Neridronate - CRPS / RSD TREATMENT

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What is Neridronate?
Neridronate is an amino-bisphosphonate designed specifically for the treatment of Complex Regional Pain Syndrome. Differently from the molecules of the same drug class, it has no side effects, as it is a salt compound that recalcifies affected bones. The first night of infusions may induce flu-like symptoms, but it does not have any other interactions or reactions apart from that. Differently from Ketamine or opioids, Neridronate has no impairing side effects and only requires one or two treatments in a life time. Neridronate is the only recognized permanent treatment for CRPS.
Other treatments which are used as protocol for CRPS treatment in the United States only mask the pain, such as the aforementioned Ketamine infusions, the implantation of Spinal Cord Stimulators, or a plethora of pain relievers. Neridronate changes your body’s chemistry in a long-lasting, essential way. By recalcifying the bone, it reestablishes the communication highway of your nervous system, allowing what was once a gap in the transmission of pain receptors to reconnect. This allows the body to function as it normally once did.
Dr. Adami, whom we worked hand-in-hand with until his passing in 2016 (and whose team of doctors we work with now), discovered the molecular structure of Neridronate and published his findings in 2012 after performing a comprehensive study of its effectiveness on existing CRPS patients. This publication lead to the approval of Neridronate as the primary, protocol treatment for any diagnosed case of CRPS in Italy. Thus far, over 10,000 Italian patients have undergone the infusions, with 80% experiencing full remission and 97% experiencing partial remission.
The only case in which such complications could happen is when these infusions are given to a patient with kidney failure, are planning to have some major dental surgery in the prior or following two months of treatment, or if the patient is pregnant.
Neridronate, as we said, is a bisphosphonate that has no contraindications. The AIFA (the equivalent to the FDA in Italy, known to be one of the strictest in the world) approved the drug, which reifies that Neridronate is the real deal, and that it is truly a breakthrough for the rare and disabling CRPS. The FDA also approves Neridronate as a Breakthrough Drug. They are currently testing its effects on CRPS patients and designated the infusions as Breakthrough Therapy but, for now, the treatment is available only in Italy.
Neridronate inhibits bone reabsorption with no modification of the mineralizing process. This causes a prevailing of the osteosynthesis with a consequential reduction of Calcium in the extracellular environment and a temporary boost of PTH. The insurgence of secondary hyperparathyroidism contrasts the loss of calcium causing the production of calcitriol, which stimulates the absorption of calcium in gastrointestinal tract. The infusions to treat CRPS consist on a dosage of 100 mg of Neridronate per infusion, requiring 4 total infusions.

Side effects:
Neridronate might cause flu-like symptoms, such as an increase in body temperature, some bone pain, arthralgia, myalgia or chills, but these side effects tend to disappear completely within days or even hours from the first infusion so there is normally no need for any extra treatment. Also, after the treatment one might feel a slight pain on the injection site.
It is advised against patients having some kind of hypersensibility towards the active principle, even if it is another type of bisphosphonates, in the case of severe kidney failure and in case of pregnancy or breast feeding.
Conclusion:
While, unfortunately, there is not a true cure for CRPS yet, doctors state that this the right path towards an actual cure. Since it affects the actual problem at hand within the body, rather than masking the pain, it is the closest treatment to a cure known to date. If caught in time, though, in 80% of cases CRPS actually disappears and none of the patients notice a return of the symptoms, not even one year after the treatment. If the infusions start after one year from the diagnosis great pain relief and improvement in the lifestyle can be expected. Also, Neridronate is a long term to permanent solution, with the possibility of just one recall infusion if the symptoms persist, three months after.
Treatment of complex regional pain syndrome type I with neridronate: a randomized, double-blind, placebo-controlled study

Massimo Varenna, Silvano Adami, Maurizio Rossini, Davide Gatti,
Luca Idolazzi, Francesca Zucchi, Nazzarena Malavolta and Luigi Sinigaglia
Abstract from RHEUMATOLOGY
Objective. Complex regional pain syndrome type I (CRPS-I) is a severely disabling pain syndrome for which no definite treatment has been established. The aim of this multi-centre, randomized, double-blind placebo-controlled trial was to test the efficacy of the amino-bisphosphonate neridronate in patients with CRP-I.
Methods. Eighty-two patients with CRP-I at either hand or foot were randomly assigned to i.v. infusion of 100 mg neridronate given four times over 10 days or placebo. After 50 days the former placebo patients were given open label the same regimen of neridronate.
Results. Within the first 20 days, visual analogue scale (VAS) score decreased significantly more in the neridronate group. In the following 20 days, VAS remained unchanged in the placebo group and further decreased in the active group by 46.5 mm (95% CI −52.5, −40.5) vs 22.6 mm (95% CI −28.8, −16.3) for placebo group (P < 0.0001). Significant improvements vs placebo were observed also for a number of other indices of pain and quality of life. During the open-extension phase in the formerly placebo group the results of treatment were superimposable on those seen during the blind phase in the active group. A year later none of the patients was referring symptoms linked to CRPS-I.
Conclusion. In patients with acute CRPS-I, four i.v. infusions of neridronate 100 mg are associated with clinically relevant and persistent benefits. These results provide conclusive evidence that the use of bisphosphonates, at appropriate doses, is the treatment of choice for CRPS-I.

