Evaluation of Neuropatic Pain Features in COVID-19 Patients
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.344625
Source of Support: None, Conflict of Interest: None
Keywords: COVID-19, neuropathic pain, PCR test
The International Association for the Study of Pain defines neuropathic pain as the pain result of a primary lesion or dysfunction in the nervous system. In this broad category, clinical pictures, etiology of the primary lesion, and causative neurobiological mechanisms may differ. Neuropathic pain is the most widely accepted term for nonnociceptive pain. The most obvious difference from nociceptive pain is the absence of a continuous nociceptive stimulus. Neuropathic pain is a condition that can have extremely disturbing effects on the patient and may become chronic if it is not treated timely and correctly. Most patients with neuropathic pain complain of throbbing, piercing, or burning pain. Apart from the pain, patients may complain of hyperalgesia (feeling more pain than should be felt with a stimulus that normally causes pain) or allodynia (pain caused by a painless stimulus, for example, feeling pain with cotton touch). Although it is difficult to determine the etiology of neuropathic pain precisely, its presence in patients can be determined by questioning the patients with screening tests.
Many viral infections are known to cause neuropathy and neuropathic pain. Viral genome studies support that peripheral neuropathy develops by immune-mediated mechanisms rather than direct nerve infection and replication of the virus in tissue. Pain is thought to develop as a result of tissue damage as well as inflammation of the peripheral nerves and ganglia. Although cases with neuropathy have been reported during COVID-19, no study has yet been conducted to question neuropathic pain specifically.
In our study, we aimed to determine the frequency of neuropathic pain in COVID-19 patients at the onset of the disease. In this way, the nature of COVID-19 disease can be better understood and the treatment of patients with neuropathic pain can be arranged more successfully.
This is a cross-sectional descriptive study. The data collection phase of the study was carried out between December 21, 2020 and January 22, 2021. All adult patients (18 years and over) who applied to the COVID outpatient clinic were invited to the study. Patients with diseases known to cause neuropathy (diabetes, chronic renal failure, oncological diseases, etc.) and those who used chemotherapy were excluded. Patients who gave consent to participate in the study were asked to fill in the demographic data form and neuropathic pain questionnaire online. Ethics committee approval was obtained for the study from Çanakkale Onsekiz Mart University Ethics Committee for Clinical Studies with decision number 14-18 dated December 09, 2020.
The demographic data form was developed by the researchers for this study. It included questions about the patients' age, gender, marital status, educational status, occupation, employment status, smoking and alcohol habits. Information about the COVID-19 disease processes of the patients was also questioned with this form.
The Neuropathic Pain Questionnaire determines the neuropathic component in patients' pain complaints with 12 questions. The questionnaire score is calculated by multiplying the rates given by the patient for each of the 12 questions by the predetermined coefficients. The presence or absence of neuropathic pain is predicted according to the score. The score of the questionnaire provides a variable that can be used to compare the neuropathic pain component among the patients. Neuropathic Pain Questionnaire, which can be applied without patient contact, was preferred due to concerns about the spread of disease.
The patients were divided into positive (+) and negative (-) according to the PCR test results; admissions were classified as primer and control visits and data analyzed accordingly. Repeated admissions and invalid questionnaires were excluded.
Electroneurological tests and biochemical analyzes were not performed to determine the etiological causes of neuropathic pain. The results to be obtained will only provide observational data on the neuropathic characteristics of pain present in the participants.
After the data were digitalized and corrected, the ordinal data were presented with frequency and percent; the categorical data were presented with mean and standard deviation for descriptive information. The presence of neuropathic pain and neuropathic pain questionnaire scores were analyzed with statistical tests according to the variables of patients' demographic characteristics in COVID-19 disease process. Since the sample size is larger than 30, the normal distribution assumption has been neglected in parametric tests based on the central limit theorem. Analyses were carried out using Chi-square or Fisher's Exact test, Student's t-test, Mann–Whitney U test, and Pearson correlation test in accordance with variable characteristics. Test constants and absolute P values were presented for all analyses; P < 0.05 was accepted as the general significance limit. Odd's ratio of PCR test positivity for the presence of neuropathic pain calculated and presented with 95% confidence intervals.
