Observational Study Medicine ® OPEN Association between chronic pain medications and the severity and mortality of COVID-19 Study protocol for a case-population study ∗ Andrés Ancor Serrano Afonso, MDa, , Concepción Pérez Hernández, MD, PhDb, Dolores Ochoa Mazarro, MD, PhDc, Manuel Román Martínez, SC, CRAc, Inmaculada Failde Martínez, MD, PhDd, Antonio Montes Pérez, MD, PhDe, Pablo López Pais, MDf, Luz Cánovas Martínez, MD PhDg, Miren Revuelta Rizo, MD, PhDh, María Luz Padilla del Rey, MDi, Ana Peiró Perió, MDj, Teresa Aberasturi Fueyo, MDk, César Margarit Ferrí, MDj, Elena Rojo Rodríguez, MDb, Agustín Mendiola de la Osa, MD, PhDl, Manuel José Muñoz Martinez, MDb, María Jesus Domínguez Bronchal, MDm, Manuel Herrero Trujillano, MDl, José Cid Calzada, MD, FIPPm, Gustavo Fabregat-Cid, MD, PhDn, María José Hernández-Cádiz, MDn, Manuel Mareque Ortega, MDm, Leticia Gómez-Caro Álvarez Palencia, MDm, Víctor Mayoral Rojals, MDa Abstract In patients with coronavirus disease 2019 (COVID-19) infection, common drugs may exacerbate symptoms and negatively impact outcomes. However, the role of chronic medications on COVID-19 effects remains poorly understood. We hypothesized that certain chronic pain medications would influence outcomes in patients with COVID-19. Editor: Ahmed Nasar. This study was registered in the European Union Electronic Register of Post-Authorization Studies (EU PAS Register with number EUPAS34604). The results will be disseminated at scientific meetings and published in a peer-reviewed journal. The first patient will be recruited in March 2020. Recruiting is ongoing. The Clinical Research Ethics committee of the University Hospital La Princesa approved the study on March 26, 2020 (approval code: DC-COVID-19, assigned by AEMPS VMA-BUP-2020-01). Although personal data is required to access the clinical records, after extraction the data will be encoded to de-identify the individual participants. The clinical record number will remain cross-linked to this code and kept under the custody of the lead investigator at each centre. Due to the large number of patients, the emergency situation, and the de-identification of personal data, the study investigators requested exemption from the need to obtain informed consent from the patients. This exemption was requested and granted. The study will comply with the provisions of current Spanish legislation on research with medicines and health products (Orden SAS 3470/2009, Real Decreto 1090/2015, and Ley Orgánica 3/2018), as well as the principles of the Declaration of Helsinki (2013). The final trial dataset will be available by contacting the study coordinator, who is responsible for quality control of the data. The authors have no funding and conflicts of interests to disclose. Supplemental Digital Content is available for this article. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. The datasets generated and/or analyzed during the current study are not publicly available due to individual privacy could be compromised, but all datasets are available from the corresponding author or study coordinator on reasonable request. a Pain Unit, Anthesthesiology Department. Hospital Universitari de Bellvitge - IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain, b Pain Unit, Anthesthesiology Department. Hospital Universitario de la Princesa, Madrid, Spain, c Department of Clinical Pharmacology. Hospital Universitario de la Princesa, Madrid, Spain, d Department of Preventive Medicine and Public Health. Universidad de Cádiz, Cadiz, Spain, e Pain Unit, Anthesthesiology Department. Hospital del Mar-IMIM, Barcelona, Spain, f Pain Unit, Anthesthesiology Department. Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain, g Pain Unit, Anthesthesiology Department. Complejo Hospitalario Universitario de Ourense, Ourense, Spain, h Pain Unit, Anthesthesiology Department. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, i Pain Unit, Anthesthesiology Department, Complejo Hospitalario Universitario de Cartagena, Murcia Spain, j Pain Unit, Anthesthesiology Department. Hospital General Universitario de Alicante, Alicante, Spain, k Pain Unit, Anthesthesiology Department. Hospital Comarcal Alt Penedes, Barcelona, Spain, l Pain Unit, Anthesthesiology Department. Hospital Puerta de Hierro, Madrid, Spain, m Pain Unit, Anthesthesiology Department. Complejo Hospitalario Universitario de Toledo, Toledo, Spain, n Pain Unit, Anthesthesiology Department. Consorcio Hospital General Universitario de Valencia, Valencia, Spain. ∗ Correspondence: Andrés Ancor Serrano Afonso, Pain Unit, Anthesthesiology Department. Hospital Universitari de Bellvitge - IDIBELL, Av. Feixa Llarga s/n., 08907 L’Hospitalet de Llobregat, Barcelona, Spain (e-mail: a.serrano@bellvitgehospital.cat). Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite this article: Serrano Afonso AA, Pérez Hernández C, Ochoa Mazarro D, Román Martínez M, Failde Martínez I, Montes Pérez A, López Pais P, Cánovas Martínez L, Revuelta Rizo M, Padilla del Rey ML, Peiró Perió A, Aberasturi Fueyo T, Margarit Ferrí C, Rojo Rodríguez E, Mendiola de la Osa A, Muñoz Martinez MJ, Domínguez Bronchal MJ, Herrero Trujillano M, Cid Calzada J, Fabregat-Cid G, Hernández-Cádiz MJ, Mareque Ortega M, Gómez-Caro Álvarez Palencia L, Mayoral Rojals V. Association between chronic pain medications and the severity and mortality of COVID-19: Study protocol for a case-population study. Medicine 2021;100:30 (e26725). Received: 14 April 2021 / Received in final form: 10 June 2021 / Accepted: 7 July 2021 http://dx.doi.org/10.1097/MD.0000000000026725 1 Serrano Afonso et al. Medicine (2021) 100:30 Medicine The main aim is to assess the effect of these medications on the course of the disease in COVID-19 patients. Secondary aims are to compare disease severity and outcomes in patients with COVID-19 receiving chronic treatment with analgesics or other medications versus untreated patients and to determine prevalence of chronic pain medications in specific subgroups of hospitalized patients for COVID-19. Multicenter case-population study in 15 care centers for patients ≥18 years of age diagnosed and hospitalized with COVID-19. Controls will include patients treated at participating centers for chronic pain during the six-month period prior to March 15th, 2020. Each case will be age- and sex-matched to 10 controls. Patients will be grouped according to disease severity criteria. The primary outcome measures in patients admitted for COVID-19 will be: 1. statistical association between chronic pain medication and disease severity; 2. association between chronic pain treatment and survival. Secondary outcome measures include: 1. prevalence of chronic pain medications in patients with COVID-19 by age and sex; 2. prevalence of chronic pain medications in patients with COVID-19 vs controls. Patients and controls will be paired by age, sex, and geographic residence. Odds ratios with 95% confidence intervals will be calculated to determine the association between each drug and clinical status. Univariate and multivariate analyses will be performed. This is a study protocol. Data is actually being gathered and results are yet not achieved. There is no numerical data presented, so the conclusions cannot be considered solid at this point. Pain medications are likely to influence severity of COVID-19 and patient survival. Identifying those medications that are most closely associated with severe COVID-19 will provide clinicians with valuable data to guide treatment and reduce mortality rates and the long-term sequelae of the disease. Abbreviations: ACE = angiotensin-converting enzyme, ACE2 = angiotensin-converting enzyme type 2, Ang 1-7 = angiotensin 1- 7, ARB = angiotensin II receptor blockers, AT1 = angiotensin II type 1, CI = confidence intervals, CRH = corticotropin-releasing hormone, COVID-19 = coronavirus disease 2019, COX-2 = cyclooxygenase-2, ECMO = extracorporeal membrane oxygenation, eCRF = electronic case report form, EMA = European Medicines Agency, HPA = hypothalamic-pituitary-adrenal axis, ICH-GCP = International Conference of Harmonization for Good Clinical Practice, ICU = intensive care unit, iNOS = inducible nitric oxide synthase, IL-6 = interleukin-6, NF-kB = nuclear factor kappa B, NSAIDs = non-steroidal anti-inflammatory drugs, OR = odds ratio, PG = proteoglycans, RAAS = renin-angiotensin-aldosterone system, RT-PCR = reverse-transcription polymerase chain reaction, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2, TNF = tumor necrosis factor, WHO = World Health Organization. Keywords: analgesics, chronic pain, coronavirus disease 2019, glucocorticoids, non-steroidal anti-inflammatory drugs, opioids 1. Introduction drugs have been shown to block RAAS, primarily ACE inhibitors In the recent year, numerous studies have been performed to (i.e., enalapril or fosinopril), angiotensin II receptor blockers better understand the novel coronavirus SARS-CoV-2, the (ARB) (i.e., candesartan or valsartan), and anti-aldosterone disease it causes, coronavirus disease 2019 (COVID-19), and agents (i.e., spironolactone or eplerenone). These drugs have all other medical problems related to it, particularly the factors been shown to increase ACE2 expression,[6] which could associated with the risk of severe disease and mortality.