A Review: The Manifestations, Mechanisms, and Treatments of Musculoskeletal Pain in Patients With COVID-19

Introduction

In December 2019, COVID-19, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV2), occurred in China and rapidly spread to every corner of the world. The virus posed a serious threat to global health and the world economy. The high infectivity of the initial strain and the emergence of new variants with higher transmissibility increased immune escape and reduced the efficacy of vaccines, thus increasing international spread (1). As of March 28, 2020, the virus has spread to over 200 countries (2). Since the outbreak, more than 224 million cases and 4.6 million deaths have been confirmed worldwide (3). Unfortunately, this number continues to rise. The pandemic has led to tremendous economic and social instability. An estimated number of $77 billion to $2.7 trillion of economic losses are occurring world wide (4). In light of this, the Chinese government has allocated about RMB 110.48 billion for epidemic prevention and control in 2020.

Previous studies have confirmed that the most common symptoms of COVID-19 are fever (98%), cough (76%), fatigue, or myalgia (44%). Less common symptoms include sputum production (28%), headache (13%), taste impairment (21%), smell impairment (19%), hemoptysis (5%), and diarrhea (3%) (5–9). The common characteristics of the virus appear to change with its frequent mutations. Real-time reverse transcriptase-polymerase chain reaction tests (RT-PCR) for the detection of the SARS-CoV-2 viral nucleic acid is the gold standard for diagnosis (10).

Historically, it has been reported that musculoskeletal (MSK) pain is the greatest contributor to the global burden of disability. It is also a major reason for people to seek healthcare (11, 12). Recently, MSK symptoms (36%) have been reported as one of the most common symptoms among patients with COVID-19 aside from fever (82%) and cough (61%) (13). In addition, MSK pain has been frequently reported by patients suffering from long-term post-COVID-19 sequelae (14, 15). Quality of life for patients suffering from post-COVID-19 syndrome and fatigue is significantly worsened by the presence of MSK pain. However, MSK symptoms in patients with COVID-19 have not attracted the same level of attention from the medical profession and scientists compared to other symptoms, such as fever, cough, anosmia, and ageusia. The intent of this review is to describe and present the current science related to MSK pain associated with COVID-19.

Musculoskeletal Manifestations of COVID-19

COVID-19, as well as other coronaviruses, such as Severe Acute Respiratory Syndrome Coronavirus (SARS-COV) and Middle East Respiratory Syndrome Coronavirus (MERS-COV), cause respiratory symptoms ranging from mild to life-threatening (7, 16). Coronaviruses can have extensive systemic effects including attacking the neurological, urinary, cardiovascular, gastrointestinal, hematological, hematopoietic, and reproductive systems (17, 18). Neurologic manifestations of COVID-19 can be divided into 3 categories: central nervous system manifestations, peripheral nervous system manifestations, and skeletal muscular symptoms. Central nervous system manifestations include headache, dizziness, impaired consciousness, acute cerebrovascular diseases, and seizures. Peripheral nervous system manifestations include the loss of taste and smell, as well as neuralgias (8, 19). The most common MSK symptoms include fatigue, myalgias, arthralgias, and back pain (20, 21).

Xu and Huang et al. reported that myalgia or fatigue were the most common symptoms at the onset of COVID-19 and were observed in up to 30–50% of patients (7, 22, 23). Myalgias, arthralgias, and fatigue are frequently present in patients with COVID-19 and have been reported in as many as 90% of them. Interestingly, there is no reported difference in the incidence of fatigue and myalgias between mild and severe cases of COVID-19 (24). The incidence of arthralgia is inversely related to the severity of COVID-19, with 49.5% of patients with mild disease and 29.8% of patients with severe cases reporting its presence (25). In general, the presence of these symptoms increases the likelihood of a COVID-19 diagnosis (26). In a 2021 report, 25% of patients with COVID-19 presented with only MSK symptoms and fever and without respiratory symptoms (27). A recent study reported that the back was the most common region of pain for patients seen in an outpatient clinic (21). In the current pandemic, it is important that clinicians be aware of patients who could be presenting atypical or nonspecific symptoms. Awareness of these symptoms and atypical presentations could help improve the speed of an accurate initial diagnosis, reducing transmission.

Post-COVID-19 syndromes develop during or after COVID-19. These syndromes last for more than 12 weeks and are a diagnosis of exclusion (14). Post-COVID-19 syndromes are being reported more frequently and often include MSK symptoms. Particularly, joint and muscle pain are typically reported by those having post-COVID-19 syndromes (14). A meta-analysis published by Fernández-de-Las-Peñas et al. noted that the incidence of musculoskeletal pain in patients with post-COVID-19 syndrome in their first year after infection approached 10% (28). The prevalence of post-COVID-19 MSK pain has been reported to reach 38% at 7 months after hospitalization (15).

When patients developed symptoms of focal muscle pain and fatigue, clinicians should consider the diagnosis of rhabdomyolysis.

Rhabdomyolysis, is a well-known life-threatening disorder that has been reported to be a late complication of COVID-19 (29). Patients developing significant focal muscle pain, especially in the presence of myoglobinuria should be considered for a diagnosis of rhabdomyolysis. Rhabdomyolysis is conclusively diagnosed by serologic testing, namely, by determining the level of serum creatine phosphokinase (CK) (30). Rapid clinical recognition and treatment of rhabdomyolysis associated with COVID-19 can reduce the risk for serious complications and death.

