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. 2022 Nov 23;27(1):44–53. doi: 10.1002/ejp.2055

A systematic review and meta‐analysis of neuropathic pain associated with coronavirus disease 2019

Giulia Di Stefano 1, Pietro Falco 1, Eleonora Galosi 1, Giuseppe Di Pietro 1, Caterina Leone 1, Andrea Truini 1,✉
PMCID: PMC9877974  PMID: 36367322

Abstract

Background and Objective

Neuropathic pain is an occasionally reported complication of coronavirus disease 2019 (COVID‐19) that has received increased attention in scientific literature. In this systematic review and meta‐analysis, we aimed to provide information on the frequency of neuropathic pain associated with COVID‐19.

Databases and Data Treatment

We systematically reviewed and analysed literature regarding neuropathic pain associated with COVID‐19. Literature searches were conducted in PubMed, EMBASE and Cochrane Library databases. We considered prospective and retrospective studies published up until September 2022 (limitations included English language, full‐text publications and studies including at least 10 patients). A random effects meta‐analysis was performed and heterogeneity and publication bias were assessed.

Results

We identified 149 studies. We included 17 studies in the systematic review, and six studies reporting the frequency of neuropathic pain in the acute/subacute phase of COVID‐19 in the meta‐analysis. The estimated frequency of neuropathic pain ranged between 0.4 and 25%. Forest plot analysis showed that the random effect overall frequency was 10% (95% confidence interval: 5%–15%), with a high level of heterogeneity (Chi2 = 104; Tau2 = 0.004; df = 5; I 2 = 95%; test for overall effect: Z = 3.584; p < 0.0005). The overall risk of bias was moderate in all studies selected, particularly due to the poor description of neuropathic pain diagnostic criteria.

Conclusions

The pooled estimated frequency of neuropathic pain associated with COVID‐19 should be considered with caution due to the high heterogeneity across studies and the poor description of the neuropathic pain diagnostic criteria applied.

Significance

Emerging evidence supports the development of neuropathic pain as a complication of COVID‐19. However, longitudinal studies enrolling consecutive patients with COVID‐19 that detail the diagnostic criteria for neuropathic pain are needed to better assess the frequency of this condition.

1. INTRODUCTION

Pain is a commonly reported complication accompanying and following coronavirus disease 2019 (COVID‐19) (Attal et al., 2021; Carfì et al., 2020; Correia et al., 2020; Joshi et al., 2022; Meyer‐Frießem et al., 2021; Odozor et al., 2021). The mechanisms underlying pain associated with COVID‐19 are likely heterogeneous and are not completely understood.

Pain associated with COVID‐19 most commonly includes nociceptive pain, namely joint pain, muscle pain and headache (Fernández‐de‐Las‐Peñas et al., 2021; Fernández‐de‐Las‐Peñas, Giordano, et al., 2022; Fernández‐de‐Las‐Peñas, Valera‐Calero, et al., 2022; Li et al., 2021; Lopez‐Leon et al., 2021; Tana et al., 2022). In particular, headache affects about 50% of patients in the acute phase of COVID‐19 (Sampaio Rocha‐Filho, 2022). Pain may also arise as a possible complication due to treatment, e.g., critical illness myopathy/neuropathy, prolonged immobility and mechanical ventilation (Clauw et al., 2020; Kemp et al., 2019, 2020). However, patients may also suffer from COVID‐19‐induced neuropathic pain because of specific COVID‐19‐related neurological complications including stroke, myelitis and peripheral neuropathies. Neuropathic pain in the acute phase of COVID‐19 may occur due to the neurotropic properties of the coronavirus, direct involvement of peripheral nerves, or activation of nociceptive sensory neurons by cytokines and chemokines (Berger, 2020; Cantuti‐Castelvetri et al., 2020; McFarland et al., 2021; Nazarinia et al., 2022). Neuropathic pain has been recently recognized as a long‐term complication of COVID‐19, in the framework of a long COVID syndrome (Davis et al., 2021; Ursini et al., 2021).