[1] The facilitate viral entry into the targeted cells.[8] COVID-19 virus penetrates cells by binding to the angiotensin- The available evidence indicates that certain factors—primari- converting enzyme type 2 (ACE2) receptor, widely expressed ly older age and the presence of pre-existing medical conditions throughout the body, through the spike protein,[2,3] in a manner such as hypertension, diabetes, and ischemic heart disease—are similar to the coronavirus responsible for the SARS epidemic in the main variables associated with poor outcomes in patients 2002 to 2003.[4] It has been hypothesized that severe acute with COVID-19.[9] These conditions are associated with RAAS respiratory syndrome coronavirus 2 has a high affinity for this imbalances, even in the absence of an active medication that receptor, which allows the virus to enter the cell and replicate. directly acts on RAAS. Importantly, these pre-existing comor- ACE2 is a homologue of the angiotensin-converting enzyme bidities are more prevalent in older people, who are also more (ACE), which plays a key role in regulating blood pressure by likely to be taking medications—often in polypharmacy—such as converting angiotensin I to angiotensin II, which acts on the thiazolidinediones, non-steroidal anti-inflammatory drugs angiotensin II type 1 (AT1) receptor to produce vasoconstric- (NSAIDs), ACE inhibitors, ARBs, and corticosteroids. Indeed, tion.[5] In addition, angiotensin II increases production of several studies suggest that some of these drugs may exacerbate aldosterone to promote the reabsorption of sodium and water. symptoms of COVID-19, leading to worse outcomes.[10–12] This can result in an increase of blood pressure.[6] In contrast, These aggravating factors are all associated with the use of ACE2 inactivates angiotensin II, leading to an increase in RAAS blockers, which—together with the increased expression angiotensin 1–7 (Ang 1—7), a peptide with a potent vasodilator of ACE2 induced by these drugs—suggests that the use of RAAS action. This increase of Ang 1—7 serves as a negative regulator of blockers (particularly ACE inhibitors) could be a risk factor for the renin-angiotensin-aldosterone system (RAAS).[7] But this is disease severity and poor prognosis in patients with COVID- not the only action of angiotensin 1–7. It also has anti- 19.[10,11] Nonetheless, there is some evidence to suggest that inflammatory properties. In addition, several other groups of ARBs could protect against lung injury in COVID-19.[8] Clearly, 2 Serrano Afonso et al. Medicine (2021) 100:30 www.md-journal.com there are many open questions and controversies surrounding the among older people and those with pre-existing conditions, there effect of these and other medications on the course of disease in is an urgent need to determine whether and how these commonly patients with COVID-19.[11] used drugs influence outcomes of this novel disease. The AT1 receptor mediates most of the activity of angiotensin II The main aim of this study is to assess the effect of the type 2 (AT2) and is implicated in multiple pathways related to aforementioned medications on the course of the disease in stress response regulation. Stimulation of the AT1 receptor COVID-19 patients. Moreover, we also want to compare disease contributes to the release of different types of markers. For severity and outcomes in patients with COVID-19 receiving instance, AT2 interacts with the AT1 receptor, activating the chronic treatment with analgesics or other medications before NADPH-oxidase complex, the microglial complex via RhoA/ acquiring the disease, with untreated patients. Furthermore, Rho kinase, nuclear factor kappa B, inducible nitric oxide another aim is to determine the prevalence of chronic pain synthase, and cyclooxygenase-2. In turn, activated cyclooxygen- medications in specific subgroups of hospitalized patients for ase-2 produces central and peripheral inflammation as well as COVID-19. oxidative and nitrosative stress.[13] Stimulation of the AT1 receptor also releases tumor necrosis factor, which plays an important role in various neurodegenerative disorders and 2. Methods different pain disorders and also regulates activation of the hypothalamic-pituitary-adrenal axis (HPA).