The Possible Mechanisms of Myalgia in COVID-19

The angiotensin-converting enzyme 2 (ACE-2) has been shown to be the functional receptor of the SARS-COV (31). SARS-CoV-2 (COVID-19) was named for its similarity to the SARS virus. Genomic analysis revealed that the novel SARS-COV-2 and SARS were highly homologous, sharing 79.5% of the same sequences (32, 33). Zhou et al. reported that ACE-2 was also the main receptor of COVID-19 (31, 33). The spike protein on COVID-19 uses the ACE-2 receptor to enter cells (34). The ACE-2 receptor is widely distributed in the body, especially in the lungs and epithelial cells of the small intestine (6, 35). The expression of ACE-2 in lungs and small intestine may help explain the routes of infection via the respiratory tract and fecal-oral route. ACE-2 receptors are also found in nerve tissue and the endothelial cells of many other organs. The wide distribution of ACE-2 may account for the multisystem involvement of COVID-19. Related to myalgias, ACE-2 is found in skeletal muscle as well as the central nervous system. Yamagata et al. found that the angiotensin-converting enzyme (ACE)/angiotensin (Ang) II/Ang II type 1 (AT1) receptor pathway promotes spinal pain transmission, but the ACE2/Ang (1-7) receptor pathway could alleviate hyperalgesia by inhibiting phosphorylation of p38 MAPK (36, 37). Therefore, it is possible that COVID-19 affects the ACE2-positive cells in the human spinal cord, causing the reduction of ACE-2 and Ang (1–7). The reduction of Ang (1–7) caused an increase in p38 MAPK phosphorylation, which results in hyperalgesia (34).

Another mechanism of MSK pain may be related to a cytokine storm. Among cytokine storms, interleukin-6 (IL-6) is a pivotal element of cytokine storm (38). The admission level of IL-6 is considered as a predictor to determine whether patients with COVID-19 need mechanical ventilation (39). In addition, what makes the preceding statement true is that IL-6 receptor blockade-tocilizumab is proven to be effective in patients with COVID-19 pneumonia and elevated IL-6 (40, 41). IL-6 acts on musculoskeletal tissue and can cause myalgias by inducing prostaglandin E2 production (42, 43). Besides IL-6, patients with severe cases of COVID-19 have higher plasma levels of other elements of cytokine storms, including IL-2, IL-7, IL-8, IL-10, and tumor necrosis factor-α (TNF-α) (7). These findings are supported by additional studies which also indicate that those cytokine storms are related to disease severity and mortality in patients with COVID-19 (44). Rapid replication of SARS-CoV-2 is responsible for the production of mass proinflammatory cytokines (45). Therefore, there is the strong possibility that COVID-19 myalgia pathogenesis refers to the cytokine storm.

Further studies have suggested that direct injury from the virus might be another mechanism for myalgias in patients with COVID-19 (46). However, Sansin Tuzun et al. found that CK, an indicator of muscle damage, was not associated with the development of myalgia and proposed that myalgia in patients with COVID-19 may mainly be related to functional impairment as opposed to true tissue damage (25). Immune dysfunction and hypoxic injury have been proposed as mechanisms that account for myalgias in viral infections (47–51). Whether these pathogenesis account for the manifestations of COVID-19 needs to be further investigated. Pain pathogenesis is multifactorial. The mechanisms of MSK symptoms in COVID-19 are still under investigation.

Treatment

Musculoskeletal (MSK) pain, as a symptom of COVID-19, causes significant suffering and reduces the quality of life of many patients. Treatment of pain in patients with COVID-19 should not be neglected. Conventional treatments for myalgia are varied, including pharmacological agents, non-pharmacological interventions, including psychosocial interventions and exercise therapy, and complementary therapies, such as acupuncture and Shiatsu (52). These three therapeutic approaches have varying levels of efficacy. The most commonly used drugs for treating MSK pain are opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and corticosteroids. Due to pathological changes and clinical manifestations of COVID-19, the application of these drugs for the treatment of myalgia in patients with COVID-19 might subtly produce different results.

Currently, there are no specific drugs for the treatment of MSK pain in patients with COVID-19.

