Investigating the role of opium consumption in the severity, and outcome of COVID-19

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Some people are more susceptible to coronavirus. The impact of opium use as a risk factor for COVID-19 is yet uncertain. This study investigate the effect of opium consumption on the severity of COVID-19, and its adverse consequences in opium users compared to the general population. Methods This study included 2945 COVID-19 patients that had been referred to health care centers affiliated to Rafsanjan University of Medical Sciences. The personal, and clinical data including clinical presentation, the severity of symptoms, and outcome were collected. Then, the COVID-19 severity, and outcome between opium users and opium non-users were compared. Results The rate of opium users was 5.13% that 87.42% of them recovered while this percentage for non-users was 86.07% (p ꞊ 0.641). In the crude regression model, the odds of the death due to COVID-19 is 0.88 (95%CI 0.54 to 1.45). The odds of the severity of COVID-19 is almost half among opium users compared with non-users (odds ratio (OR): 0.48, 95%CI 0.34 to 0.66). This association persisted after adjustment for confounders. We observed that with adjustment for confounders, opium consumption decreases the severity of COVID-19 but has no significant effect on mortality. Conclusion There was a negative association between opium use with the severity, and death due to COVID-19. However, it is suggested more laboratory and clinical trial studies using pharmaceutical morphine products, the main component of opium. COVID-19 Opium Severity Outcome Background The COVID-19 pandemic has become a major challenge to healthcare systems and public health policies globally since it requires new treatment and prevention strategies to decrease its mortality (1). Respiratory droplets and physical contact are transmission factors of COVID-19 and the latency period of the virus is 4–7 days (2). Viral properties and immune system condition participate in the duration and severity of the disease, patient state, and reinfection (3). People with underlying diseases, such as diabetes, asthma and heart disease, and the elderly are more susceptible to coronavirus with more severe symptoms (4). Some studies have shown that increased IL6 concentration in blood and hyper inflammation might be the reason for fatality in COVID-19 patients. Therefore, immunotherapy with several immunomodulating agents, such as convalescent plasma, immunoglobulins, glucocorticoids, recombinant human IL-6 receptor monoclonal antibody (Tocilizumab), JAK inhibitors (Jakotinib, Ruxolitinib), and chloroquine/ hydroxychloroquine is being experimented. Also, opioid agents (morphine or fentanyl) are used for relieving discomfort, and treating pain (5). The impact of opium use as a risk factor for COVID-19 is yet uncertain (6) despite being one of the most effective. One of the most important problems of modern human societies is opioid addiction (7). Opium contains various alkaloids, such as morphine and codeine, that causing pain palliation and cough elimination to euphoria, sleepiness, and addiction (8). Morphine as a traditional pain controller, analgesic drug, and a natural opioid can mediate their effects via three receptors termed of δ, µ, and κ (9, 10). These receptors are found in the perception of pain, dyspnea, as well as in the digestive system, inhibiting bowel movement and having immunomodulatory effects on the surface of immune cells.. Opioid receptors present in the CNS and the cardio-respiratory systems are responsible for developing the mechanisms of their anti dyspnoeic effects (11). Although angiotensin-converting enzyme 2 (ACE2(, as the main receptor for COVID-19, is overexpressed in opium users morphine and codeine extensively compete with the virus for binding to the receptor.(12–14). According to the National Health Service (NHS) in England, breathlessness in severe COVID-19 patients can be decreased in their last days and hours of life with morphine sulfate administration (15). Indeed, in COVID-19 patients, morphine could be a prime therapy to reduce pain, breath shortness, and coughing (16). Based on experimental investigations, morphine treatment mitigates hyper-inflammatory status and suppresses some inflammatory cytokines such as IL-6, interferon (IFNs(, and tumor necrosis factor-alpha (TNF-a), significantly (14). On the other hand, researchers claim that a history of opium abuse does not significantly raise the mortality risk of COVID-19. however, the opium abusers confront many complications (2). Other studies have shown that opium-addicted persons are more susceptible to COVID-19, among whom the rate of mortality is higher than others in the community (17). Elevated levels of Interleukin-6 (IL-6) followed by a cytokine storm in such patients is expressed as the etiology of mortality (18). It is anticipated that opioid consumption suppresses the immune system and increases the probability of end-organ damage phase of COVID-19, leading to endothelium injury of lung alveolar and bacterial pneumonia (3). Thus, more investigation about the correlation between opium and COVID-19 is necessary to determine an exact risk of incidence, severity, and outcome of COVID-19 among abusers. This accurate observational study is conducted to investigate the COVID-19 severity and adverse consequences in the abusers compared to the general population. Methods This cross-sectional study included 2945 COVID-19 patients (tested positive (through real-time reverse-transcriptase–polymerase-chain-reaction (RT-PCR)) and negative coronavirus with corona symptoms) that had been referred to health care centers affiliated to Rafsanjan University of Medical Sciences, in the southeast of Iran, from February 11 to December 15, 2020. The personal data including sex, age, history of cigarette smoking or opium use, and underlying diseases (e.g., respiratory diseases, cancer, hypertension, cardiovascular disease, liver and renal diseases, hyperlipidemia, and diabetes) and clinical data of patients including clinical presentation, the severity of symptoms, and outcome were collected from medical records. In this study, an opium user is defined as a participant who reports using opium at least once per week (19). Participants were divided into two groups of opium users (OUs = 151 subjects) and opium non-users (ONUs = 2794 subjects).). Then, the COVID-19 severity, and outcome between the groups were compared. The severity of the disease was measured using the severity of symptoms such as body temperature, and cough, dyspnea, respiratory rate, O2 saturation, chest X-ray and CT scan (20). This study is observational and has been approved by the ethics committee of Rafsanjan University of Medical Sciences (Ethical codes: IR.RUMS.REC.1399.195). Statistical analysis To analyze categorical variables across opium use categories the chi-square test was used. t-test was used to compare continuous variables among the groups. Logistic regression models were used to investigate the relationships between opium use and the severity, and outcome of COVID-19. Adjusted model 1 included socio-demographic characteristics (age and gender) considered to be the most strongly related to both opium use and COVID-19. Adjusted model 2 adjusted for underlying disease and smoking to additionally confound opium use – COVID-19 associations. All analyses were conducted in State V.12. P-values < 0.05 and 95% confidence intervals were considered statistically significant. Results From 2945 participants, 1,436 (48.76%) were male and 1,509 (51.24%) were female. The demographic and clinical characteristics of participants are shown in Table 1. The mean age of the patients was 58.85 ± 20.60 