Update sulla Terapia delle Sindromi Algodistroche Dipartimento Multidisciplinare di Specialità Medico-Chirugiche ed Odontoiatriche Seconda Università degli Studi di Napoli Centro Ricerche su Osteoporosi e Malattie dell’Osso Update sulla Terapia delle Sindromi Algodistroche G. Iolascon

utilità di un farmaco Farmaci eziologici: agiscono direttamente sugli agenti causali di una patologia Farmaci sintomatici : alleviano i sintomi collegati a una certa patologia Farmaci sostitutivi: integrano una carenza dovuta a cause diverse

curare l’algodistrofia

Marinus J, Lancet Neurol 2011 Epidemiology 5·5 cases per 100.000 person-years in the USA 26·2 per 100 000 person-years in the Netherlands. Incidence increases with age until 70 years of age 3–4 times more women than men The arm is affected in about 60% of cases and the leg in about 40%. Resolution rate differs greatly between studies, ranging from 74% in the first year to 36% within 6 years Triggers : fractures 45%, joint sprain 18%,surgery12% deMos M, Pain 2007 Marinus J, Lancet Neurol 2011 Sandroni P, Pain 2003

Demographic and medical parameters in the development of complex regional pain syndrome type 1 (CRPS1): Prospective study on 596 patients with a fracture Patients >18 years with a single fracture of the wrist, scaphoid, ankle, or metatarsal V 596 patients: male 36.4% and female 63.6% (median age was 52.8) In 311 patients (52.2%) the upper extremity was affected, and in 285 patients (47.8%) the lower extremity Patients were treated conservatively with plaster cast (88.1%), with tape (0.7%), or with both plaster and surgery (10.9%); of 0.3% of the participants the type of treatment is unknown. Of the 596 participants, 42 (7.0%) were diagnosed with CRPS1 according to the Harden and Bruehl criteria, 289 (48.5%) according to the International Association for the Study of Pain criteria, and 127 (21.3%) according to the criteria of Veldman. Beerthuizen et al. 2012

Perioperative factors affecting the occurrence of acute complex regional pain syndrome following limb bone fracture surgery Masahiko Sumitani et al. 2014

Arch Orthop Trauma Surg 2014 Multivariate logistic regression analyses for the prediction of CRPS I after distal radius surgery Arch Orthop Trauma Surg 2014

Mechanisms involved in CRPS Nerve injury Ischemic re-perfusion injury or oxidative stress Central sensitization Peripheral sensitization Altered sympathetic nervous system function or sympatho‐afferent coupling Inflammatory and immune related factors Brain changes Genetic factors Psychological factors and disuse Bruehl 2015

Frequency of signs and symptoms among CRPS patients Harden et al. Pain 1999

Complex regional pain syndrome severity score Symptoms (reported) Allodynia, hyperpathia Temperature asymmetry Skin color asymmetry Sweating asymmetry Asymmetric edema Trophic changes Motor changes Decreased active range of motion Complex regional pain syndrome severity score Signs observed Hyperpathia to pinprick Allodynia Temperature asymmetry by palpation Skin color asymmetry Sweating asymmetry Asymmetric edema Trophic changes Motor changes Decreased active range of motion Score (maximum 17 points) Harden , Pain 2010

innesco patogenetico periferico Varenna et al. 2010

Clinical features and proposed pathophysiological mechanisms of CRPS Three major pathophysiological pathways: aberrant inflammatory mechanisms vasomotor dysfunction maladaptive neuroplasticity Marinus et al. Lancet Neurology, 2011

characteristics of stressful event epigenetics characteristics of stressful event genetics response to injury adaptative=healing maladaptative=CRPS

Pathophysiology and mechanism-based treatment options in CRPS NATURE REVIEWS NEUROLOGY , 2014

Trials clinici randomizzati con Bisfosfonati Giusti A et al., RMD Open 2015

BPs BPs BPs BPs

Twenty patients with RSDS of foot and hand Alendronate intravenously 7.5 mg dissolved in 250 ml saline solution or placebo daily for three days. Two weeks later all patients had an identical treatment course with open labelled alendronate (7.5 mg/day for three days), independent from the results of the first blind treatment. Conclusion: results indicate that bisphosphonates should be considered for the treatment of RSDS, producing consistent and rapid remission of the dis- ease.