Pharmacological Treatments

Opioids are one of the most potent and oldest classes of drugs for the treatment of acute and chronic pain. However, opioids, especially morphine and fentanyl, have been demonstrated to induce immune suppression (53, 54). The immune system of patients infected with COVID-19 can be significantly abnormal (55, 56). Aside from comorbidities, such as age, diabetes, and HTN, chronic opioid use may augment the risk of immunosuppression and worsen a COVID-19 infection (57). Clinicians should consider the possibility of increased susceptibility to COVID-19 infections and other secondary infections caused by immunosuppression associated with opioids. Furthermore, opioid addiction and misuse have caused a public health crisis, resulting in death and major social and economic consequences separate from the pandemic (58). Indirectly, the COVID-19 pandemic has already worsened the catastrophic opioid crisis (59). In comparison, buprenorphine seems to be safer to use in immunocompromised patients who are susceptible to infection (60). William et al. noted that buprenorphine is safe and supported by new dose titration protocols, reducing concerns about opioid withdrawal (59, 61). Fever in patients with COVID-19 can cause flushing and vasodilation, possibly increasing the absorption of opioids if transdermal patches are used to treat pain (46). Caution should generally be used when applying transdermal opioid patches in febrile patients. Opioids should not be the first choice of treatment for any patient with MSK pain, including those with COVID-19. If an opioid is considered appropriate for the treatment of moderate-to-severe MSK pain, buprenorphine may be a preferred option for several reasons, including its reduced level of immunosuppression.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for controlling fever and MSK pain. NSAIDs exert their analgesic effect through the peripheral inhibition of the synthesis of peripheral prostaglandins by the enzyme cyclo-oxygenase (COX) (62). In a clinical study, Covi et al. found that prostaglandins stimulated the antihypertensive effects of ACE inhibitors. In contrast, anti-inflammatory drugs decreased this effect by inhibiting prostaglandin synthetase (63). It has been speculated that NSAIDs could increase ACE tissue levels and indirectly worsen the severity of COVID-19. Therefore, it should be avoided. Moreover, a multi-source analysis from the Regional Pharmacovigilance Centers (CRPV) suggests that NSAIDs, such as ibuprofen and ketoprofen, would aggravate bacterial infections, especially pulmonary infections (64). However, The European Medicine Agency announced that NSAID use was unrelated to worsening of COVID-19 infections. There is currently no clear contraindication for using NSAIDs in patients with COVID-19 (65). According to European Union's (EU) National Treatment Guidelines, patients with COVID-19 can continue to take NSAIDs (like ibuprofen) in the lowest effective dose for the shortest required time (66). There is no clear evidence demonstrating a relationship between NSAIDs and disease prognosis in patients with COVID-19. Besides NSAID, paracetamol may be a good option as it has both antipyretic and analgesic effects. The EU National Treatment Guidelines recommend paracetamol as the first option for symptomatic treatment of mild symptoms of COVID-19, especially for fever and myalgias (65).

Corticosteroids have been used to treat painful MSK disorders, such as osteoarthritis, partially due to their anti-inflammatory action and rapid onset (67). However, higher doses and long-term use may lead to significant side-effects which include osteoporosis, osteonecrosis, myopathy, immunosuppression, and myalgias. These adverse effects would clearly negatively impact the well-being of patients (68). Corticosteroids, in a dose-dependent manner, were implicated as a cause of osteonecrosis in patients with SARS (69). However, a study including seven international clinical trials demonstrated that corticosteroids produced a 20% relative reduction in the risk of death in critically ill patients with COVID-19 (70). Hence, in September 2020, the WHO updated its guidance that recommends the use of systemic corticosteroids to treat patients with severe COVID-19 or in the state of refractory shock (46, 71). For patients with mild COVID-19, the WHO discourages the use corticosteroids as a first-line treatment. Corticosteroids do not appear to provide many benefits and may even be harmful (71). With these considerations in mind, it is recommended to avoid the use of corticosteroids alone in treating COVID-19 MSK pain.

Non-Pharmacological Interventions

During a pandemic, lockdowns and quarantining help reduce the spread of disease by restricting mass movements (72). Protective measures may also cause a number of harmful effects, including psychological stress and a worsening of musculoskeletal symptoms that is especially notable in women (73). Psychological stress can originate from long periods of isolation, fear of infection, lack of daily supplies, and financial losses (74). An online survey from China indicated that 16.5 to 28.8% of the respondents living through the pandemic reported moderate-to-severe depression and anxiety, the presence of which was significantly associated with physical symptoms, such as myalgias (75). Hence, the establishment of a social-psychological-biomedical treatment model and the adoption of a combination treatment of psychological and drug therapy may be ideal.

Physical inactivity caused by the social restrictions in place may worsen MSK pain (72). Regular physical exercise plays a significant role in modulating the immune system. Exercise stimulates the release of pro- and anti-inflammatory cytokines and increase of lymphocyte circulation, as well as cell recruitment. Regular physical activity is also associated with a lower incidence of mortality in patients with viral infections (76). Other studies have shown that regular and moderate exercise help to reduce the risk for upper respiratory tract infections in general (77). Another benefit of physical exercise is the overall reduction of communicable diseases, including viral pathologies (78). Exercise therapy has also been proven to be beneficial for pain and quality of life in patients with myalgia (52). An emphasis on maintaining exercise during the COVID pandemic will help improve overall health and potentially reduce other complications.

Telemedicine

Telemedicine is emerging as a valuable technology to both patients and health care providers. It can be used to reduce the risk of the spread of COVID-19 while providing ongoing care to patients with chronic pain and/or COVID-19. Telemedicine removes the need for patients to travel to healthcare centers and eliminates physical contact between patients and medical workers, thereby reducing the risk of COVID-19 transmission. Telemedicine can facilitate consultation, diagnosis, monitoring, and mentoring through virtual encounters and e-visits (79, 80).

Commonly used instruments for pain-intensity assessment are the Visual Analog Scale (VAS), Graphic Rating Scale (GRS), and Verbal Rating Scale (VRS). Other instruments to measure pain include Pain-O-Meter and McGill Pain Questionnaire (MPQ) (81). All of these tests can be conducted via telemedicine/eHealth interviews (82). Patients with mild-to-moderate post-COVID-19 pain, who have returned home and are continuing pain treatment may also benefit from telemedicine support (82). Telemedicine can also help facilitate follow-up visits of patients after discharge and allows patients to maintain the continuity of care while remaining at home (82, 83). Further, during the COVID-19 epidemic, patients who are prescribed opioids can be closely monitored without the need for frequent office visits. It is hoped that this kind of intense monitoring will help reduce opioid abuse (84).

Telemedicine has some obvious shortcomings. The use of audio and video cannot replace physical examination which plays a significant role in clinical evaluation. Depending on their social situation, telemedicine could reduce privacy for some patients (85). There are also a series of other medico-legal issues that can arise with its use, such as practicing across territorial lines (85, 86). In general, telemedicine is a good choice for pain patients and clinical workers during the COVID-19 pandemic or in the presence of an infectious disease.