years old. 1,357 patients were aged ≤57 years, and 1,588 were aged ≥58 that 66 (16.18%) and 342 (83.82%) of them died, respectively (p < 0.001). In addition, 8.69% (n=256), 58.23% (n=1715) and 33.07% (n=974) of patients had severe, moderate and slight form of the disease, respectively. The rate of opium users was 5.13% corresponding to 151 patients that 87.42 % of them recovered while this percentage for non-users was 86.07% (p ꞊ 0.641). The amount of underlying disease in all of the participants was 1326 (45.03 %) that 19.32% of them died (p < 0.001). The more frequent of this disease were diabetes, hypertension, and cardiovascular disease. Prevalence of COVID-19 with mild symptoms was more common among men and with moderate symptoms was more in women (p<0.001) but the patients with severe symptoms did not differ according to gender. Also, the severity of the disease was higher in participants with underlying disease (p< 0.001). Table 1. The demographic and clinical characteristics of participants ( n = 2,945) Characteristics All (n=2,945) Slight ( n =974) Moderate ( n =1,715) Severe (n= 256) P -Value Age ‑ yr. Mean± SD Age‑ no. (%) ≤57 ≥58 57 ± 20 1357 (47.57) 1588 (52.43) 974 422 (43.33) 552 (56.67) 1715 878 (51.20) 837 (48.80) 256 57 (22.27) 199 (77.73) < 0.001 Gender‑ no. (%) Female Male 1,436 (48.76) 1,509(51.24) 452 (46.41) 522 (53.59) 929 (54.17) 786 (45.83) 128 (50.00) 128 (50.00) 0.001 Cigarette smoking‑no. (%) Yes No 40 (1.36) 2,905 (98.64) 22 (2.26) 952 (97.74) 13 (0.76) 1,702 (99.24) 5 (1.95) 251 (98.05) 0.004 Opium use-no. (%) Yes No 75 (7.7) 899 (92.3) 52 (49.67) 1,663 (33.65) 52 (3.03) 1678 (96.97) 24 (9.38) 232 (90.63) < 0.001 Underlying disease-no. (%) Yes No 1,326 (45.03) 1619 (54.97) 449 (46.10) 525 (53.90) 694 (40.47) 1021 (59.53) 183 (71.48) 73 (28.52) < 0.001 Symptoms-no. (%) Fever Yes no Cough Yes No Muscular pain Yes No Respiratory distress Yes No Decreased sense smell Yes No Decreased sense taste Yes No Nausea Yes No Vomiting Yes No Diarrhea Yes No Headache Yes No 1,061 (36.03) 1,884 (63.97) 776 (26.35) 2,169 (73.65) 1,133 (38.47) 1,812 (61.53) 1,603 (54.43) 1,342 (45.57) 11 (.37) 2,934 (99.63) 3 (0.1) 2,942 (99.90) 133 (4.52) 2,812 (95.48) 125 (4.24) 2820 (95.76) 83 (2,82) 2,862 (97.18) 184 (6.25) 2,761 (93.75) 330 (33.88) 644 (66.12) 182 (18.69) 792 (81.31) 328 (33.68) 646 (66.32) 440 (45.17) 534 (54.83) 1 (0.1) 973 (99.90) 0 (0.00) 974 (100) 41 (4.21) 933 (95.79) 43 (4.41) 931 (95.59) 27 (2.77) 947 (97.23) 46 (4.72) 928 (95.28) 645 (37.61) 1,070 (62.39) 520 (30.32) 1,195 (69.68) 734 (42.80) 981 (57.20) 978 (57.03) 737 (42.97) 7 (0.41) 1708 (99.59) 3 (0.17) 1,712 (99.83) 70 (4.08) 1,645 (95.92) 61 (3.56) 1654 (96.44) 42 (2.45) 1673 (97.55) 116 (6.76) 1599 (93.24) 86 (33.59) 170 (66.41) 74 (28.91) 182 (71.09) 71 (27.73) 185 (72.27) 185 (72.27) 71 (27.73) 3 (1.27) 253 (98.83) 0 (0.00) 256 (100) 22 (8.59) 234 (91.41) 21 (8.20) 235 (91.80) 14 (5.47) 242 (94.53) 22 (8.59) 234 (91.41) = 0.1 < 0.001 < 0.001 < 0.001 0.04 0.34 0.004 0.003 0.02 0.02 Table 2 presents the association of opium use with severity, and outcome of COVID-19, using the crude and two adjusted models. In the crude regression model, the odds of the death due to COVID-19 is 0.88 (odds ratio (OR): 0.88, 95%CI 0.54 to 1.45). The odds of the severity of COVID-19 is almost half among opium users compared with non-users (odds ratio (OR): 0.48, 95%CI 0.34 to 0.66). Hence, opium consumption decreased effect on the severity of COVID-19. This association persisted after adjustment for confounders (adjusted models 1 and 2). The corresponding adjusted ORs calculated for opium users in comparison to non-users are 0.52 (95% CI 0.37 to 0.72) and 0.54 (95% CI 0.39 to 0.76) respectively for adjusted model 1 and 2. Also, we observed that opium consumption has no significant effect on mortality (p ꞊ 0.641). The corresponding adjusted ORs calculated for opium users in comparison to non-users is available in Table 2. Table2. Association of opium consumption with severity and outcome of COVID-19 diseases (n= 2945*) Crude model OR (95%Ci) a Adjusted model 1 OR(95%Ci) b Adjusted model 2 OR (95%Ci) c Severity of COVID-19 Opium use Yes No Outcome of COVID-19 (Recover or death) Opium use Yes No 0. 48 (0. 34-0.66) 1 0.88 (0.54- 1.45) 1 0.52 (0.37-0.72) 1 0.74 (0.44- 1.23) 1 0.54 (0.39-0.76) 1 0.66 (0.39- 1.10) 1 a The baseline model is stratified on the status of opium consumption b The adjusted model 1 is adjusted for confounding variables age (continuous variable), gender (male/ female). C The adjusted model 2 has additional adjustment for confounding the variables underlying disease and smoking (yes/no) Discussion This study aims to investigate the effect of opium consumption on the severity, and outcome of COVID-19. The results show that the rate of opium users is lower in symptomatic COVID- 19 patients than in the general population. According to a recent cohort study, 23.81% of the Rafsanjanian adults population (46.19% of men and 4.27% of women) use opium at least once per week for 6 months further, opium consumption has a low social stigma in this population (19). In the present research, the rate of opium user' patients is 5.13%. According to these two studies, although opium users compose approximately a quarter the population, they included just about one twentieth of symptomatic COVID-19 patients, Thus it could be concluded that opium users may have a lower probability of developing symptomatic COVID- 19 infection than the general population. However, it is possible that some participants have not completely reported their status of opium consumption. The sensibility of reporting in participants of both groups may have been different and has not been declared something. The main finding of the current study is that the severity of COVID-19 is lower in opium users than in the general population however, there is no significant difference in mortality. Some studies have shown that opium consumption causes increased severity and mortality in COVID-19 patients. Various reasons have been reported for this claim, including changes in the immune system, changes in the amount of TNF-α, IL-1, and IL-6, and an increase in ACE2 expression in the opium users (2, 3, 21, 22). The presents research results are contrary to those of these studies, possibly due to the difference in the type of narcotic substances and others factors. On the other hand, researchers have shown more than 70 different types of alkaloids and compounds in opium some of which are anti-inflammatory and antioxidant agents. One of the main is morphine, with an anti-inflammatory effect even in low doses. Morphine as a traditional pain controller, analgesic drug, and a natural opioid can mediate their effects via three receptors of δ, µ, and κ (9, 10). These receptors are found in the perception of pain, dyspnea, and have immunomodulatory effects on the surface of immune cells (11). The lower severity of COVID-19 observed in opium users can be due to these morphine features, especially its anti-inflammatory effects. Some studies are in line results with the present research. Khoshab et al. have stated that opium consumption could have prophylactic effects on COVID-19 (23). Cismaru et al. have also declared that opioids can potentially be used in the treatment of COVID-19 through their effects on both the viral infectious cycle and the host response to the infection (11). Opioids are the best pharmacological agents in the palliation of dyspnea recommended by European and US therapeutic guidelines (11). Furthermore, According to the National Health Service (NHS) in England, breathlessness in severe COVID-19 patients can be decreased in their last days and hours of life with morphine sulfate administration (15). In COVID-19 patients, morphine