key: cord-0894201-p4rfo2zs
authors: Knox, Nigel; Lee, Chang-Soon; Moon, Jee Youn; Cohen, Steven P.
title: Pain Manifestations of COVID-19 and Their Association With Mortality: A Multi-Center Prospective Observational Study
date: 2020-12-26
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2020.12.014
sha: 97e49f3ab9394f8123c1ce8a1a842dd61490090a
doc_id: 894201
cord_uid: p4rfo2zs

Objectives To determine the prevalence and breakdown of pain complaints among COVID-19 patients admitted for non-pain symptoms, and the association between the presence of pain and ICU admission and death. Patients and Methods In this multi-center prospective study, data on the intensity and type of pain was collected on 169 patients with active SARS-CoV-2 infection at 2 teaching hospitals in the U.S. and Korea and on 8 patients with acute pain at another large teaching hospital between February 1, 2020 and June 15, 2020. Results Sixty-five (38.5%) of 169 patients reported an active pain condition. The most common pain complaints were headache (n=22, 30.1%), chest pain (n=17, 23.6%), spinal pain (n=18, 24.7%), myalgia (n=13, 18.1%), abdominal or pelvic pain (n=13, 17.8%), arthralgia (n=11, 15.3%), and generalized pain (n=9, 12.5%). Those reporting headache as their main complaint were less likely to require intensive care unit (ICU) admission (P = .003). Acetaminophen or NSAIDs were prescribed to 80.8%, opioids to 17.8%, adjuvants to 8.2% and ketamine to 5.5% of pain patients. When age ≥ 65 years and sex were controlled for in multivariable analysis, the absence of pain was associated with ICU admission (OR 2.92; 95% CI 1.42–6.28; P = .004) and death (OR 3.49; 95% CI 1.40–9.76; P = .01). Conclusions Acute pain is common during active COVID-19, and may affect multiple organ systems. Reasons why pain may be associated with reduced mortality include that an intense systemic stimulus (e.g. respiratory distress) might inhibit pain signals or that the catecholamine surge associated with severe respiratory distress might attenuate nociceptive signaling.

The global pandemic has affected health systems, providers and patients, cutting across all geographical, specialty and socioeconomic boundaries. SARS-CoV-2, the novel coronavirus that causes COVID-19, can affect nearly every organ system, causing cardiovascular, gastrointestinal, musculoskeletal, respiratory and neurological symptoms. [1] [2] [3] [4] [5] Previous epidemics have also resulted in an increase in nociplastic pain (e.g. fibromyalgia, irritable bowel syndrome), a new pain category in which central sensitization is believed to play a major role. 6 In addition to directly infiltrating pain-sensitive organ systems (e.g. HIV neuropathy), other mechanisms by which pathogens such as COVID-19 may precipitate pain include deconditioning from quarantine, the well-known ability of viral illnesses to cause myalgias and headaches, via psychological stress as an inciting event (biopsychosocial model), and as a direct trigger for pain (e.g. Epstein Barr Virus causing a post-viral syndrome that includes pain, SARS-2 causing postviral diffuse myalgias, infection as a precursor for irritable bowel syndrome). [6] [7] [8] [9] If acute pain was associated with viral load or virulence, then pain might serve as a marker for more severe illness (e.g. requirement for admission or mortality), potentially altering the decision tree for frontline healthcare providers such as emergency room doctors.

The field of pain medicine covers numerous specialties, such that postgraduate pain programs train residents from numerous specialties, and articles on pain medicine are published in specialty journals in every medical discipline. Among the more than 50,000 peer-reviewed articles that have been published since January 2020 on COVID-19, only a handful have been devoted to how the disease affects pain, with nearly all focusing on logistical (e.g. risk mitigation strategies, patient triage) and educational issues. [10] [11] [12] To date, there have been no major studies on pain manifestations caused by COVID-19. We hypothesized that pain might be a biomarker J o u r n a l P r e -p r o o f for virulence or viral load, and be associated with poorer outcomes. The objectives of this study are: 1) to describe the major pain complaints caused by active COVID-19 infections, and how they are treated; 2) to determine whether pain complaints are associated with overall outcome (e.g. admission rates and mortality). including questions pertaining to the location of pain, baseline magnitude of pain on a 0-10 numerical rating scale (NRS) before analgesic interventions, and prior pain conditions. In addition, to pain complaints and analgesic treatment, disposition was recorded. At Johns Hopkins, patients who were referred for pain medicine services for either a primary (reason for admission) or secondary pain complaint were included, with data on diagnosis, location of pain, and pain scores on a 0-10 NRS recorded prospectively.

Data included the following information: age, sex, primary pain diagnosis, presence of pre-existing concomitant pain condition, baseline pain score, and opioid and non-opioid analgesic medications. A pain condition was defined as a pain score > 2/10 at baseline or during the course of treatment as recorded by both numerical and verbal rating scales. Pain diagnoses were primarily based on history, limited physical exam, and other diagnostic test reports when available. Treatments were broken down into opioids, adjuvants (e.g. antidepressants, anticonvulsants), ketamine, non-steroidal anti-inflammatory drugs or acetaminophen, and others.

