Prevalence of and factors associated with inadequate pain relief in people with knee and hip osteoarthritis: a cross-sectional population-based study

Background: Pain due to knee or hip osteoarthritis (HKOA) is the most common symptom for seeking health care given its interference on daily activities, social and occupational participation. The goal of this study is to estimate the prevalence of inadequate pain relief (IPR) among people with hip and/or knee osteoarthritis (HKOA), characterize this population and identify factors associated with IPR, and compare therapeutic strategies used by people with IPR versus adequate pain relief (APR). Methods: We analyzed a representative sample of 1081 participants with a validated diagnosis of HKOA, from the population-based study EpiReumaPt. Sociodemographic, lifestyle and health-related data were collected in a structured interview. Pain intensity (NPRS) data were collected in a medical appointment. IPR was dened as a mean pain intensity in the previous week of ≥ 5 points on 11-point numeric pain rating scale. Intake of regular medication for pain relief (last month), physiotherapy and surgery were considered as therapies for pain management. The factors associated with IPR were analyzed with logistic regression (p<0.05, 95%CI). To assess the effects of inadequate pain relief in the HOOS/KOOS activities of daily living and quality of life subscales and in the presence of anxiety and depression symptoms, linear and logistic regression were used. All analysis were weighted. Results: The estimated prevalence of IPR among people with HKOA was 68.8%. IPR was associated with being female (odds ratio (OR)=2.36, p<0.01), being overweight (OR=1.84, p=0.035) or obese (OR=2.26, p=0.006), and having multimorbidity (OR=2.08, p=0.002). People with IPR reported worse performance in activities of daily living and lower quality of life (b=-21.28, p<0.001 and b=–21.19, p<0.001, respectively) than people with APR. People with IPR consumed more NSAIDs (22.0%, p=0.003), opioids (4.8%, p=0.008), paracetamol (2.7%, p=0.033), and overall analgesics (7.3%, p=0.013) than people with APR. A higher proportion of people with IPR underwent physiotherapy (17.5%, p=0.002) than people with APR. Conclusion: These results indicate that most people with HKOA have poor control of pain, highlighting the need for further research and implementation of effective interventions. modiable risk factors associated with IPR. Overall, recommended management strategies appear to be offered to a small proportion of people with HKOA. These results reveal an opportunity for pain control improvement in the HKOA population and highlight the need for further research on effective pain relief interventions.


Introduction
Osteoarthritis (OA) is the most common joint disease, affecting more than 300 million people worldwide.
The hip and knee are the most affected joints and are responsible for 9.6 million years lived with disability (1). The direct annual costs of hip and/or knee OA (HKOA) per patient are estimated at 6.7K€ worldwide, reaching 10.8K€ if total joint replacement surgery is considered (2), and indirect annual costs per patient are estimated at 0.2K-12.3K€. In Portugal, indirect costs represent 0.4% of the national gross domestic product (3). Moreover, the incidence of total joint replacement surgery in Portugal has increased by 20% annually since 1990 and is the highest growth rate among Organisation for Economic Cooperation and Development countries (4).
People with HKOA often live with chronic pain, physical disability, and mental health and sleep problems, which impairs their quality of life (QoL) and prevents their participation in social and occupational activities (5). Pain is the most disabling symptom of OA and a major driver of clinical decision-making and healthcare resource use (5). Pain severity is more indicative of functional impairment than radiographic severity (6-8) and is strongly associated with disability, medication use (9,10), healthcare resource use, impact on daily and occupational activities, loss of productivity, early retirement, and absenteeism (11,12). Moreover, poor pain management is a major predictor of total joint replacement surgery (13). Recent literature raises concerns over the poor control of pain and low QoL among people with HKOA (10,14), as current management strategies are focused on symptomatic control, involving medication as rst-line intervention and an over-prescription of opioids (14,15). Additionally, the use of end-stage interventions such as surgery is becoming more common, even among people with early-stage OA (14,15).
Information on pain control, offered interventions, and factors associated with inadequate pain relief (IPR) among Portuguese people with HKOA is scarce but is crucial for evaluating current patient management strategies. Therefore, the aims of this study were to: 1) estimate the prevalence of IPR among Portuguese people with HKOA, 2) characterize the HKOA population in terms of sociodemographic, lifestyle, and health-related variables and identify factors associated with IPR; and 3) compare performance in activities of daily living (ADL), QoL, anxiety and depression symptoms, and therapies used between people with IPR versus people with adequate pain relief (APR). This knowledge will help determine whether current care effectively controls symptoms among people with HKOA in Portugal and whether improvements in offered interventions are needed.