can be used as a prime therapy for diminution of pain, breath shortness, and coughing (16). The effect of opioids on the outcome of the viral infection depends on the type of virus. Activation of opioid receptors is useful for the controlling immunopathology in viral infection with an immunopathogenic response (such as COVID-19) (24). Generally, opioids may be used in COVID-19 for three effects: inhibiting the cytokine storm, improving dyspnea, and disturbing lysosomal acidification (11). Increasing the levels of inflammatory cytokines and chemokines increase bronchoalveolar infection. Chronic morphine treatment can reduce IL-1 and IL-6 production (3) thus, immunosuppression by using opium might have a potential role in the treatment of COVID-19 patients (14). ACE2 has been shown to be a receptor for COVID-19 to enter host cells (12, 13), and the use of inhibitors of the ACE2 receptor has been proposed prevent the disease. Although is ACE2 overexpressed in opium users morphine and codeine extensively compete with the virus for binding to the receptor (6, 14). The anti-inflammatory, anti-fibrotic, antitumor, cardioprotective, and renoprotective effects of morphine have been demonstrated in in-vitro and in-vivo animal experiments. These effects could nullify the inordinate inflammation, fibrosis, as well as cardiac and renal charges associated with COVID-19 (11). The present research results could confirm these findings since the severity of COVID-19 has been lower in opium users. In patients with systemic infection, an increased amount of endogenous opioids could have a protective function and reduces inflammatory processes (25). Analgesia based on opioids is one of the most effective and cheap treatments for the palliation of severe pain (8). Opioids may be used for the treatment of pain and palliation of suffocation sense in COVID-19 patients (26). However, due to the high potential for addiction to opioids, adequate attention should be paid when them. In critical situations such as ARDS due to COVID-19, the advantages of using opioids could dominate their undesirable side-effects (11). Hudzik et al. have concluded that morphine in the primary stages of COVID-19 could have a useful effect by inhibiting the cytokine storm however, in late stages it could be damaging (such as making septic shock) (5). The study has attempted to adjust confounding factors further, a hypothesis has been proposed, based on which opium may reduce the severity of COVID-19. More investigations are needed through laboratory and clinical trials using pharmaceutical morphine products, the main component of opium. Although the results approve that, the severity of COVID-19 in opium users is lower than the general population, this study does not support the view that opium consumption acts as a factor to reduce COVID-19 prevalence or its severity. Conclusion The present research results suggest that opium consumption may reduce the severity of COVID-19. The physiopathological reason underlying this effect may involve morphine and its features such as anti-inflammatory, and immunomodulatory pain, reduction breath shortness palliation, and cough elimination. Opium consumption is deviancy and harmful comportment however, morphine, as the most important component of opium, can be an auxiliary and temporary treatment for the COVID-19. Nevertheless, our findings need careful consideration in light of the possible increased risk of the long-term harmful consequences of morphine consumption. Declarations Ethics approval and consent to participate This study has been approved by the ethics committee of Rafsanjan University of Medical Sciences with Ethical codes of IR.RUMS.REC.1399.195. Clinical Trial Not applicable Consent for publication Not applicable Availability of data and materials All data that support the conclusions of this manuscript are included within the article. Competing interests The authors declare that they have no competing interests. Funding This study has also been supported by the Vice Chancellery for Research & Technology of Rafsanjan University of Medical Sciences. The context of this article is the views of the authors and the funder had no role in the design of the study and collection, analysis, and interpretation of data, the decision to publish, and writing the manuscript. Authors' contributions FA, HO and HE analyzed and interpreted the data and contributor in writing the manuscript. FA, NP, HM and SK performed the data collection, methodology and contributor in writing the manuscript. All authors read and approved the final manuscript. Acknowledgements We thank the people who participated in the study and health care center personnel in Rafsanjan University of Medical Sciences, Rafsanjan, Iran. References Ornell F, Moura HF, Scherer JN, Pechansky F, Kessler F, von Diemen L. The COVID-19 pandemic and its impact on substance use: implications for prevention and treatment. Psychiatry research. 2020:113096. Alamdari NM, Afaghi S, Rahimi FS, Tarki FE, Tavana S, Zali A, et al. Mortality risk factors among hospitalized COVID-19 patients in a major referral center in Iran. The Tohoku Journal of Experimental Medicine. 2020;252(1):73–84. DOLATI-SOMARIN A, Bahareh A-N. 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Opioids/cannabinoids as a potential therapeutic approach in COVID-19 patients. Expert review of respiratory medicine. 2020;14(10):965-7. Yarahmadzehi S, Fanaei H, Mirshekar MA, Atashpanjeh AR. Opium consumption exerts protective effect against cerebral ischemia through reducing inflammation and enhancing antioxidant defense in male rats. Neurology, Psychiatry and Brain Research. 2020;37:15–20. Lambert D. Opioids and the COVID-19 pandemic: does chronic opioid use or misuse increase clinical vulnerability? BJA: British Journal of Anaesthesia. 2020. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 30 Jan, 2026 Read the published version in BMC Infectious Diseases → Version 1 posted Editorial decision: Revision requested 13 Jan, 2025 Editor assigned by journal 10 Jan, 2025 Submission checks completed at journal 10 Jan, 2025 First submitted to journal 31 Dec, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5741046","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":400469987,"identity":"8fe3ad3a-4418-429f-b896-bb3cd17e3fbe","order_by":0,"name":"Fatemeh Amin","email":"","orcid":"","institution":"Rafsanjan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Fatemeh","middleName":"","lastName":"Amin","suffix":""},{"id":400469988,"identity":"e2fe5bad-7b25-4d44-8376-18afcdc302ee","order_by":1,"name":"Hamid Ostadebrahimi","email":"","orcid":"","institution":"Rafsanjan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Hamid","middleName":"","lastName":"Ostadebrahimi","suffix":""},{"id":400469989,"identity":"7a9de2b5-d41e-485a-83fa-fdefb4566c87","order_by":2,"name":"Najmeh Parvaz","email":"","orcid":"","institution":"Rafsanjan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Najmeh","middleName":"","lastName":"Parvaz","suffix":""},{"id":400469990,"identity":"a176f6fa-2e92-491d-91fb-67d8fe35935d","order_by":3,"name":"Hadi Eslami","email":"","orcid":"","institution":"Rafsanjan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Hadi","middleName":"","lastName":"Eslami","suffix":""},{"id":400469991,"identity":"3ebc744a-203a-43cb-8a0f-e57548eb3baf","order_by":4,"name":"Haniyeh Maleki","email":"","orcid":"","institution":"Rafsanjan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Haniyeh","middleName":"","lastName":"Maleki","suffix":""},{"id":400469992,"identity":"51ddc18b-1df2-4c59-9b6a-fa5667904cd2","order_by":5,"name":"Somayeh