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16 May 2024: Clinical Research  

Prevalence and Management of Chronic Pain, Including Neuropathic Pain, in Dialysis Patients with End-Stage Renal Disease

Klaudia Kitala-Tańska ORCID logo1ABDEF*, Ewa Kania-Zimnicka2AB, Damian Tański ORCID logo3CDEF, Norbert Kwella ORCID logo4BDE, Tomasz Stompór ORCID logo4ADEF, Małgorzata Stompór ORCID logo5ADEF

DOI: 10.12659/MSM.943808

Med Sci Monit 2024; 30:e943808

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Abstract

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BACKGROUND: Chronic kidney disease (CKD) is a growing global health concern. Chronic pain, as a common symptom of CKD, particularly among patients with end-stage renal disease (ESRD), is influenced by complications, dialysis procedures, and comorbidities. We aimed to evaluate chronic pain and probable neuropathic pain in 96 dialysis patients with ESRD using the Douleur Neuropathique 4 (DN4) questionnaire.

MATERIAL AND METHODS: A total of 96 patients from a single dialysis center were enrolled for the purpose of this study. ESRD was caused by diseases causing kidney damage, such as diabetes. The average duration of maintenance dialysis was 4.6±5.67 years. Comorbidities, functional and mental assessment, and pharmacological treatment data were collected using a questionnaire. The satisfaction with life scale was also used. Chronic pain was defined as lasting more than 3 months. The DN4 was used to determine the neuropathic component of pain.

RESULTS: Chronic pain was observed in 63.5% of the study participants, with 47.5% of them reporting the presence of neuropathic pain accompanied by a neuropathic component. Significantly more patients with chronic pain reported mood disorders and reduced life satisfaction, but there was no difference in their activities of daily living–assessed functional status or duration of dialysis. Patients experiencing chronic pain received non-steroidal anti-inflammatory drugs, paracetamol, and opioids.

CONCLUSIONS: Chronic pain, especially with a neuropathic component, is highly prevalent in patients with CKD, and its treatment remains ineffective. Undiagnosed components of pain can contribute to underdiagnosis and inadequate therapy. Further studies and staff education are needed to address this important issue.

Keywords: chronic pain, Neuralgia, Renal Insufficiency, Chronic, Dialysis

Introduction

The prevalence of chronic kidney disease (CKD) is estimated to affect more than 10% of the world population and is continuously increasing [1,2]. Various chronic illnesses can lead to end-stage renal disease (ESRD). Diabetes mellitus stands as the primary cause in numerous developed and developing countries [3]. There are various factors that can contribute to the condition, such as high blood pressure, certain medications, such as non-steroidal anti-inflammatory drugs (NSAIDs), calcineurin inhibitors, and antiretrovirals, vascular disease, tubulointerstitial disease, glomerular disease (primary or secondary), recurrent kidney stone disease, cystic kidney diseases, unrecovered acute kidney injury, congenital defects of the kidney or bladder, and urinary tract obstruction or dysfunction [3]. There are certain indications that suggest the need for renal replacement therapy in patients with CKD, including severe metabolic acidosis, hyperkalemia, encephalopathy, experiencing failure to thrive and malnutrition, pericarditis, stubborn cases of volume overload, gastrointestinal symptoms that are difficult to manage, peripheral neuropathy, and glomerular filtration rate of 5 to 9 mL/min/1.73 m2, regardless of symptoms or other comorbidities [3]. Patients with worsening kidney function develop multiple complications, which lead to many burdensome symptoms, including pain, which is most prevalent in patients with ESRD [2]. Pain can be a result of dialysis itself (for example, painful muscle cramps resulting from high-volume ultrafiltration), of uremic pruritus, or related to diseases that led to ESRD, such as diabetic polyneuropathy. Pain can also result from comorbidities, such as osteoarthritis, diabetes, and others highly prevalent in patients with CKD [4]. Depending on reports, 21% to 92% of patients with CKD have acute pain, whereas 33% to 88% report chronic pain [5]. Patients have various ailments according to the nature of the pain, for example, whether it is neuropathic or nociceptive [6]. Approximately 5% of the general population and 10% of patients with CKD are estimated to experience neuropathic pain [7,8]. It is even more common among patients undergoing dialysis: 90% are affected by peripheral neuropathy in CKD, also known as uremic neuropathy [9]. Neuropathic pain is one of the most challenging types of pain to treat, and, consequently, patients frequently report unsatisfactory outcomes. Untreated pain reduces health-related quality of life, healthcare utilization, dialysis adherence, and mortality [10]. Pain can exacerbate other physical and psychological symptoms, such as anxiety, depression, and fatigue [10]. The frequency of chronic pain in CKD patients in Poland, particularly in those with a neuropathic component, has not yet been assessed; however, it is important with regard to the implementation of proper treatment and quality of life improvement. In this study, we aimed to evaluate chronic and neuropathic pain in 96 dialysis patients with ESRD using the Douleur Neuropathique 4 (DN4) questionnaire. This questionnaire is recommended to assess the probability of the existence of neuropathic pain according to neuropathic pain diagnosis and treatment guidelines [11]. The aim was also to determine current pain management methods in patients with ESRD.