[14] 2.1. Hypothesis Stimulation of the AT1 receptor in the hypothalamus increases We hypothesized that certain analgesics and other chronic pain production of corticotropin-releasing hormone, which in turn medications (see Supplemental Digital Content - Annex S1, http:// stimulates secretion of adrenocorticotropic hormone in the links.lww.com/MD2/A290) could influence disease severity and anterior pituitary gland, initiating the stress response cascade. mortality in patients with COVID-19. To assess the influence of Consequently, in humans, blockade of the AT1 receptor activates these drugs, we grouped patients into different categories the HPA pathway.[14] The role of angiotensin II receptors in the according to their clinical status (severity criteria): production of cytokines and proteoglycans has led to numerous 1. hospital admission without need for oxygen therapy warning about the use of NSAIDs (particularly ibuprofen) in 2. admission requiring oxygen therapy support alone, patients with COVID-19, although the potential negative effects 3. admission (inpatient ward or emergency department) requir- of these drugs have not been confirmed by the European ing non-invasive ventilation; Medicines Agency.[15] Similarly, the effects of corticosteroids also 4. admission to intensive care unit requiring mechanical remain unclear.[16] By contrast, the role of interleukin 6 (IL-6) in ventilation (supine, prone, or extracorporeal membrane the production of cytokines, especially in patients with severe oxygenation) and COVID-19, has been well-established. In fact, the IL6 receptor 5. death due to COVID-19. inhibitor tocilizumab has been used extensively to treat these patients. Relevantly, many drugs routinely used for chronic pain management have been shown to decrease IL-6 levels, especially 2.1.1. Main objective. To determine whether the use of lidocaine IV, cannabinoids, and (indirectly) anticonvulsants.[17– analgesics and chronic pain medications influence the course 26] of disease in patients with COVID-19 based on severity criteria According to the 2017 National Health Survey in Spain,[27] (groups 3, 4, and 5). low back pain and osteoarthritis are the second and third most 2.1.2. Secondary objectives. common health problems in Spain, affecting 18.5% and 17.5%, respectively, of the population. Given this high prevalence, the a) To evaluate survival in patients with COVID-19 receiving potential effects of drugs used to treat these and other chronic treatment with analgesics and other medications comorbidities in patients with COVID-19 may be particularly versus patients with COVID-19 not taking those drugs. To relevant for individuals receiving medical treatment for chronic identify the factors associated with survival in these patients. pain, which include NSAIDs, paracetamol, metamizole, cortico- steroids, opioids, anticonvulsants, antidepressants, lidocaine, ketamine, cannabinoids, and naltrexone. However, some of these Table 1 medications may actually have a beneficial effect; for example, Participating hospitals. intravenous lidocaine[17,26] and cannabinoids may reduce IL-6, Hospital name Abbreviation an inflammatory cytokine that is often significantly elevated in 1) Hospital Universitario Bellvitge HUB patients with COVID-19, particularly in severe cases.[28] By 2) Hospital Universitario La Princesa HLPR contrast, other analgesics, particularly those that produce 3) Complejo Hospitalario de Toledo CHUT pulmonary vasoconstriction, such as opioids (e.g., buprenor- 4) Hospital Comarcal L’Alt Penedes HCAP phine and tramadol) and antidepressants that inhibit serotonin 5) Hospital HM Madrid HMM reuptake, could negatively impact the course of COVID-19.[29] 6) Hospital Universitario y Politécnico La Fe de Valencia HUYPLF Similarly, the effect of other opioids widely used to treat chronic 7) Puerta de Hierro-Majadahonda HPH pain are also unknown and may have contradictory effects on the 8) Hospital Clínico de Santiago de Compostela CHUS lung and possibly on the effects of ARBs (e.g., serotonin reuptake 9) Consorcio Hospital General de Valencia CHGUV inhibition, decrease in the HPA axis, and immunomodulator 10) Hospital Universitario de Ourense CHUO effects on interleukins).[25,26,30–38] Regrettably, at present, the 11) Hospital General Universitario Santa Lucía HGUSL 12) Hospital Universitario de la Santa Cruz i Sant Pau HUSCSP potential effects of most of these chronic pain medications on the 13) Hospital General Universitario de Alicante HGUA clinical course of patients with COVID-19 are not well- 14) Hospital del Mar de Barcelona HMar understood.