Kazempour","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDklEQVRIiWNgGAWjYDACHnQBfhCRUECKFskGkBYDUrQYHACTuHXI9xx+/OFjzh05g9sHmD/z7riTuPn86sQPDwwY5PnFDmDVYnC2zcBw5rZnxgbnEtikec88S9x24+1mCaDDDGfOTsCuhZ/BIJl32+HEDWcY2Jh52w4DtZzdANKSYHAbuxb5fvYPh/9CtAAdBtSyecbZzT/waWE422PYzAjRwiAN0rKBv3cbXlsMzpwpZuwF+kXyDGOb5Ny2w8YzbvBus0gwkMDpF/me9M0ffm67I8d3hvnwh7dth2X7+89uvvmjwkaeXxqHwyDgABAzNoBYjg0SYJUS+JTDtECAPQP/AZzKRsEoGAWjYGQCAKYCaN9Q+yX4AAAAAElFTkSuQmCC","orcid":"","institution":"Rafsanjan University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Somayeh","middleName":"","lastName":"Kazempour","suffix":""}],"badges":[],"createdAt":"2024-12-31 09:53:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5741046/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5741046/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12879-026-12719-7","type":"published","date":"2026-01-30T15:59:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":101690532,"identity":"3d6b1dba-a7e5-4c87-b96b-18603bbd5575","added_by":"auto","created_at":"2026-02-02 16:04:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":521227,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5741046/v1/ea553a87-ee43-4e75-ae5e-a1ec1d4704c4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Investigating the role of opium consumption in the severity, and outcome of COVID-19","fulltext":[{"header":"Background","content":"\u003cp\u003eThe COVID-19 pandemic has become a major challenge to healthcare systems and public health policies globally since it requires new treatment and prevention strategies to decrease its mortality (1). Respiratory droplets and physical contact are transmission factors of COVID-19 and the latency period of the virus is 4\u0026ndash;7 days (2). Viral properties and immune system condition participate in the duration and severity of the disease, patient state, and reinfection (3). People with underlying diseases, such as diabetes, asthma and heart disease, and the elderly are more susceptible to coronavirus with more severe symptoms (4). Some studies have shown that increased IL6 concentration in blood and hyper inflammation might be the reason for fatality in COVID-19 patients. Therefore, immunotherapy with several immunomodulating agents, such as convalescent plasma, immunoglobulins, glucocorticoids, recombinant human IL-6 receptor monoclonal antibody (Tocilizumab), JAK inhibitors (Jakotinib, Ruxolitinib), and chloroquine/ hydroxychloroquine is being experimented. Also, opioid agents (morphine or fentanyl) are used for relieving discomfort, and treating pain (5).\u003c/p\u003e \u003cp\u003eThe impact of opium use as a risk factor for COVID-19 is yet uncertain (6) despite being one of the most effective. One of the most important problems of modern human societies is opioid addiction (7). Opium contains various alkaloids, such as morphine and codeine, that causing pain palliation and cough elimination to euphoria, sleepiness, and addiction (8). Morphine as a traditional pain controller, analgesic drug, and a natural opioid can mediate their effects via three receptors termed of δ, \u0026micro;, and κ (9, 10). These receptors are found in the perception of pain, dyspnea, as well as in the digestive system, inhibiting bowel movement and having immunomodulatory effects on the surface of immune cells.. Opioid receptors present in the CNS and the cardio-respiratory systems are responsible for developing the mechanisms of their anti dyspnoeic effects (11). Although angiotensin-converting enzyme 2 (ACE2(, as the main receptor for COVID-19, is overexpressed in opium users morphine and codeine extensively compete with the virus for binding to the receptor.(12\u0026ndash;14). According to the National Health Service (NHS) in England, breathlessness in severe COVID-19 patients can be decreased in their last days and hours of life with morphine sulfate administration (15). Indeed, in COVID-19 patients, morphine could be a prime therapy to reduce pain, breath shortness, and coughing (16). Based on experimental investigations, morphine treatment mitigates hyper-inflammatory status and suppresses some inflammatory cytokines such as IL-6, interferon (IFNs(, and tumor necrosis factor-alpha (TNF-a), significantly (14). On the other hand, researchers claim that a history of opium abuse does not significantly raise the mortality risk of COVID-19. however, the opium abusers confront many complications (2). Other studies have shown that opium-addicted persons are more susceptible to COVID-19, among whom the rate of mortality is higher than others in the community (17). Elevated levels of Interleukin-6 (IL-6) followed by a cytokine storm in such patients is expressed as the etiology of mortality (18). It is anticipated that opioid consumption suppresses the immune system and increases the probability of end-organ damage phase of COVID-19, leading to endothelium injury of lung alveolar and bacterial pneumonia (3).\u003c/p\u003e \u003cp\u003eThus, more investigation about the correlation between opium and COVID-19 is necessary to determine an exact risk of incidence, severity, and outcome of COVID-19 among abusers. This accurate observational study is conducted to investigate the COVID-19 severity and adverse consequences in the abusers compared to the general population.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e This cross-sectional study included 2945 COVID-19 patients (tested positive (through real-time reverse-transcriptase\u0026ndash;polymerase-chain-reaction (RT-PCR)) and negative coronavirus with corona symptoms) that had been referred to health care centers affiliated to Rafsanjan University of Medical Sciences, in the southeast of Iran, from February 11 to December 15, 2020. The personal data including sex, age, history of cigarette smoking or opium use, and underlying diseases (e.g., respiratory diseases, cancer, hypertension, cardiovascular disease, liver and renal diseases, hyperlipidemia, and diabetes) and clinical data of patients including clinical presentation, the severity of symptoms, and outcome were collected from medical records. In this study, an opium user is defined as a participant who reports using opium at least once per week (19). Participants were divided into two groups of opium users (OUs\u0026thinsp;=\u0026thinsp;151 subjects) and opium non-users (ONUs\u0026thinsp;=\u0026thinsp;2794 subjects).). Then, the COVID-19 severity, and outcome between the groups were compared. The severity of the disease was measured using the severity of symptoms such as body temperature, and cough, dyspnea, respiratory rate, O2 saturation, chest X-ray and CT scan (20). This study is observational and has been approved by the ethics committee of Rafsanjan University of Medical Sciences (Ethical codes: IR.RUMS.REC.1399.195).