Material and Methods

PARTICIPANTS:

An independent Ethics Committee of the local Chamber of Physicians in Olsztyn evaluated and approved the study. All patients provided their written informed consent. The inclusion criteria for the study were as follows: patients with ESRD treated with dialysis (peritoneal dialysis or hemodialysis), signed informed consent, and willingness to participate. The study included 96 patients receiving dialysis treatment at the Dialysis Center of the Regional Specialist Hospital in Olsztyn. The study’s exclusion criteria were participants who demonstrated an inability to respond to the inquiries posed and those who did not provide informed consent to partake in the study. Data were collected at the Dialysis Center at the Regional Specialist Hospital in Olsztyn, Poland in 2020–2021.

STUDY PROCEDURES:

We conducted a cross-sectional observational study. The data were collected using standardized questionnaires and the files of patients undergoing dialysis. Chronic pain was defined as pain lasting more than 3 months. The survey questionnaires had been validated worldwide, including in Poland [12].

MENTAL DISORDERS:

The 10-item Abbreviated Mental Test score (AMTS) was used to assess the mental status of the participants aged 60 years and older. A score below 8 indicated mild cognitive impairment, and score between 7 and 5 indicated moderate cognitive impairment. Patients who scored <5 points were excluded from the study because of the suspicion of severe cognitive impairment [13].

The clock-drawing test (CDT) was used for participants under 60 years of age, with a score less than 5/7 points indicating moderate/severe cognitive impairment.

The 4-item Geriatric Depression Scale (GDS) was used to assess the mood of patients over 60 years of age, with values of 1 to 4 indicating the likelihood of depression [14].

The Patient Health Questionnaire (PHQ-9) was used to evaluate the mood of patients younger than 60 years of age, with 5 to 9 points indicating mild depression, 10 to 14 points indicating moderate depression, 15 to 19 points indicating moderately severe depression, and 20 to 27 points indicating severe depression [15].

Patients rated insomnia on a scale from 1 to 10, where 1 represented no sleep problems and 10 indicated serious problems with sleeping.

SATISFACTION WITH LIFE:

The satisfaction with life scale (SWLS) in the Polish adaptation by Jurczyński includes 5 statements that assess overall life satisfaction. These statements are positively phrased and cover various aspects of life, such as how close one’s life is to one’s ideal, the conditions of one’s life, satisfaction levels, attainment of important things, and the desire for change if given the chance to live life again. Each item is evaluated using a 7-point rating scale that ranges from 1, “strongly disagree”, to 7, “strongly agree”, with higher score indicating greater life satisfaction. The obtained result determines the degree of satisfaction with life (ranging from 5–35 points) [16].

FUNCTIONAL STATUS:

The Activities of Daily Living (ADL) scale was used to evaluate the functional status of the participants. A score of less than 5/6 indicated that the patient was functionally impaired or dependent on others [17].