Scientific literature on COVID‐19 has primarily focused on nociceptive pain (Carfì et al., 2020; Garrigues et al., 2020), while the frequency of neuropathic pain associated with COVID‐19 has not been systematically addressed. More precise information on neuropathic pain associated with COVID‐19 might direct scientific research towards specific pharmacological targets, thus improving the management of this difficult‐to‐treat COVID‐19 complication.

The aim of this systematic review and meta‐analysis was to provide information on the frequency of neuropathic pain associated with COVID‐19.

2. METHODS

2.1. Search process

We did not previously register this systematic review on the PROSPERO website. In accordance with Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines, we systematically reviewed and analysed literature regarding neuropathic pain associated with COVID‐19. We searched for relevant studies on PubMed, EMBASE and Cochrane Library databases and considered publications up until 30 September 2022 (Data S1). The primary search was supplemented by a secondary search using the bibliographies of retrieved articles. Our search process did not cover grey literature or unpublished data.

2.2. Selection criteria and data extraction

We limited the search to English language publications. Studies published only as abstracts were excluded. The target population included patients of any age with a current or previous COVID‐19 diagnosis (in the acute phase or after recovery, including hospitalized and non‐hospitalized patients and critically ill survivors). We included both prospective and retrospective studies, with assessment done in person or by phone/email survey, without any restrictions on follow‐up duration. Animal studies, meta‐analysis, systematic reviews and studies including less than 10 patients were excluded.

We included studies providing estimated neuropathic pain frequency in the meta‐analysis. From each study we extracted author name(s), publication date, the total number of patients included, age, gender, study setting, time of evaluation, neuropathic pain diagnostic criteria, data collection, pain distribution and neuropathic pain frequency.

2.3. Bias assessment

We assessed the risk of bias at the study level with the tool developed by Munn et al. (2014). A total score was calculated for each study, reflecting the overall risk of bias. A total score between 0 and 3 corresponded to a low risk, 4–6 to a moderate risk, and ≥7 to a high risk of bias. A funnel plot analysis for the assessment of publication bias was also performed (Figure S1).

Two independent authors (GdS, PF) performed the search process, including data extraction, bias assessment and selection of studies for the meta‐analysis. A third author (AT) resolved possible disagreements.

2.4. Meta‐analysis

We included selected articles in the meta‐analysis to determine the overall frequency of neuropathic pain associated with COVID‐19. The standard error associated with each frequency p was computed using the formula p1−pn, with n being the number of subjects in each study. The standard error, in turn, was used to compute the amplitude of the 95% confidence interval (CI). We used the heterogeneity index I2 as a measure of inconsistency among study results. In case of high heterogeneity index values (> 50% for overall pooled data and subgroup analyses), the pooled frequency and relevant CI were computed using a random effects model. Otherwise, a fixed effects model was used. In the pooled meta‐analysis, the total variance Chi2, the variance among studies Tau2, and the overall effect (Z, P) were computed and reported.

3. RESULTS

We identified 149 studies. After abstract screening, 60 full‐text studies were assessed for eligibility (Figure 1). We excluded 16 studies that were not relevant and 21 studies that included less than 10 patients.

FIGURE 1.

FIGURE 1

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Flowchart of the search process of papers included in the meta‐analysis.

In this systematic review, we selected 17 studies that addressed neuropathic pain associated with COVID‐19 and investigated patients across different phases of disease, including the acute phase and long COVID syndrome. In the meta‐analysis, we included six studies that reported the frequency of neuropathic pain in the acute and subacute phase of COVID‐19.

3.1. Neuropathic pain in the acute phase

Six studies reported neuropathic pain frequency in the acute phase of COVID‐19 in hospitalized and non‐hospitalized patients (Ermis et al., 2021; Jena et al., 2022; Mahammedi et al., 2020; Mao et al., 2020; Ocak & Sahin, 2022; Oguz‐Akarsu et al., 2022). Of the six studies in the acute phase, four studies, which enrolled 1174 patients, investigated the frequency of neuropathic pain in hospitalized adult patients (Ermis et al., 2021; Jena et al., 2022; Mahammedi et al., 2020; Mao et al., 2020). Of these four studies, two retrospective studies, which included 939 hospitalized patients, reported a neuropathic pain frequency of 0.4 and 2%, respectively (Mahammedi et al., 2020; Mao et al., 2020). In the other two prospective studies (Ermis et al., 2021; Jena et al., 2022), which enrolled 182 and 53 patients, respectively, the frequency of neuropathic pain ranged between 8 and 13%. In the study including 182 patients, logistic regression analysis showed an association between pain and COVID‐19 severity, male sex, higher body mass index and a history of addiction (Jena et al., 2022).

