Review Article

Does Opium Consumption Have Shared Impact on Atherosclerotic Cardiovascular Disease and Cancer?

Cite this article as: Masoudkabir F, Malekzadeh R, Yavari N, Zendehdel K, Mani A, Vasheghani-Farahani A, et al. Does opium consumption have shared impact on atherosclerotic cardiovascular disease and cancer? Arch Iran Med. 2022;25(1):50-63. doi: 10.34172/aim.2022.08

Introduction

Atherosclerotic cardiovascular disease (ASCVD) and cancer are the two main causes of mortality and morbidity globally, accounting for two-thirds of all deaths in 2012.^1,2 The occurrence of ASCVD and cancer is rising in all socioeconomic classes throughout the world over due to population aging and changes in the distribution of major lifestyle-related risk factors. Although globally, there are 4 major shared risk factors for ASCVD and cancer (viz, unhealthy diet, sedentary lifestyle, chronic alcohol and tobacco consumption), there may be local or regional habits that may significantly contribute to the increasing burden of both ASCVD and cancer.^1,3-6 The importance of common adjustable risk factors for both ASCVD and cancer is redirected in our understanding of the mutual genetics and molecular mechanisms that are essential to the pathogenesis of both diseases.⁷ Moreover, modifiable risk factors are promising targets for joint preventive efforts against ASCVD and cancer.⁸

The United Nations Office of Drugs and Crime (UNODC) estimates that in 2019, almost 30 million people consumed opium or its derivatives illegally around the globe.⁹ Very recently, opium consumption was classified into Group I as carcinogenic by the International Agency for Research on Cancer (IARC).¹⁰ While opium use and availability in developed countries have decreased over the years, opium is still the most regularly abused substance after tobacco, in developing countries such as the Middle East region, and many Asian countries.^11-13 In addition to availability, another reason for the high consumption of opium in these countries could be a traditional belief among Eastern people and even medical staff that opium consumption may have beneficial effects on health, particularly ASCVD as well as other cardiovascular risk factors including diabetes mellitus, hypertension, and dyslipidemia.^11,14-16 In the recent decade, numerous studies have been presented on humans and animals to evaluate the effect/association of opium consumption on/with various health outcomes.^17-21 Previously, we have reviewed the shared pathophysiologic pathways of ASCVD and cancer to show that these two are unexpectedly similar to each other.⁸ In this narrative review, we will review the available evidence on the relationship between opium consumption and ASCVD as well as various kinds of cancer. Additionally, we will discuss the potential shared pathophysiologic mechanisms underlying the association between opium abuse and both ASCVD and cancer.

Association between Opium Consumption and ASCVD

There is a traditional belief among Asians that opium consumption may exert a beneficial effect on the cardiovascular system such as preventing heart attacks. During the past 15 years, many observational studies have been conducted to evaluate such beliefs, and they have found interesting results. We will separately review the studies on the association between opium consumption and each of stable coronary artery disease (CAD), acute coronary syndromes, and the outcomes of coronary revascularization.

Stable Coronary Artery Disease

Clinical Studies

The paucity of studies on mortality and morbidity among opium users has prompted scientists to conduct research on individuals with opium consumption and its relationship with ASCVD. A cross-sectional study by Sadeghian and colleagues on 2405 patients demonstrated that after adjustment for cardiac risk factors, opium consumption was significantly associated with the presence of CAD (odds ratio [OR] = 1.8, 95% confidence interval [CI] = 1.1 to 3.1; P =  0.015), and a dose-response relationship was observed between the dosage of opium consumption and the severity of CAD.²² In another cross-sectional study, which investigated the predictors of premature CAD in the Iranian population, Sadeghian and colleagues found that high prevalence of opium consumption was the most important risk factor for premature CAD in male patients (OR = 4.47, 95% CI = 1.49 to 13.38; P < 0.01).²³ In another cross-sectional study, Hosseini et al evaluated 2874 opium consumers compared with 2568 non-consumers and found that opium use was an independent risk factor for CAD (OR = 1.31, 95% CI = 1.01 to 1.69; P =  0.042).²⁴ Darabad and colleagues conducted a survey on 1170 patients, including 121 opium-using patients, who underwent coronary angiography. They showed that opium addiction was associated with angiographically confirmed CAD. Nonetheless, they did not find any significant association between opium use and the number of affected coronary vessels.²⁵

In addition to atherosclerotic disease of the major epicardial coronary arteries, it has been shown that opium use is related with microvascular coronary dysfunction (MCD). In a cross-sectional study on 250 Iranian patients with confirmed ischemic heart disease by exercise test and coronary angiography, Nadimi et alobserved that opium addiction was the only factor associated with MCD (OR = 3.57, 95% CI = 1.42 to 9.02, P =  0.0069).²⁶

There are other several studies on the association between opium consumption and CAD occurrence that have shown an increased risk of CAD in association with opium use.^27-30 One exception is an investigation by Rezvani et alwho showed no significant association between opium consumption and ischemic heart disease.³¹

A summary of studies on the association between opium consumption and stable CAD and its outcomes is presented in Table 1.