PAIN TESTS:

Using whole-body pain drawings, patients were questioned about the presence and location of chronic pain. The numeric rating scale (NRS), which ranges from 0 to 10 points (where 10 represents the most intense imaginable pain), was used to calculate pain intensity. Patients also completed the DN4 questionnaire to assess the neuropathic component of pain, based on symptoms such as burning, electric shocks, painful response to cold, tingling, pins and needles, itching, numbness, hypoesthesia to touch, hypoesthesia to prick, and pain during brushing painful areas. A score of 4 or higher indicated that the discomfort might have been neuropathic in nature [18].

STATISTICAL ANALYSIS:

Statistical analyses were conducted using Statistica 13.3 and Excel 2021. Means and standard deviations were used to describe clinical and sociodemographic features for continuous numeric data, while categorical parameters, median, and interquartile range were used to characterize quantitative variables. The chi-squared test was used to compare the distributions of categorical variables. Final values between groups were compared using Mann-Whitney U and ANOVA tests.

The Shapiro-Wilk and Levene tests were used to assess the normality of continuous variable distributions. Non-parametric tests were used when the distribution deviated from normality. Numbers were used to represent categorical data, and the Fisher exact test or Pearson chi-squared test were used to compare them as needed. Post-hoc comparisons were conducted using the Scheffé correction for multiple comparisons. A P value less than 0.05 was considered statistically significant.

Results

CHARACTERISTICS OF THE STUDY GROUP:

Our study included 96 patients undergoing long-term dialysis from the Dialysis Center at the Regional Specialist Hospital in Olsztyn, Poland. There were 32 women (33.3%) and 64 men (66.7%). Eighty-six patients undergoing hemodialysis and 10 patients undergoing peritoneal dialysis were recruited into the study. Hemodialysis was performed 3 times a week for 4 to 4.5 h per session using high-flux dialysers (Fresenius, Bad Homburg, Germany), and automated peritoneal dialysis or continuous ambulatory peritoneal dialysis was performed using biocompatible (physioneal and extraneal) peritoneal dialysis fluids (Baxter Healthcare, Castlebar, Ireland). The mean age of the study group was 65.5±14.60 years (range, 28–95 years) and the mean duration of maintenance dialysis was 4.6±5.67 years (hemodialysis 4.8±5.87 years, peritoneal dialysis 2.5±2.47 years). Patients experienced several comorbidities (mean, 5.5±2.29 diseases; Table 1). Fourteen patients were functionally impaired or dependent on others, and AMTS indicated dementia/moderate cognitive impairment among 23 patients. Forty-three older patients aged ≥60 years demonstrated the likelihood of depression in the GDS, and 13 patients showed symptoms of depression in the PHQ-9 scale.

PREVALENCE OF CHRONIC AND PROBABLE NEUROPATHIC PAIN AMONG DIALYSIS PATIENTS:

In the study, 61 patients (63.5%) reported chronic pain, and 29 of them (47.5%) reported probable neuropathic pain. There were no significant differences between sexes and chronic pain, or probable neuropathic pain. There was no correlation between age and the prevalence of chronic pain and various kinds of pain that were experienced.

INFLUENCE OF CHRONIC PAIN ON PATIENT MOOD, COGNITIVE AND FUNCTIONAL STATUS:

No significant relationship was found between chronic pain and probable neuropathic pain and cognitive status (as assessed using the AMTS or CDT), but a trend toward probable neuropathic pain experience among patients with dementia was observed (P=0.08). However, patients with pain, when compared to those without pain, more frequently manifested low mood. Among participants experiencing chronic pain, we found higher depression scale (GDS/PHQ-9) scores (P≤0.001). There was no statistically significant relationship between GDS/PHQ-9 scores and probable chronic neuropathic pain frequency. Patients with neuropathic pain were statistically significantly less satisfied with life, based on the SWLS, than were patients with chronic pain without a neuropathic component (P=0.03) and patients without pain at all (P=0.001; Figure 1). A statistically significant relationship was found between pain and insomnia: 40 out of 61 (65.6%) of the patients who had chronic pain in our study experienced sleep disturbances, compared with 12 out of 35 (34.3%) of the patients who did not report chronic pain (P=0.003). There was no significant relationship between disability reported using the ADL and chronic pain (P=0.21) or chronic pain with a neuropathic component (P=0.06, Tables 2, 3).