Of the six studies in the acute phase, one study included 222 non‐hospitalized COVID‐19 adult patients in the acute phase who completed a dedicated questionnaire on pain via phone interview (Oguz‐Akarsu et al., 2022). Tingling, burning, hot, cold or freezing pain, electric shocks or shooting pain evoked by touch and limited to a dermatome or specific neuronal distribution were all accepted as clinical signs compatible with neuropathic pain. Of the 222 patients included in this study, 71.6% complained of pain and 49.1% reported neuropathic pain symptoms. Logistic regression analysis showed a strong association between neuropathic pain and headache, suggesting the presence of common etiologic factors.

Of the six studies in the acute phase, a cross‐sectional study, which included 429 patients attending a COVID‐19 outpatient clinic, reported neuropathic pain in 12.6% of participants. This cohort study, however, also included patients with negative PCR test results (Ocak & Sahin, 2022).

One retrospective study, which investigated the prevalence of brachial plexus injury in patients hospitalized in COVID‐19 critical care facilities, indirectly provided information on neuropathic pain frequency (Miller et al., 2021). Out of 114 patients requiring prone ventilation, 15 patients had peripheral nerve injuries affecting the upper limbs, and all of them complained of neuropathic pain. Acro‐ischemic lesions, with neuropathic‐pain‐like symptoms according to the Douleur Neuropathique 4 (DN4) questionnaire, were described in a study enrolling asymptomatic and mildly symptomatic children with COVID‐19 (Papa et al., 2021).

3.2. Neuropathic pain in recovered COVID‐19 patients

Several studies investigated neuropathic pain in recovered COVID‐19 patients.

One study analysed the frequency of pain in 65 previously critically ill COVID‐19 survivors 1 month after hospital discharge. Pain was assessed using the Brief Pain Inventory, the DN4 questionnaire and the Pain Catastrophizing Scale (Ojeda et al., 2022). Of these 65 patients, 50.8% reported pain and 16.9% suffered from neuropathic pain. Of those with neuropathic pain, 70% reported pain in the lower extremities, an anatomical distribution compatible with polyneuropathy, possibly related to the previous critical illness.

Five studies investigated the characteristics of pain and/or incidence of small fibre neuropathy in patients with long‐term complications after COVID‐19 (long COVID syndrome) (Davis et al., 2021; Eliaçik & Çelikbas, 2022; Magdy et al., 2022; Novak et al., 2022; Oaklander et al., 2022).

A case–control study that included 45 patients with pain who were previously affected by COVID‐19 and 45 age‐ and sex‐matched healthcare workers who recovered from COVID‐19 without pain used the DN4 screening questionnaire to diagnose neuropathic pain (Magdy et al., 2022). In this study, depression, azithromycin use and severe COVID‐19 were independent predictors of persistent pain in patients with long COVID syndrome. Patients with pain had significantly higher neurofilament light chain than the control group. The level of this biomarker was positively correlated with neuropathic pain intensity.

Two studies investigated the characteristics of pain and the incidence of small fibre neuropathy in the framework of a long COVID syndrome (Novak et al., 2022; Oaklander et al., 2022). Novak and colleagues evaluated consecutive patients with chronic fatigue, brain fog and orthostatic intolerance consistent with post‐acute sequela of COVID‐19. This study supported evidence of long COVID multisystemic involvement, including small fibre neuropathy, dysautonomia, cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction, respiratory dysregulation and chronic inflammation (Novak et al., 2022). In a retrospective study involving 17 patients with long COVID syndrome, skin biopsy, electrodiagnostic tests and autonomic function tests were abnormal in 63%, 17% and 50% of patients, respectively (Oaklander et al., 2022), thus indicating that small fibre neuropathy is a relatively common complication in patients with long COVID.

