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. Author manuscript; available in PMC: 2025 Aug 1.
Published in final edited form as: Brain Behav Immun. 2024 Jun 3;120:199–207. doi: 10.1016/j.bbi.2024.06.001

The Association between Changes in Clinical Pain Severity and IL-6 Reactivity among Patients Undergoing Total Knee Arthroplasty: The Moderating Role of Change in Insomnia

Jenna M Wilson 1,*, JiHee Yoon 1,*, Chung Jung Mun 2,3, Samantha M Meints 1, Claudia M Campbell 2, Jennifer A Haythornthwaite 2, Michael T Smith 2, Robert R Edwards 1, Kristin L Schreiber 1
PMCID: PMC11269019  NIHMSID: NIHMS2000262  PMID: 38838835

Abstract

Knee osteoarthritis (KOA) is linked to an enhanced release of interleukin-6 (IL-6). Increased levels of IL-6 are associated with greater pain and insomnia. While total knee arthroplasty (TKA) typically results in the reduction of pain, for a subgroup of patients, pain does not improve. Understanding patients’ propensity to upregulate IL-6 may provide insight into variation in the clinical success of TKA for improving pain, and insomnia may play an important modulatory role. We investigated the association between pre- and post-surgical changes in clinical pain and IL-6 reactivity, and whether change in insomnia moderated this association.

Patients (n=39) with KOA came in-person before and 3-months after TKA. At both visits, patients completed validated measures of clinical pain and insomnia, as well as underwent quantitative sensory testing (QST). Blood samples were collected to analyze IL-expression both before and after QST procedures to assess changes in IL-6 in response to QST (IL-6 reactivity). Patients were categorized into two groups based on change in clinical pain from pre- to post-surgery: 1) pain decreased >2 points (pain improved) and 2) pain did not decrease >2 points (pain did not improve). Based on this definition, 49% of patients had improved pain at 3-months. Among patients with improved pain, IL-6 reactivity significantly decreased from pre- to post-surgery, whereas there was no significant change in IL-6 reactivity among those whose pain did not improve. There was also a significant interaction between pain status and change in insomnia, such that among patients whose insomnia decreased over time, improved pain was significantly associated with a reduction in IL-6 reactivity. However, among patients whose insomnia increased over time, pain status and change in IL-6 reactivity were not significantly associated.

Our findings suggest that the resolution of clinical pain after TKA may be associated with discernible alterations in pro-inflammatory responses that can be measured under controlled laboratory conditions, and this association may be moderated by perioperative changes in insomnia. Randomized controlled trials which carefully characterize the phenotypic features of patients are needed to understand how and for whom behavioral interventions may be beneficial in modulating inflammation, pain, and insomnia.

Keywords: knee osteoarthritis, total knee arthroplasty, pain severity, interleukin-6 (IL-6), insomnia

1. Introduction

Pain is one of the primary reasons that patients with knee osteoarthritis (KOA), the most common form of arthritis [1], seek medical attention [2]. One of the pathophysiological processes implicated in KOA is chronic low-grade inflammation [3]. Specifically, KOA has been linked to an enhanced release of pro-inflammatory cytokines [3] and patients with KOA exhibit elevated levels of interleukin-6 (IL-6), a key pro-inflammatory cytokine, in comparison to healthy, pain-free controls [4]. Additionally, studies have shown that higher levels of IL-6 are associated with impaired physical function [5]. The expression of inflammatory cytokines plays a crucial role in the physiology of nociception, with evidence of action both directly at receptors on peripheral and central neurons, as well as indirectly through augmentation of analgesic mediator release, with these cytokines meaningfully contributing to enhanced sensitivity in pathophysiological pain states [6]. Increased levels of IL-6 have been associated with more severe clinical pain among patients with KOA [7]. While total knee arthroplasty (TKA) is a common procedure to treat KOA and typically results in the reduction of clinical pain (i.e., improved pain) [4], for a subgroup of patients, clinical pain does not improve, persisting or even worsening after TKA [5]. Understanding a patient’s propensity to upregulate cytokines such as IL-6, both before and after TKA, may provide insight into variation in the clinical success of TKA for improving KOA pain.

Several studies have demonstrated that exposure to an acute stressor in a controlled laboratory setting can lead to a rapid increase in the production and circulation of IL-6 levels [6–8]. The degree to which IL-6 levels rise (i.e., IL-6 reactivity) in response to stressors, including standardized acute painful stimulation, appears to vary across individuals [9–12]. Notably, among patients with KOA, IL-6 is a prominently upregulated marker in response to pain stimulation compared to several other inflammatory cytokines (e.g., IL-1β, C-reactive protein, and tumor necrosis factor α) [9]. Individual variability in the degree of IL-6 reactivity in response to acute painful stimulation suggests that it might potentially serve as a mechanistic contributor to differences in this aspect of pain processing and may provide useful insight into why patients respond more (or less) favorably to TKA. However, links between IL-6 reactivity in response to lab-based painful stimulation (quantitative sensory testing) and clinical pain have not yet been explored.