INTENSITY AND DURATION OF CHRONIC PAIN AND CHRONIC PAIN WITH A NEUROPATHIC COMPONENT:

On average, patients were experiencing severe pain, as indicated by the mean value of 6.1±2.07 points on the NRS (5.7±1.84 among patients with chronic pain, and 6.5±2.24 among patients with chronic pain with neuropathic component, P=NS). There was no statistically significant difference in mean duration of pain for patients with chronic pain than in patients with chronic pain that included a neuropathic component.

PAINFUL SITES:

The number of pain locations was significantly higher (P=0.03) among patients with chronic pain with a neuropathic component (2.2±1.13 pain sites, n=29), as compared with those without a neuropathic component (1.6±0.87, n=32; Figure 2). Lower limbs (n=35), back (n=19), and head (n=9) were reported most frequently as painful sites (some of the participants chose more than 1 location).

CHARACTERISTICS OF PROBABLE NEUROPATHIC PAIN:

Based on the medical records of the patients, the most likely causes of the symptoms were identified (Table 4). Most patients reported 4 of 10 symptoms in the DN4 questionnaire, but 12 patients reported 6 to 8 symptoms. Patients most commonly reported burning, tingling, and numbness. The lower limbs (n=21) and the back (n=12) were reported most frequently as painful areas probably due to neuropathic origin.

CHRONIC PAIN AND ASSOCIATED CONDITIONS:

There was no relation found between any comorbidities, for example, endocrine, nutritional, and metabolic diseases (ICD 10: code E) and COVID-19 (ICD-10: code U07.1), and prevalence of probable neuropathic pain. In addition, there was neither a statistically significant difference between the time on dialysis and levels/nature of pain (with/without neuropathic component), nor any correlation found between the type of dialysis received and levels/nature of pain. There were also no significant differences between duration of hemodialysis/peritoneal dialysis and chronic pain or probable neuropathic pain (Tables 2, 3).

CURRENT TREATMENT OF CHRONIC PAIN:

Study participants were using between 2 and 20 drugs (mean, 9.4±3.24). Analgesics were administered to 29 patients (47.5% of all patients with chronic pain), 31.5% of patients with chronic pain were treated with non-steroidal anti-inflammatory medications (NSAIDs), 11.5% with paracetamol, and 11.5% with opioids (Table 5). Twenty-eight patients who had chronic pain with significant intensity (more than 4 points on the NRS) received no analgesics. Finally, we investigated the adherence of probable neuropathic pain treatment to the most recent guidelines for pain management, such as treatment with opioids, anticonvulsants, and antidepressants. Only 8 patients (27.6%) with probable neuropathic pain were treated with appropriate drugs. Those who had a higher probability of having neuropathic pain were more likely to receive opioids (P=0.04), but there was no such correlation for antiepileptic or antidepressant medications.

Discussion

This study was designed to establish the prevalence of chronic pain, with a specific focus on neuropathic pain and its management among patients with ESRD. We found that many patients had chronic pain (63.5%), and more than half had moderate-to-severe pain (56.3%). A similar prevalence of pain in patients with CKD was reported by Davison et al in their 2021 meta-analysis including 68 studies and 16 558 patients (43.6% range: 34.8–52.7%) [19].