Thirty-two patients with RSDS randomized to receive either i. v Thirty-two patients with RSDS randomized to receive either i.v. clodronate 300 mg daily for 10 consecutive days or placebo. Forty days later, the placebo treated patients received the clodronate treatment. A 10 day i.v. clodronate course is better than placebo and effective in the treatment of RSDS. NTx seems to be a predictive factor for clodronate efficacy

Twenty-seven patients (18 female, 9 male; average age 45 years) who fulfilled the IASP criteria for CRPS Type I were administered, intravenously, either pamidronate, 60mg as a single dose, or normal saline. Results. Overall improvements in pain score, patient’s global assessment of disease severity score, and physical function (SF-36) score were noted in the pamidronate group at 3 months, and improvements in role physical (SF-36) score were noted at 1 and 3 months. Conclusions.Although treatment response was variable, the majority of patients improved. Early administration in tandem with other treatment measures is recommended.

40 pts affected by CRPS I (IASP criteria revised by Harden) Results. Alendronate-treated patients (n 19) exhibited a marked and sustained improvement in levels of spontaneous pain, pressure tolerance, and joint mobility, as well as a significant reduction in urinary levels of NTX at weeks 4 and 8. The improvement was maintained at week 12. Conclusion. oral alendronate in posttraumatic CRPS I reduces local acceleration of bone remodeling, might relieve pain by effects on nociceptive primary afferents in bone, pain-associated changes in the spinal cord, and possibly also through a central mechanism.

82 pazienti affetti da algodistrofia randomizzati al trattamento con: Endpoint primario Valutare l’effetto di neridronato sulla sintomatologia dolorosa di pazienti affetti da algodistrofia alla mano o al piede dopo 40 gg dalla prima infusione NER giorni 1 2 3 4 5 6 7 8 9 10 FASE DOPPIO CIECO 82 pazienti affetti da algodistrofia randomizzati al trattamento con: NERIDRONATO 100 mg EV/3 gg per 4 volte (n=41) PLACEBO (n=41) FASE IN APERTO I pazienti in placebo, dopo 40 giorni, sono passati a neridronato

Fase in Doppio Cieco Entro i primi 20 giorni dall’inizio del trattamento la VAS del dolore si è ridotta in entrambi i gruppi, ma maggiormente nel gruppo trattato con neridronato (p=0,043) riduzione ulteriore del dolore solo nei pazienti precedentemente trattati con neridronato.

Fase in Doppio Cieco Il 73,2% dei pazienti in neridronato ha ottenuto una risposta clinicamente significativa (VAS ≥ 50% dal basale)

Fase in Aperto Dopo 50 giorni, nei pazienti precedentemente trattati con placebo che sono passati al trattamento attivo, sono stati osservati analoghi benefici del trattamento con neridronato

la somministrazione di neridronato per via intramuscolare ha la stessa efficacia di quella endovenosa nella CRPS 1? OBIETTIVO PRINCIPALE: valutare l’efficacia di Neridronato 25 mg fiale di soluzione iniettabile (i.m.) dopo somministrazioni ripetute rispetto al placebo, in pazienti con sindrome da dolore regionale complesso di tipo I (CRPS-I). Dovranno essere arruolati nello studio 90 soggetti Lo studio coinvolge 9 centri italiani

approccio globale Pain Medicine, 2013 L'approccio interdisciplinare per il trattamento di pazienti affetti da algodistrofia rimane il più pragmatico, disponibile, e conveniente approccio terapeutico disponibile oggi Pain Medicine, 2013

approccio globale (neridronato) Iolascon et al. 2014

take home messages l’algodistrofia è una sindrome clinica che riconosce fattori favorenti, un processo patogenetico multifattoriale (con meccanismi sia periferici che centrali) ed un’espressione clinica estremamente variabile la diagnosi ed il trattamento precoci sono mandatori per il successo terapeutico e l’outcome funzionale l’approccio terapeutico che ha maggior possibilità di successo è di tipo globale con interventi farmacologici, di terapia fisica ed esercizio terapeutico, di modulazione del dolore cronico con tecniche neuroriabilitative, di interventi psicologici ed educativi la terapia farmacologica, da intraprendere con tempi e farmaci appropriati, ha nel neridronato l’unico farmaco indicato per questa patologia