Insomnia symptoms (i.e., difficulty initiating or maintaining sleep with associated daytime impairment) are highly prevalent among patients with KOA [13,14] and are associated with worse knee-related pain severity and physical disability [15–17]. We have previously shown that patients with persistent insomnia had worse postoperative pain compared to patients with improved insomnia following TKA [18]. Insomnia is also associated with increased markers of systemic inflammation [19], including inflammatory cytokine expression in response to stress [20]. One study of patients with KOA found that IL-6 reactivity in response to lab-based painful stimulation was higher among those with insomnia compared to those without insomnia [21]. Another study showed that decreased insomnia over time among patients with KOA was associated with improved clinical pain and attenuated IL-6 reactivity [22]. Thus, emerging evidence suggests that the presence and degree of insomnia symptoms may play an important modulatory role in the relationship between changes in clinical pain severity and IL-6 reactivity, although these relationships within the context of surgical treatment (TKA) remain understudied.

The present longitudinal study investigated the relationship between changes in clinical pain severity and IL-6 reactivity after QST among patients with KOA from pre- to 3-months post-TKA surgery. Three months after surgery is an important timepoint to assess patients’ recovery progress, particularly the presence and severity of postsurgical pain, and intervene as needed to improve longer-term outcomes. We examined whether change in clinical pain severity was associated with change in IL-6 reactivity from pre- to 3-months post-surgery. We hypothesized that a decrease in IL-6 reactivity would be associated with an improvement in clinical pain severity. We also explored whether change in insomnia symptoms over time moderated the relationship between changes in clinical pain severity and IL-6 reactivity.

2. Methods

2.1. Participants and Procedure

This prospective, observational cohort study recruited patients undergoing unilateral total knee arthroplasty (TKA) from Brigham and Women’s Hospital (BWH, Boston, MA) and Johns Hopkins University (JHU, Baltimore, MD). Patients were recruited via announcements on clinical research websites, mailed letters, flyers, and in local orthopedic clinics through direct in-person information and advertisements. Eligibility criteria included diagnosis of knee osteoarthritis (KOA) meeting the American College of Rheumatology criteria for KOA, age ≥45, and fluency in English to complete questionnaires. Patients were excluded if they had a diagnosis of certain sleep disorders (i.e., restless legs syndrome and periodic limb movement disorder), recent myocardial infarction or other serious cardiovascular condition in the past 12 months, current infection, history of Raynaud’s disease or severe neuropathy, systematic inflammatory or autoimmune disorder, recent history of substance misuse or dependence, use of oral steroids in past 30 days, and cognitive impairment (i.e., dementia) that prevented completion of the study procedures. The Institutional Review Boards at JHU and BWH approved the study protocol and all patients provided written and verbal informed consent before participating in the study. The study was registered as NCT01370421, and the parent prospective cohort study investigated predictors of pain and functional outcomes 6 months after TKA [23].

Approximately 2 weeks before surgery (preoperatively), patients attended an in-person initial study visit. Before the initial visit, patients were asked to abstain from taking NSAIDs and pain medications for 24 hours. Once patients arrived for their visit, they completed validated questionnaires to assess demographic and clinical characteristics, clinical pain, and psychosocial factors. Blood samples were also collected at periodic intervals (Figure 1A), both before and after patients underwent quantitative sensory testing (QST). All QST sessions were conducted between 11-11:30am to reduce variation due to the diurnal fluctuation of IL-6 levels. First, an intravenous (IV) catheter was placed, and patients rested in a recliner for 15 minutes. Then, 2 baseline blood samples were collected, approximately 15 minutes prior to QST and immediately prior to the start of QST. Next, patients underwent QST procedures, which took approximately 75 minutes. Last, 5 additional blood samples were collected at 30-minute intervals starting immediately after QST and ending at 120 minutes post-QST. All blood samples were collected using 10 mL EDTA vacutainers. Each sample was centrifuged immediately, if possible, or was placed on ice and centrifuged within 30 minutes. Plasma was removed and aliquoted for storage at −80°C. A standard high-sensitivity enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN, USA; lower limit of detection: 0.16 pg/mL; sensitivity: 0.04 pg/mL; intra-assay coefficient of variation: <5%) was conducted on all samples to assess levels of IL-6. Patients then attended a second in-person visit 3 months after TKA surgery (postoperatively). The follow-up visit adhered to the same procedures as the initial visit, including the completion of questionnaires, collection of blood samples, and QST procedures.