The experience of chronic pain is related to everyday functioning impairment, such as low mood, attention and night sleep deterioration, and physical disability [20–22]. The bidirectional association between chronic pain and depression has been well documented [21–23]. Our results also demonstrated such a link. In addition, in the present study, a clear dependence was found between reports of pain and low mood, as well as a low level of life satisfaction. This link was found most frequently in patients experiencing severe pain, particularly with symptoms of probable neuropathic pain. Our findings about chronic pain are consistent with the results of other surveys [24,25]. In addition, as found by other authors, patients undergoing dialysis had an increased incidence of depression, regardless of pain perception [26,27]. We also clearly showed the connection between chronic pain symptoms and sleep disturbances; in the present study, 65.6% of patients with chronic pain reported sleep disturbances (P=0.003). Davison et al, using another questionnaire, the Pittsburgh Sleep Quality Index, demonstrated that even up to 75% of patients undergoing dialysis with moderate-to-severe chronic pain experienced sleep disorders [28]. Other studies showed a similar dependence [29,30]. Moreover, Scott et al showed that 55% of patients with CKD had sleep disorders, regardless of the presence of pain [31].

The association between chronic pain experience and cognitive impairment has also been described in the literature. Some researchers found that chronic pain negatively affects cognitive functions [32,33]. Ojeda et al demonstrated that, among patients with fibromyalgia and musculoskeletal diseases, patients with chronic pain had lower “Test Your Memory” scores than did matched controls. By contrast, Palomo-Osuna et al found no significant differences in cognitive impairment between patients with and without neuropathic pain [34,35]. Our study results did not confirm any association between chronic pain and cognitive impairment, as measured using AMTS/CDT scores. Similarly, we did not find a relationship between chronic pain and disability based on the ADL scores, although it has been established by other groups of researchers. In other research, patients with neuropathic pain had more difficulties with basic activities of their daily life [36,37].

Trigeminal neuralgia, peripheral nerve damage, painful polyneuropathy, postherpetic neuralgia, and painful radiculopathy are the most prevalent peripheral neuropathic pain syndromes listed in the new classification. Central neuropathic pain conditions include spinal cord or brain injury-related pain, post-stroke pain, and multiple sclerosis-related pain [38]. In our research, diabetic neuropathy was the most common cause of neuropathic pain, followed by neuropathy caused by vascular abnormalities; none of the patients presented signs of trigeminal neuralgia or post-herpetic neuropathy. Few articles discussed the association between neuropathy and COVID-19 [39]. In our study sample, only 1 patient reported experiencing probable neuropathic pain after COVID-19. Some case reports described a similar relationship [40,41]. Additionally, uremic neuropathy can be a potential etiology of neuropathic pain among patients on dialysis and those with advanced CKD not yet on dialysis. The pathogenesis of uremic neuropathy is characterized by the deleterious effects of renal dysfunction, which results in the accumulation of waste products with neurotoxic potential, such as phenols, myoinositol, beta2-microglobulin, and other middle-molecular-weight substances, together with deficiencies of thiamine, zinc, and biotin and decreased transketolase activity. Hyperparathyroidism and hyperkalemia have also been suggested to contribute to neuropathic pain. Uremic polyneuropathy is a distal, symmetrical, mixed sensorimotor neuropathy due to demyelination and axonal degeneration [42]. Electrophysiological signs of impaired nerve function were found among 60% to 100% of patients on dialysis, although a lower percentage of them were symptomatic [43]. Potential therapeutic interventions that could mitigate the impact of uremic neuropathy and enhance neural activity include renal transplantation, dialysis with the use of biocompatible, high-flux membranes, and hemodiafiltration [44].

The localization of pain in patients on renal replacement therapy has been described only in a handful of publications. Moore et al demonstrated that joint pain was the most common type of pain, experienced by 57% of participants. This was followed by headaches (24%) and back pain (11%) [45]. Marzouq et al discovered that the upper and lower limbs (41.2%), knees (28.6%), and back (26.6%) were the most frequent locations of pain [46]. These findings are in agreement with our results and reports suggesting that joint and skeletal system symptoms are highly prevalent among patients with CKD [4].