Statistical analysis was performed using R 3.6.3 (R Core Team, Vienna, Austria).

Continuous variables are reported as mean ± standard deviation (SD) or median [interquartile J o u r n a l P r e -p r o o f range (IQR)] depending on the result of Shapiro-Wilk normality test. Categorical demographic and clinical data are reported using numbers of subjects and percentage. Normally distributed continuous variables were compared using the unpaired t-test and non-normally distributed continuous variables were compared using the Mann-Whitney U-test. Categorical variables were compared using the Chi-square test or Fisher's exact test. Multivariable logistic regression was used to estimate the odds ratios for death and ICU admission adjusted for age ≥ 65 years and sex, as these variables have been shown to affect outcomes. 13 All P values presented are 2tailed, with P values < 0.05 considered to indicate statistical significance. (table 1) . We separately examined patients with the most common diagnosis, headache, which represents a continuum of conditions with multiple mechanisms. Four patients exhibited migraine headaches, 12 had tension-type headaches, 2 presented with cervicogenic headaches, and 4 others had indeterminate or mixed headache features. Only 1 of the 2 patients with a preexisting pain condition had a prior headache history (pre-existing migraines in a patient who presented with a tension-type headache). One of the 4 patients who developed a migraine headache with COVID-19 continues to have persisting migraine headaches 8-months after other symptom resolution despite having no prior past medical or family history. Headaches may result from numerous etiologies including myofascial pathology, psychological stress and vascular pathology (e.g. temporal arteritis, microbleeds, thromboembolic disease, vasospasm and dilation), all of which are common with COVID-19. [16] [17] [18] The prevalence of pain in our study was 39% among patients admitted with COVID-19 to WMC and SNU, which is significantly higher than other studies that have examined clinical symptoms in COVID-19. In a retrospective study performed in 99 patients admitted to a Wuhan, China hospital with active disease, 11% reported myalgias, 8% headache, 2% chest pain, and 3% gastrointestinal complaints, though the proportion with abdominal pain was not noted. 19 A similar study from a different hospital in Wuhan performed in 138 patients found that 35% reported myalgias, 7% headache, and 2% abdominal pain. 20 However, research conducted in other viral illnesses report much higher rates of pain, with over 50% of patients with the common cold and flu experiencing myalgias and headaches, and disabling arthralgias and myalgias being J o u r n a l P r e -p r o o f reported in upwards of 90% of individuals with Chikingunya viral infection. 21, 22 In addition to differences in virulence, organ infectivity, and ability to stimulate the inflammatory cascade, another reason for the discrepancy in pain incidence is the method of surveillance, with higher rates reported with greater surveillance frequency and questions directed towards specific symptoms. 23, 24 Thirty percent of patients had a history of a preexisting pain condition, 41% (n=9) of whom experienced a recurrence, which is common with acute, life-threatening infectious diseases, including COVID-19. 6, 25 Mechanisms by which viral infections may exacerbate pain include directly increasing pain sensitivity through metabolic pathways, and by physical and psychological stressors including through anxiety and depression, sleep deprivation, activation of the sympathetic nervous system and deconditioning (i.e. biopsychosocial model). 26, 27 We hypothesized that those individuals with significant pain would be more likely to experience adverse outcomes including ICU admission and death, but when controlling for age and gender, the opposite was true. It was thought that pain might be a marker for either virulence or viral burden, both of which might lead to a higher rate of chronic pain. In previous studies that correlated viral load with acute pain symptoms, some (e.g. acute herpes zoster) have found a direct relationship between viral burden and pain, 28 while others examining the relationship in Chikunguna and HIV have failed to demonstrate an association. 29, 30 The observation that an absence of pain was associated with a poorer prognosis could be explained by the fact that pain assumed a lower priority for those with life-threatening symptoms, while those with less severe respiratory symptoms focused more on somatic complaints. Reasons why pain could have been associated with better outcomes include that an intense systemic stimulus (e.g. respiratory distress or anxiety) might inhibit pain signals (similar to conditioned pain modulation), or that J o u r n a l P r e -p r o o f the catecholamine surge associated with severe respiratory distress might attenuate nociceptive signaling. 31 This phenomenon whereby more severe injury is associated with lesser degrees of pain has previously been described for traumatic brain injury (i.e. greater burden is associated with less pain). 32 Two patients (2.7%) were treated with NSAIDs, 74.3% with acetaminophen, 6.8% with adjuvants, 16.2% with opioids, and 5.1% with intravenous ketamine. A substantial proportion of patients, 96% at WMC, received acetaminophen, which has less analgesic and antipyretic efficacy than NSAIDs. 33, 34 In mid-March 2020, non-peer-reviewed anecdotal reports emerged linking NSAIDs to exacerbation of COVID-19 illness, which led to warnings against their use by the World Health Organization and some national health agencies, a position that has since been refuted. 35, 36 No patients at SNU received opioids, which have well-known respiratory depressant effects and may inhibit one's ability to cough. Adjuvants such as antidepressants (4.1%) and anticonvulsants (2.7%) were administered to only a small number of people, as few people had non-radicular neuropathic pain and adjuvants have scant evidence in radiculopathy.