Figure 1.

Figure 1.

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A) Timeline of blood draws and QST procedures, and B) Average levels of IL-6 across all 7 blood draws pre-surgery (purple) and 3-months post-TKA surgery (green). Abbreviations: m=minutes; IV=Intravenous; QST=quantitative sensory testing.

The parent prospective cohort study, which included 248 patients, investigated predictors of pain and functional outcomes 6 months after TKA [23]. Of this cohort, a subset of patients (n=162; 65%) had at least one IL-6 measurement at the initial preoperative study visit, and 70 (43%) patients had all 7 IL-6 measurements at the initial visit. Of these 70 patients with complete preoperative IL-6 data, 40 (57%) also had complete IL-6 data at the 3-month postoperative follow-up visit. Several factors contributed to missing IL-6 data since this was not a primary outcome of the parent cohort study. Most of the study visits were scheduled around patients’ clinic appointments, and as such, not all patients were able to be scheduled or to complete the full in-person study visits. Some patients also completed their follow-up for primary outcomes remotely, precluding the opportunity to collect blood samples. While we have previously reported on the relationship between IL-6 reactivity and sex at the initial study visit (pre-surgery) in a subset of these patients [12], the current study focused on change in IL-6 reactivity from the preoperative to 3-month postoperative visits, assessing how this change related to change in clinical pain severity.

2.2. Quantitative Sensory Testing (QST)

As previously described in greater detail [12,23], several modalities of QST were performed during the initial preoperative study visit and again at the 3-month postoperative follow-up visit. A digital pressure algometer was used to assess pressure pain threshold (PPTh) at the trapezius, thumb, patella, medial and lateral joint line of the knee, and middle insertion point of the quadriceps. A Hokanson rapid cuff inflator was applied to the calf and initially inflated to a pressure of 60 mmHg, and then steadily increased until each patient reported a pain intensity rating of 4/10. Nylon monofilament probes were used to assess mechanical temporal summation of pain by applying the probes to the dorsal aspect of the nondominant middle finger and the patella. Contact heat stimuli were delivered using a computer controlled CHEPS system (Medoc) to assess heat threshold and tolerance, pain ratings with suprathreshold thermal pain stimuli, and severity of any painful aftersensations after heat stimuli. Cold pain was induced by having patients submerge their dominant hand up to the wrist in a circulating cold-water bath (4°C) for up to 3 minutes. While their hand was submerged, PPTh was re-assessed on the nondominant trapezius muscle, and conditioned pain modulation was assessed. Patients also rated the maximum intensity of cold pain during and at the conclusion of the cold pressure task, and painful aftersensations were assessed after the completion of the task.

2.3. Questionnaires

Both before (preoperatively) and 3-months after TKA surgery (postoperatively), patients completed measures to assess clinical pain severity and insomnia. The validated Brief Pain Inventory (BPI) was used to assess clinical pain severity (BPI mean) by averaging patients’ self-reported current, worst, least, and average pain over the past week (0=no pain, 10=pain as bad as it could be) [24,25]. Higher scores indicated greater pain severity. The Insomnia Severity Index (ISI), a widely used and validated self-report assessment, asked patients about their experience with insomnia (e.g., sleep onset and maintenance difficulties, severity of symptoms) [26]. Higher scores indicated greater insomnia symptoms.

At the preoperative study visit, patients self-reported their age, sex, race, ethnicity, body mass index (BMI), and whether they had any other chronic pain conditions (no/yes). Patients also completed psychosocial assessments, including the Patient Reported Outcome Measurement Information System (PROMIS) short forms to measure depression and anxiety and the Pain Catastrophizing Scale (PCS) to measure general pain-related catastrophic thinking. Both the PROMIS and PCS have been validated and used in pain studies [27–29].

2.4. Data Analysis Plan

We assessed improvement in clinical pain by examining the change in BPI pain severity over time. We subtracted the BPI pain severity score from the preoperative visit from the BPI pain severity score at the 3-month postoperative visit. Positive scores indicated that pain increased (i.e., worsened) from pre- to 3-months post-surgery, whereas negative scores indicated that pain decreased (i.e., improved) over time. Using this change in BPI pain severity score, patients were then dichotomized into two groups based on their pain status: 1) pain decreased >2 points over time (i.e., improved pain) and 2) pain did not decrease >2 points over time (i.e., pain remained the same or worsened) [30].