Acute Coronary Syndromes

Despite consistency in the findings of studies evaluating the association between opium consumption and stable CAD, there is controversy among investigations regarding the possible association between opium consumption and the occurrence of acute MI and its short- and medium-term outcomes such as prolonged hospitalization, atrial fibrillation, and heart failure.³² In a cross-sectional research, which was followed by a 1-year longitudinal cohort study on 690 patients with acute myocardial infarction (AMI), Roohafza and colleagues investigated the prevalence of opium dependency and the occurrence of short- and long-term events following AMI. They found that out of the 690 patients, 118 were opium-dependent. Opium dependency decreased age by 3.6 years (95% CI = 1.2 to 6.0; P =  0.003) for the occurrence of post-MI mortality and morbidity independent of cigarette smoking.³³ Harati et al³⁴ observed that those with opium dependency had almost significantly higher in-hospital mortality (11.5% vs 5.9%; P =  0.072) and significantly higher rehospitalization rates than nonusers (38.5% vs 13.7%; P < 0.001). Currently, many physicians do not advise their patients to quit opium consumption because of the fear of inducing a heart attack. Masoomi and colleagues conducted a remarkable study to evaluate whether opium withdrawal was a trigger for AMI. They evaluated 81 patients who had discontinued opium consumption and observed that after adjustments for demographic characteristics, marital status, education level, and common CAD risk profiles, opium withdrawal was not a trigger for AMI (OR = 0.920, 95% CI = 0.34 to 2.42; P =  0.866).³⁵ Dehghani et al also demonstrated that in-hospital mortality was not significantly different between 239 opium-addicted patients and 221 nonaddicted patients. Opium addiction was associated with lower occurrence of anterior wall MI (26.4% vs 36.4% in nonaddicted patients) and its related early mortality.³⁶ Recently, a systematic review and meta-analysis by Nakhaee et al evaluated the association between opium and CVD. They demonstrated a significant association between opium use and CAD but not in-hospital mortality (OR = 2.75, 95% CI = 2.04 to 3.75; I²= 47% vs OR = 1.44, 95% CI = 0.88 to 2.36; I² = 51%).³²

There are a few studies that have indicated no association between opium consumption and the increased incidence of MI³⁷ or in-hospital mortality.^14,38-40 Still, vis-à-vis the effects of opium on the cardiovascular system, there is always the presence of such intervening factors as the dose of drugs and the length and frequency of opium use, which should be considered. Additionally, research should take into account different routes of drug administration (e.g. inhalation, oral use, and injection), for which opium absorption and blood levels are different.³⁰

The association between opium consumption and acute coronary syndromes and the related outcomes is demonstrated in Table 2.

Revascularization Studies

Based on traditional beliefs among people as well as some physicians, patients tend to continue opium consumption after coronary artery bypass grafting (CABG) surgery to improve the outcome of the operation. A cohort study on 566 isolated CABG patients was performed by Najafi and colleagues, who reported that opium consumption conferred no cardioprotective effects on addicted patients who underwent the operation. Nevertheless, they could not ignore the concurrent impact of cigarette smoking as a confounding variable.⁴² Najafi et al also carried out a study on 268 patients with a confirmed diagnosis of CAD who had undergone isolated CABG. Of the 268 patients, only 38 were addicted at the time of the surgery. However, the authors found no significant vessel involvement in any of the groups, but the mean EuroSCORE was higher in the opium addicts than that in the nonaddicts.⁴³ Given the controversy surrounding the post-intervention continuation of opium consumption, in a retrospective study on 1545 patients with percutaneous coronary interventions history, Sharafi and colleagues evaluated the association between preprocedural opium consumption and major cardio-cerebrovascular events (MACCE). They found no significant correlation with MACCE between opium users and nonusers after percutaneous coronary interventions (11 [3.1%] vs 53 [4.4%]; P = 0.286, respectively). The unadjusted hazard of 1 year’s MACCE in the opium users and nonusers was 0.704 (95% CI = 0.367 to 1.347; P = 0.289).⁴⁴