Data source
We analyzed data from EpiReumaPt, a national cross-sectional, population-based study with a representative sample of the Portuguese population that aimed to analyze the burden of rheumatic and musculoskeletal diseases (RMDs) in Portugal. As described in detail elsewhere (16), participant recruitment was conducted between September 2011 and December 2013 using a random selection of private households in Portugal strati ed by administrative territorial units (NUTS II: Norte, Centro, Lisboa and Vale do Tejo, Alentejo, Algarve, Azores, and Madeira) and the size of the population within each locality. In each household, an individual ≥18 years old with permanent residence and the most recently celebrated birthday was selected to participate in the study. In total, 28,502 households were contacted, 8,041 individuals refused to participate, and 10,661 were included in the study. The EpiReumaPt population was similar to the Portuguese population (Census 2011) in age strata, sex, and NUTII distribution (16).
EpireumaPt data collection was performed using a three-staged approach. In the rst stage, participants completed a face-to-face interview to collect sociodemographic and health-related information and to screen for RMDs. Interviews were conducted by a team of non-medical healthcare professionals trained for this purpose, and data were collected using a computer-assisted personal interview system. Screening was considered positive if a participant mentioned a previously known RMD, if any algorithm in the screening questionnaires was positive, or if the participant reported muscle, vertebral, or peripheral joint pain in the previous 4 weeks. When the overall performance of the RDM screening algorithm was evaluated using nal diagnosis after the third stage as the gold standard, its sensitivity and speci city were 98% and 22% and positive and negative predictive value were 85% and 71%, respectively.
In the second stage, participants who screened positive for at least one RMD (n=7,451) and approximately 20% of participants who screened negative for RMDs (n=701) were invited to a clinical appointment at the primary care center of the participant's neighborhood. Participants were seen by a multidisciplinary team consisting of a rheumatologist, X-ray technician, and nurse. Clinical assessment consisted of a structured evaluation, laboratory tests, and imaging exams, if needed, to establish a diagnosis and evaluate disease-related information. According to participants' complaints, simple X-rays were performed in 122 hips and 479 knees, among other joints. Rheumatologists were blind to prior health-related data. Of the participants in the second stage, 4,275 did not attend the clinical appointment. Therefore, at the end of the second stage, there were 3,877 clinical observations: 3,198 participants received an RMD diagnosis, and 679 did not receive an RMD diagnosis.
In the third stage, three experienced rheumatologists reviewed all data and validated the RMD diagnosis.
Diagnostic agreement among the three rheumatologists was 98.3%, with a Cohen's K coe cient of 10.87 (95% con dence interval (CI): 0.83, 0.91) (16). When data were insu cient to ful ll international classi cation criteria for an RMD, ve rheumatologists met to reach agreement on the nal diagnosis.

Case de nition and measurement
Mean pain intensity in the previous week, measured on a 11-point numeric pain rating scale in the second stage of EpiReumaPt, was used to categorize participants with HKOA into APR (<5 points) and IPR (≥5 points), which was validated by Zelman et al. (2003) using the question 5 of Brief Pain Inventory scale, as the average pain in the previous week on an 11-point NPRS. The optimal cut-off point found for manageable day pain in OA was 5 (F (7,9)=7.08, p<0.001) (19). When both the hip and knee were affected, the worst score was considered. Sociodemographic, clinical, and lifestyle variables Sociodemographic, clinical, and lifestyle variables were collected during the rst and second phases of EpiReumaPt. To assure better clinical interpretation, some variables were subjected to categorical transformation.

Sociodemographic and anthropometric variables
Sociodemographic variables were age, sex, and geographic location according to NUTS II territorial units.
Madeira and Azores were merged in the analysis as the Islands region. Marital status was categorized as "partner" (married or consensual union) or "no partner" (single, widowed, or divorced). Education level was categorized according to years of education completed: <4 years (less than primary education), 4-9 years (primary or secondary education), or ≥10 years (secondary or higher education).