Vaccine

Prevention is at the heart of public health. Safe and effective vaccines are critical to control the occurrence and prevalence of COVID-19. It is hoped that through vaccination and natural immunity, the pandemic will eventually end. Currently, there are 8 vaccines that have been shown to be safe and efficacious and are approved for use by the WHO (87). In clinical trials, some vaccines have been reported to have efficacy exceeding 90% against COVID-19 (88). Fundamentally, interrupting the transmission of COVID-19 is the best method of reducing the incidence of COVID-19-induced MSK pain. COVID-19 vaccine breakthrough infections, defined as an infection occurring in fully vaccinated people, appear to be associated with less severe MSK pain compared to patients with MSK from COVID-19 who are unvaccinated (89–91). However, literatures about clinical features of breakthrough cases are limited, thereby emphasizing the need for such research. Recently, Fikadu G et al. reported that levels of antibody and variant cross-neutralization were increased after COVID-19 vaccine breakthrough infection (91). Patients with breakthrough infections might develop stronger immunity, especially when it occurs in the presence of prior vaccination. In addition, the possibility of variant infections after vaccine breakthrough infection might further decline. Hence, it is still worthwhile to promote vaccination.

Conclusion

COVID-19 poses a great threat to global, economic, and social health. MSK pain is the most frequent symptom reported by COVID-19 patients and is one of the greatest contributors to the global burden of disability which affects daily life. At the onset of a COVID-19 infection, myalgia or fatigue may have a high degree of specificity for the disease and is one of the most common reported symptoms. The presence of these symptoms can help clinicians in making an accurate initial diagnosis. Patients who have recovered from COVID-19 often experience MSK symptoms, with fatigue, myalgia, arthralgia, and back pain being the most reported. The ACE2/Ang (1–7) receptor pathway and cytokine storms may play a role in the possible mechanism of myalgia seen in COVID-19 disease. Treatments for myalgias may include pharmacological treatments and non-pharmacological interventions. Paracetamol is recommended as the first option for the symptomatic treatment of COVID-19, especially for patients with fever and myalgia. For other pharmacological management, opioids could be considered, taking into consideration appropriate selection, dosage, duration, and tracking, along with appropriate discontinuation and evaluation of risks. Opioids should not be considered as first-line treatment for COVID-19-induced MSK pain. If opioids are considered for moderate-to-severe MSK pain, due to their limited effects on immunosuppression, buprenorphine is highly suggested to be the preferred agent. NASIDS, in general, are the most common choice for the treatment of MSK pain and are proven to be useful in patients with COVID-19. Systemic corticosteroids should only be used in patients with severe COVID-19. Non-pharmacological interventions can play a significant role in the treatment of myalgia in patients with COVID-19. Telemedicine, which is conducive to reducing the spread of COVID-19 while guaranteeing timely and effective treatment for the pain patients, may prove to be very useful. Finally, prevention of the virus and infection reduction is probably the most important method to reduce MSK-related symptoms.

Further research is required to fully understand the mechanisms causing myalgia and MSK pain from COVID-19. Moreover, additional studies are needed to reveal the optimal treatment regimens for patients suffering from COVID-19-related symptoms.

Author Contributions

LW and NY conceived and wrote the article. JY, SZ, and CS revised and reviewed the article. All authors contributed to the article and approved the submitted version.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81901141) and the Scientific Research Project of Hunan Provincial Health Commission (202204114480).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. Li J, Lai S, Gao G, Shi W. The emergence, genomic diversity and global spread of SARS-CoV-2. Nature. (2021) 600:408–18. doi: 10.1038/s41586-021-04188-6

PubMed Abstract | CrossRef Full Text | Google Scholar

2. WHO. Coronavirus disease 2019 (COVID-19) Situation Report−67 (2020). Available online at: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200327-sitrep-67-covid-19.pdf?sfvrsn=b65f68eb_4.

Google Scholar

3. WHO. COVID-19 Weekly Epidemiological Update 2021. Available online at: https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19—14-september-2021.

Google Scholar

4. Rezapour A, Souresrafil A, Peighambari M, Heidarali M, Tashakori-Miyanroudi M. Economic evaluation of programs against COVID-19: a systematic review. Int J Surg. (2021) 85:10–8. doi: 10.1016/j.ijsu.2020.11.015

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Ge H, Wang X, Yuan X, Xiao G, Wang C, Deng T, et al. The epidemiology and clinical information about COVID-19. Eur J Clin Microbiol Infect Dis. (2020) 39:1011–9. doi: 10.1007/s10096-020-03874-z

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Berger JR. COVID-19 and the nervous system. J Neurovirol. (2020) 26:143–8. doi: 10.1007/s13365-020-00840-5

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. (2020) 395:497–506. doi: 10.1016/S0140-6736(20)30183-5

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. (2020) 77:683–90. doi: 10.1001/jamaneurol.2020.1127

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Misra S, Kolappa K, Prasad M, Radhakrishnan D, Thakur K, Solomon T, et al. Frequency of neurologic manifestations in COVID-19: a systematic review and meta-analysis. Neurology. (2021) 97:2269–81. doi: 10.1212/wnl.0000000000012930

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Surkova E, Nikolayevskyy V, Drobniewski F. False-positive COVID-19 results: hidden problems and costs. Lancet Respir Med. (2020) 8:1167–8. doi: 10.1016/S2213-2600(20)30453-7

