**6. Pain generation and pain generators**

Diseases or injuries that affect the knee joint cause biochemical reactions leading to the stimulation of pain receptors present on various structures that contribute to developing significant pain. Nociception is the normal body response to subthreshold noxious stimuli. In comparison, the pain generation process results from the interplay between noxious stimuli, nociceptors, and the central nervous system (CNS). It involves four major processes: transduction, transmission, modulation, and perception [17].


#### **6.1 Knee joint nociceptors**

Knee joint nociceptors are of two types, slow conducting C-fibers and fast conducting A-delta fibers. They are scattered in the skin, subcutaneous tissue, muscles, joint capsule, intraarticular structures, periosteum of the bone, infrapatellar fat pad, and extra-articular retinacular ligament. The joint cartilages with adjacent cortical and trabecular bone contain no nociceptors.

These nociceptors get activated by mechanical (pressure, pinch), heat, and chemical stimuli. The mechanical and heat stimuli are shorter (fast pain) than the chemical stimuli (slow pain). Chemicals activating or sensitizing primary afferent nociceptors include potassium, histamine, serotonin, bradykinin, prostaglandins, leukotrienes, and substance P [18, 19]. These chemicals are released from damaged tissues and circulating blood cells (migrated to the damaged area). For this reason, the concentration of these chemicals increases in regions of inflammation as well as pain.

#### **6.2 Causes of knee joint pain**

The knee joint pain arises due to joint-related and non-joint-related causes [20]. Joint-related causes include infections/inflammation (osteoarthritis), instability (ligament injury or malalignment/loosening of the implant), fractures, femoropatellar problems, and damage to the structures responsible for knee joint stability. Non-joint causes include soft tissue irritation (impingement due to oversize implants and muscle/tendon overuse during aggressive physiotherapy), neurological disease (neuropathies and spine disorders), hip disease (osteoarthritis and hip necrosis), vascular disease (aneurysm and thrombosis), and reflex sympathetic dystrophy.

#### **6.3 Perioperative knee pain**

The injury or pathology in the knee joint mainly initiates the pain generation process. Before surgery, the pain usually arises from the damaged or diseased tissues that stimulate free nerve endings and nociceptors. Postsurgical pain is mainly due to surgical insult leading to tissue damage, nerve irritation, microfractures, tendinitis, and inflammation. Postoperative knee pain is of 2 types:


the pain pathway, leading to an alteration in the pain processing. The hypersensitivity and hyperexcitability of the neurons result in dysesthesia, allodynia, and hyperalgesia. In addition, psychological factors like stress, fear, and anxiety can influence the experience and extent of pain, known as modulatory influences prolonging the pain episodes in susceptible individuals.