Next, using the preoperative IL-6 measurements, we calculated the average of the 2 baseline IL-6 measurements taken prior to QST procedures. The absolute degree of increase in IL-6 expression following the QST procedures was of interest, which sometimes occurred at different timepoints among individuals, and thus, we subsequently determined the peak (maximum) value among the 5 preoperative IL-6 measurements obtained after QST procedures. A preoperative IL-6 reactivity score was then created by subtracting the average baseline IL-6 measurement pre-QST from the peak IL-6 measurement post-QST. A 3-month postoperative IL-6 reactivity score was also calculated using the same approach. Finally, a change in IL-6 reactivity score was created by subtracting the preoperative IL-6 reactivity score from the 3-month postoperative IL-6 reactivity score. Positive scores indicated an increase in IL-6 reactivity from pre- to 3-months post-surgery.

Kruskal Wallis, Mann-Whitney U tests, chi-square tests, and Spearman correlations were used to explore whether preoperative demographic, clinical, and psychosocial characteristics were associated with changes in clinical pain or IL-6 reactivity. To examine differences in IL-6 reactivity based on pain status (i.e., pain improved >2 points vs. pain did not improve >2 points), a two-way mixed design analysis of covariance (mixed-design ANCOVA) was conducted with time (preoperative visit, 3-month postoperative visit) as the within-subject factor, pain status as the between-subjects factor, and pain status x time as the interaction term. Sex was significantly related to IL-6 reactivity, and thus, was included as a covariate in the model. Effect sizes were calculated using partial eta squared (ηp2) and were considered small (ηp2=0.01), medium (ηp2=0.06), or large (ηp2=0.14) [31].

We also created a change score for ISI insomnia symptoms by subtracting preoperative insomnia symptoms from 3-month postoperative insomnia symptoms. Positive scores indicated that insomnia increased (i.e., worsened) from pre- to 3-months post-surgery, whereas negative scores indicated that insomnia decreased (i.e., improved) over time. Next, to explore the potential interactive effects of change in insomnia symptoms and pain status on change in IL-6 reactivity, a bootstrapped moderation analysis was conducted using 5,000 bootstrapped resamples with the PROCESS macros for SPSS (v29.0) [32]. Sex was included as a covariate in the moderation model.

3. Results

We directly compared preoperative and 3-month postoperative data, including patients with complete IL-6 data at both study visits, to allow estimation of change in IL-6 reactivity after surgery, with each patient serving as their own control. Of the 40 patients with complete IL-6 data at both pre- and post-surgical visits, 1 patient reported a BPI pain severity score of 0 at both visits, and as such, was also excluded from this analysis regarding change in clinical pain. Therefore, the present analysis is based on a subset of patients (n=39) with complete IL-6 data at both timepoints and BPI pain scores >0. Patients included in the final analysis (n=39) did not significantly differ from those excluded from the original cohort (n=209) based on preoperative demographic or clinical characteristics (age, sex, race, BMI, other chronic pain conditions), clinical pain severity (BPI), or psychosocial characteristics (ISI insomnia, PROMIS depression or anxiety, PCS pain catastrophizing) (ps>.05).

3.1. Patient Characteristics

Patients were an average age of 65.5 years (SD=8.2), 62% female, and had an average BMI of 32.7 (SD=6.5) (Table 1). Patients were 89.7% White, 7.7% African American/Black, and 2.6% American Indian/Alaskan Native. All patients identified as non-Hispanic/Latino. The majority of patients did not have any other chronic pain condition (72%). For medications, 51% reported taking NSAIDS, 30% reported taking acetaminophen, 24% reported taking antidepressants, 24% reported taking opioids, and 8% reported taking sleep medications (e.g., Ambien, melatonin). A total of twelve different surgeons performed the TKA surgeries.

Table 1.