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Global regional and national incidence prevalence and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries 1990-2013: 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. (2015) 386:743–800. doi: 10.1016/S0140-6736(15)60692-4

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Lin I, Wiles L, Waller R, Goucke R, Nagree Y, Gibberd M, et al. Poor overall quality of clinical practice guidelines for musculoskeletal pain: a systematic review. Br J Sports Med. (2018) 52:337–43. doi: 10.1136/bjsports-2017-098375

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Nascimento IJBd, Cacic N, Abdulazeem HM, Groote TCv, Jayarajah U, Weerasekara I, et al. Novel coronavirus infection (COVID-19) in humans: a scoping review and meta-analysis. J Clin Med. (2020) 9:941. doi: 10.3390/jcm9040941

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Shah W, Hillman T, Playford E, Hishmeh L. Managing the long term effects of covid-19: summary of NICE, SIGN, and RCGP rapid guideline. BMJ. (2021) 372:n136. doi: 10.1136/bmj.n136

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Fernández-de-Las-Peñas C, Rodríguez-Jiménez J, Fuensalida-Novo S, Palacios-Ceña M, Gómez-Mayordomo V, Florencio L, et al. Myalgia as a symptom at hospital admission by severe acute respiratory syndrome coronavirus 2 infection is associated with persistent musculoskeletal pain as long-term post-COVID sequelae: a case-control study. Pain. (2021) 162:2832–40. doi: 10.1097/j.pain.0000000000002306

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Perlman S. Another decade, another coronavirus. N Engl J Med. (2020) 382:760–2. doi: 10.1056/NEJMe2001126

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Zheng K, Feng G, Liu W, Targher G, Byrne C, Zheng M. Extrapulmonary complications of COVID-19: a multisystem disease? J Med Virol. (2021) 93:323–35. doi: 10.1002/jmv.26294

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Gupta A, Madhavan M, Sehgal K, Nair N, Mahajan S, Sehrawat T, et al. Extrapulmonary manifestations of COVID-19. Nat Med. (2020) 26:1017–32. doi: 10.1038/s41591-020-0968-3

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Barker-Davies R, O'Sullivan O, Senaratne K, Baker P, Cranley M, Dharm-Datta S, et al. The Stanford Hall consensus statement for post-COVID-19 rehabilitation. Br J Sports Med. (2020) 54:949–59. doi: 10.1136/bjsports-2020-102596

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Karaarslan F, Demircioglu Güneri F, Kardeş S. Postdischarge rheumatic and musculoskeletal symptoms following hospitalization for COVID-19: prospective follow-up by phone interviews. Rheumatol Int. (2021) 41:1263–71. doi: 10.1007/s00296-021-04882-8

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Gökmen I, Ortanca B, Uçan A, Eker Güvenç S, Sahin Mutlu F, Gökmen H, et al. Musculoskeletal symptoms and related factors in post acute COVID-19 patients. Int J Clin Pract. 2021:e14734. doi: 10.1111/ijcp.14734

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Xu X, Wu X, Jiang X, Xu K, Ying L, Ma C, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ. (2020) 368:m606. doi: 10.1136/bmj.m606

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Ding Q, Lu P, Fan Y, Xia Y, Liu M. The clinical characteristics of pneumonia patients coinfected with 2019 novel coronavirus and influenza virus in Wuhan, China. J Med Virol. (2020) 92:1549–55. doi: 10.1002/jmv.25781

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Lippi G, Wong J, Henry B. Myalgia may not be associated with severity of coronavirus disease 2019 (COVID-19). World J Emerg Med. (2020) 11:193–4. doi: 10.5847/wjem.j.1920-8642.2020.03.013

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Tuzun S, Keles A, Okutan D, Yildiran T, Palamar D. Assessment of musculoskeletal pain, fatigue and grip strength in hospitalized patients with COVID-19. Eur J Phys Rehabil Med. (2021) 57:653–62. doi: 10.23736/S1973-9087.20.06563-6

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Struyf T, Deeks J, Dinnes J, Takwoingi Y, Davenport C, Leeflang M, et al. Signs and symptoms to determine if a patient presenting in primary care or hospital outpatient settings has COVID-19 disease. Cochrane Database Syst Rev. (2020) 7:CD013665. doi: 10.1002/14651858.CD013665

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Hoong C, Amin M, Tan T, Lee J. Viral arthralgia a new manifestation of COVID-19 infection? A cohort study of COVID-19-associated musculoskeletal symptoms. Int J Infect Dis. (2021) 104:363–9. doi: 10.1016/j.ijid.2021.01.031

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Fernández-de-Las-Peñas C, Navarro-Santana M, Plaza-Manzano G, Palacios-Ceña D, Arendt-Nielsen L. Time course prevalence of post-COVID pain symptoms of musculoskeletal origin in patients who had survived to SARS-CoV-2 infection: a systematic review and meta-analysis. Pain. (2021). doi: 10.1097/j.pain.0000000000002496

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Jin M, Tong Q. Rhabdomyolysis as Potential Late Complication Associated with COVID-19. Emerg Infect Dis. (2020) 26:1618–20. doi: 10.3201/eid2607.200445

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Parekh R, Care D, Tainter C. Rhabdomyolysis: advances in diagnosis and treatment. Emerg Med Pract. (2012) 14:1–15.