Lifestyle and clinical variables
Lifestyle variables were alcohol intake ("no" or "occasionally or daily"), smoking habits ("never" and "occasionally or daily"), and regular exercise/sports ("yes" or "no").
The number of chronic non-communicable diseases was calculated as the numeric count of the following self-reported conditions: high blood pressure, high cholesterol, cardiac disease, diabetes mellitus, chronic lung disease, problems in the digestive tract, renal colic, neurological disease, allergies, mental or psychiatric illness, cancer, thyroid or parathyroid problems, hypogonadism, and hyperuricemia.
Multimorbidity was de ned as having two or more chronic non-communicable diseases (20).
In addition to pain intensity, other clinical variables were considered: performance in ADL, QoL, and the presence of depression and/or anxiety symptoms. Performance in ADL and QoL related to HKOA were evaluated with the Portuguese version of the Knee Injury and Osteoarthritis Outcome Scale (KOOS) (21) and Hip Disability and Osteoarthritis Outcome Scale (HOOS) (22). These self-reported outcome measures evaluate short-and long-term consequences of HKOA in ve dimensions: pain, symptoms, ADL, sports and leisure, and QoL. For this study, we used only the HOOS/KOOS ADL and HOOS/KOOS QoL subscales. Scores for each dimension were transformed on a 0-100 scale, with 0 representing extreme hip/knee problems and 100 representing no hip/knee problems (21,22). For both subscales, if more than one joint was affected, the worst score was considered.
Anxiety and depression symptoms were evaluated using the Hospital Anxiety and Depression Scale subscales for depression (HADS-D) and anxiety (HADS-A). Both scales have a range of 0 to 21, with higher values representing more severe symptoms of anxiety or depression. Final HADS-A and HADS-D scores were categorized using validated cut-offs as: "with anxiety" (HADS-A ≥11) or "without anxiety" (HADS-A <11) and "with depression" (HADS-D ≥11) or "without depression" (HADS-D <11) (23).

Use of therapies
Information on pharmacological therapies, de ned as daily medications taken in the previous month, was collected in the rst-stage interviews. Medication for pain relief was classi ed according to the Anatomical Therapeutic Chemical Classi cation System as: glucosamine (M01AX05); analgesics/antipyretics (N02B), speci cally paracetamol (N02BE01); simple (N02A) and combined (N02AJ) opioids; non-steroidal anti-in ammatory drugs (NSAIDs; M01A); and topical agents (M02A). Information on physiotherapy attendance in the previous 12 months, was also collected in the rst-stage interviews. Information on previous hip or knee surgery was collected during the second-stage clinical appointments, which occurred no more than 15 days after the rst stage.
After participants were categorized into IPR and APR subgroups, weighted proportions of participants with IPR were computed taking sampling design into account as described elsewhere (16). The logit transformation method was used to calculate 95% CIs. Analysis of the proportion of participants with IPR and APR (relative and absolute frequencies) was conducted separately for participants with hip OA and those with knee OA.
Descriptive statistics were used to characterize all participants and, separately, the APR and IPR subgroups, according to sociodemographic, lifestyle, and health-related variables as well as use of therapy. Differences between subgroups were analyzed using independent samples t-tests for continuous variables and Chi-square tests for categorical variables.
We rst analyzed associations between sociodemographic, lifestyle, and health-related variables and pain relief. Variables with p<0.25 were included in a univariate logistic regression model in a forward selection process (24) to avoid early exclusion of potentially important variables (Additional File 1). Variables with p<0.05 were then kept in a backward selection process to construct a multivariable model. We next analyzed associations between IPR and clinical outcomes. Associations between IPR and HOOS/KOOS ADL and QoL subscale scores were analyzed using linear regression models adjusted for the variables retained in the multivariable model. Associations between IPR and the presence of anxiety and depression symptoms were analyzed using logistic regression models adjusted for the same variables.
Given the scarcity of data, normal and underweight BMI categories were merged into a single category (<25 kg/m 2 ).
All analyses were weighted and performed with SPSS 26 complex samples for MacOS (IBM Corp., Armonk, NY, USA). Statistical signi cance was de ned as p<0.05.