Patient Characteristics among the Total Sample and based on Pain Status

Total Sample
(n=39)		 Pain improved
(n=19)		 Pain did not improve
(n=20)
M±SD, % M±SD (min, max) or % M±SD (min, max) or %
Preoperative Characteristics
 Other chronic pain conditions 28% 37% 20%
 Female sex 62% 74% 50%
 Race
  White 89.7% 90% 90%
  African American/Black 7.7% 5% 10%
  American Indian/Alaskan Native 2.6% 5% -
 Age 65.5±8.2 66.8±7.0 (57.0, 78.0) 64.4±9.3 (50.0, 81.0)
 BMI 32.7±6.5 32.0±5.9 (23.2, 44) 33.4±7.1 (21.8, 52.0)
 PROMIS Depression 12.2±5.8 14.1±7.0 (8.0, 29.0) 10.4±3.6 (7.0, 23.0)
 PROMIS Anxiety 13.3±4.8 14.0±5.6 (7.0, 25.0) 12.6±3.8 (8.0, 22.0)
 Pain Catastrophizing 15.3±13.6 19.3±15.1 (0.0, 52.0) 11.5±11.0 (0.0, 37.0)
BPI Pain Severity
 Preoperative* 4.8±1.6 5.8±1.1 (5.0, 9.0) 3.8±1.4 (1.0, 7.0)
 3-months postoperative * 1.8±1.4 1.0±0.9 (0.0, 3.0) 2.6±1.3 (1.0, 6.0)
 Change in pain* −3.0±2.2 −4.8±1.5 (−9.0, −33.0) −1.2±1.0 (−2.0, 2.0)
IL-6 Levels
 Preoperative
  Pre-QST 3.4±1.9 3.7±2.3 (1.3, 10.2) 3.1±1.4 (0.9, 6.3)
  Post-QST 6.5±4.5 7.7±5.9 (1.9, 20.6) 5.4±2.2 (1.7, 9.2)
  IL-6 Reactivity 3.2±3.7 4.0±4.9 (0.1, 14.4) 2.4±1.6 (0.5, 6.3)
 3-months postoperative
  Pre-QST 3.6±2.3 3.9±3.0 (0.5, 14.0) 3.4±1.6 (1.1, 6.9)
  Post-QST 6.3±4.1 6.0±3.5 (1.9, 16.0) 6.6±4.6 (1.0, 21.4)
  IL-6 Reactivity 2.7±3.1 2.1±2.1 (−0.8, 6.9) 3.3±3.8 (−0.4, 15.8)
 Change in IL-6 reactivity −0.5±4.2 −1.9±4.3 (−11.9, 3.3) 0.9±3.7 (−4.2, 11.2)
ISI Insomnia Symptoms
 Preoperative 10.4±7.6 10.8±7.6 (0.0, 27.0) 10.0±7.8 (1.0, 25.0)
 3-months postoperative 9.8±6.3 9.2±6.5 (0.0, 25.0) 10.4±6.3 (0.0, 23.0)
 Change in insomnia −0.6±7.4 −1.6±7.5 (−19.6, 11.6) 0.3±7.4 (−15.0, 18.8)
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Note. PROMIS=Patient Reported Outcome Measurement Information System; IL-6=Interleukin-6; QST=Quantitative Sensory Testing; BPI=Brief Symptom Inventory; ISI=Insomnia Severity Index.

*

=significant difference between those whose pain improved vs. those whose pain did not improve (p<.05).

At the group level, patients’ clinical pain severity (BPI mean) significantly decreased from pre- to 3-months post-surgery (mean±SD: 4.8±1.6 vs. 1.8±1.4; p<.001), corresponding to an average change in pain severity score of −3.0 (SD=2.2, range: −9.0 to 2.0). Using this calculated pain severity change score for each patient, we dichotomized patients into two groups based on what had occurred to their pain from pre- to 3-months post-surgery: 1) pain decreased >2 points (i.e., BPI change scores < −2.0; pain improved) and 2) pain did not decrease >2 points (i.e., BPI change score ≥ −2.0; pain did not improve). Based on this definition, 49% (n=19) of the sample was categorized into the improved pain group (Figure 2). Patients’ pain status was not significantly related to their preoperative demographic, clinical, or psychosocial characteristics (ps>.05; Table 1).

Figure 2.

Figure 2.

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Individual differences in change in pain severity based on pain status.

On average, patients’ IL-6 levels tended to increase after pain testing with QST. This occurred both at the preoperative visit (pre-QST:3.4±1.9 vs. post-QST:6.5±4.5) and the 3-month postoperative visit (pre-QST:3.6±2.3 vs. post-QST:6.3±4.1) (Figure 1B). Accordingly, the degree of increase (IL-6 reactivity score) was similar between the preoperative (3.2±3.7) and 3-month postoperative (2.7±3.1) visits (Table 1). Patients’ preoperative demographic, clinical, and psychosocial characteristics were not significantly related to IL-6 reactivity at the preoperative visit or 3-month postoperative visit, with one exception. At 3-months post-surgery, females had a significantly larger increase in IL-6 reactivity than males (3.1±2.4 vs. 2.1±4.0; p<.05). Change in IL-6 reactivity (−0.5±4.2) over time was not significantly related to any of the preoperative characteristics of patients (ps>.05).