[39] Given the severity of COVID-19, particularly 3 Serrano Afonso et al. Medicine (2021) 100:30 Medicine 2. The association between chronic pain treatment (analgesics Table 2 and adjuvant medications) and survival risk for patients Formula to match cases and controls based on prevalence rates admitted for COVID-19. for given drugs. Prevalence of use Odds ratio of a given drug (%) Cases, n Controls, n 2.5. Secondary outcomes ≥1.5 5 918 9172 10 499 4987  To verify whether the use of chronic pain medications in 15 363 3624 patients hospitalized for COVID-19 is greater in specific 20 298 2973 subgroups (age and sex). 30 240 2396  To identify the prevalence of use of certain analgesics and other ≥2.0 5 277 1763 chronic medications in patients with COVID-19. 10 154 1540 15 115 1146 ^ In Phase I of this study, we will examine the prevalence of 20 97 962 these medications in the patients admitted for COVID-19. 30 81 809 ^ In Phase II, we will compare the prevalence of use of each individual medication (analgesics and non-analgesics) in patients admitted for COVID-19 and controls. If a sufficient b) To determine whether the use of chronic pain medications in number of controls are COVID-19+, we will perform a sub patients hospitalized for COVID-19 is greater in specific analysis to compare patients to COVID-19+ controls. subgroups (age and sex). c) To compare the prevalence of these drugs in patients admitted for COVID-19 vs sex- and age- matched controls (patients 2.6. Data collection for phases I and II with chronic pain receiving treatment at the hospital pain Each patient’s medical record number will be obtained and management units). searched for the required data (Supplemental Digital Content - Design: This is a case-population study. Annex S2, http://links.lww.com/MD2/A290). All relevant study This multicenter study involves 15 tertiary care hospitals in variables will be extracted from these medical records and Spain (Table 1). recorded in an electronic case report form (electronic case report form; Microsoft Excel; see Supplemental Digital Content Annex S3, http://links.lww.com/MD2/A290) for complete list of 2.2. Participants and eligibility criteria variables and codes). Patients will be identified by the hospital PHASE 1: SELECTION OF CASES acronym chosen by local investigators (e.g., Hospital La Princesa Participants: Adult patients (≥18 years) admitted to one of the - HLPR) and assigned a consecutive number. The data collected participating hospitals with a diagnosis of COVID-19 based on a (de-identified) will be sent on a weekly basis to the lead positive reverse-transcription polymerase chain reaction test. investigator as pseudo anonymized data in accordance with the Study period for phase 1: The starting date is pretended to be recommendations of the International Conference of Harmoni- March 15, 2020. The study finalization date may be extended zation for Good Clinical Practice. All data will be verified and depending on the number of cases. Recruitment may take more validated by a biostatistician at the University of Cádiz. The than 12 months. Clinical Pharmacology Unit at the HLPR will conduct quality PHASE 2. SELECTION OF CONTROLS control measures to ensure data integrity. Controls will be obtained from the database of the individual pain management units at each participating hospital. Controls 2.7. Statistical analysis will be selected from patients treated at these pain management units in the 6 month period prior to the official onset of the We will perform both univariate and multivariate analyses. For pandemic (declared by the World Health Organization on March the univariate analysis, a descriptive analysis of the data will be 11, 2020). Controls will be age- and sex-matched to the carried out to show the distribution of the qualitative variables as hospitalized patients diagnosed with COVID-19. All controls will absolute (n) and relative frequencies (%) and central tendency be classified as COVID-19 positive, negative, or status unknown. (mean) and dispersion (standard deviation) for quantitative variables. The Kolmogorov-Smirnov test will be applied to check 2.3. Recruitment of cases and controls distribution normality of the quantitative variables. We will calculate the proportion of patients with COVID-19 Data will be obtained