title: Evaluation of the protein biomarkers and the analgesic response to systemic methylene blue in patients with refractory neuropathic pain: a double-blind, controlled study.
abstract: OBJECTIVE
  This study was carried out in patients with neuropathic pain in order to assess the analgesic effects and changes in protein biomarkers after the administration of methylene blue (MB), a diaminophenothiazine with antioxidant and anti-inflammatory properties, and with inhibitory effects on nitric oxide.
  
  
  METHODS
  Ten patients with chronic refractory neuropathic pain were randomized to receive either MB (10 mg/mL Methylthioninium chloride) 2 mg/kg (MB group) or MB 0.02 mg/kg (control group) infused over 60 minutes. Sensory function and pain (Numerical Rating Scale) were evaluated at baseline and at 60 minutes after the start of the infusion. The patients kept a pain diary during the next 24 hours and for the following 4 days. Plasma and urinary concentrations of 8-isoprostane-prostaglandin F2α (8-iso-PGF2α) and plasma protein biomarkers prior to and after the infusions were measured with radioimmunoassay and with proximity extension assay.
  
  
  RESULTS
  A decrease of the Numerical Rating Scale at 60 minutes in comparison with baseline was observed in the MB (P=0.047) group. The decrease was significant between the MB and the control group on the day of and day after MB infusion (P=0.04 and P=0.008, respectively). There was no difference in systemic protein expressions between groups except for prolactin (PRL) (P=0.02). Three patients demonstrated diminished dynamic mechanical allodynia.
  
  
  CONCLUSIONS
  MB decreased the pain levels in patients with chronic therapy-resistant neuropathic pain on the first 2 days after administration. Known as an endocrine modulator on the anterior pituitary gland, MB infusion produced a decrease of PRL. The detailed role of PRL effects in chronic neuropathic pain remains undetermined.
authors.affiliation: Multidisciplinary Pain Clinic, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Adriana A
authors.initials: AA
authors.lastname: Miclescu
authors.affiliation: Multidisciplinary Pain Clinic, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Svahn
authors.affiliation: Multidisciplinary Pain Clinic, Uppsala University Hospital, Uppsala, Sweden ; Pain Research, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Torsten E
authors.initials: TE
authors.lastname: Gordh
keywords: methylene blue; neuropathic pain; nitric oxide