Antidepressants, gabapentinoids and muscle relaxants all act centrally to depress the nervous system, and may increase the likelihood of opioid-related complications, including respiratory depression. 37, 38 Ketamine is a powerful non-opioid analgesic that maintains minute ventilation at therapeutic doses, but may precipitate arrhythmias, angina and cardiac depression in catecholamine-depleted ICU patients. 39 Yet, despite these risks, which can be minimized or eliminated in a controlled hospital setting, the risks of under-treating pain may be more consequential. Poorly treated acute pain has been shown in observational studies to increase the risk for persistent post-injury pain and have long-term psychological consequences, including higher rates of anxiety and depression. 40 

Several limitations of our study should be acknowledged. As the virus evolves, and all of centers were major teaching hospitals with sufficient resources and expertise, our results may not be generalizable to different times and settings. Second, the relatively small sample size calculated from 2 sites may raise questions regarding reproducibility of our results, as evidenced by the wide confidence intervals for pain prevalence. Finally, since few patients were admitted primarily for pain, diagnoses may have lacked precision (e.g. causes of abdominal and neuropathic pain, precision on headache types).

The results of our study may have implications beyond the immediate course of illness.

Post-infectious chronic pain syndromes have been reported for a whole host of pathogens including the corona virus that causes subacute respiratory syndrome (SARS). 7, 41, 42 Although there are scant data on the prognostic value of acute pain during an active infection for the development of chronic pain, there is evidence that the severity of pain during acute herpes zoster significantly increases the risk for postherpetic neuralgia, which is consistent with the overarching literature suggesting that severe acute pain predisposes patients to chronic pain after injury. 43, 44 

In summary, we found that pain during active COVID-19 was common, occurring in 38.5% of infected individuals, with the most frequent complaints being headache, chest pain, spine pain, myalgias and pelvic/ abdominal pain. Individuals without pain were more likely to be admitted to an ICU and expire than those with pain. More research in the form of larger, multicenter studies are needed to provide better precision for pain prevalence rates, and determine the optimal means to treat it. 

Musculoskeletal symptoms in SARS-CoV-2 (COVID-19) patients

Impact of COVID-19 on the cardiovascular system: A review

Neurological manifestations of COVID-19 and other coronavirus infections: A systematic review

COVID-19 diagnosis and management: A comprehensive review

Gastrointestinal features in COVID-19 and the possibility of faecal transmission

Potential for a surge in nociplastic pain syndromes in the wake of COVID-19

Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study

Severe acute respiratory syndrome (SARS): epidemiology and clinical features

Long-term assessment of fibromyalgia in patients with culture-confirmed Lyme disease. Arthritis & rheumatology (Hoboken

Pain management best practices during the COVID-19 pandemic and public health crises

Pain management during the COVID-19 pandemic in China: Lessons learned

Maintaining high quality multidisciplinary pain medicine fellowship programs: Part I: Innovations in pain fellows' education, research, applicant selection process, wellness, and ACGME implementation during the COVID-19 pandemic

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

Myalgia and Fatigue: Translation from mouse sensory neurons to fibromyalgia and chronic fatigue syndromes

Viral arthritis

The role of muscles in tension-type headache

Psychological generators of stress-headaches

Virus infections incite pain hypersensitivity by inducing indoleamine 2,3 dioxygenase

Effect of viral load on the outcome of herpes zoster

Virus load and clinical features during the acute phase of Chikungunya infection in children

Identifying symptom patterns in people living with HIV disease

Conditioned pain modulation

Traumatic brain injury and chronic pain: Differential types and rates by head injury severity

Systemic pharmacologic ther.apies for low back pain: A systematic review for an American College of Physicians Clinical Practice Guideline

Antipyretic efficacy of ibuprofen vs acetaminophen

Covid-19: European drugs agency to review safety of ibuprofen

FDA advises patients on use of non-steroidal anti-inflammatory drugs (NSAIDs) for COVID-19

Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study

Opioid deaths in rural Virginia: a description of the high prevalence of accidental fatalities involving prescribed medications

Consensus guidelines on the use of intravenous ketamine infusions for chronic pain from the American Society of Regional Anesthesia and Pain Medicine (.ASRA)

Poorly controlled postoperative pain: prevalence, consequences, and prevention

Postinfectious irritable bowel syndrome--a meta-analysis

Urinary tract infection and inflammation at onset of interstitial cystitis/painful bladder syndrome

A systematic review and meta-analysis of risk factors for postherpetic neuralgia