Despite the high incidence of moderate and severe pain in the present study, the use of analgesics was low. In our study, 72.4% of patients with pain and neuropathic component did not receive neuropathic pain medications. It might have been connected with the potential presence of an unacknowledged neuropathic element, but also with the fear among patients with ESRD of using particular medications [12]. Neuropathic pain is characterized by a low response to paracetamol, NSAIDs, and most of the opioids [47]. According to the neuropathic pain treatment guidelines, treatment should be started with an adjuvant medication, including anticonvulsants, mostly gabapentinoids, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, tramadol, and topical capsaicin and lidocaine [12]. On the other hand, nonopioid and opioid analgesics other than tramadol are effective in treating nociceptive pain, at least in the short term [47,48]. Many of the sensations experienced by people with CKD are of a mixed character, such as the pain that is associated with ischemia and calciphylaxis [47].

Therapy of pain in this population needs a thorough evaluation of drug characteristics, including their accumulation, metabolism, dialysability, and drug-drug and drug-disease interactions. Given the scarce pharmacokinetic data in patients with ESRD, the therapeutic window and potential hazards of drugs should be considered in the decision-making process, coupled with continued therapy monitoring [49]. Gabapentin and pregabalin must be administered after hemodialysis. Many adverse effects of medications that are efficient in neuropathic pain treatment were observed among patients with ESRD. Gabapentin and pregabalin were linked to an increased risk of mental status changes, fractures, and falls in patients with ESRD [50]. Tricyclic antidepressants are associated with dose-dependent anticholinergic and antihistaminic adverse effects, whereas serotonin and norepinephrine reuptake inhibitors are often better tolerated. The syndrome of inappropriate antidiuretic hormone secretion can be induced or exacerbated by both of these types of medications. Due to the possible accumulation of serotonergic drugs, serotonin syndrome can occur among patients with CKD more frequently than in the regular population, and is mostly treated with tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, and opioids [51]. Oxycodone, hydromorphone, fentanyl, methadone, and buprenorphine are known as safer choices in patients with kidney impairment [10]. Tramadol provides pain relief by functioning as both a central opiate agonist and a central nervous system reuptake inhibitor of norepinephrine and serotonin. Tramadol is the common choice for moderate pain in patients with CKD because of its lack of direct nephrotoxicity. Tramadol and its metabolite build up in the body in cases of advanced CKD (estimated glomerular filtration rate <30 mL/min/1.73 m2). Patients with advanced with CKD should not take more than 100 mg of tramadol orally twice daily, while patients undergoing dialysis should not exceed 50 mg twice daily [52]. Furthermore, it is worth noting that difelikefalin has emerged as a novel therapeutic intervention for the management of uremic pruritus, a distressing condition commonly experienced by individuals undergoing hemodialysis. This innovative treatment holds significant potential in alleviating the symptoms of uremic pruritus and may offer considerable benefits to a substantial number of patients undergoing hemodialysis [53]. Aside from medical treatments, additional nonpharmacologic interventions should be considered when appropriate. Exploring the combination of topical thermal therapy and exercise programs, along with physical modalities, such as transcutaneous electrical stimulation, can be beneficial for managing different pain conditions [52].

The problem with undertreatment also applies to therapy of depression, which was observed in the study group, considering the prevalence of low mood. The undertreatment of depression might also be due to a concern about the potential toxicity and adverse effects of antidepressants in patients with CKD.

We are aware of several limitations of this paper. The primary constraint pertained to the inability to determine the precise etiology of the pain, because individuals diagnosed with CKD often present with a multitude of coexisting medical conditions. However, this is what a group of patients undergoing dialysis look like in reality. It was intended to conclude that according to the high prevalence of pain, whatever the cause, our goal should be to recognize it and try to improve the quality of life of patients.

Conclusions

The prevalence of chronic pain, particularly with a neuropathic component, in patients with CKD in Poland is substantial, and its treatment appears to be unsuccessful. The undetected neuropathic pain components can contribute to underdiagnosis and inadequate therapy. Patients with CKD and chronic pain were considerably more likely to have mood disorders, sleep disturbances, and decreased life satisfaction. This issue calls for additional study clarifying the possible etiology of pain as well as medical staff education regarding the proper diagnosis and treatment of chronic pain, particularly that which has a neuropathic component. To solve these significant problems, additional research and training for staff members are required.

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750