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eTo analyze categorical variables across opium use categories the chi-square test was used. t-test was used to compare continuous variables among the groups. Logistic regression models were used to investigate the relationships between opium use and the severity, and outcome of COVID-19. Adjusted model 1 included socio-demographic characteristics (age and gender) considered to be the most strongly related to both opium use and COVID-19. Adjusted model 2 adjusted for underlying disease and smoking to additionally confound opium use \u0026ndash; COVID-19 associations. All analyses were conducted in State V.12. P-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 and 95% confidence intervals were considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eFrom 2945 participants, 1,436 (48.76%) were male and 1,509 (51.24%) were female. The demographic and clinical characteristics of participants are shown in Table 1. The mean age of the patients was 58.85 \u0026plusmn; 20.60 years old. 1,357 patients were aged \u0026le;57 years, and 1,588 were aged \u0026ge;58 that 66 (16.18%) and 342 (83.82%) of them died, respectively (p \u0026lt; 0.001). In addition, 8.69% (n=256), 58.23% (n=1715) and 33.07% (n=974) of patients had severe, moderate and slight form of the disease, respectively. The rate of opium users was 5.13% corresponding to 151 patients that 87.42 % of them recovered while this percentage for non-users was 86.07% (p ꞊ 0.641). The amount of underlying disease in all of the participants was 1326 (45.03 %) that 19.32% of them died (p \u0026lt; 0.001). The more frequent of this disease were diabetes, hypertension, and cardiovascular disease. Prevalence of COVID-19 with mild symptoms was more common among men and with moderate symptoms was more in women (p\u0026lt;0.001) but the patients with severe symptoms did not differ according to gender. Also, the severity of the disease was higher in participants with underlying disease (p\u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e The demographic and clinical characteristics of participants (\u003cem\u003en\u003c/em\u003e= 2,945)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.129%;\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.0323%;\"\u003e\n \u003cp\u003eAll (n=2,945)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.0323%;\"\u003e\n \u003cp\u003eSlight\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003en\u0026nbsp;\u003c/em\u003e=974)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.1613%;\"\u003e\n \u003cp\u003eModerate (\u003cem\u003en\u0026nbsp;\u003c/em\u003e=1,715) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.129%;\"\u003e\n \u003cp\u003eSevere (n= 256)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.51613%;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-Value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.129%;\"\u003e\n \u003cp\u003eAge ‑ yr. Mean\u0026plusmn; SD\u003c/p\u003e\n \u003cp\u003eAge‑ no. (%)\u003c/p\u003e\n \u003cp\u003e\u0026le;57\u003c/p\u003e\n \u003cp\u003e\u0026ge;58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.0323%;\"\u003e\n \u003cp\u003e57 \u0026plusmn; 20\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1357 (47.57)\u003c/p\u003e\n \u003cp\u003e1588 (52.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.0323%;\"\u003e\n \u003cp\u003e974\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e422 (43.33)\u003c/p\u003e\n \u003cp\u003e552 (56.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.1613%;\"\u003e\n \u003cp\u003e1715\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e878 (51.20)\u003c/p\u003e\n \u003cp\u003e837 (48.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.129%;\"\u003e\n \u003cp\u003e256\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e57 (22.27)\u003c/p\u003e\n \u003cp\u003e199 (77.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.51613%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.129%;\"\u003e\n \u003cp\u003eGender‑ no. (%)\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.0323%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1,436 (48.76)\u003c/p\u003e\n \u003cp\u003e1,509(51.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.0323%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e452 (46.41)\u003c/p\u003e\n \u003cp\u003e522 (53.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.1613%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e929 (54.17)\u003c/p\u003e\n \u003cp\u003e786 (45.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.129%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e128 (50.00)\u003c/p\u003e\n \u003cp\u003e128 (50.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.51613%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.129%;\"\u003e\n \u003cp\u003eCigarette smoking‑no. (%)\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.0323%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e40 (1.36)\u003c/p\u003e\n \u003cp\u003e2,905 (98.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.0323%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e22 (2.26)\u003c/p\u003e\n \u003cp\u003e952 (97.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.1613%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13 (0.76)\u003c/p\u003e\n \u003cp\u003e1,702 (99.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.129%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 (1.95)\u003c/p\u003e\n \u003cp\u003e251 (98.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.51613%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.129%;\"\u003e\n \u003cp\u003eOpium use-no. (%)\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.0323%;\"\u003e\n \u003cp\u003e\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003e75 (7.7)\u003c/p\u003e\n \u003cp\u003e899 \u0026nbsp;(92.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.0323%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e52 (49.67)\u003c/p\u003e\n \u003cp\u003e1,663 (33.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.1613%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e52 (3.03)\u003c/p\u003e\n \u003cp\u003e1678 (96.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.129%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e24 (9.38)\u003c/p\u003e\n \u003cp\u003e232 (90.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.51613%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.129%;\"\u003e\n \u003cp\u003eUnderlying disease-no. (%)\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.0323%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1,326 (45.03)\u003c/p\u003e\n \u003cp\u003e1619 (54.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.0323%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e449 (46.10)\u003c/p\u003e\n \u003cp\u003e525 (53.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.1613%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e694 (40.47)\u003c/p\u003e\n \u003cp\u003e1021 (59.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.129%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e183 (71.48)\u003c/p\u003e\n \u003cp\u003e73 (28.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.51613%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.129%;\"\u003e\n \u003cp\u003eSymptoms-no. (%)\u003c/p\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003cp\u003eCough\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eMuscular pain\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eRespiratory distress\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eDecreased sense smell\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eDecreased sense taste\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.0323%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1,061 (36.03)\u003c/p\u003e\n \u003cp\u003e1,884 (63.97)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e776 (26.35)\u003c/p\u003e\n \u003cp\u003e2,169 (73.65)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1,133 (38.47)\u003c/p\u003e\n \u003cp\u003e1,812 (61.53)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1,603 (54.43)\u003c/p\u003e\n \u003cp\u003e1,342 (45.57)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (.37)\u003c/p\u003e\n \u003cp\u003e2,934 (99.63)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (0.1)\u003c/p\u003e\n \u003cp\u003e2,942 (99.90)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e133 (4.52)\u003c/p\u003e\n \u003cp\u003e2,812 (95.48)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e125 (4.24)\u003c/p\u003e\n \u003cp\u003e2820 (95.76)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e83 (2,82)\u003c/p\u003e\n \u003cp\u003e2,862 (97.18)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e184 (6.25)\u003c/p\u003e\n \u003cp\u003e2,761 (93.