ABSTRACT
Glial activation via Toll-like receptor (TLR) signaling has been shown in animals to play an important role in the initiation and establishment of chronic pain. However, our ability to assess this central immune reactivity in clinical pain populations is currently lacking. Peripheral blood mononuclear cells (PBMCs) are an accessible source of TLR expressing cells that may mirror similarities in TLR responsiveness of the central nervous system. The aim of this study was to characterize the IL-1ß response to various TLR agonists in isolated PBMCs from chronic pain sufferers (on and not on opioids) and pain-free controls. Venous blood was collected from 11 chronic pain sufferers on opioids (≥ 20 mg of morphine / day), 8 chronic pain sufferers not on opioids and 11 pain-free controls. PBMCs were isolated and stimulated in vitro with a TLR2 (Pam3CSK4), TLR4 (LPS) or TLR7 (imiquimod) agonist. IL-1ß released into the supernatant was measured with ELISA. Significantly increased IL-1ß expression was found in PBMCs from chronic pain sufferers (on and not on opioids) compared with pain-free controls for TLR2 (F((6, 277)) = 15, P<0.0001), TLR4 (F((8, 263)) = 3, P = 0.002) and TLR7 (F((2,201)) = 5, P = 0.005) agonists. These data demonstrate that PBMCs from chronic pain sufferers were more responsive to TLR agonists compared with controls, suggesting peripheral cells may have the potential to become a source of biomarkers for chronic pain.
Subject(s)
Chronic Pain/immunology , Leukocytes, Mononuclear/drug effects , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 7/metabolism , Adolescent , Adult , Aged , Aminoquinolines/pharmacology , Chronic Pain/metabolism , Cross-Sectional Studies , Female , Humans , Imiquimod , Interleukin-1beta/metabolism , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Lipopeptides/pharmacology , Lipopolysaccharides/pharmacology , Male , Middle Aged , Pain MeasurementABSTRACT
BACKGROUND: Studies have consistently shown the superior dosing efficiency of subcutaneous (s.c.) compared to intravenous (i.v.) erythropoietin (r-HuEPO). Unlike r-HuEPO, data from pivotal darbepoetin trials support s.c. and i.v. dosing equivalence, however, no blinded cross-over randomized studies of s.c. and i.v. dose efficiency or intra-patient variability in response have been published. METHODS: During this 12-month study, 53 haemodialysis patients were randomized to s.c. or i.v. darbepoetin for a 6-month period and then switched to the alternative route for a second 6-month period. Darbepoetin dose was titrated during the first 4-months of each period to achieve a stable haemoglobin during the final 2-month observation period of each arm. RESULTS: Twenty-four patients were included in analysis. No significant difference between s.c. and i.v. administration was observed for any measured parameter. Patients achieved a non-significantly higher haemoglobin (123.6 +/- 3.76 vs 120.9 +/- 4.42 g/L, P = 0.11) from a non-significantly lower darbepoetin dose (40.8 +/- 10.7 vs 42.5 +/- 11.0 mcg/week, P = 0.23) with i.v. administration. The population-based weight normalized s.c./i.v. dose ratio was 1.04 (0.97-1.11). Despite no significant overall difference, some patients experienced changes in individual dose efficiency response. Three of 24 patients recorded a greater than 30% change, four of 24 recorded between a 20 and 30% change, and five of 24 patients recorded between a 10 and 20% change relative to i.v. dose efficiency. CONCLUSIONS: This study further supports s.c. and i.v. dosing equality and that overall the more convenient i.v. route can be used with equal dosing efficiency. However, patients switching routes of administration should be monitored due to the wide range in individual response.
