Spinal Cord Stimulation Alters Protein Levels in the Cerebrospinal Fluid of Neuropathic Pain Patients: A Proteomic Mass Spectrometric Analysis.

OBJECTIVES: Electrical neuromodulation by spinal cord stimulation (SCS) is a well-established method for treatment of neuropathic pain. However, the mechanism behind the pain relieving effect in patients remains largely unknown. In this study, we target the human cerebrospinal fluid (CSF) proteome, a little investigated aspect of SCS mechanism of action. METHODS: Two different proteomic mass spectrometry protocols were used to analyze the CSF of 14 SCS responsive neuropathic pain patients. Each patient acted as his or her own control and protein content was compared when the stimulator was turned off for 48 hours, and after the stimulator had been used as normal for three weeks. RESULTS: Eighty-six proteins were statistically significantly altered in the CSF of neuropathic pain patients using SCS, when comparing the stimulator off condition to the stimulator on condition. The top 12 of the altered proteins are involved in neuroprotection (clusterin, gelsolin, mimecan, angiotensinogen, secretogranin-1, amyloid beta A4 protein), synaptic plasticity/learning/memory (gelsolin, apolipoprotein C1, apolipoprotein E, contactin-1, neural cell adhesion molecule L1-like protein), nociceptive signaling (neurosecretory protein VGF), and immune regulation (dickkopf-related protein 3). CONCLUSION: Previously unknown effects of SCS on levels of proteins involved in neuroprotection, nociceptive signaling, immune regulation, and synaptic plasticity are demonstrated. These findings, in the CSF of neuropathic pain patients, expand the picture of SCS effects on the neurochemical environment of the human spinal cord. An improved understanding of SCS mechanism may lead to new tracks of investigation and improved treatment strategies for neuropathic pain.

"Opioids are opioids" - A phenomenographic analyses of physicians' understanding of what makes the initial prescription of opioids become long-term opioid therapy.

OBJECTIVES: To explore prescribers' understanding of what makes initial prescription of opioids become long-term opioid therapy (opioids >90 days). METHODS: A qualitative research design, phenomenography, was used for this study. Fifteen attending physicians working within primary, secondary and tertiary care in Sweden in the fields of general practice, rehab medicine, orthopedic surgery, neurosurgery, or obstetrics and gynecology were purposively recruited consecutively until categorical saturation was reached. Semi-structured interviews were used for data collection. The transcripts were analyzed and categorized by two researchers. A third researcher checked for consistency between the data and the categories. An outcome space was constructed representing the logical relationship between the categories. RESULTS: The analysis identified six categories: The addictive opioid, The deserving patient, The ignorant prescriber, The lost patient, The compassionate prescriber, and The exposed prescriber. The differences in conceptions among the categories were clarified through three main contributors related to opioid therapy: prescriber's characteristics, patient's characteristics, and the healthcare organization. CONCLUSIONS: Opioids were understood as being addictive with long-term use promoting a downward spiral of tolerance and withdrawal driving the pain, leading to continued prescription. Long-term opioid therapy could be justified for patients who improved in function, and who were perceived as trustworthy. Inadequate follow-up of patients, poor training in pain management and addiction medicine, personal attitudes and beliefs about opioids, a perceived professional obligation to treat patients with pain, and lack of collegial support, were factors understood to promote clinically unindicated long-term opioid therapy.

A Multiplex Protein Panel Applied to Cerebrospinal Fluid Reveals Three New Biomarker Candidates in ALS but None in Neuropathic Pain Patients.

The objective of this study was to develop and apply a novel multiplex panel of solid-phase proximity ligation assays (SP-PLA) requiring only 20 µL of samples, as a tool for discovering protein biomarkers for neurological disease and treatment thereof in cerebrospinal fluid (CSF). We applied the SP-PLA to samples from two sets of patients with poorly understood nervous system pathologies amyotrophic lateral sclerosis (ALS) and neuropathic pain, where patients were treated with spinal cord stimulation (SCS). Forty-seven inflammatory and neurotrophic proteins were measured in samples from 20 ALS patients and 15 neuropathic pain patients, and compared to normal concentrations in CSF from control individuals. Nineteen of the 47 proteins were detectable in more than 95% of the 72 controls. None of the 21 proteins detectable in CSF from neuropathic pain patients were significantly altered by SCS. The levels of the three proteins, follistatin, interleukin-1 alpha, and kallikrein-5 were all significantly reduced in the ALS group compared to age-matched controls. These results demonstrate the utility of purpose designed multiplex SP-PLA panels in CSF biomarker research for understanding neuropathological and neurotherapeutic mechanisms. The protein changes found in the CSF of ALS patients may be of diagnostic interest.