A retrospective study described 13 patients who developed paraesthesia within 2 months following SARS‐CoV‐2 infection, with an acute onset and coexisting autonomic symptoms in seven. Skin biopsy confirmed a diagnosis of small fibre neuropathy with a length‐dependent pattern in six patients (Abrams et al., 2022).

A recent study involving previously hospitalized COVID‐19 survivors selected 77 patients reporting pain as a long‐term complication, including widespread pain and pain affecting different body regions (head, cervical or lumbar spine, shoulder and knee). The frequency of neuropathic pain symptoms in this selected sample of patients, as assessed with the Self‐Administered Leeds Assessment of Neuropathic Symptoms and Signs (S‐LANSS) screening questionnaire was 12.7% (Herrero‐Montes et al., 2022).

An online survey analysed responses from 3762 COVID‐19 survivors from 56 countries with illness lasting over 28 days. Patients suffering from long COVID reported prolonged multisystemic involvement and significant disability, brain fog, neuropathic pain (defined as neuralgia, electric‐shock‐like sensations) and other neuropsychiatric symptoms in a significant percentage of cases (Davis et al., 2021). A cross‐sectional prospective study involving 169 participants showed that both S‐LANSS and DN4 total scores were higher, compatible with neuropathic pain, in patients with long COVID syndrome as compared to a control group of recovered COVID‐19 patients without pain (Eliaçik & Çelikbas, 2022). In a study including 146 COVID‐19 survivors with pain, the PainDETECT and S‐LANSS questionnaires were positively associated with pain intensity, anxiety, sensitization‐associated symptoms, catastrophism and kinesiophobia, and negatively associated with quality of life (Fernández‐de‐Las‐Peñas, Giordano, et al., 2022; Fernández‐de‐Las‐Peñas, Valera‐Calero, et al., 2022).

3.3. Pooled analysis of neuropathic pain frequency

The meta‐analysis included six studies involving 1461 patients that provided an estimated frequency of neuropathic pain associated with COVID‐19 (Table 1). All patients included in these studies were in the acute/subacute phase of COVID‐19.

TABLE 1.

Studies included in the meta‐analysis

Reference Patients (no) Population Time of evaluation Mean age (years) (F:M) MV (no) NP criteria Data collection Pain distribution NP frequency (%)
Jena et al. (2022) 182 Hospitalized patients Acute phase 49 0.38 44 Pain descriptors In person assessment

Upper limb: 5 patients

Lower limb: 6 patients

Diffuse: 3 patients

 7.69
Ojeda et al. (2022) 65 Critically ill survivors After 1 month of hospital discharge 65 0.35 50 DN4 questionnaire In person interview

Two or more body locations: 29 patients

Widespread pain: 5 patients

 16.9
Oguz‐Akarsu et al. (2022) 222 Non‐hospitalized patients Acute phase 42 0.91 3 Pain descriptors Phone interview a 24.8
Ermis et al. (2021) 53 Hospitalized patients Acute phase 63 0.65 a Neuralgia (no specified description) In person assessment a 13.2
Mahammedi et al. (2020) 725 Hospitalized patients Acute phase 69 0.57 a Neuralgia (no specified description) Electronic medical records a 0.4
Mao et al. (2020) 214 Hospitalized patients Acute phase 53 1.46 a Nerve pain (no specified description) Electronic medical records a 2.3
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Abbreviations: no, number of patients; NP, neuropathic pain; MV, mechanical ventilation.

a

Information not available.

The estimated frequency of neuropathic pain in the acute/subacute phase of COVID‐19 ranged between 0.4 and 25% (Figure 2). Forest plot analysis showed that the random effects overall frequency was 10% (95% CI: 5%–15%), with a high level of heterogeneity (Chi2 = 104; Tau2 = 0.004; df = 5; I 2 = 95%; test for overall effect: Z = 3.584; p < 0.0005).

FIGURE 2.

FIGURE 2

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Forest plot showing overall pooled frequency estimates of neuropathic pain associated with COVID‐19.

3.4. Risk of bias

The risk of bias was moderate in all studies selected (they did not provide sample size calculation, apply widely agreed diagnostic criteria for neuropathic pain, or provide a detailed description of statistical analysis and/or cut‐off values) (Table S1). Funnel plot analysis to assess the risk of publication bias did not show a clear asymmetry (Figure S1).