3.2. Change in IL-6 Reactivity over time based on Pain Status

A mixed-design ANCOVA, with time as a within-subjects variable and pain status as a between-subjects variable, was used to assess the relationship between change in IL-6 reactivity and pain improvement status, while controlling for sex. Results showed a significant interaction of pain status x time (F(1,36)=4.3, p=.04, ηp2=0.11). As shown in Figure 3, among patients with improved pain (>2 point decrease), IL-6 reactivity significantly decreased from pre- to 3-months post-surgery (mean±SE: 3.8±0.8 vs. 2.0±0.7), whereas there was no significant change in IL-6 reactivity over time among those whose pain did not improve (2.5±0.8 vs. 3.4±0.7). There were no significant main effects of pain status (F(1,36)=0.01, p>.05) or time (F(1,36)=0.08, p>.05) on change in IL-6 reactivity.

Figure 3.

Figure 3.

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IL-6 Reactivity across time and based on pain status. A) Individual patients’ IL-reactivity based on pain status and B) Group-level average IL-6 reactivity based on pain status.

3.3. Change in Insomnia as a Moderator of the Relationship between Changes in Clinical Pain Severity and IL-6 Reactivity

On average, ISI insomnia symptoms did not significantly change from pre- to 3-months post-surgery (10.4±7.6 vs. 9.8±6.3; p>.05), with a corresponding average change in insomnia score across patients of −0.6 (SD=7.4, range: −19.6 to 18.8). Interestingly, patients’ change in insomnia symptoms over time was not significantly associated with pain status (improved vs. did not improve; Table 1) or change in IL-6 reactivity (ps>.05). However, there was a significant interaction between pain status and change in insomnia, while controlling for sex (b=0.36, 95% CI [0.01, 0.71], p=.04). As shown in Figure 4, insomnia served as a moderator in the relationship between pain status and change in IL-6 reactivity: among patients whose insomnia decreased over time, improved pain status was significantly associated with a reduction in IL-6 reactivity from pre- to 3-months post-surgery (p<.05). However, among patients whose insomnia increased over time, pain status and change in IL-6 reactivity were not significantly associated with each other (p>.05). This suggests that the relationship between changes in clinical pain severity and IL-6 reactivity varied as a function of patients’ change in insomnia. In other words, the association between improved pain status and decreased IL-6 reactivity from pre- to 3-months post-surgery was stronger for patients who experienced a decrease in insomnia symptoms.

Figure 4.

Figure 4.

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The relationship between changes in clinical pain severity and IL-6 reactivity moderated by change in insomnia.

4. Discussion

In this longitudinal study of patients with KOA undergoing TKA, we investigated whether change in clinical pain severity was related to change in IL-6 reactivity in response to painful stimulation (QST) from the preoperative to the 3-month postoperative visits. Our findings revealed that among patients whose clinical pain improved over time (>2 point decrease from the 0–10 scale), there was an associated significant reduction in IL-6 reactivity. We also explored whether the association between improved clinical pain and reduced IL-6 reactivity varied as a function of change in patients’ insomnia symptoms during the same period. Notably, among patients whose insomnia decreased over time, improved pain status was significantly associated with a reduction in IL-6 reactivity. In contrast, among patients whose insomnia increased over time, improved pain status was not significantly associated with change in IL-6 reactivity. Collectively, our findings suggest that within patients with KOA, the resolution of clinical pain severity at 3-months post-TKA is associated with discernible alterations in pro-inflammatory responses that can be measured in response to QST procedures, and that this association may be moderated by perioperative changes in insomnia symptoms.

Similar to prior studies [8–11,21,22,33], we observed an increase in levels of IL-6 after lab-based painful stimulation using QST (IL-6 reactivity). However, the meaning of this IL-6 reactivity is somewhat unclear, as there is evidence from one prior study of observed similar increases in IL-6 levels in response to both overtly painful and only minimally painful stimuli [10]. It is possible that the observed IL-6 elevations in our cohort may be attributable to a general stress response (e.g., stress/fear due to intravenous catheter placement, QST procedures, participating in a research study, etc.), rather than being specifically linked to the acute pain experienced during the QST session per se, similar to other previous work showing an increase in IL-6 levels following exposure to acute stressors [6–8]. As in those previous studies, we also observed considerable interindividual variability in IL-6 reactivity. This variable degree of IL-6 reactivity among individuals (regardless of the actual proximal cause of IL-6 reactivity in these paradigms), and how it may relate to variations in clinical outcomes, is a question of greater interest as it relates to personalized medicine. The current findings linking change in IL-6 reactivity to change in clinical pain adds support to the idea that biophysical assessment may serve as a valuable tool for exploring and gaining deeper insights into the mechanisms underlying heterogeneity in the experience of pain. In the current case, it appears that the extent to which one’s system is primed to acutely upregulate expression of IL-6 may serve as an important mechanistic contributor to pain processing, and potentially relate to the clinical success of TKA for improving KOA pain.

