Endocannabinoids and acute pain after total knee arthroplasty.

Osteoarthritis (OA) is a musculo-skeletal disease defined by progressive cartilage degradation leading to increasing joint pain and functional disability [39,50]. Patients suffering from painful knee OA and increasing disability in activities of daily living are prime candidates for total knee arthroplasty (TKA) [8]. TKA is a surgical procedure that resurfaces the damaged articular cartilage surface with metal, aiming to reduce pain and restore function to patients suffering from OA. The socioeconomic impact of knee OA and subsequent dramatic rise in the annual number of TKA procedures worldwide have led to numerous investigations focused on understanding the pathophysiological, molecular, and biochemical mechanisms that underlie cartilage degradation, associated pain in OA [23,50], and perioperative TKA pain (i.e. persistent knee pain develops in 10-20% of TKA patients) [15]. It is now well-established that dysregulated biosynthesis and degradation of extracellular matrix components (e.g. collagen type II) by chondrocytes secondary to increased production of cytokines and matrix-degenerating enzymes leads to the breakdown of the extracellular matrix and cartilage [50]. Arthritic pain arises via nociceptors located in the affected joint triggered by inflammatory and catabolic mediators [23,37]. A host of pro-inflammatory mediators that contribute to painful OA have been identified including interleukins (e.g., IL-6) and prostaglandins [26,50]. The endocannabinoid system has recently emerged as a promising target for the development of novel analgesics [12,31,48]. For example, activation of cannabinoid receptors by their endogenous ligands, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), or by synthetic agonists have been shown to reduce nociception in preclinical models of pain including OA [1,8,10,28,33,48]. Furthermore, the structurally related N-acylethanolamines (NAEs), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), activate the nuclear receptor peroxisome proliferator-activated receptor alpha, thereby producing antinociceptive and anti-inflammatory effects in preclinical pain models including OA [24,34,35]. Interestingly, recent data suggest that in addition to activating cannabinoid receptors, 2-AG is also a major source of arachidonic acid in numerous tissues and is therefore a precursor to pro-inflammatory eicosanoids [41], which could in principle contribute to OA pain. To date a detailed analysis of endocannabinoid levels in OA patients and their influence upon OA-associated pain has not been reported despite the well-documented role of endocannabinoids in the modulation of pain and the recognized presence of cannabinoid receptors on chondrocytes [14]. A single clinical study has examined endocannabinoid levels in the synovial fluid of OA patients and found elevated AEA and 2-AG levels and reduced content of the anti-inflammatory PEA [45], possibly reflecting a pro-inflammatory and proalgesic environment. However, the association of the endocannabinoid tone with OA pain was not reported. Furthermore, the influence of the endocannabinoid tone upon post-operative pain and opioid usage in a clinical setting has likewise never been reported. Here, we begin to address these outstanding questions by providing the first comprehensive profile of endocannabinoid/NAE levels in serum, synovial fluid, and cerebrospinal fluid (CSF) in patients with painful OA and explore whether endocannabinoid levels correlate with baseline functional pain disability status, acute post-operative pain, and post-operative opioid use following TKA.