Stroke

Hamzei-Moghadam et alconducted a cross-sectional study on 97 patients with ischemic stroke (38 addicts). They observed that one-third of the patients with ischemic stroke were addicted to opium and that the rate was higher than that in the general population.⁴⁵ In another case-control study, 672 patients with ischemic stroke were compared with 293 controls with no stroke or CAD history. In that study, Ebrahimi and colleagues found that opium addiction was independently associated with ischemic stroke (OR = 2.36, 95% CI = 1.16 to 4.85; P =  0.018).⁴⁶ More studies on the association between opium consumption and stroke are needed to clarify this relationship.

Peripheral Arterial Disease

Most studies indicate an association between ASCVD and opium consumption. There are limited studies evaluating the effects of opium on peripheral vascular disease. In a study by Shirani and colleagues, opium was assessed as a risk factor for significant carotid stenosis (≥ 70% the luminal diameter) in 939 patients with CABG. Although the authors did not detect any difference in the prevalence of significant carotid artery stenosis in opium-addicted versus nonaddicted patients, it should be noted that the opium-addicted patients had lower prevalence rates of hypertension (88.6% vs 11.4%) and diabetes (17% vs 11.4%) and a higher prevalence rate of smoking (27.1% vs 65.5%) than the nonaddicts.⁴⁷ However, Shirani et al did not adjust for confounding variables, and their findings should be interpreted cautiously. In another study, Jafarian et al⁴⁸ evaluated factors affecting graft patency in 85 patients who had undergone infrainguinal revascularization. They demonstrated that the patency rate was significantly lower in patients with opium use (32%) than nonusers (67%) (P = 0.030). It seems that more well-designed studies should be performed in the future to elucidate the effects of opium on peripheral vascular disease.

Association between Opium Consumption and ASCVD in Cohort Studies

The best corroborating evidence for a potential hazardous role of opium use in ASCVD derived from the Golestan Cohort Study.⁴⁹ The Golestan Cohort Study enrolled 50 045 individuals between 40 and 75 years of age from January 2004 to June 2008 from the Golestan province, located in northern Iran. After a follow-up median of 4.7 years, the adjusted hazard ratio (HR) was 1.86 (95% CI = 1.68 to 2.06) for all-cause mortality associated with the opium consumption. The study also revealed that opium consumers were at 90% increased risk of mortality from ischemic heart disease (adjusted HR = 1.90; 95% CI = 1.57 to 2.29). Moreover, after omitting the subjects who had started opium use after receiving a diagnosis of a major illness (e.g. ischemic heart disease, cerebrovascular events, diabetes mellitus, and hypertension), the researchers discovered a dose-response association between the duration of opium consumption and ASCVD as well as all-cause mortality.³⁰ In a very recent publication of the Golestan Cohort Study, Nalini et al investigated the effects of long-term opiate use (crude opium or shireh [a derivative of opium made by boiling and filtering the opium, which has higher concentrations of morphine]) on cardiovascular mortality. They observed a significantly increased risk of mortality in opium users by comparison with nonusers (adjusted HR = 1.63; 95% CI = 1.49 to 1.79).⁵⁰ We think that there is a strong correlation between opium use and ASCVD based on the Golestan Cohort Study.

Association between Opium Consumption and Cancer

A popular belief among laypeople and also some physicians is that the use of opium can improve the survival of patients with malignancy. This belief might be due to the analgesic properties of opium that relieves pain in these patients. During the past few years, many studies have demonstrated a positive connection between opium consumption and the development of various types of cancers. More recent studies have explored the effects of opium consumption on cell proliferation and metastasis. In the next section, we are going to review the evidence on the association between opium consumption and cancer and the biological basis for such an association.

