Prevalence, associated factors, and short-term impact of central sensitization in high-altitude patients undergoing total knee arthroplasty

Pain management is crucial in total knee arthroplasty (TKA), a well-established treatment for end-stage knee osteoarthritis (OA). Despite advances in surgical techniques and pain management, about 20% of TKA patients experience prolonged postoperative pain and dissatisfaction [1]. Traditionally, OA pain was attributed to joint structural changes, with treatment focusing on nociceptive pain [2]. However, recent studies have found that structural damage is not directly correlated with pain severity [3, 4], and mechanisms such as central sensitization (CS) may play a more significant role in pain perception [5, 6].

CS involves heightened pain sensitivity due to altered processing in the central nervous system and can occur alongside nociceptive and neuropathic pain [7]. It results from mechanisms such as increased neuronal excitability and weakened inhibitory pathways [7]. Evidence indicates that CS affects 20–40% of OA patients, particularly those with knee OA [5, 6]. Preoperative CS is associated with longer hospital stays, chronic postoperative pain, worse functional outcomes, higher costs, and reduced surgical benefits in TKA patients [8‐10]. These patients also tend to respond poorly to standard pain management strategies, like non-steroidal anti-inflammatory drugs (NSAIDs), and report higher dissatisfaction after surgery [11].

People living at high altitudes, including around 140 million residing above 2,500 m and over 12 million at elevations above 4,000 m, have a higher prevalence of symptomatic knee OA [12]. In these populations, knee disorders often develop earlier and persists longer, increasing the likelihood of undergoing TKA [13, 14]. Chronic exposure to hypoxic environments may lead to physiological adaptations, such as altered pain perception and shifts in pain thresholds, potentially influencing both peripheral and central pain mechanisms [15]. While some studies suggest that individuals newly exposed to high altitudes experience reduced pain thresholds due to acute hypoxia, long-term residents may develop higher pain thresholds [16]. However, these conclusions remain controversial. Despite the distinct characteristics of high-altitude populations, no studies have explored the prevalence or role of central sensitization (CS) in TKA patients living at high altitudes, highlighting a critical gap in current research.

This study aimed to examine the incidence of CS in this population, identify associated factors, and assess short-term postoperative outcomes following TKA.

This study is the first to examine the prevalence of CS, its associated factors, and its impact on clinical outcomes in high-altitude TKA patients. We found that 15.7% of these specific patients exhibited CS, as measured by the CSI. Patients with CS were more likely to be female, have higher BMIs, and reside at altitudes above 4,000 m. In terms of short-term outcomes, the CS group experienced significantly worse postoperative results, including higher pain levels at 24, 48, and 72 h, more PONV, increased opioid consumption, longer hospital stays, and a higher incidence of chronic postoperative pain and dissatisfaction.

This study is the first to investigate the relationship between altitude and CS in TKA patient. We observed an overall CS prevalence of 15.7%, which is lower than the 20–40% typically reported in non-altitude-specific populations [5, 6]. However, when stratifying the population by altitude, notable differences emerged. Among patients living at altitudes between 2,500 and 4,000 m, the prevalence of CS was 9.5% (16/168). In contrast, for those residing above 4,000 m, the prevalence significantly increased to 32.3% (20/62). Our multivariable logistic regression analysis identified altitude as a significant factor in CS development. Patients living at elevations above 4,000 m were more than five times more likely to develop CS compared to those at lower altitudes (OR: 5.1, 95% CI: 1.7–15.1, P = 0.003), indicating a strong relationship between extreme altitude and the risk of CS.

Previous research provides some insight into this phenomenon. Individuals from low-altitude regions tend to experience a substantial reduction in pain thresholds, up to 30%, when they first ascend to high altitudes due to acute hypoxia, which can increase pain sensitivity [21]. In contrast, long-term residents of moderate high altitudes, such as between 2,500 and 4,000 m, typically develop higher pain thresholds [16], offering some degree of protection against the development of CS. This corresponds to the relatively lower prevalence of CS at these altitudes in our study. However, at extreme altitudes above 4,000 m, this protective effect appears to diminish. Long-term exposure to severe hypoxia at such elevations may alter pain processing in the central nervous system, aggravate joint inflammation, and accelerate the progression of osteoarthritis [22]. In addition, residents of remote, high-altitude regions may have limited access to medical care, leading to inadequate treatment of pain, which could further contribute to the heightened risk of developing CS.

In addition to altitude, we found that female gender and higher BMI are associated with central sensitization. Females, who are generally more prone to chronic pain conditions and often exhibit heightened pain sensitivity, have been shown to have a higher prevalence of CS [23]. Similarly, elevated BMI not only increases mechanical stress on the joints but is also linked to metabolic disorders, both of which contribute to the progression of osteoarthritis and are well-established risk factors for CS [24]. These associations are consistent with existing literature on CS risk factors, reinforcing the alignment of our findings with previous studies.

Our postoperative findings align with previous research, emphasizing the negative impact of CS on surgical outcomes [8‐11]. In this study, patients with CS reported significantly higher pain levels at 24, 48, and 72 h post-surgery, along with more episodes of PONV, longer hospital stays, and greater opioid consumption. Additionally, the higher incidence of chronic postoperative pain and dissatisfaction in the CS group supports the idea that CS prolongs pain sensitization and recovery. Studies have shown that knee OA patients with preoperative CS experience worse pain scores, lower patient-reported outcomes, and higher dissatisfaction rates two years after TKA. Moreover, CS has been linked to an increased risk of wound complications and persistent pain following both primary and revision TKA [8‐11]. These findings underscore the importance of preoperative CS assessments for identifying at-risk patients, managing expectations, and optimizing postoperative recovery to reduce complications.

While our study provides valuable insights into CS in high-altitude TKA patients, several limitations should be noted. First, the study was conducted at a single centre with a relatively small sample size, which may limit the generalizability of our findings to other high-altitude populations, especially considering potential institutional biases. Second, although the CSI is a validated tool for assessing CS, it remains inherently subjective. More objective methods, such as QST, could provide a more comprehensive evaluation of CS severity, but resource limitations prevented their use in this study. Additionally, our follow-up period focused primarily on short-term postoperative outcomes, which may not fully capture the long-term impact of CS on recovery or the incidence of complications over time. Furthermore, due to the constraints of our prospective cohort design, we did not collect standardized intraoperative data, such as blood loss, despite evidence suggesting that high-altitude populations have an increased risk of intraoperative bleeding, which may influence postoperative outcomes [25]. Finally, the study design did not investigate potential interventions for CS, leaving the effects of treatment options unexamined.

This study found a 15.7% prevalence of CS among high-altitude TKA patients. Female gender, higher BMI, and residence at altitudes above 4,000 m were identified as factors associated with CS. Furthermore, CS was linked to worse short-term postoperative outcomes, including higher pain levels, increased incidence of PONV, greater opioid consumption, longer hospital stays, and a higher prevalence of chronic postoperative pain and dissatisfaction.