consecutively from all patients admitted to receiving any of the following medications prior to hospital the participating hospitals for COVID-19. Each case will be admission (index date): NSAIDs, corticosteroids, opioids, matched to 10 controls. The sample size will vary based on the anticonvulsants, antidepressants, lidocaine, and cannabinoids prevalence of a given drug (alpha error = 0.05, beta error = 0.20) (together and separately). These values will then be compared to in the sample according to the data in Table 2. the exposure to these drugs in a random sample of controls treated in the pain management units of the participating hospital 2.4. Primary outcome measures during the 6 months prior to study initiation. Patients and controls will be paired by age, sex, and residence (regions). 1. The statistical association between chronic pain medication The crude odds ratio and 95% confidence intervals will be usage (analgesics and adjuvant medications) and calculated to determine the association between each drug and disease severity (according to the aforementioned group the patient’s clinical status based on the severity criteria of the classification). aforementioned groups: 4 Serrano Afonso et al. Medicine (2021) 100:30 www.md-journal.com 1. admission (inpatient ward or emergency department) requir- and other variables (i.e., disease stage, patient-specific variables, ing non-invasive ventilation; treatments, etc.). Another confounding factor is that some 2. admission to intensive care unit requiring mechanical therapies used to treat patients with COVID-19, such as ventilation (supine, prone, or extracorporeal membrane hydroxychloroquine[48] or lopinavir/ritonavir,[49] can be neuro- oxygenation, toxic while others, such as azithromycin[50] or tocilizumab,[51] 3. death due to COVID-19, and among others, have neuroprotective properties. 4. a single variable that combines the 3 previous variables. Given the potential severity of this disease, particularly in patients with pre-existing conditions, together with the likelihood A multivariate analysis will be performed and, for each of the that the COVID-19 pandemic seems likely to be with us for an variables, a conditioned logistic regression model will be extended period of time, with ongoing outbreaks,[52] it is crucial constructed and the adjusted odds ratio for comorbidities and that we make every effort to identify the medications most likely other treatments will be estimated. We will assess whether sex to negatively impact the clinical course in these patients. and age act as effect modifiers. Particularly when the scope of COVID-19 being an endemic Survival in patients hospitalized for COVID-19 will be virus increases over time and with new strains appearing over and analyzed using the Kaplan–Meier method. The start and end over. dates will be symptom onset (start) and the outcome (death or In the present study, we expect to identify those medications discharge) as the end date of the study (only for Phase 1). that are most closely associated with severe COVID-19. If To identify the factors associated with overall survival time, an successful, these findings will provide clinicians with valuable adjusted Cox regression model will be performed with hazard data to help guide and improve treatment of COVID-19 in the ratios (HR) and 95% confidence intervals for each of the near future, potentially reducing mortality rates and reducing pharmacological groups for the treatment of pain and adjuvants, the long-term sequelae of the disease. We also expect to help and others factors of known clinical relevance for the survival of clinicians attending chronic pain patients to be able to choose COVID-19 patients. between those drugs, so that the likelihood of an increase in The statistical analyzes will be performed with the IBM-SPSS severity of SARS-CoV-2, after getting infected with COVID-19, is statistical software package, v.24.0 (IBM-SPSS, Chicago, IL). diminished. These data may also provide clinicians with a tool to In phase 1, intermediate analyses will be performed as the total treat pain patients in the context of the pandemic until an number of patients increases (e.g., at 100, 250, and 500 cases). At effective treatment or vaccine for COVID-19 has been obtained. each point, we will collect data for the matching controls. The Scientific Committee will assess the need to continue or not with data collection at each of these intermediate points. Ethics 4.1. Limitations