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.0323%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e330 (33.88)\u003c/p\u003e\n \u003cp\u003e644 (66.12)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e182 (18.69)\u003c/p\u003e\n \u003cp\u003e792 (81.31)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e328 (33.68)\u003c/p\u003e\n \u003cp\u003e646 (66.32)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e440 (45.17)\u003c/p\u003e\n \u003cp\u003e534 (54.83)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (0.1)\u003c/p\u003e\n \u003cp\u003e973 (99.90)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0 (0.00)\u003c/p\u003e\n \u003cp\u003e974 (100)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e41 (4.21)\u003c/p\u003e\n \u003cp\u003e933 (95.79)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e43 (4.41)\u003c/p\u003e\n \u003cp\u003e931 (95.59)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e27 (2.77)\u003c/p\u003e\n \u003cp\u003e947 (97.23)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e46 (4.72)\u003c/p\u003e\n \u003cp\u003e928 (95.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.1613%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e645 (37.61)\u003c/p\u003e\n \u003cp\u003e1,070 (62.39)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e520 (30.32)\u003c/p\u003e\n \u003cp\u003e1,195 (69.68)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e734 (42.80)\u003c/p\u003e\n \u003cp\u003e981 (57.20)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e978 (57.03)\u003c/p\u003e\n \u003cp\u003e737 (42.97)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7 (0.41)\u003c/p\u003e\n \u003cp\u003e1708 (99.59)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (0.17)\u003c/p\u003e\n \u003cp\u003e1,712 (99.83)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e70 (4.08)\u003c/p\u003e\n \u003cp\u003e1,645 (95.92)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e61 (3.56)\u003c/p\u003e\n \u003cp\u003e1654 (96.44)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e42 (2.45)\u003c/p\u003e\n \u003cp\u003e1673 (97.55)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e116 (6.76)\u003c/p\u003e\n \u003cp\u003e1599 (93.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.129%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e86 (33.59)\u003c/p\u003e\n \u003cp\u003e170 (66.41)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e74 (28.91)\u003c/p\u003e\n \u003cp\u003e182 (71.09)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e71 (27.73)\u003c/p\u003e\n \u003cp\u003e185 (72.27)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e185 (72.27)\u003c/p\u003e\n \u003cp\u003e71 (27.73)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (1.27)\u003c/p\u003e\n \u003cp\u003e253 (98.83)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0 (0.00)\u003c/p\u003e\n \u003cp\u003e256 (100)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e22 (8.59)\u003c/p\u003e\n \u003cp\u003e234 (91.41)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e21 (8.20)\u003c/p\u003e\n \u003cp\u003e235 (91.80)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14 (5.47)\u003c/p\u003e\n \u003cp\u003e242 (94.53)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e22 (8.59)\u003c/p\u003e\n \u003cp\u003e234 (91.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.51613%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e= 0.1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 2 presents the association of opium use with severity, and outcome of COVID-19, using the crude and two adjusted models. In the crude regression model, the odds of the death due to COVID-19 is 0.88 (odds ratio (OR): 0.88, 95%CI 0.54 to 1.45). The odds of the severity of COVID-19 is almost half among opium users compared with non-users (odds ratio (OR): 0.48, 95%CI 0.34 to 0.66). Hence, opium consumption decreased effect on the severity of COVID-19. This association persisted after adjustment for confounders (adjusted models 1 and 2). The corresponding adjusted ORs calculated for opium users in comparison to non-users are 0.52 (95% CI 0.37 to 0.72) and 0.54 (95% CI 0.39 to 0.76) respectively for adjusted model 1 and 2. \u0026nbsp; Also, we observed that opium consumption has no significant effect on mortality (p ꞊ 0.641). The corresponding adjusted ORs calculated for opium users in comparison to non-users is available in Table 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable2.\u003c/strong\u003e Association of opium consumption with severity and outcome of COVID-19 diseases (n= 2945*)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCrude model\u003c/p\u003e\n \u003cp\u003eOR (95%Ci) \u003csub\u003ea\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAdjusted model 1\u003c/p\u003e\n \u003cp\u003eOR(95%Ci) \u003csub\u003eb\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAdjusted model 2\u003c/p\u003e\n \u003cp\u003eOR (95%Ci) \u003csub\u003ec\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSeverity of COVID-19\u003c/p\u003e\n \u003cp\u003eOpium use\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eOutcome of COVID-19\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(Recover or death)\u003c/p\u003e\n \u003cp\u003eOpium use\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.\u0026nbsp;48 (0.\u0026nbsp;34-0.66)\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.88 (0.54-\u0026nbsp;1.45)\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.52 (0.37-0.72)\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.74 (0.44-\u0026nbsp;1.23)\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.54 (0.39-0.76)\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.66 (0.39- 1.10)\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003ea The baseline model is stratified on the status of opium consumption\u003c/p\u003e\n\u003cp\u003eb The adjusted model 1 is adjusted for confounding variables age (continuous variable), gender (male/ female).\u003c/p\u003e\n\u003cp\u003eC The adjusted model 2 has additional adjustment for confounding the variables underlying disease and smoking (yes/no)\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study aims to investigate the effect of opium consumption on the severity, and outcome of COVID-19. The results show that the rate of opium users is lower in symptomatic COVID- 19 patients than in the general population. According to a recent cohort study, 23.81% of the Rafsanjanian adults population (46.19% of men and 4.27% of women) use opium at least once per week for 6 months further, opium consumption has a low social stigma in this population (19). In the present research, the rate of opium user' patients is 5.13%. According to these two studies, although opium users compose approximately a quarter the population, they included just about one twentieth of symptomatic COVID-19 patients, Thus it could be concluded that opium users may have a lower probability of developing symptomatic COVID- 19 infection than the general population. However, it is possible that some participants have not completely reported their status of opium consumption. The sensibility of reporting in participants of both groups may have been different and has not been declared something.\u003c/p\u003e \u003cp\u003eThe main finding of the current study is that the severity of COVID-19 is lower in opium users than in the general population however, there is no significant difference in mortality. Some studies have shown that opium consumption causes increased severity and mortality in COVID-19 patients. Various reasons have been reported for this claim, including changes in the immune system, changes in the amount of TNF-α, IL-1, and IL-6, and an increase in ACE2 expression in the opium users (2, 3, 21, 22). The presents research results are contrary to those of these studies, possibly due to the difference in the type of narcotic substances and others factors. On the other hand, researchers have shown more than 70 different types of alkaloids and compounds in opium some of which are anti-inflammatory and antioxidant agents. One of the main is morphine, with an anti-inflammatory effect even in low doses. Morphine as a traditional pain controller, analgesic drug, and a natural opioid can mediate their effects via three receptors of δ, \u0026micro;, and κ (9, 10). These receptors are found in the perception of pain, dyspnea, and have immunomodulatory effects on the surface of immune cells (11). The lower severity of COVID-19 observed in opium users can be due to these morphine features, especially its anti-inflammatory effects. Some studies are in line results with the present research. Khoshab et al. have stated that opium consumption could have prophylactic effects on COVID-19 (23). Cismaru et al. have also declared that opioids can potentially be used in the treatment of COVID-19 through their effects on both the viral infectious cycle and the host response to the infection (11).\u003c/p\u003e \u003cp\u003e Opioids are the best pharmacological agents in the palliation of dyspnea recommended by European and US therapeutic guidelines (11). Furthermore, According to the National Health Service (NHS) in England, breathlessness in severe COVID-19 patients can be decreased in their last days and hours of life with morphine sulfate administration (15). In COVID-19 patients, morphine can be used as a prime therapy for diminution of pain, breath shortness, and coughing (16). The effect of opioids on the outcome of the viral infection depends on the type of virus. Activation of opioid receptors is useful for the controlling immunopathology in viral infection with an immunopathogenic response (such as COVID-19) (24). Generally, opioids may be used in COVID-19 for three effects: inhibiting the cytokine storm, improving dyspnea, and disturbing lysosomal acidification (11). Increasing the levels of inflammatory cytokines and chemokines increase bronchoalveolar infection. Chronic morphine treatment can reduce IL-1 and IL-6 production (3) thus, immunosuppression by using opium might have a potential role in the treatment of COVID-19 patients (14). ACE2 has been shown to be a receptor for COVID-19 to enter host cells (12, 13), and the use of inhibitors of the ACE2 receptor has been proposed prevent the disease. Although is ACE2 overexpressed in opium users morphine and codeine extensively compete with the virus for binding to the receptor (6, 14). The anti-inflammatory, anti-fibrotic, antitumor, cardioprotective, and renoprotective effects of morphine have been demonstrated in in-vitro and in-vivo animal experiments. These effects could nullify the inordinate inflammation, fibrosis, as well as cardiac and renal charges associated with COVID-19 (11). The present research results could confirm these findings since the severity of COVID-19 has been lower in opium users. In patients with systemic infection, an increased amount of endogenous opioids could have a protective function and reduces inflammatory processes (25). Analgesia based on opioids is one of the most effective and cheap treatments for the palliation of severe pain (8). Opioids may be used for the treatment of pain and palliation of suffocation sense in COVID-19 patients (26).\u003c/p\u003e \u003cp\u003eHowever, due to the high potential for addiction to opioids, adequate attention should be paid when them. In critical situations such as ARDS due to COVID-19, the advantages of using opioids could dominate their undesirable side-effects (11). Hudzik et al. have concluded that morphine in the primary stages of COVID-19 could have a useful effect by inhibiting the cytokine storm however, in late stages it could be damaging (such as making septic shock) (5).\u003c/p\u003e \u003cp\u003eThe study has attempted to adjust confounding factors further, a hypothesis has been proposed, based on which opium may reduce the severity of COVID-19. More investigations are needed through laboratory and clinical trials using pharmaceutical morphine products, the main component of opium. Although the results approve that, the severity of COVID-19 in opium users is lower than the general population, this study does not support the view that opium consumption acts as a factor to reduce COVID-19 prevalence or its severity.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe present research results suggest that opium consumption may reduce the severity of COVID-19. The physiopathological reason underlying this effect may involve morphine and its features such as anti-inflammatory, and immunomodulatory pain, reduction breath shortness palliation, and cough elimination. Opium consumption is deviancy and harmful comportment however, morphine, as the most important component of opium, can be an auxiliary and temporary treatment for the COVID-19. Nevertheless, our findings need careful consideration in light of the possible increased risk of the long-term harmful consequences of morphine consumption.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has been approved by the ethics committee of Rafsanjan University of Medical Sciences with Ethical codes of IR.RUMS.REC.1399.195.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data that support the conclusions of this manuscript are included within the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;This study has also been supported by the Vice Chancellery for Research \u0026amp; Technology of Rafsanjan University of Medical Sciences. The context of this article is the views of the authors and the funder had no role in the design of the study and collection, analysis, and interpretation of data, the decision to publish, and writing the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFA, HO and HE analyzed and interpreted the data and contributor in writing the manuscript. FA, NP, HM and SK performed the data collection, methodology and contributor in writing the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the people who participated in the study and health care center personnel in Rafsanjan University of Medical Sciences, Rafsanjan, Iran.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOrnell F, Moura HF, Scherer JN, Pechansky F, Kessler F, von Diemen L. The COVID-19 pandemic and its impact on substance use: implications for prevention and treatment. Psychiatry research. 2020:113096.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlamdari NM, Afaghi S, Rahimi FS, Tarki FE, Tavana S, Zali A, et al. Mortality risk factors among hospitalized COVID-19 patients in a major referral center in Iran. The Tohoku Journal of Experimental Medicine. 2020;252(1):73\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDOLATI-SOMARIN A, Bahareh A-N. The Reasons for Higher Mortality Rate in Opium Addicted Patients with COVID-19: A Narrative Review. Iranian Journal of Public Health. 2021;50(3):470-9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrganization WH. Novel Coronavirus (2019-nCoV) Advice for the Public: Myth Buster.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHudzik B, Nowak J, Zubelewicz-Szkodzinska B. Consideration of immunomodulatory actions of morphine in COVID-19-Short report. European review for medical and pharmacological sciences. 2020;24(24):13062-4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAtaei M, Shirazi FM, Lamarine RJ, Nakhaee S, Mehrpour O. A double-edged sword of using opioids and COVID-19: a toxicological view. Substance Abuse Treatment, Prevention, and Policy. 2020;15(1):1\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRafsanjani AT, Haghparast A, Shamsizadeh A, Rohani SAH, Roohbakhsh A, Hakimizadeh E, et al. The effect of nicotine administration on physical and psychological signs of withdrawal syndrome induced by single or frequent doses of morphine in rats. J Basic Clin Neurosci. 