Google Scholar

31. Li W, Moore M, Vasilieva N, Sui J, Wong S, Berne M, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. (2003) 426:450–4. doi: 10.1038/nature02145

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Li Y, Bai W, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. (2020) 92:552–5. doi: 10.1002/jmv.25728

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. (2020) 579:270–73. doi: 10.1038/s41586-020-2012-7

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Su S, Cui H, Wang T, Shen X, Ma C. Pain: a potential new label of COVID-19. Brain Behav Immun. (2020) 87:159–60. doi: 10.1016/j.bbi.2020.05.025

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Hamming I, Timens W, Bulthuis M, Lely A, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. (2004) 203:631–7. doi: 10.1002/path.1570

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Nemoto W, Nakagawasai O, Yaoita F, Kanno S, Yomogida S, Ishikawa M, et al. Angiotensin II produces nociceptive behavior through spinal AT1 receptor-mediated p38 mitogen-activated protein kinase activation in mice. Mol Pain. (2013) 9:38. doi: 10.1186/1744-8069-9-38

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Yamagata R, Nemoto W, Nakagawasai O, Takahashi K, Tan-No K. Downregulation of spinal angiotensin converting enzyme 2 is involved in neuropathic pain associated with type 2 diabetes mellitus in mice. Biochem Pharmacol. (2020) 174:113825. doi: 10.1016/j.bcp.2020.113825

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Garg R. Spectrum of neurological manifestations in Covid-19: a review. Neurol India. (2020) 68:560–72. doi: 10.4103/0028-3886.289000

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Herold T, Jurinovic V, Arnreich C, Lipworth B, Hellmuth J, von Bergwelt-Baildon M, et al. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol. (2020) 146:128–36.e4. doi: 10.1016/j.jaci.2020.05.008

PubMed Abstract | CrossRef Full Text | Google Scholar

40. Mehta P, McAuley D, Brown M, Sanchez E, Tattersall R, Manson J. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. (2020) 395:1033–4. doi: 10.1016/S0140-6736(20)30628-0

PubMed Abstract | CrossRef Full Text | Google Scholar

41. Salama C, Han J, Yau L, Reiss W, Kramer B, Neidhart J, et al. Tocilizumab in patients hospitalized with covid-19 pneumonia. N Engl J Med. (2021) 384:20–30. doi: 10.1056/NEJMoa2030340

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Baracos V, Rodemann H, Dinarello C, Goldberg A. Stimulation of muscle protein degradation and prostaglandin E2 release by leukocytic pyrogen (interleukin-1). A mechanism for the increased degradation of muscle proteins during fever. N Engl J Med. (1983) 308:553–8. doi: 10.1056/NEJM198303103081002

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Nakamura K, Saito K, Hara Y, Aoyagi T, Kitakawa K, Abe Y, et al. Severe epidemic myalgia with an elevated level of serum interleukin-6 caused by human parechovirus type 3: a case report and brief review of the literature. BMC Infect Dis. (2018) 18:381. doi: 10.1186/s12879-018-3284-5

PubMed Abstract | CrossRef Full Text | Google Scholar

44. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. (2020) 323:1061–9. doi: 10.1001/jama.2020.1585

PubMed Abstract | CrossRef Full Text | Google Scholar

45. Öztürk R, Taşova Y, Ayaz A. COVID-19: pathogenesis, genetic polymorphism, clinical features and laboratory findings. Turk J Med Sci. (2020) 50:638–57. doi: 10.3906/sag-2005-287

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Widyadharma I, Sari N, Pradnyaswari K, Yuwana K, Adikarya I, Tertia C, et al. Pain as clinical manifestations of COVID-19 infection and its management in the pandemic era: a literature review. Egypt J Neurol Psychiatr Neurosurg. (2020) 56:121. doi: 10.1186/s41983-020-00258-0

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Baig A, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 Virus Targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci. (2020) 11:995–8. doi: 10.1021/acschemneuro.0c00122

PubMed Abstract | CrossRef Full Text | Google Scholar

48. Leber A, Everhart K, Balada-Llasat J, Cullison J, Daly J, Holt S, et al. Multicenter Evaluation of BioFire FilmArray meningitis/encephalitis panel for detection of bacteria, viruses, and yeast in cerebrospinal fluid specimens. J Clin Microbiol. (2016) 54:2251–61. doi: 10.1128/JCM.00730-16

PubMed Abstract | CrossRef Full Text | Google Scholar

49. Swanson P, McGavern D. Viral diseases of the central nervous system. Curr Opin Virol. (2015) 11:44–54. doi: 10.1016/j.coviro.2014.12.009

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Unni S, RuŽek D, Chhatbar C, Mishra R, Johri M, Singh S. Japanese encephalitis virus: from genome to infectome. Microbes and infection. (2011) 13:312–21. doi: 10.1016/j.micinf.2011.01.002

PubMed Abstract | CrossRef Full Text | Google Scholar

51. Jin Y, Yang H, Ji W, Wu W, Chen S, Zhang W, et al. Virology, epidemiology, pathogenesis, and control of COVID-19. Viruses. (2020) 12:372. doi: 10.3390/v12040372

PubMed Abstract | CrossRef Full Text | Google Scholar

52. Babatunde O, Jordan J, Van der Windt D, Hill J, Foster N, Protheroe J. Effective treatment options for musculoskeletal pain in primary care: A systematic overview of current evidence. PLoS ONE. (2017) 12:e0178621. doi: 10.1371/journal.pone.0178621

PubMed Abstract | CrossRef Full Text | Google Scholar

53. Shavit Y, Ben-Eliyahu S, Zeidel A, Beilin B. Effects of fentanyl on natural killer cell activity and on resistance to tumor metastasis in rats. Dose and timing study. Neuroimmunomodulation. (2004) 11:255–60. doi: 10.1159/000078444

