Methylene Blue Intravenously and Chronic Neuropathic Pain
Condition: Neuropathic Pain
MeSH terms: Neuralgia
Study type: Interventional

Summary: 
      Aim of Investigation Methylene blue (MB) is a diaminophenothiazine with antioxidant,
      anti-inflammatory properties and with inhibitory effects on nitric oxide. The aim of this
      study was to determine the clinical effectiveness of MB in the treatment of neuropathic pain.

      Methods Ten patients with neuropathic pain were randomized to receive one of the two
      treatments: methylene blue (MB1) 2 mg/kg (10 mg/mL Methyltioninklorid, Apoteket, Umeå,
      Sweden) or methylene blue (MB2) 0.02 mg/kg. Both MB solutions were infused intravenously over
      60 minutes. The sensory function and the pain were evaluated at baseline and at 60 min after
      the start of infusions. A pain journal was kept by the patients in the following 5 days.
      Plasma and urinary concentrations of 8-isoprostane-prostaglandin F2α (8-iso-PGF2α) an
      indicator of oxidative injury, were measured with radioimmunoassay (RIA). A panel of 92
      proteins biomarkers were determined with Proximity Extension Assay (PEA) prior and after
      infusions.

      comparison with the control group. MB infusion produced an enhancement of prolactin.
    

Detailed description: 
      Patients Study participants were screened from a pool of patients with chronic treatment
      resistant neuropathic pain and were eligible to participate in the study after giving written
      informed consent Study design The patients visited the Pain Clinic twice. Oral and written
      information about the study was provided and informed consent obtained. Demographic data
      (date of birth, sex, and ethnic background, medical and surgical history) were recorded.
      Information about the patients' assessments were recorded before the injection, including
      current medication and other (successful or non-successful) treatment attempts. The same
      investigator (AM) performed all study procedure assessments. Assessments of sensory function
      were performed before drug administration.

      Administration of study drug Ten patients were randomized by a computer generated random list
      to receive either methylene blue 2mg/kg (10 mg/mL Methyltioninklorid, Apoteket, Umeå, Sweden)
      or methylene blue 0.02 mg/kg (that served as control), both infused intravenously over 60
      minutes. After monitors for electrocardiography, noninvasive arterial blood pressure, and
      pulse oximetry were attached, a dedicated 20-gauge cannula was inserted into the dorsum of
      the nondominant hand for administration of the study drugs. The pain was measured at baseline
      and at 60 min after the start of infusion (NRS scale) and also with a pain diary during the
      next 24 hours and the following 5 days. ECG, pulse, blood pressure, O2 saturation, were
      continuously recorded during the infusion. Blood and urine samples were taken before and
      after the infusion of MB. Neither the subjects of the experiment nor the person examining the
      patients knew the concentration of MB in the infusion. The infusions of methylene blue in
      sterile saline (NaCl 0.9%) were prepared by another person who had access to the
      randomization list but not involved in the monitoring of the patients. The infusions bags
      were covered in opaque red wrappes and the infusions sets were opaque.

      Pain Assessment were performed Before and after MB administration, Evaluation of sensory
      function was performed using bedside examination according to EFNS guidelines: light touch,
      pinprick sense, warmth (40°) and cold (25°) temperature stimuli were tested. The
      contralateral uninjured side served as within-patient control. The patient compared the
      sensations in both between sides and reported if there was any hypoesthesia, hyperesthesia,
      allodynia or simply normal sensations to the different stimuli. The pain recordings were
      determined before and after infusion of MB. Patients kept a diary where they could pick their
      pain levels on a scale between 0 and 10 (NRS) at every 6 hours after the infusion in the
      first 24 hours and at 8 hours in the next 5 days.

      Peripheral venous blood was drawn from fasting subjects using a 19-gauge needle. Urine was
      collected into additive-free tubes. Plasma was prepared from blood collected into tubes
      containing heparin by centrifugation (3500x g for 12 min). Urine and plasma samples were
      stored at -70◦C until analysis. Blood and urine samples were collected before and after the
      infusion of MB.

      Plasma and urine concentrations of isoprostane 8-iso-PGF2 alpha (an indicator of oxidative
      injury),Proximity Extension Assay (PEA) has been found to have specificity of detection and
      analysis of an increased range of target molecules. PEA technology involved in this study a
      panel of 92 oligonucleotide labeled antibody probe pairs (Proseek assay kit), Non-parametric
      statistical methods were performed by the author with GraphPad PRISM 5.0 (GraphPad Software,
      La Jolla, San Diego, CA, www.graphpad.com 5.0). Data are presented as mean and SD with 95%
      confidence intervals. The level of significance was set at a p value <.05.
    

Intervention name(s): Methylene blue; Methylene blue
Intervention type(s): Drug; Drug
Intervention description(s): In NaCL0.9% 100 ml; in NaCl 0.9% 100 ml
Other intervention name(s): methylthioninium chloride; methylthioninium chloride
Intervention MeSH terms: Methylene Blue
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment