Leukocyte-Rich Platelet-Rich Plasma Is Predominantly Anti-inflammatory Compared With Leukocyte-Poor Platelet-Rich Plasma in Patients With Mild-Moderate Knee Osteoarthritis: A Prospective, Descriptive Laboratory Study.

BACKGROUND: Platelet-rich plasma (PRP) has been used extensively in clinical practice to treat patients with symptomatic knee osteoarthritis (OA). Leukocyte-poor PRP (LP-PRP) has been clinically preferred over leukocyte-rich PRP (LR-PRP); however, it is unclear which cytokine mediators of pain and inflammation are present in LR-PRP and LP-PRP from patients with mild to moderate knee OA in order to rationalize a specific formulation. HYPOTHESIS: LP-PRP would be predominantly anti-inflammatory and have reduced nociceptive pain mediators compared with LR-PRP from the same individual with mild to moderate knee OA. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 24 unique samples of PRP were prepared in order to assess 48 samples of LR-PRP and LP-PRP taken from 12 patients (6 male and 6 female) with symptomatic knee OA of Kellgren-Lawrence grade 2 to 3. Patients underwent blood collection for LR-PRP and LP-PRP preparation through a double-spin protocol to obtain baseline whole blood, platelet concentration, and white blood cell subtypes. LR-PRP and LP-PRP from the same patient were produced at the same time and underwent a comprehensive panel through Luminex (multicytokine profiling) to assess key mediators of inflammation: interleukin 1 receptor antagonist (IL-1Ra), interleukin 4, 6, 8, and 10 (IL-4, IL-6, IL-8, and IL-10), IL-1ß, tissue necrosis factor α (TNF-α), and matrix metalloproteinase 9 (MMP-9). To assess mediators of nociceptive pain, nerve growth factor (NGF) and tartrate resistant acid phosphatase 5 (TRAP5) were also assessed. RESULTS: LR-PRP from patients with mild to moderate knee OA expressed significantly more IL-1Ra, IL-4, IL-8, and MMP-9 compared with LP-PRP formulations from the same patients. No significant differences were found between LR-PRP and LP-PRP in mediators of nociceptive pain-namely, NGF and TRAP5. Other mediators including TNF-α, IL-1ß, IL-6, and IL-10 were also found to have no significant expression differences between LR-PRP and LP-PRP. CONCLUSION: LR-PRP expressed significantly more IL-1Ra, IL-4, and IL-8, suggesting that LR-PRP may be more anti-inflammatory than LP-PRP. MMP-9 was expressed in higher concentrations in LR-PRP, suggesting that LR-PRP may be more chondrotoxic than LP-PRP. CLINICAL RELEVANCE: LR-PRP was found to have a robust expression of anti-inflammatory mediators compared with LP-PRP and may be beneficial to patients with long-term knee OA where chronic low-grade inflammation is present. Mechanistic clinical trials are needed to elucidate the key mediators in both LR-PRP and LP-PRP to assess their effect on long-term progression of knee OA.

Are Invasive Procedures Effective for Chronic Pain? A Systematic Review.

OBJECTIVE: To assess the evidence for the safety and efficacy of invasive procedures for reducing chronic pain and improving function and health-related quality of life compared with sham (placebo) procedures. DESIGN: Systematic review with meta-analysis. METHODS: Studies were identified by searching multiple electronic databases, examining reference lists, and communicating with experts. Randomized controlled trials comparing invasive procedures with identical but otherwise sham procedures for chronic pain conditions were selected. Three authors independently extracted and described study characteristics and assessed Cochrane risk of bias. Two subsets of data on back and knee pain, respectively, were pooled using random-effects meta-analysis. Overall quality of the literature was assessed through Grading of Recommendations, Assessment, Development, and Evaluation. RESULTS: Twenty-five trials (2,000 participants) were included in the review assessing the effect of invasive procedures over sham. Conditions included low back (N = 7 trials), arthritis (4), angina (4), abdominal pain (3), endometriosis (3), biliary colic (2), and migraine (2). Thirteen trials (52%) reported an adequate concealment of allocation. Fourteen studies (56%) reported on adverse events. Of these, the risk of any adverse event was significantly higher for invasive procedures (12%) than sham procedures (4%; risk difference = 0.05, 95% confidence interval [CI] = 0.01 to 0.09, P = 0.01, I2 = 65%). In the two meta-analysis subsets, the standardized mean difference for reduction of low back pain in seven studies (N = 445) was 0.18 (95% CI = -0.14 to 0.51, P = 0.26, I2 = 62%), and for knee pain in three studies (N = 496) it was 0.04 (95% CI = -0.11 to 0.19, P = 0.63, I2 = 36%). The relative contribution of within-group improvement in sham treatments accounted for 87% of the effect compared with active treatment across all conditions. CONCLUSIONS: There is little evidence for the specific efficacy beyond sham for invasive procedures in chronic pain. A moderate amount of evidence does not support the use of invasive procedures as compared with sham procedures for patients with chronic back or knee pain. Given their high cost and safety concerns, more rigorous studies are required before invasive procedures are routinely used for patients with chronic pain.

To what extent are surgery and invasive procedures effective beyond a placebo response? A systematic review with meta-analysis of randomised, sham controlled trials.

OBJECTIVES: To assess the quantity and quality of randomised, sham-controlled studies of surgery and invasive procedures and estimate the treatment-specific and non-specific effects of those procedures. DESIGN: Systematic review and meta-analysis. DATA SOURCES: We searched PubMed, EMBASE, CINAHL, CENTRAL (Cochrane Library), PILOTS, PsycInfo, DoD Biomedical Research, clinicaltrials.gov, NLM catalog and NIH Grantee Publications Database from their inception through January 2015. STUDY SELECTION: We included randomised controlled trials of surgery and invasive procedures that penetrated the skin or an orifice and had a parallel sham procedure for comparison. DATA EXTRACTION AND ANALYSIS: Three authors independently extracted data and assessed risk of bias. Studies reporting continuous outcomes were pooled and the standardised mean difference (SMD) with 95% CIs was calculated using a random effects model for difference between true and sham groups. RESULTS: 55 studies (3574 patients) were identified meeting inclusion criteria; 39 provided sufficient data for inclusion in the main analysis (2902 patients). The overall SMD of the continuous primary outcome between treatment/sham-control groups was 0.34 (95% CI 0.20 to 0.49; p<0.00001; I(2)=67%). The SMD for surgery versus sham surgery was non-significant for pain-related conditions (n=15, SMD=0.13, p=0.08), marginally significant for studies on weight loss (n=10, SMD=0.52, p=0.05) and significant for gastroesophageal reflux disorder (GERD) studies (n=5, SMD=0.65, p<0.001) and for other conditions (n=8, SMD=0.44, p=0.004). Mean improvement in sham groups relative to active treatment was larger in pain-related conditions (78%) and obesity (71%) than in GERD (57%) and other conditions (57%), and was smaller in classical-surgery trials (21%) than in endoscopic trials (73%) and those using percutaneous procedures (64%). CONCLUSIONS: The non-specific effects of surgery and other invasive procedures are generally large. Particularly in the field of pain-related conditions, more evidence from randomised placebo-controlled trials is needed to avoid continuation of ineffective treatments.