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Mellon R, Bayer B. Evidence for central opioid receptors in the immunomodulatory effects of morphine: review of potential mechanism(s) of action. J Neuroimmunol. (1998) 83:19–28. doi: 10.1016/S0165-5728(97)00217-8

PubMed Abstract | CrossRef Full Text | Google Scholar

55. Wu H, Zhu H, Yuan C, Yao C, Luo W, Shen X, et al. Clinical and immune features of hospitalized pediatric patients with coronavirus disease 2019 (COVID-19) in Wuhan, China. JAMA network open. (2020) 3:e2010895. doi: 10.1001/jamanetworkopen.2020.10895

PubMed Abstract | CrossRef Full Text | Google Scholar

56. Guo Y, Cao Q, Hong Z, Tan Y, Chen S, Jin H, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak-an update on the status. Mil Med Res. (2020) 7:11. doi: 10.1186/s40779-020-00240-0

PubMed Abstract | CrossRef Full Text | Google Scholar

57. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. (2020) 395:1054–62. doi: 10.1016/S0140-6736(20)30566-3

PubMed Abstract | CrossRef Full Text | Google Scholar

58. Coussens N, Sittampalam G, Jonson S, Hall M, Gorby H, Tamiz A, et al. The opioid crisis and the future of addiction and pain therapeutics. J Pharmacol Exp Ther. (2019) 371:396–408. doi: 10.1124/jpet.119.259408

PubMed Abstract | CrossRef Full Text | Google Scholar

59. Becker W, Fiellin D. When epidemics collide: coronavirus disease 2019 (COVID-19) and the opioid crisis. Ann Intern Med. (2020) 173:59–60. doi: 10.7326/M20-1210

PubMed Abstract | CrossRef Full Text | Google Scholar

60. Pergolizzi J, Böger R, Budd K, Dahan A, Erdine S, Hans G, et al. Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone). Pain Pract. (2008) 8:287–313. doi: 10.1111/j.1533-2500.2008.00204.x

PubMed Abstract | CrossRef Full Text | Google Scholar

61. Becker W, Frank J, Edens E. Switching from high-dose, long-term opioids to buprenorphine: a case series. Ann Intern Med. (2020) 173:70–1. doi: 10.7326/L19-0725

PubMed Abstract | CrossRef Full Text | Google Scholar

62. Cashman J. The mechanisms of action of NSAIDs in analgesia. Drugs. (1996) 52:13–23. doi: 10.2165/00003495-199600525-00004

PubMed Abstract | CrossRef Full Text | Google Scholar

63. Covi G, Minuz P, Capuzzo G, Lechi C, Delva P, Lechi A. Reduction of the antihypertensive effect of captopril induced by prostaglandin synthetase inhibition. Int J Clin Pharmacol Res. (1984) 4:47–52.

PubMed Abstract | Google Scholar

64. Micallef J, Soeiro T, Jonville-Béra A. Non-steroidal anti-inflammatory drugs, pharmacology, and COVID-19 infection. Therapie. (2020) 75:355–62. doi: 10.1016/j.therap.2020.05.003

PubMed Abstract | CrossRef Full Text | Google Scholar

65. EMA advice on the use of NSAIDs for Covid-19. Drug Ther Bull. (2020) 58:69. doi: 10.1136/dtb.2020.000021

PubMed Abstract | CrossRef Full Text | Google Scholar

66. EMA. EMA gives advice on the use of non-steroidal anti-inflammatories for COVID-19 (2020). Available online at: https://www.ema.europa.eu/en/news/ema-gives-advice-use-non-steroidal-anti-inflammatories-covid-19.

Google Scholar

67. Kapugi M, Cunningham K. Corticosteroids. Orthop Nurs. (2019) 38:336–9. doi: 10.1097/NOR.0000000000000595

PubMed Abstract | CrossRef Full Text | Google Scholar

68. Frieze D. Musculoskeletal pain associated with corticosteroid therapy in cancer. Curr Pain Headache Rep. (2010) 14:256–60. doi: 10.1007/s11916-010-0120-z

PubMed Abstract | CrossRef Full Text | Google Scholar

69. Griffith J. Musculoskeletal complications of severe acute respiratory syndrome. Semin Musculoskelet Radiol. (2011) 15:554–60. doi: 10.1055/s-0031-1293500

PubMed Abstract | CrossRef Full Text | Google Scholar

70. Sterne J, Murthy S, Diaz J, Slutsky A, Villar J, Angus D, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. (2020) 324:1330–41. doi: 10.1001/jama.2020.17023

PubMed Abstract | CrossRef Full Text | Google Scholar

71. WHO. WHO updates clinical care guidance with corticosteroid recommendations (2020). Available online at: https://www.who.int/news-room/feature-stories/detail/who-updates-clinical-care-guidance-with-corticosteroid-recommendations.