Although methods for estimating the prevalence of persistent postsurgical pain vary widely, the range and magnitude of pain scores observed in our study closely align with those reported in prior research [5,34,35]. In line with the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) guidelines [30,36,37], we employed a validated pain measurement tool (BPI), and considered a clinically meaningful improvement in pain as a BPI mean score change of >2 points on the traditional 11-point pain scale [30]. Using this as the criterion for pain improvement, we observed that 49% of patients experienced improvement in clinical pain severity from pre- to 3-months post-surgery. Among this subgroup of patients, we found that IL-6 reactivity also significantly decreased. Notably, we did not observe a significant change in IL-6 reactivity among patients whose pain remained unchanged or worsened over time. These findings are consistent with prior literature highlighting general associations between clinical pain severity and levels of IL-6 among patients with KOA [38,39]. Previous studies have demonstrated that IL-6 is an important mediator that can act both directly and indirectly on peripheral and central nociceptors, thereby affecting both the development and maintenance of persistent pain [40]. Our findings, although preliminary, provide further evidence for the link between clinical pain severity and IL-6 reactivity, and suggest that IL-6 reactivity may be a mechanistic contributor to the resolution of pain after TKA. An important consideration is that there is likely a bidirectional relationship between clinical pain and IL-6 expression, and that no conclusions regarding causal relationships can be drawn from the current findings. Thus, whether the improvement in clinical pain was due to a reduction in pro-inflammatory responses, or vice versa, or even a third factor impacting both, cannot be discerned due to the observational nature of the study.

Insomnia has been linked to both clinical KOA pain severity [17] and increased IL-6 reactivity [21], raising a question of whether it could serve as an important link between the two. In the current study, we did not observe an overall group-level change in insomnia from pre- to 3-months post-surgery. This lack of change in insomnia at the group level may be related to the high degree of heterogeneity in pain and insomnia profiles in this population. Previous studies have categorized around this heterogeneity, defining clinical subgroups based on their insomnia trajectory from pre- to 6-weeks post-surgery, and shown that these distinct subgroups significantly differed in knee-related outcomes one year after TKA [18]. Further investigations in larger samples are needed to develop and build evidence regarding the clinical utility of this type of grouping. At least one previous study found that improved sleep quality was associated with a decrease in IL-6 levels from pre- to post-surgery [41], which we did not observe in the current cohort.

Interestingly, while we did not find a direct association between change in insomnia symptoms with either changes in IL-6 reactivity or clinical pain severity, we did find a significant moderating effect of change in insomnia symptoms on the relationship between changes in clinical pain and IL-6 reactivity. Specifically, we found that the association between improved pain and reduced IL-6 reactivity after TKA was stronger among patients whose insomnia symptoms also decreased over time. These findings highlight the important modulatory role of insomnia in the relationship between pain severity and IL-6 among patients undergoing TKA, suggesting that improving sleep quality may be particularly beneficial in decoupling the link between pain and inflammation. Although we cannot deduce causality from our observational data, prior studies have shown that experimental sleep disruption leads to increases in IL-6 and inflammatory markers, as well as increased pain severity and sensitivity [42–44]. IL-6 has also been linked to both sensitization of peripheral nociceptors and central/spinal sensitization when expressed by glia [45–48]. It is possible that insomnia may shift the balance towards a more pro-inflammatory state, leading to a stronger or more prolonged pro-inflammatory response, including sustained expression of IL-6 peripherally and centrally. Consequently, this could contribute to sustained pain sensitization and unresolved pain. Future research is needed to delineate the exact mechanistic sequence of events, which we propose here as a speculative hypothesis.

Our findings have some potential clinical implications. While performing QST and collecting multiple blood samples during all preoperative visits is impractical, measuring IL-6 during the surgical encounter, where blood draws are common, may be feasible. However, assessing IL-6 levels at the time of surgery, rather than before, may not be ideal for planning interventions. This underscores the importance of the modulating effect of insomnia, both from a mechanistic and practical perspective. Compared to QST and blood sampling, assessing insomnia symptoms can be easily achieved through validated questionnaires or actigraphy on patient-owned smart devices, enabling more accessible and less burdensome evaluation during the preoperative period, as well as remote monitoring. Therefore, it could be advantageous to assess insomnia symptoms preoperatively to equip patients with the necessary tools and interventions to address their insomnia in the peri- and postoperative periods.

