## 3 Results
### Mechanisms of BFRT
#### 3.2.7 Pain  
Pain symptoms are associated with increased physical disability in patients with knee osteoarthritis [60; 61]. Therefore, the primary objective of managing KOA is to alleviate pain while minimizing treatment-related adverse events. To control pain and improve physical function, oral non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are the two most prescribed analgesics, as 10% to 35% of OA patients report frequently using these drugs [62; 63]. However, as these drugs involve an increased risk for gastrointestinal or cardiovascular complications, international guidelines as well as the National Institution for Health and Care Excellence strongly recommend exercise as a core therapy for reducing pain in KOA [7; 8].  
Indeed, resistance training has been found to be effective in reducing pain through the mechanism of exercise-induced hypoalgesia (EIH). The magnitude of this EIH appears to be greater with higher loads or prolonged exercise, as previous studies have shown that using an external load of >75% of 1 RM resulted in significant pain reduction [64]. Unfortunately, regardless of its benefits for pain, joint function, and general (physical) health and well-being, HLRT is not feasible for many KOA patients due to their limitations in load-bearing capacity, pain threshold, and training background, making it very difficult to persevere and potentially harmful for some patients.  
However, by applying BFR combined with LLRT, patients with a reduced load capacity might experience pain reduction while simultaneously benefiting from effects similar to HLRT, albeit without the need to implement heavy loads and high training intensities.  
Indeed, several studies have found that BFRT with 80% of the limb occlusion pressure resulted in a greater EIH response compared to light and heavy load resistance, which was prolonged for 24 h in the exercising limb [65]. Furthermore, in contrast to LLRT alone, [PERSON] et al. (2018) found significant pain reduction after LLRT + BFR during functional testing in patients with anterior knee pain, which was also sustained after a 45 min physiotherapy session [66]. In line with this, KOA patients reported less knee pain and discomfort in the BFR group compared to traditional HLRT [24]. Interestingly, while a recent study by [PERSON] and colleagues found an increase in pain pressure thresholds (PPTs) following leg extension with BFR at 80% Limb Occlusion Pressure (LOP) in end-stage KOA patients, their self-reported pain significantly worsened [67]. While this is in contrast to previous research claiming a pain-reducing effect with BFR, it can be argued that leg extensions with such high occlusion pressures are not suitable for end-stage KOA patients without gradual exposure to BFR, and the visual analog scale (VAS) does not differentiate between muscle pain and knee pain and does not take into account possible confounders such as the discomfort caused by the cuff pressure, mechanical load, or the nocebo effect of physiological stress [68].  
Furthermore, the study by [PERSON] and [PERSON] (2020) found that BFRT led to a significant increase in peripheral blood beta-endorphin (BE) concentration, suggesting that BFRT may involve an opioid-mediated mechanism in EIH [65]. The activation of the endogenous opioid system and stimulation of BE production may contribute to EIH by inhibiting noxious-evoked activity, as BFRT evokes a high level of metabolic stress, which subsequently activates type III and IV afferents, thereby leading to a greater perception of intensity and discomfort. Additionally, other mechanisms have been proposed to explain the occurrence of EIH, including the recruitment of type II muscle fibers, a link between baroreceptors and pain pathways, ischemically and metabolically induced pain, as well as conditioned pain modulation (CPM) [69].