Committee approval, if applicable, will be requested at that time. As the knowledge of the COVID-19 has been increasing through time, treatment strategies have been continuously developing and changing. As a consequence, study results can be biased. Also, 3. Results there will be limitations on the control group on phase 2. This is a study protocol. Data is actually being gathered and Undoubtedly, the results are to be conditioned to the time when results are yet not achieved. There is no numerical data presented, the study is done, and the characteristics of the patients admitted so the conclusions cannot be considered solid at this point. We at that time. As the epidemiological situation is changing very intend to get full data in late 2021 and present results on quickly and differs from country to country, a study on a different congresses and publish them in a peer reviewed journal, period of time or country could not achieve the same results. independently of what we find. At the beginning of the pandemic the available COVID-19 tests were scarce. So there is the possibility that we can count control group populations that were on COVID-19, but asymptomatic, 4. Discussion or even mildly symptomatic but not enough even to go to the It is highly likely that certain analgesics and other drugs used to emergency room. We know that this is a main limitation and treat chronic pain could influence the prevalence and severity of confusion factor for the study. Another limitation, or confusion COVID-19. Data on the potential influence of most of these drugs factor would be overestimating impact of severity. As we are in patients with COVID-19 is lacking, yet urgently needed.[35] looking only on patients admitted to hospital, we can be Several medical societies have published recommendations on overestimating the impact of such drugs. Finally, as this study has pain treatments in these patients[12,39–45] —mainly NSAIDs, not received any specific grant nor funding, and, thus, data is corticosteroids, and opioids— but recommendations for the use going to be gathered by authors on their available spare free time, of other pain treatments are scant.[40,44,45] The rationale there is the likelihood that data captures are not finished in time, underlying these recommendations for limiting the use of all of or that we are not able to include a big amount of control group the aforementioned drugs is based on the immunosuppressive population. This limitation also applies to the possibility that the effects that these drugs trigger.[39,40,43,45,46]. Immunosuppression number of patients included on each site are not proportional to can increase susceptibility to secondary infections, although these the hospital or the population corresponding to the site, but to the depends on the specific opioid, as the effects on the immune spare free time of the site team. system can vary.[47] However, at present, there is no evidence regarding the effects of opioids on COVID-19, and pain per se is also a well-known immunosuppressive agent. 5. Conclusion Disentangling the specific contribution of individual medi- In the present study protocol, we expect to be able to identify cations on the clinical course of patients with COVID-19 is highly those medications that are most closely associated with severe challenging due to the complex interplay between these agents COVID-19. If successful, these findings will provide clinicians 5 Serrano Afonso et al. Medicine (2021) 100:30 Medicine with valuable data to help guide and improve treatment of Failde Martínez, Antonio Montes Pérez, Pablo López Pais, COVID-19 in the near future, potentially reducing mortality rates Ana Peiró Perió, Víctor Mayoral Rojals, María Luz Padilla and decreasing the long-term sequelae of the disease. We also del Rey. expect to help managing chronic pain patients avoiding those drugs that could increase severe acute respiratory syndrome coronavirus 2 severity. These data may also provide clinicians References with a tool to treat pain patients in the context of the pandemic [1] Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities and its effects until an effective treatment or vaccine for COVID-19 has been in patients infected with SARS-CoV-2: a systematic review and meta- analysis. Int J Infect Dis 2020;94:91–5. obtained. [2] Luo H, Tang QL, Shang YX, et al. Can Chinese medicine be used for prevention of corona virus disease 2019 (COVID-19)? 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