4. DISCUSSION

Our meta‐analysis showed that the pooled estimated frequency of neuropathic pain associated with the acute/subacute phase of COVID‐19 was 10% (95% CI: 5–15%). This finding is in line with previous studies suggesting an increased risk of neuropathic pain in patients with COVID‐19 (Herrero‐Montes et al., 2022). Admittedly, the high level of heterogeneity indicates that the pooled estimated frequency we found should be interpreted with caution.

Since its emergence in late 2019, extensive research into SARS‐CoV‐2 and its clinical presentation has indicated that COVID‐19 is frequently associated with neurological complications, possibly due to the neurotropism and neuroinvasiveness of SARS‐CoV‐2 (Bauer et al., 2022; Notz et al., 2021; Varatharaj et al., 2020). Cohort studies reported neurological complications such as stroke, myelitis and peripheral neuropathies in over a third of patients during the acute disease phase (Balcom et al., 2021). Accordingly, several case reports and case series have described neuropathic pain that was directly associated with neurological complications of COVID‐19 (Aksan et al., 2020; Cao et al., 2020; Molina‐Gil et al., 2021; Odriozola et al., 2021; Shors, 2020; Tiet & AlShaikh, 2020). For example, 46% of patients with Guillain‐Barré syndrome related to SARS‐CoV‐2 infection complained of pain (Luijten et al., 2021).

However, we found that several studies also reported neuropathic pain during different disease phases without explicitly detailing peripheral and central nervous system involvement related to COVID‐19 (Jena et al., 2022; Oguz‐Akarsu et al., 2022).

The studies that we selected for the meta‐analysis did not follow widely agreed criteria for a definite neuropathic pain diagnosis (Finnerup et al., 2016). In these studies, diagnostic criteria for neuropathic pain were poorly specified and neuropathic pain was defined with different and indefinite terms and descriptions (e.g., nerve pain, neuralgic pain). The high heterogeneity (I 2 = 95%) we found in our meta‐analysis probably reflects the different diagnostic criteria used in these studies and raises the possibility that these studies had poor precision in defining the frequency of neuropathic pain in patients in the acute/subacute phase of COVID‐19. Additional sources of statistical heterogeneity should be considered. Differences in clinical assessment may have an impact. Although most studies conducted in‐person clinical assessment, the study by Oguz‐Akarsu and colleagues collected data through phone interviews. While most studies examined acute pain in hospitalized patients, the study by Ojeda and colleagues focused on pain persisting 1 month after hospital discharge. Other possible sources of heterogeneity may include differences in study design (prospective or retrospective), clinical characteristics (severe, moderate or mild infection), and demographics (mean age, gender distribution and geographic origin).

The scarce information on the diagnostic criteria for neuropathic pain in the studies we selected may therefore dispute current evidence that neuropathic pain is a commonly encountered complication in the acute disease phase. Additionally, the estimated prevalence of neuropathic pain in the general population, which is between 7 and 10% (van Hecke et al., 2014), seems to further contradict the hypothesis of an increased risk of neuropathic pain associated with COVID‐19. However, many studies have indicated that SARS‐CoV‐2 has the potential to trigger neuropathic pain through multiple mechanisms. Indirect evidence suggests that SARS‐CoV‐2 may trigger nociceptor sensitization through cytokines and proinflammatory mediators (McFarland et al., 2021). Furthermore, SARS‐CoV‐2 spike protein binds to ACE2 receptors to infect human cells (Scialo et al., 2020). ACE2 receptors are also expressed by human dorsal root ganglia (DRG), thus raising the possibility that SARS‐CoV‐2 might directly target sensory neurons in the DRG (Shiers et al., 2020). It follows that all these phenomena might trigger neuropathic pain without clinically evident somatosensory system damage. Therefore, the grading system for neuropathic pain diagnosis (Finnerup et al., 2016), the current reference standard method for diagnosing neuropathic pain, might have poor sensitivity in detecting neuropathic pain in patients with COVID‐19. Furthermore, it is also possible that the frequency of neuropathic pain in patients with COVID‐19 might be even underestimated since it is well‐established that chronic neuropathic pain may also develop several weeks after injury to the nervous system (Jang et al., 2018).