The study consisted data of 440 participants, 232 (52.7%) of them were male and 208 (47.3%) were female. Their average age was 40.8 ± 15.4 (minimum 18, maximum 88). Ages were not significantly different between genders (t = 3.094; P = 0.210). In total, 262 of the participants (59.6%) were married, 147 (33.4%) were single, and 31 (7.0%) were widowed or divorced. Six of the participants (1.4%) were illiterate, 2 (0.5%) were literate, 91 (20.7%) were primary school graduates, 35 (8.0%) were secondary school graduates, 97 (22.0%) were high school graduates, 209 (47.5%) were university graduates. Of the participants, 273 (62.0%) were currently working, 91 (20.7%) were not working actively (students, housewives, etc.), 60 (13.6%) were retired, and 16 (3.6%) were unemployed.
Of the participants, 183 (41.6%) were never smoked, 91 (20.7%) were quiters, and 166 (37.7%) were active smokers. In total, 214 of the participants (48.6) were never drinked, 189 (43.0%) were using alcohol in social settings, and 36 (8.2%) were using alcohol regularly.
Primer visits accounted for 62.0%; rest were control visits. In total, 26 of the primer visits (9.5%) consisted of those who remained in isolation at home after contact with Covid-19 patients. Of the control visits, 96 (57.5%) were posttreatment controls and 22 (12.7%) were postisolation controls. PCR tests were positive in 44 (16.5%) of the 266 primer visits and 69 (44.8%) of the 154 control visits. The patients had various complaints in 205 (75.1%) of the primer visits and 96 (57.5%) of the control visits. Among all patients, 132 (31.4%) of them were asymptomatic.
Among the 301 patients who reported having symptoms, 197 (65.4%) had pain in any part of their body. The rate of those with pain was not significantly different for the primer and control visits (X2 = 0.227; P = 0.634). The presence of pain did not differ significantly according to PCR test results (X2 = 0.833; P = 0.361).
The presence of pain did not differ significantly according to gender (X2 = 0.636; P = 0.425). The mean age of those who reported having pain (37.2 ± 13.5) was significantly lower than the age of those who did not (44.7 ± 14.8) (t = 4.442; P < 0.001). Those who stated that they had pain were significantly higher educational status (U = 7536.5; P < 0.001). The frequency of pain complaints differed significantly according to working status (X2 = 15.946; P = 0.001); it was significantly lower in those who did not work (housewife, student, etc.) and retirees.
The presence of pain complaints differed significantly according to smoking status (X2 = 10.429; P = 0.005); it was significantly lower in quitters than never or active smokers. Drinkers had higher rate of pain (71.5%) than nondrinkers (59.2%) (X2 = 4.709; P = 0.030).
The body regions affected by the reported pain complaints are listed in [Table 1]. The most common pain areas are muscles and joints. For the duration of pain, 15 participants reported 1 day, 50 participants 2 days, 49 participants 3 days, 15 participants 4 days, 28 participants 5 days, and 33 participants more than 5 days.
Their pain was described as intense enough to limit their ability to work, study or do something for at least 1 day by 116 of the participants (61.4%). This did not differ between primer or control visits (X2 = 1.462; P = 0.222) or according to the PCR test result (X2 = 3.657; P = 0.056). When questioned about the relevance of their pain to the period of discomfort that caused their admission to the Covid-19 policlinic, 38 participants stated that their pain increased during this period, 13 participants stated that it reappeared, 116 participants stated that it started in this period, other participants did not respond.
When the patients were asked to rate the intensity of their pain between 0 (no pain) and 10 (the most severe pain in my life), the mean intensity for 196 valid responses was 5.8 ± 2.4. Pain intensity was not significantly different between primer and control visits or according to the PCR test result (t = 1.054; P = 0.293, t = 1.907; P = 0.058, respectively). The average pain intensity reported by women (6.2 ± 2.4) was significantly higher than that of men (5.3 ± 2.4) (t = 2.747; P = 0.007). There was no significant correlation between pain intensity and age (r = 0.011; P = 0.877).
Eight of the participants were excluded from the neuropathic pain assessment because they had diabetes mellitus disease, one had chronic kidney disease, and twowere using chemotherapy. According to 185 valid results, 54 of the participants (29.2%) had the neuropathic component of their pain. The presence of neuropathic pain did not differ significantly according to gender (X2 = 1.889; P = 0.169). The mean ages of those with neuroptic pain were not significantly different from those without (t = 0.254; P = 0.799). The educational status of those with neuropathic pain was significantly lower than those without (U = 2766.5; P = 0.017). The presence of neuropathic pain showed a significant difference in terms of working status (Fisher's exact test X2 = 14.780; P = 0.002); it was significantly higher in nonworkers (housewife, student, etc.). The presence of neuropathic pain did not differ significantly in terms of smoking or alcohol use (X2 = 1.502; P = 0.472, X2 = 0.006; P = 0.939, respectively).
