Rev Dor. São Paulo, 2011 jan-mar;12(1):71-73
`
`CASE REPORT
`
`Zoledronic acid to treat complex regional pain syndrome type I in
`adult. Case report*
`Ácido zoledrônico como tratamento para síndrome dolorosa complexa regional tipo I
`em adulto. Relato de caso
`Anita Perpétua Carvalho de Castro1, Lilian Mendes de Vasconcelos1, Jedson dos Santos Nascimento1
`
`* Received from Santa Casa de Misericórdia da Bahia Santa Izabel Hospital. Salvador, BA.
`
`SUMMARY
`
`BACKGROUND AND OBJECTIVES: Complex
`regional pain syndrome (CRPS) is a difficult to treat dis-
`abling disease. Positive results with bisphosphonates in
`CRPS type I patients refractory to multimode therapy
`have been described. This study aimed at reporting the
`use of zoledronic acid in CRPS type I patient refractory
`to traditional therapy.
`CASE REPORT: Female patient, 31 years old, with
`CRPS for 16 years, refractory to multiprofessional and
`multimode treatment. Due to persistence of symptoms,
`zoledronic acid administration was proposed with ef-
`fective control of symptoms and without adverse effects.
`CONCLUSION: Zoledronic acid was effective to treat
`CRPS type I refractory to conventional treatment.
`Keywords: Bisphosphonate, Complex regional pain
`syndrome, Pain.
`
`RESUMO
`
`JUSTIFICATIVA E OBJETIVOS: A síndrome dol-
`orosa complexa regional (SDCR) é incapacitante e de
`difícil tratamento. Resultados positivos com a utilização
`de bifosfonatos em pacientes com SDCR tipo I refratária
`a terapêutica multimodal tem sido descritos. O objetivo
`deste estudo foi relatar a utilização do ácido zoledrônico
`em paciente portador de SDCR tipo I refratária à tera-
`pêutica tradicional.
`
`1. Anesthesiologist, Santa Casa de Misericórdia da Bahia,
`Santa Izabel Hospital. Salvador, BA, Brazil.
`
`Correspondence to:
`Anita Perpétua Carvalho de Castro, MD
`Rua Pacífico Pereira, 1303 – Garcia
`Phone: (71) 3350-6232
`40100-170 Salvador, BA.
`E-mail: anitaperpetuacrc@yahoo.com.br
`
`c
`
`Sociedade Brasileira para o Estudo da Dor
`
`RELATO DO CASO: Paciente do sexo feminino, 31
`anos, com história de SDCR há 16 anos, refratária ao
`tratamento multiprofissional e multimodal. Diante da
`persistência dos sintomas foi proposta a administração
`de ácido zoledrônico, com controle efetivo dos sintomas
`e sem a presença de efeitos adversos.
`CONCLUSÃO: O ácido zoledrônico foi efetivo no
`tratamento da SDCR tipo I refrataria ao tratamento con-
`vencional.
`Descritores: Bifosfonato, Dor, Síndrome dolorosa com-
`plexa regional.
`
`INTRODUCTION
`
`Complex regional pain syndrome (CRPS) is a regional
`pain condition associated to sensory changes caused by
`a noxious event, be it fracture, surgery or other type of
`injury. CRPS diagnosis is clinical, based on the presence
`of specific signs and symptoms; the presence of initial
`injury may be disregarded; signs and symptoms should
`be divided in different groups; patients should have at
`least two of the following symptoms: sensory (hyper-
`esthesia), vasomotor (change in temperature, skin color
`or both), sudomotor / water balance (edema, sweating
`or both), and motor (decreased mobility, weakness,
`shivering, functional limb amputation) or all of them;
`and patients should present at least two of the following
`signs: vasomotor, sudomotor / water balance and motor1.
`So, CRPS is a neuropathic and disabling pain syndrome
`made up of motor, autonomic and sensory changes1.
`According to the Consensus of the International Asso-
`ciation for the Study of Pain, CRPS may be classified in
`types I and II. Type II pain is different from type I due to
`the presence of nervous injury, where pain is not limited
`to the innervation site of the injured nerve. Regardless
`of CRPS type, it is known that it significantly interferes
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`PGR for U.S. Patent No. 9,539,268
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`Rev Dor. São Paulo, 2011 jan-mar;12(1):71-73
`
`Castro, Vasconcelos e Nascimento
`
`with patient’s quality of life, impairing their daily activ-
`ities. Pain intensity and functional incapacity are dispro-
`portional to the baseline injury implying the need for a
`multiprofessional and multimode therapeutic approach.
