER*, P.L. KWEI [double dagger] Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Perth, Western Australia, Australia

*M.B.B.S., F.A.N.Z.C.A., F.F.P.M.A.N.Z.C.A., Consultant.

[double dagger]M.B.B.S., Registrar.

Address for correspondence, reprints: Dr E.J. Visser, Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Box X2213 GPO, Perth, WA. 6847.
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Author:Visser, E.J.; Kwei, P.L.
Publication:Anaesthesia and Intensive Care
Date:Oct 1, 2006
Words:2759
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