While the effects of adjunct interventions aimed at improving sleep have not been extensively explored in the context of TKA, other research focusing on behavioral interventions, such as cognitive behavioral therapy for insomnia (CBT-I), in patients with KOA have shown promise [49,50]. For instance, one study demonstrated that CBT-I, compared to a waitlist-control, significantly improved insomnia symptoms among patients with KOA, and patients with improved insomnia also reported less knee pain and had less IL-6 reactivity in response to painful stimulation [22]. Similarly, other studies have demonstrated reduced levels of systemic inflammation following CBT-I among individuals with insomnia [21,51]. However, one study showed that CBT-I, compared to behavioral desensitization (placebo), was not effective in reducing resting levels of IL-6 at a 6-month follow-up, although CBT-I demonstrated greater improvement in sleep maintenance disturbance at mid-treatment, which, in turn, was associated with lower levels of IL-6 at a 3-month follow-up [51]. The non-efficacy in the overall group observed in some studies may suggest that the benefits of these behavioral therapies may not be equally shared among individuals. Therefore, additional randomized controlled trials which carefully characterize the phenotypic features of patients are needed to better understand how and for whom CBT-I may be beneficial in modulating inflammation, pain, and insomnia.

4.1. Limitations and Future Directions

Several important limitations should be considered when interpreting our findings. First, we had a small sample size of patients who completed blood draws and QST at both the pre-surgical and 3-month follow-up study visits, which might make Type II error more likely, given the associated lack of statistical power to detect effects. For example, we did not observe any significant differences between patients with improved pain versus patients whose pain did not improve based on preoperative demographic, clinical, or psychosocial characteristics. Identifying the unique characteristics of patients who did not experience improvement in pain may provide valuable prognostic and mechanistic insights, and thus, future studies with larger samples should further investigate this. Similarly, there are undoubtedly additional important confounder variables that should be considered when investigating the complex relationship between pain and IL-6 reactivity (e.g., age, medication use) [52–54], although the small sample size in the current study likely precluded our ability to statistically identify these variables. Second, while we explored peak levels of IL-6 after QST, extending the duration of blood sample collection may allow researchers to delineate the time course of resolution of IL-6 expression. Third, although the prospective, longitudinal nature of this study allowed us to demonstrate that improved clinical pain was associated with decreased IL-6 reactivity, as noted above, we cannot infer causality. Future longitudinal studies should recruit a larger sample of patients, employ randomization to interventions to improve sleep, collect data at more than two timepoints, and utilize a cross-lagged analysis in order to determine whether a causal relationship exists.

5. Conclusion

This longitudinal study of patients with KOA undergoing TKA found that clinical pain improved over time (>2 point decrease on the BPI pain severity) in 49% of patients from pre- to 3-months post-surgery. Among patients with improved pain, IL-6 reactivity in response to lab-based painful stimulation (QST) significantly decreased from pre- to 3-months post-surgery, whereas there was no significant change in IL-6 reactivity among those whose pain did not improve. Further, we found that change in insomnia symptoms over time moderated the relationship between changes in pain and IL-6 reactivity. Among patients whose insomnia decreased over time, improved pain was significantly associated with a reduction in IL-6 reactivity over time, whereas for patients whose insomnia increased over time, changes in pain and IL-6 reactivity were not significantly related. Our findings suggest that the resolution of clinical pain 3-months after TKA may be associated with discernible changes in pro-inflammatory responses that can be assessed under controlled laboratory conditions, and this association may be modulated by change in insomnia symptoms.

Highlights:

  1. Improved pain after total knee arthroplasty may be related to alterations in IL-6

  2. 49% of patients had improved clinical pain 3-months after TKA surgery

  3. In patients with improved pain, IL-6 reactivity decreased from pre- to post-surgery

  4. Change in insomnia moderated the association between pain and IL-6 reactivity

  5. In patients with decreased insomnia, improved pain was related to a reduction in IL-6

Funding:

This work was supported by the US National Institutes for Health (NIH) National Institute for Arthritis and Musculoskeletal and Skin Diseases (NIAMS; R01-AG034982 to RRE and JAH, PIs; K23-077088 to SM; K24 AR081143 to CMC), National Institute of General Medical Sciences (R35-GM128691 to KLS), and National Institute of Neurological Disorders and Stroke (R01NS129887 to CJM).

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Declarations of Interest: None.

Data Statement:

The corresponding dataset for the current study is available from the corresponding author on reasonable request. This study was registered as NCT01370421.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The corresponding dataset for the current study is available from the corresponding author on reasonable request. This study was registered as NCT01370421.

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