`Although several studies are carried out with therapeutic
`proposals2, few have shown a really effective analgesic
`regimen. So, the search for a really effective treatment
`has become mandatory.
`Positive results with bisphosphonates in patients with
`CRPS refractory to multimode therapy have been de-
`scribed. Bisphosphonates relieve bone pain in patients
`with osteoporosis, Paget’s disease and malignant bone
`pain and their specific action varies according to their
`chemical structure3,4. Zoledronic acid acts specifically
`on the bone and inhibits osteoclasts-mediated bone re-
`absorption, having as major target the farnesyl pyrophos-
`phate synthase enzyme. Exact bisphosphonates analgesic
`mechanism in CRPS patients is not clear, although these
`patients manifest some level of regional osteoporosis in
`the involved extremity5,6. Several bisphosphonates have
`been used to treat CRPS in adults.
`This study aimed at reporting the use of zoledronic acid
`in CRPS type I patient refractory to traditional therapy.
`
`CASE REPORT
`
`Female patient, 31 years old, with history of neuropathic
`pain for 16 years. She reported that pain was spontan-
`eous, very severe with intensity 10 in the worst mo-
`ments, according to verbal numerical scale. Worsening
`factors were: physical contact, change in temperature
`and emotional stress. Improvement factors were: rest
`and analgesic drugs. Associated symptoms: mechanical
`allodynia, primary and secondary hyperalgesia and de-
`creased function of left upper and lower limbs. Patient
`was investigated to rule out oncologic and rheumatho-
`logical disease, with negative results. Lab tests and elec-
`troneuromyography were normal, however conventional
`X-Rays of affected limbs has shown decreased bone
`calcification. She had already used normal analgesics,
`steroids and non-steroid anti-inflammatory drugs, with
`mild improvement of symptoms after the use of steroids.
`Medical history: thrombophilia in regular follow-up
`with angiologist and indication of total anticoagulation.
`At physical exam she presented signs of autonomic dys-
`function, upper and lower limbs edema and pain when
`moving them. Other findings: triggering point in scapu-
`lar waist. Diagnostic suspicion: CRPS type I associated
`to myofascial pain syndrome.
`Adopted approach: amitriptyline and carbamazepine in
`72
`
`increasing regimen until the dose of 75 mg and 1200 mg
`of these drugs, respectively, sympathetic venous block
`with 2% lidocaine without vasoconstrictor and trig-
`gering point infiltration with 0.125% bupivacaine.
`There has been good initial response, however with fre-
`quent recurrence of symptoms. Analgesic regimen was
`modified replacing amitriptyline by other antidepres-
`sants and carbamazepine by other anticonvulsants.
`Opioids, neuromuscular blockers, dexmedetomidine,
`magnesium sulfate and chlorpromazine were intro-
`duced. After several failures, patient changed behavior,
`becoming depressive and anxious. Multiprofessional
`follow-up was started with the help of the psychology
`and psychiatry teams.
`After two years of treatment, due to persistence of symp-
`toms, parenteral zoledronic acid (5 mg) was introduced.
`Patient was hospitalized due to CRPS type I decompen-
`sation and was submitted to lab tests for five days, in-
`cluding calcium serum dosage and monitoring of vital
`signs when the drug was administered and every 6 hours
`in subsequent days. During treatment patient received
`calcium supplementation to minimize the development
`of hypocalcaemia.
`No zoledronic acid adverse effect was identified and
`patient was discharged after total regression of edema
`and pain. There has been no CRPS type I recurrence in
`the six months following the administration of zoled-
`ronic acid.
`
`DISCUSSION
`
`CRPS type I is a progressive disease with increasing
`pain and inactivity, generating anguish and anxiety for
`patients and health teams following them1. However,
`when CRPS affects children and adolescents, its clinical
`characteristics are different from those of adults. Chil-
`dren are predominantly affected in lower limbs and have
`better prognosis as compared to adults.