Google Scholar

72. Joseph S, Shoib S, Sg T, Bhandari S. Psychological concerns and musculoskeletal pain amidst the COVID-19 lockdown. Open J Psychiatry Allied Sci. (2020) 11:137–9. doi: 10.5958/2394-2061.2020.00026.9

PubMed Abstract | CrossRef Full Text | Google Scholar

73. Kirmizi M, Yalcinkaya G, Sengul Y. Gender differences in health anxiety and musculoskeletal symptoms during the COVID-19 pandemic. J Back Musculoskelet Rehabil. (2021) 34:161–7. doi: 10.3233/BMR-200301

PubMed Abstract | CrossRef Full Text | Google Scholar

74. Brooks S, Webster R, Smith L, Woodland L, Wessely S, Greenberg N, et al. The psychological impact of quarantine and how to reduce it: rapid review of the evidence. Lancet. (2020) 395:912–20. doi: 10.1016/S0140-6736(20)30460-8

PubMed Abstract | CrossRef Full Text | Google Scholar

75. Wang C, Pan R, Wan X, Tan Y, Xu L, Ho C, et al. Immediate psychological responses and associated factors during the initial stage of the 2019 coronavirus disease (COVID-19) epidemic among the general population in China. International journal of environmental research and public health. (2020) 17:1729. doi: 10.3390/ijerph17051729

PubMed Abstract | CrossRef Full Text | Google Scholar

76. da Silveira M, da Silva Fagundes K, Bizuti M, Starck É, Rossi R, de Resende E Silva DT. Physical exercise as a tool to help the immune system against COVID-19: an integrative review of the current literature. Clin Exp Med. (2021) 21:15–28. doi: 10.1007/s10238-020-00650-3

PubMed Abstract | CrossRef Full Text | Google Scholar

77. Nieman D. Is infection risk linked to exercise workload? Med Sci Sports Exerc. (2000) 32:S406–11. doi: 10.1097/00005768-200007001-00005

PubMed Abstract | CrossRef Full Text | Google Scholar

78. Laddu D, Lavie C, Phillips S, Arena R. Physical activity for immunity protection: Inoculating populations with healthy living medicine in preparation for the next pandemic. Prog Cardiovasc Dis. (2021) 64:102–4. doi: 10.1016/j.pcad.2020.04.006

PubMed Abstract | CrossRef Full Text | Google Scholar

79. Shanthanna H, Strand N, Provenzano D, Lobo C, Eldabe S, Bhatia A, et al. Caring for patients with pain during the COVID-19 pandemic: consensus recommendations from an international expert panel. Anaesthesia. (2020) 75:935–44. doi: 10.1111/anae.15076

PubMed Abstract | CrossRef Full Text | Google Scholar

80. Waller M, Stotler C. Telemedicine: a primer. Curr Allergy Asthma Rep. (2018) 18:54. doi: 10.1007/s11882-018-0808-4

PubMed Abstract | CrossRef Full Text | Google Scholar

81. Haefeli M, Elfering A. Pain assessment. Eur Spine J. (2006) 15:S17–24. doi: 10.1007/s00586-005-1044-x

PubMed Abstract | CrossRef Full Text | Google Scholar

82. El-Tallawy S, Nalamasu R, Pergolizzi J, Gharibo C. Pain management during the COVID-19 pandemic. Pain Ther. (2020) 9:453–66. doi: 10.1007/s40122-020-00190-4

PubMed Abstract | CrossRef Full Text | Google Scholar

83. Song X, Xiong D, Wang Z, Yang D, Zhou L, Li R. Pain management during the COVID-19 pandemic in China: lessons learned. Pain Med. (2020) 21:1319–23. doi: 10.1093/pm/pnaa143

PubMed Abstract | CrossRef Full Text | Google Scholar

84. Khatri U, Perrone J. Opioid use disorder and COVID-19: crashing of the crises. J Addict Med. (2020) 14:e6–7. doi: 10.1097/ADM.0000000000000684

PubMed Abstract | CrossRef Full Text | Google Scholar

85. Emerick T, Alter B, Jarquin S, Brancolini S, Bernstein C, Luong K, et al. Telemedicine for chronic pain in the COVID-19 era and beyond. Pain Med. (2020) 21:1743–8. doi: 10.1093/pm/pnaa220

PubMed Abstract | CrossRef Full Text | Google Scholar

86. Ghai B, Malhotra N, Bajwa S. Telemedicine for chronic pain management during COVID-19 pandemic. Indian J Anaesth. (2020) 64:456–62. doi: 10.4103/ija.IJA_652_20

PubMed Abstract | CrossRef Full Text | Google Scholar

87. WHO. 8 Vaccines Approved for Use by WHO (2021). Available online at: https://covid19.trackvaccines.org/agency/who/.

Google Scholar

88. Knoll M, Wonodi C. Oxford-AstraZeneca COVID-19 vaccine efficacy. Lancet. (2021) 397:72–4. doi: 10.1016/S0140-6736(20)32623-4

PubMed Abstract | CrossRef Full Text | Google Scholar

89. COVID-19 Vaccine Breakthrough Infections Reported to CDC-United States January 1-April 30 2021. MMWR Morb Mortal Wkly Rep. (2021) 70:792–3. doi: 10.15585/mmwr.mm7021e3

PubMed Abstract | CrossRef Full Text | Google Scholar

90. Duarte L, Gálvez N, Iturriaga C, Melo-González F, Soto J, Schultz B, et al. Immune profile and clinical outcome of breakthrough cases after vaccination with an inactivated SARS-CoV-2 vaccine. Front Immunol. (2021) 12:742914. doi: 10.3389/fimmu.2021.742914

PubMed Abstract | CrossRef Full Text | Google Scholar

91. Bates T, McBride S, Winders B, Schoen D, Trautmann L, Curlin M, et al. Antibody response and variant cross-neutralization after SARS-COV-2 breakthrough infection. JAMA. (2021) 327:179–81. doi: 10.1001/jama.2021.22898

PubMed Abstract | CrossRef Full Text | Google Scholar