Introduction
Complex regional pain syndrome type I (CRPS-I) is a severely disabling pain syndrome characterized by sensory and vasomotor disturbance, oedema and functional impairment [1] that in most cases develop following a trauma or surgery [2]. No specific test is currently available to diagnose CRPS-I and the recently updated Budapest Criteria are widely accepted to make a clinical diagnosis due to their sensitivity and specificity [3, 4]. To date, the treatment of CRPS-I remains a medical challenge and no definite treatment has been established. A number of therapeutic approaches have been proposed with varying success. The limited number of randomized controlled trials [5], the heterogeneity of the proposed treatments and the methodological limitations in terms of homogeneity and size of the study samples preclude any definitive conclusion about the efficacy of these different therapeutic modalities [6]. Among pharmacological treatments, bisphosphonates appear to offer clear benefits as documented by the results of four randomized controlled trials, all of them showing positive results in controlling pain, oedema and functional impairment [7]. However, none of these trials provided sufficient data to make the use of a bisphosphonate formally indicated for the treatment of CRPS-I.
Neridronate is an amino-bisphosphonate structurally similar to alendronate and pamidronate, differing only in the number of methyl groups of the side chain: five for neridronate, three for alendronate and two for pamidronate. It has been shown to be effective and then registered for the treatment of Paget's disease of bone and osteogenesis imperfecta [8, 9]. In this study we evaluated the efficacy of neridronate administered by i.v. infusion in patients with CRPS-I by a prospective, double-blind, placebo-controlled study.

Methods
Patients
Patients were included over 20 months from the outpatient services of six Italian rheumatology centres. All patients included in the study fulfilled the Budapest criteria for research purposes [3]. Only patients with involvement of the hands or feet were included. Additional inclusion criteria were age of at least 18 years, disease duration no longer than 4 months, spontaneous pain intensity in the affected limb of at least 50 mm on a visual analogue scale (VAS) ranging from 0 (no pain) to 100 mm (maximal pain) [10]. In all patients, a three-phase bone scintigraphy was obtained before study entry and an abnormal uptake of the bone-seeking agent in both early and late phases [11] was an indispensable prerequisite for being included in the study. Women of childbearing potential were required to have a negative pregnancy test before entering the study. Exclusion criteria were hepatic, renal, endocrine, haematological, cardiac, pulmonary or neurological diseases or routine laboratory abnormalities and prior treatment with bisphosphonates. The study complied with the amended Declaration of Helsinki and was approved by each local ethics committee (Comitato Etico, Ospedale G. Pini, Milan; Comitato Etico Provinciale, Ospedale Regionale, Lecce; Comitato Etico, Ospedale O Molinette, Torino; Comitato Etico, Ospedale Forlanini, Roma; Comitato Etico Ospedale S Orsola-Malpighi, Bologna). All patients gave written informed consent to participate in the study.

Study design
A centrally computer-generated table of random numbers was used for the treatment assignment. Patients were treated with either neridronate (Abiogen Pharma, Pisa, Italy) 100 mg/8 ml i.v. ampoules or placebo with an identical appearance in a 1:1 ratio. Both neridronate and placebo were diluted in a 500 ml saline isotonic solution and infused in the morning over 2 h.
Neither patients nor investigators knew whether assignment would be to the placebo or neridronate group. The treatment was administered every third day four times, starting from day 1 (first infusion) and ending on day 10 (fourth infusion). After 40 days from the first infusion, the last blind assessment of clinical results was immediately sent to the coordinating centre. The results were reviewed and locked and eventually the codes were unblinded. The patients who had been receiving neridonate exited the study, while 10 days after the last assessment, those who had been on placebo were given neridronate following the same regimen (four 100-mg infusions over 10 days) and a follow-up obtained at 40 days.

Statistical analysis
Sample size calculation was performed assuming a two-tailed probability of type I error equal to 0.05. The planned total sample size of 80 subjects, randomized in a 1:1 ratio for neridronate and placebo, achieves a 90% power to detect a proportion of 50% of patients in the neridronate group showing ≥50% VAS score reduction when a 35% difference is expected vs placebo.
The statistical analysis was carried out according to the intention-to-treat principle, including all randomized patients who received at least one dose of the study medication. Baseline characteristics were compared with the use of Student’s t-test for quantitative variables and Fisher’s exact test for binary ones. VAS score changes were evaluated using an analysis of covariance (ANCOVA) model for repeated measures using the change from baseline as the dependent variable; treatment, visit, centre and the treatment-by-visit interaction as factors and baseline as covariates. Differences between treatments were reported as least-square mean estimates together with associated two-sided 95% confidence limits. The proportion of responders (VAS reduction ≥ 50%) as well as dichotomous variables (allodynia and hyperalgesia) were compared with Fisher’s exact test while results were reported as risk difference together with associated two-sided 95% confidence limits. The results of the McGill Pain Questionnaire and SF-36 questionnaire were analysed using repeated-measure analysis of variance (ANOVA) models. The comparison of clinical parameters evaluated by means of rating scales were performed using the Wilcoxon rank sum test. Multivariate regression analysis was performed to assess the potential influence of baseline variables on treatment effect [site of disease: (upper/lower limb), disease duration and precipitating event (none/trauma, surgery)]. The statistical analysis was performed using SAS (version 9.2; SAS Institute, Cary, NC, USA). Significance was taken at two-tailed P < 0.05.

Results
Between January 2008 and May 2010, 84 patients were screened and 82 were recruited from six Italian rheumatology units from Milan, Verona, Bologna, Lecce, Rome and Turin. Most patients (71) were coming from the two centres operating in a hospital devoted to bone and joint diseases: Hospital G. Pini (Milan) and Orthopaedic Rehabilitation of Valeggio (Verona). In these centres, the patients were almost invariably referred to the rheumatology centres immediately at the onset of the symptoms. One screening failure was due to previous bisphosphonate treatment for osteoporosis and one to refusal to participate in a randomization including a placebo arm. No other exclusion criteria were applied. Participating patients were randomized to treatment or placebo in two equal (n = 41) groups.
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