2012;3(3):49\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo L, Winzer T, Yang X, Li Y, Ning Z, He Z, et al. The opium poppy genome and morphinan production. Science. 2018;362(6412):343-7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlimian M, Pournajafian A, Kholdebarin A, Ghodraty M, Rokhtabnak F, Yazdkhasti P. Analgesic effects of paracetamol and morphine after elective laparotomy surgeries. Anesthesiology and pain medicine. 2014;4(2).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eB\u0026ouml;rner C, H\u0026ouml;llt V, Kraus J. Mechanisms of the inhibition of nuclear factor-κB by morphine in neuronal cells. Molecular pharmacology. 2012;81(4):587\u0026thinsp;\u0026minus;\u0026thinsp;97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCismaru CA, Cismaru GL, Nabavi SF, Ghanei M, Burz CC, Nabavi SM, et al. Multiple potential targets of opioids in the treatment of acute respiratory distress syndrome from COVID-19. Journal of Cellular and Molecular Medicine. 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaur G, Lungarella G, Rahman I. SARS-CoV-2 COVID-19 susceptibility and lung inflammatory storm by smoking and vaping. Journal of Inflammation. 2020;17(1):1\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eG\u0026uuml;lsen A, Yigitbas BA, Uslu B, Dr\u0026ouml;mann D, Kilinc O. The effect of smoking on COVID-19 symptom severity: Systematic review and meta-analysis. Pulmonary medicine. 2020;2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoshanravan N, Ghaffari S, Hedayati M. Angiotensin converting enzyme-2 as therapeutic target in COVID-19. Diabetes \u0026amp; Metabolic Syndrome: Clinical Research \u0026amp; Reviews. 2020;14(4):637-9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEngland N, Improvement N. Primary Care and Community Respiratory Resource pack for use during COVID-19. London: NHS. 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEkstr\u0026ouml;m M, Dahlander B. Palliation in patients with severe covid-19. Lakartidningen. 2020;117.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaeedi M, Omrani-Nava V, Maleki I, Hedayatizadeh-Omran A, Ahmadi A, Moosazadeh M, et al. Opium Addiction and COVID-19: Truth or False Beliefs. Iranian Journal of Psychiatry and Behavioral Sciences. 2020;14(2):e103509.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. The lancet. 2020;395(10229):1033-4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhalili P, Ayoobi F, Mohamadi M, Jamalizadeh A, La Vecchia C, Esmaeili-Nadimi A. Effect of opium consumption on cardiovascular diseases\u0026ndash;a cross-sectional study based on data of Rafsanjan cohort study. BMC Cardiovascular Disorders. 2021;21(1):1\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalunke AA, Pathak SK, Dhanwate A, Warikoo V, Nandy K, Mendhe H, et al. A proposed ABCD scoring system for patient's self assessment and at emergency department with symptoms of COVID-19. Diabetes \u0026amp; Metabolic Syndrome. 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVahabzadeh M, Mostafazadeh B. Clinical Poisonings Imposed by the COVID-19 Pandemic. International Journal of Medical Toxicology and Forensic Medicine. 2021;11(1):33859-.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhiasmand M, Moghadamnia M, Khoshamouz S, Maroufizadeh S, Ebrahimzade S, Tafakory M. The Comparison of Demographic Indicators and Clinical Risk Factors in Discharged and Dead Patients Due to COVID-19. Journal of Disaster and Emergency Research. 2021;4(1):20\u0026thinsp;\u0026minus;\u0026thinsp;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhoshab H, Rajabalipour M. The Relationship between Opium Use and Coronavirus Infection: A Brief Research Report from Iran.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTahamtan A, Tavakoli-Yaraki M, Salimi V. Opioids/cannabinoids as a potential therapeutic approach in COVID-19 patients. Expert review of respiratory medicine. 2020;14(10):965-7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYarahmadzehi S, Fanaei H, Mirshekar MA, Atashpanjeh AR. Opium consumption exerts protective effect against cerebral ischemia through reducing inflammation and enhancing antioxidant defense in male rats. Neurology, Psychiatry and Brain Research. 2020;37:15\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLambert D. Opioids and the COVID-19 pandemic: does chronic opioid use or misuse increase clinical vulnerability? BJA: British Journal of Anaesthesia. 2020.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, Opium, Severity, Outcome","lastPublishedDoi":"10.21203/rs.3.rs-5741046/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5741046/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe coronavirus disease 2019 (COVID-19) pandemic has become a major challenge to healthcare systems and public health policies globally. Some people are more susceptible to coronavirus. The impact of opium use as a risk factor for COVID-19 is yet uncertain. This study investigate the effect of opium consumption on the severity of COVID-19, and its adverse consequences in opium users compared to the general population.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e This study included 2945 COVID-19 patients that had been referred to health care centers affiliated to Rafsanjan University of Medical Sciences. The personal, and clinical data including clinical presentation, the severity of symptoms, and outcome were collected. Then, the COVID-19 severity, and outcome between opium users and opium non-users were compared.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe rate of opium users was 5.13% that 87.42% of them recovered while this percentage for non-users was 86.07% (p ꞊ 0.641). In the crude regression model, the odds of the death due to COVID-19 is 0.88 (95%CI 0.54 to 1.45). The odds of the severity of COVID-19 is almost half among opium users compared with non-users (odds ratio (OR): 0.48, 95%CI 0.34 to 0.66). This association persisted after adjustment for confounders. We observed that with adjustment for confounders, opium consumption decreases the severity of COVID-19 but has no significant effect on mortality.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThere was a negative association between opium use with the severity, and death due to COVID-19. However, it is suggested more laboratory and clinical trial studies using pharmaceutical morphine products, the main component of opium.\u003c/p\u003e","manuscriptTitle":"Investigating the role of opium consumption in the severity, and outcome of COVID-19","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-13 06:29:03","doi":"10.21203/rs.3.rs-5741046/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-01-13T10:43:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-01-10T12:20:25+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-01-10T12:20:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2024-12-31T09:39:11+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e057524a-2be7-4758-926b-73d23f4cb3be","owner":[],"postedDate":"January 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-02T16:01:36+00:00","versionOfRecord":{"articleIdentity":"rs-5741046","link":"https://doi.org/10.1186/s12879-026-12719-7","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2026-01-30 15:59:02","publishedOnDateReadable":"January 30th, 2026"},"versionCreatedAt":"2025-01-13 06:29:03","video":"","vorDoi":"10.1186/s12879-026-12719-7","vorDoiUrl":"https://doi.org/10.1186/s12879-026-12719-7","workflowStages":[]},"version":"v1","identity":"rs-5741046","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5741046","identity":"rs-5741046","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}