Intramuscular neridronate for the treatment of complex regional pain syndrome type 1: a randomized, double-blind, placebo-controlled study

Abstract

Background: Complex regional pain syndrome type-1 (CRPS-1) is a severely disabling painful disease challenging to treat. This multicenter, randomized, double-blind placebo-controlled trial examined the efficacy of intramuscular (i.m.) neridronate in CRPS-1 patients.

Methods: A total of 78 patients diagnosed with CRPS-1 (aged 59.5 ± 10.3, 66.7% female) were randomly assigned to 25 mg (i.m.) neridronate (N = 41) given once daily for 16 consecutive days or placebo control (N = 37). Efficacy was assessed after 30 days using a visual analogue scale (VAS) pain score and the number of patients achieving ⩾50% reduction in VAS score. Change in clinical signs and symptoms, quality of life (QoL) using Short Form Health Survey (SF-36) and the McGill Pain Questionnaire were also assessed.

Results: After 30 days, VAS score decreased significantly to a greater extent in neridronate-treated patients versus placebo (31.9 ± 23.3 mm versus 52.3 ± 27.8 mm, p = 0.0003). Furthermore, the proportion of patients achieving a VAS reduction of ⩾50% was greater in the neridronate group (65.9% versus 29.7%, p = 0.0017). Clinical signs and symptoms were improved significantly in the neridronate group versus placebo for edema (72.5% versus 79.9%, p = 0.03), pain during motion (70% versus 83.3%, p = 0.0009), allodynia (20% versus 63.3%, p = 0.0004), and hyperalgesia (20% versus 56.7%, p = 0.0023). Whereas no difference was observed for QoL measures using the SF-36 questionnaire, three of the four pain variables using the McGill Pain Questionnaire improved significantly in the neridronate group. No serious drug-related adverse events were reported during the study.

Conclusion: In patients with acute CRPS-1, i.m. injections of 25 mg neridronate were associated with clinically relevant benefit compared with placebo controls.

Trial registration: EU Clinical Trials Register: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001156-28.

Keywords: algodystrophy; bisphosphonates; complex regional pain syndrome type 1; neridronate; randomized clinical trial.

Figure 1.

Flowchart according to CONSORT statement for the report of randomized trials. i.m., intramuscularly.

Figure 2.

Change in VAS pain score in CRPS-I treated with neridronate or placebo. (a) Change in mean VAS pain score (mm) from baseline to day 30 in CRPS-1 patients treated with neridronate or placebo. Absolute mean differences (delta) between VAS scores for the two groups are shown for 8, 16, and 30 days. Data are presented as mean ± SD. (b) Proportion of patients achieving a ⩾50% reduction in pain VAS score from baseline to day 30 in the neridronate (N = 27/41) and placebo (11/37) group. Data are presented as % and 95% CIs. p values denote level of statistical significance between groups. CI, confidence interval; CRPS-I, complex regional pain syndrome type-1; SD, standard deviation; VAS, visual analogue scale.

Figure 3.

Change in clinical signs and symptoms in CRPS-I treated with neridronate or placebo. Data are presented as the proportion of patients presenting with signs/symptoms such as edema, pain on motion, allodynia, or hyperalgesia. Edema and pain on passive motion are based on a 0–3 rating scale (none, mild, moderate, severe), while allodynia and hyperalgesia are dichotomous data (present/absent). p values denote level of statistical significance between groups. CRPS-I, complex regional pain syndrome type-1.

Figure 4.

Change in McGill Pain Questionnaire items in CRPS-I treated with neridronate or placebo from baseline to 30 days. Data are presented as mean ± SD for the following items: sensory, affective, present pain intensity and VAS. p values denote level of statistical significance between groups. CRPS-I, complex regional pain syndrome type-1; PPI, present pain intensity; SD, standard deviation; SF-MPQ, short-form McGill pain questionnaire; VAS, visual analogue scale.