The rate of neuropathic pain component was 28.3% in primer visits and 31.0% in control visits (X2 = 0.139; P = 0.709). The rate of neuropathic pain was significantly higher in those with positive PCR test (48.8%) than those with negative (24.6%) (X2 = 9.000; P = 0.003). The Odd's ratio of PCR test positivity for the presence of neuropathic pain was calculated as 2.921 (95% CI, 1.428–5.975).
When only the primer visits were evaluated, the rate of neuropathic pain was significantly higher in those with positive PCR test (55.0%) than those with negative (23.8%) (X2 = 7.970; P = 0.005). The Odd's ratio of PCR test positivity for the presence of neuropathic pain among the primer admissions was calculated as 3.911 (95% CI, 1.455–10.513). The average scores of the primer visit patients to the questions of the neuropathic pain questionnaire according to PCR test results are given in [Table 2].
Neuropathic pain is the pain observed directly due to the peripheral or central nervous system dysfunction without stimulation of nociceptors. The problem in neuropathic pain is due to the abnormal processing of perception and is usually seen in people with neurological diseases. Nociceptive pain is a physiological response as a result of tissue damage that will initiate the pain. Unlike neurogenic pain, neuropathic pain does not involve transient disturbances of the peripheral or central nervous system and therefore produces prolonged pain.
Some viruses infecting humans are neurotrophic and can cause neurological complications. HIV infection has effects on the peripheral nervous system, 30–60% of AIDS patients suffer from sensory neuropathy. Neurotropic properties of RNA viruses such as West Nile virus, Hepatitis C virus, HTLV-1, and DNA viruses such as JCV, Epstein–Barr virus, human cytomegalo virus, and mouse adenovirus type 1 have been reported., Although viral infections usually cause ongoing pain during the course of the disease, some viral infections and antiviral responses can cause neuropathies that lead to chronic pain. Direct effects of viruses or early defense responses to viral infection triggering pain hypersensitivity may be possible causes of pain.
COVID-19 virus has still unknowns in terms of its identification and clinical features. Various neurological symptoms including CNS, peripheral nervous system, and skeletal muscle damage have been reported in more than a third of COVID-19 patients. Neurological complications seen in COVID-19 may result from the systemic response to infection or direct effects of the virus. Possible mechanisms effective in the neurological complications of COVID-19 include direct spread of the virus to the nervous system, immune disorder causing persistent fever and high inflammatory markers, and neurological damage caused by hypoxemia, organ failure, and metabolic disorders due to drug effects which is common in severe disease.
COVID-19 patients suffer from neurological symptoms, including peripheral neuropathies. Persistent pain such as neck, back, orofacial, headache, and cervical/lumbar pain may worsen during COVID-19. There were case reports showing peripheral nerve involvement, which may provide evidence that pain is a common symptom during COVID-19 disease. Loss of sense of smell and taste, visual damage, and neuropathic pain are the most commonly reported peripheral nerve symptoms. Pain-related symptoms include myalgia and/or joint pain (arthralgia) (14.8%), sore throat (13.9%), and headache (13.6%).
Peripheral nervous system involvement, including painful neuropathies, has been reported in many patients with COVID-19., Mao et al. reported dysgeusia (5.6%), dysosmia (5.1%), visual disturbances (1.4%), and neuralgia (2.3%) as peripheral nervous system effects. This may be the result of viral invasion of peripheral nerves (neurotropism) or prolonged immobility during severe illness, or both. Pain caused by COVID-19 infection may be due to spinal ACE2's effect on pain sensation and direct or indirect tissue damage. Since COVID-19 virus induces a strong inflammatory response, high cytokine levels (IL-6, IL-10, and TNFα) are present, especially in patients with a moderate or severe disease course. Therefore, pain pathogenesis should include the inflammatory reaction.
COVID-19 has neuroinvasion and neurotrophic effects. Although many studies have been reported about neurological findings of the COVID-19 disease, this is the first to evaluate neuropathic pain. In our study, patients who were admitted with suspicion of COVID-19 disease were evaluated and compared according to PCR test results and neuropathic pain was frequently observed at the onset of the COVID-19 disease by using the Neuropathic Pain Questionnaire, whose validity and reliability were proven to determine the presence of neuropathic pain.
As a limitation of this study, only an observational assessment of the presence of neuropathic pain was made and no conclusion about the etiological origin of neuropathic pain can be reached.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2]