Additional evidence supporting the possibility that SARS‐CoV‐2 affects the somatosensory nervous system, and thus potentially triggers neuropathic pain, comes from the observation that patients with neuropathic pain conditions report increased neuropathic pain symptom severity in association with COVID‐19, regardless of COVID‐19 disease severity (Attal et al., 2021). Although we cannot exclude that neuropathic pain worsening might be instead associated with psychological distress, this observation further supports a possible correlation between COVID‐19 and neuropathic pain.

Our systematic review also indicates that neuropathic pain might affect recovered COVID‐19 patients in the framework of a long COVID syndrome, including fatigue, brain fog and dysautonomia. Two studies (Novak et al., 2022; Oaklander et al., 2022) provided evidence that long COVID syndrome manifesting with pain was associated with skin biopsy abnormalities compatible with small fibre neuropathy. In these two studies, symptoms started approximately 1 month after COVID‐19. Due to the small sample size, these two studies were unable to provide information about possible risk factors for COVID‐19‐related small fibre neuropathy. However, women were predominantly affected in both studies, a finding possibly in line with painful neuropathies due to other aetiologies. Other studies have reported symptoms and signs of autonomic dysfunction in recovered COVID‐19 patients in the form of postural orthostatic tachycardia syndrome (Blitshteyn & Whitelaw, 2021) and hyperhidrosis (Hinduja et al., 2021), which could also be explained by autonomic fibre abnormalities in the framework of a small fibre neuropathy. However, the impact and frequency of small fibre neuropathy as a post‐acute sequela remain unclear since these studies included a small sample of patients who were all selected because they suffered symptoms compatible with small fibre neuropathy.

The association between the COVID‐19 epidemic and long‐lasting neuropathic pain resembles the association between long‐lasting neuropathic pain and Chikungunya fever. Chronic pain with neuropathic pain characteristics was described as a frequent long‐term complication of the infection, and neuropathic symptoms were associated with more severe disease (de Andrade et al., 2010).

No studies included in the present meta‐analysis reported the frequency of neuropathic pain in the framework of a long COVID syndrome. Accordingly, additional analyses are needed to increase our knowledge of the development of neuropathic pain as a long‐term complication of COVID‐19.

5. CONCLUSIONS

Our meta‐analysis shows that the frequency of neuropathic pain associated with COVID‐19 in the acute/subacute phase ranges between 0.4 and 25%, with a pooled estimated frequency of 10%. This finding should be considered with caution due to the high heterogeneity across studies and the poor description of neuropathic pain diagnostic criteria applied. Nevertheless, indirect evidence and multiple clinical observations suggest that COVID‐19 has the potential to trigger neuropathic pain. Ongoing studies with good quality protocols (Odozor et al., 2021) and further longitudinal studies enrolling consecutive patients with COVID‐19 and detailing neuropathic pain diagnostic criteria might eventually clarify the burden of neuropathic pain in patients with COVID‐19.

Our systematic review also indicates that recovered COVID‐19 patients might develop long COVID syndrome manifesting with small fibre neuropathy and pain. Further large case–control studies including consecutively recovered COVID‐19 patients are therefore needed to clarify how small fibre neuropathy affects recovered COVID‐19 patients.

FUNDING INFORMATION

This research did not receive any specific grant from any funding agency in the public, commercial or not‐for‐profit sectors.

CONFLICT OF INTEREST

Andrea Truini received consulting fees or payment for lectures from Angelini, Grunenthal, Viatris and Eliem Therapeutics. The other authors have no conflicts to declare.

Supporting information

Appendix S1.

Click here for additional data file. (15.3KB, docx)

Table S1.

Click here for additional data file. (19.1KB, docx)

Figure S1.

Click here for additional data file. (43.8KB, tif)

Di Stefano, G. , Falco, P. , Galosi, E. , Di Pietro, G. , Leone, C. , & Truini, A. (2023). A systematic review and meta‐analysis of neuropathic pain associated with coronavirus disease 2019. European Journal of Pain, 27, 44–53. 10.1002/ejp.2055

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Appendix S1.

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Table S1.

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Figure S1.

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