Results
The prevalence of IPR among people with HKOA was 68.8%. People with IPR reported a mean pain intensity of 6.85±1.54 on a 0-to 10-point numeric pain rating scale. The proportions of people with IPR who had hip OA (n=144, 69.7%) or knee OA (n=694, 69.5%) were similar (Table 1). All percentages and means±SDs are weighted.
APR, adequate pain relief; CI, con dence interval; HKOA, hip and knee osteoarthritis; IPR, inadequate pain relief; NPRS, numeric pain rating scale; OA, osteoarthritis; SD, standard deviation The proportion of people with IPR increased with age, reaching 73.3% in the oldest age class (≥75 years of age) (Figure 2a). IPR was more common in females than in males (Figure 2b).  Table 2). The IPR subgroup contained a larger proportion of people with a lower level of education (<4 years of completed schooling) than the APR subgroup. Overweight and obesity were highly prevalent among people with HKOA and were present at similar proportions between IPR and APR subgroups.
The IPR subgroup contained smaller proportions of people who smoked or consumed alcohol daily than the APR subgroup. Although regular exercise was more common within the APR subgroup than within the IPR subgroup, this difference was not signi cant. The presence of multimorbidity was more common within the IPR subgroup than within the APR subgroup. When analyzing associations between IPR and sociodemographic, lifestyle, and health-related variables, being female, being overweight or obese, and having multimorbidity were independently associated with IPR (Table 3).  (Table 4). Thus, people with IPR were more likely to have worse HOOS/KOOS ADL and QoL scores than people with APR. Although there was a signi cant association between IPR and anxiety symptoms in the unadjusted model, no signi cant association was found in the adjusted model. Overall, NSAIDs, analgesics, and physiotherapy were the most used therapies by people with HKOA (Table  5). Higher proportions of people within the IPR subgroup regularly took NSAIDS, simple opioids, and analgesics, speci cally paracetamol, than within the APR subgroup. Physiotherapy was also more commonly used by people with IPR than by people with APR. There were no signi cant differences in the proportions of people who underwent hip or knee surgery between IPR and APR subgroups. APR, adequate pain relief; CI, con dence interval; HKOA; hip and knee osteoarthritis; IPR, inadequate pain relief; NSAIDS, non-steroidal anti-in ammatory drugs; OA, osteoarthritis

Discussion
Our results indicate that 68.8% of people with HKOA in Portugal live with IPR, which is higher than the prevalence of IPR in Mexico (53%) (29), the Survey of Osteoarthritis Real World Therapies (SORT) cohort from six European countries (54%) (10), and a sample of Portuguese people with knee OA included in the SORT cohort (51%) (26). All three of these earlier studies included people who were ≥50 years old, with knee OA, and who took analgesics regularly, which may explain why we found a higher prevalence of IPR in the present study. Moreover, our study included a representative sample of the Portuguese population who live in the community, suggesting that offered interventions do not meet the need for pain relief for more than two-thirds of the Portuguese HKOA population.
We found that people with IPR had lower education levels than people with APR. This nding is consistent with previous literature reporting that low education is associated with more severe OA symptoms and is a social determinant of unhealthy lifestyles and multimorbidity (27,28), is a determinant of lack of access to and delay in seeking healthcare (32), and is associated with increased pain intensity over time (33).
The multivariable model showed that female sex, overweight and obesity, and multimorbidity were associated with IPR, similar to the results of the SORT study (10). Being female is associated with higher OA-related pain levels, and despite contradictory literature, studies suggest that psychosocial factors such as hypervigilance, catastrophizing, and passive coping strategies, which are highly variable across socio-cultural environments, may explain a lower pain threshold among women (30). Also, a systematic review of progression phenotypes among people with OA shows that overweight or obesity is a major factor in the progression of OA and is associated with worsening of pain, loss of physical function, and structural deterioration over time (31).
Additionally, our results show that having multimorbidity was associated with IPR. Multimorbidity is associated with chronic pain in a cumulative manner (32) and is related to pain intensity in people with HKOA (33). People with multimorbidity have a higher likelihood of walking impairments, which can contribute to a worsening of OA and other chronic conditions, with an additional consequence of psychological distress (32,33).
We found that IPR was negatively associated with performance in ADL and QoL. Previous research reveals that within the OA population, pain severity explains most of the variability in disability and QoL (34). High pain severity may lead to fear of movement and/or avoidance behaviors, resulting in physical inactivity and less participation in social activities and leading in turn to greater physical disability, psychological distress, and reduced QoL (35).
International clinical practice guidelines recommend that topical NSAIDs be considered before oral NSAIDs in line with the least systemic exposure principle, and oral NSAIDs are strongly recommended at the lowest possible dose (36). Given the limited e cacy of paracetamol and its potentially harmful secondary effects, it is only conditionally recommended for people with OA (36). Although tramadol is conditionally recommended, non-tramadol opioids are not recommended for the management of pain in people with OA, and both should be used only when alternatives have been exhausted. Glucosamine is strongly not recommended for people with HKOA (36). In the present study, oral NSAIDs were the most used medication followed by analgesics/antipyretic medication, whereas topical NSAIDs were the least used pharmacological modality.
People with IPR regularly took more medication for pain relief, namely NSAIDS, opioids, and analgesics, speci cally paracetamol, than people with APR, consistent with the results of the SORT study (10). A cohort study from the Netherlands also shows that that pain severity is positively related to analgesic intake; however, the authors concluded that most reasons for analgesic prescription are unknown (37).
Even though no temporal relationships can be drawn from a cross-sectional design, this study reveals that a higher proportion of people who took daily pain medication in the previous month had IPR.
Additionally, our results suggest that medication is taken by a much lower proportion of people with OA in Portugal than in other European countries (12). The reason for this may be due to the timeframe used in different studies to de ne medication intake and the adherence of patients to medication regimens. In Europe, NSAIDs and opioids are prescribed to 58.9% and 35.5% of people with OA, respectively, although medication use was de ned as "medication used at the moment" (12) rather than daily use in the previous month. Although randomized controlled trials show that analgesic drugs and other recommended interventions effectively manage pain in individuals with OA, adherence to medication and healthy lifestyle behaviors are a real-world concern that prevent the optimization of pain control in this population. A qualitative meta-ethnographic study points out that factors such as the severity of pain, perceived effect of medication, fear related to side effects, acceptability of dose regimens, education and knowledge about OA and the medication regimen, self-e cacy, and locus of control over OA in uence medication adherence (38).
Regarding conservative non-pharmacological therapies used by people with HKOA, we found that <20% of people with IPR underwent physiotherapy in the last 12 months or regularly exercised. However, current clinical guidelines recommend physiotherapy and exercise as rst-line treatments that should maintained during the progression of the disease for pain management purposes (39,40). Although, literature suggests that current management of people with HKOA, core non-pharmacological treatments are offered to <50% of patients, with symptom-driven and segmented interventions (41) centered on pharmacological (42,43) and surgical options (44).