`Pain persistence is a concern because it implies more dis-
`tress to patients and the presence of peripheral and central
`sensitization caused by cytokines production and by the
`action of nitric oxide, oxygen free radicals and excitatory
`aminoacids7. So, early diagnosis and treatment are funda-
`mental for adequate patient’s recovery. This clinical case
`reports CRPS in a young patient, however with disease
`starting in the adolescence. Adequate therapy was institut-
`ed lately, 13 years after the appearance of the first symp-
`toms, which may justify initial unfavorable evolution.
`Therapy adopted for this patient was multiprofessional,
`involving a health team composed by physicians, nurs-
`
`

`

`Zoledronic acid to treat complex regional pain
`syndrome type I in adult.
`
`Rev Dor. São Paulo, 2011 jan-mar;12(1):71-73
`
`es, psychotherapists and physical therapists, aiming at
`pain relief, functional recovery and less psychological
`distress8,9. Although some studies are favorable to multi-
`disciplinary treatment of CRPS type I patients, the litera-
`ture shows major variation in implemented treatments,
`reflecting the complexity of this disease.
`Drugs such as antidepressants, anticonvulsants and other
`adjuvants have been proposed to treat neuropathic pain;
`however there is no standard protocol for CRPS type I.
`This patient was submitted to different therapeutic regi-
`mens without adequate response, which has motivated
`the administration of zoledronic acid, which is a biphos-
`phonate which is a class being proposed as alternative to
`treat patients with refractory CPRS10.
`Bisphosphonates mechanism for CRPS is not well es-
`tablished, however it is believed that they antagonize
`osteoclastogenesis, in addition to inhibiting prosta-
`glandis E2, proteolytic enzymes and lactic acid, ele-
`ments which are involved with the inflammatory pro-
`cess and with the generation and perpetuation of pain11,
`which could justify the positive result obtained with
`their administration.
`
`CONCLUSION
`
`The use of the biphosphonate zoledronic acid was ef-
`fective to treat CRPS type I.
`
`REFERENCES
`
`1. Cordon FC, Lemonica L. Complex regional pain syn-
`drome: epidemiology, pathophysiology, clinical mani-
`festations, diagnostic tests and therapeutic proposals.
`Rev Bras Anestesiol 2002;52(5):618-27.
`2. Wilson PR. Post-traumatic upper extremity reflex sym-
`
`pathetic dystrophy. Clinical course, staging, and classi-
`fication of clinical forms. Hand Clin 1997;13(3):367-72.
`3. Purohit OP, Anthony C, Radstone CR, et al. High-
`dose intravenous pamidronate for metastatic bone pain.
`Br J Cancer 1994;70(3);334-8.
`4. Cascinu S, Graziano F, Alessandroni P, et al. Different
`doses of pamidronate in patients with painful osteolytic
`bone metastases. Support Care Cancer 1998;6(2):139-43.
`5. Manicourt DH, Brasseur JP, Boutsen Y, et al. Role
`of alendronate in therapy for posttraumatic complex
`regional pain syndrome type I of the lower extremity.
`Arthritis Rheum 2004;50(11):3690-7.
`6. Robinson JN, Sandom J, Chapman PT. Efficacy of
`pamidronate in complex regional pain syndrome type I.
`Pain Med 2004;5(3):276-80.
`7. Beilin B, Bessler H, Mayburd E, et al. Effects of pree-
`mptive analgesia on pain and cytokine production in the
`postoperative period. Anesthesiology 2003;98(1):151-5.
`8. Bukhalo Y, Mullin V. Presentation and treatment of
`complex regional pain syndrome type 1 in a 3 year old.
`Anesthesiology 2004;101(2):542-3.
`9. Forouzanfar T, Koke AJ, van Kleef M, et al. Treat-
`ment of complex regional pain syndrome type I. Eur J
`Pain 2002;6(2):105-22.
`10. Varenna M, Zucchi F, Ghiringhelli D, et al. Intra-
`venous clodronate in the treatment of reflex sympathetic
`dystrophy. A randomized, double blind, placebo con-
`trolled study. J Rheumatol 2000;27(6):1477-83.
`11. Van Offel JF, Dombrecht EJ, Bridts CH, et al. Influ-
`ence of bisphosphonates on the production of proinflam-
`matory cytokines by activated human articular chondro-
`cytes. Cytokine 2005;31(4):298-304.
`
`Presented in September 02, 2010.
`Accepted for publication in December 06, 2010.
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