Limitations
Our study has several limitations that should be considered. Due to its cross-sectional design, no causeeffect relationships can be established between IPR and sociodemographic, lifestyle, and health-related variables. Also, estimation of the proportion of people with IPR in the Portuguese population using sample weights is not free from error, although sample weights are recommended for all statistical analyses using complex samples data (45).
Although hip OA and knee OA may impose similar burdens on domains of patients' lives (1,46), previous research shows that people with hip OA have more severe disease and an earlier requirement for joint replacement (47). However, we did not thoroughly investigate differences in factors associated with IPR between people with hip OA versus knee OA.
We asked participants about their use of "regular medication". However, as people with OA often use analgesic medication sporadically for pain ares rather than daily, our results may underestimate the proportion of people that use medication for symptomatic control. Also, as physiotherapy attendance in the last 12 months was self-reported, we acknowledge the possibility that memory bias may compromise the accuracy of our results. Additionally, we did not investigate the reason for medication use or physiotherapy. "Regular exercise" was self-reported by participants and did not consider the precise amount and intensity. Hence, our data may overestimate the proportion of people who exercised. Moreover, pain intensity is multifactorial (35), and several potentially important factors were not considered in the analysis, such as fear avoidance beliefs, catastrophizing, or coping strategies.
The analyzed data were collected in 2011-2013, but due to few speci c strategies directed to RMDs in the last decade in Portugal, we cautiously believe that the current management of OA does not differ from that re ected in this study.

Strengths and implications
This is the rst population-based study in Portugal analyzing outcomes of current interventions offered to community-dwelling people with HKOA. The results of this study raise concerns regarding important factors that should be further explored in future research and addressed in national health policies to optimize the outcomes of people with HKOA, namely: 1) The high proportion of people with IPR, which may suggest the ineffectiveness of current management; 2) The high proportion of people with IPR who use pharmacological and non-pharmacological therapies, which may indicate suboptimal outcomes of current interventions; 3) Besides the low proportion of people who use therapy, the interventions offered do not seem to be aligned with international recommendations (36,39) considering the small proportion of people who underwent physiotherapy, exercised, and used pain medication and the large proportion of people who were overweight or obese.

Conclusion
Approximately two-thirds of the Portuguese population with HKOA have IPR, despite the higher use of medication and physiotherapy in the IPR subgroup than in the APR subgroup. Being overweight and having multimorbidity are modi able risk factors associated with IPR. Overall, recommended management strategies appear to be offered to a small proportion of people with HKOA. These results reveal an opportunity for pain control improvement in the HKOA population and highlight the need for further research on effective pain relief interventions.

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