Laryngeal Cancer

A case-control study by Mousavi et al on 98 patients with laryngeal cancer and 312 age- and gender-matched controls showed the possible association between opium consumption and laryngeal cancer. By adjusting for potential confounders, they demonstrated that use of opium was strongly associated with laryngeal cancer (OR = 10.74, 95% CI = 5.76 to 20.02; P <  0.002).⁵¹ Rahmati et al performed an analysis on data from the Golestan Cohort Study to investigate the relationship between opium consumption and mortality from respiratory malignancies. The results demonstrated that after adjustment for age, sex, residential place, education level, marital status, alcohol use, and the cumulative use of any type of tobacco, opium consumption was associated with an increased risk of laryngeal cancer, very close to significance, with lower bounds of CIs being 0.99.⁵² Bakhshaee et al evaluated the association between opium addiction and the risk of laryngeal carcinoma and found that the crude OR for laryngeal cancer in opium users was 9.09 (95% CI = 3.21 to 25.64; P =  0.000) relative to nonusers. Additionally, after adjustment for opium consumption with cigarette smoking, the OR for laryngeal cancer in opium users was 6.06 (95% CI = 1.10 to 33.23; P =  0.05). Laryngeal cancer was also detected in younger patients with opium dependency (54.54 ± 10.93; P =  0.02).⁵³ More recently, Sheikh et al performed an analysis on data from the Golestan Cohort Study to evaluate opium use and the subsequent incidence of cancer. They reported that the use of opium was associated with an increased risk of developing laryngeal cancer (HR = 2.53, 95% CI = 1.21 to 5.30; P <  0.05).⁵⁴ Table 3 demonstrates all studies performed on this topic and a summary of other studies on the association between opium consumption and cancer.

Lung Cancer

Lung cancer is well-known to be the most prevalent malignancy and the leading cause of mortality in the world. The results of a study by Rahmati et al on data from the Golestan Cohort Study showed that opium consumption was associated with an increased rate of lung cancer mortality (OR = 1.96; 95% CI = 1.18 to 3.25). The long-term use of opium also showed an increased rate of death due to respiratory malignancies (HR = 3.01; 95% CI = 1.55 to 5.81).⁵² In another analysis based on the Golestan Cohort Study, Sheikh et al investigated 1833 participants diagnosed with cancer during a median follow-up of 10 years and reported that opium use was associated with increased incidence of lung cancer (HR = 2.21, 95% CI = 1.44 to 3.39; P <  0.05).⁵⁴

Esophageal Cancer

Several reports have indicated a positive association between opium consumption and esophageal cancer with a dominant type of squamous cell carcinoma (ESCC). Ghadirian et al performed a case-control study on 82 patients to evaluate the association between the presence of morphine metabolites and esophageal cancer. They found that individuals with more than 1 µg/mL of morphine metabolites in their urine had a higher rate of esophageal cancer.⁵⁵ Bakhshaie et al also performed a case-control study to evaluate the association between the risk of esophageal carcinoma and opium addiction. They demonstrated that the crude OR for esophageal cancer was 1.44 (95% CI = 0.57 to 3.62; P = 0.43) relative to nonusers.⁵³ Other studies conducted on the population in the northern Iranian province of Golestan are known for a high incidence of esophageal cancer. In their case-control study, Nasrollahzadeh et al observed that 30% of patients with ESCC and 18% of controls were opium users. More interestingly, the authors observed an even stronger association between using shireh and ESCC than between usual opium and ESCC (OR = 3.41; 95% CI = 1.35 to 8.60 and OR = 1.62; 95% CI = 1.09 to 2.40, respectively).⁵⁶ These results were further supported and expanded by the Golestan Cohort Study, which demonstrated that after adjustment for potential confounding variables and the exclusion of those who started opium consumption in the wake of a major chronic disease (including CAD, stroke, diabetes mellitus, and hypertension), the use of opium was related with a 69% increased risk of ESCC-related mortality (HR = 1.69; 95% CI = 1.11 to 2.56) in a dose-dependent manner.⁵⁷ Another report of the Golestan Cohort Study demonstrated that, after adjustments for potential variables including age, gender, residence districts, ethnicity, and quartiles of the socioeconomic status, opium use was associated with a dose-response increased risk of ESCC (HR = 1.85; 95% CI = 1.18 to 2.90; P = 0.009).⁵⁸ A more recent analysis of their data also showed that opium use was associated with a risk of developing esophageal cancer (HR = 1.38, 95% CI = 1.06 to 1.80; P < 0.05), dose-dependently.⁵⁴ Studies are summarized in Table 3.

Gastric Adenocarcinomas

Different investigations have shown a strong relationship between opium use and gastrointestinal tract carcinoma, which counts as the second cause of cancer-related mortality worldwide and the most common cause of cancer in Iran. For instance, an analysis of the Golestan Cohort Study by Malekzadeh et al showed that the use of opium was associated with a 22% increase in the risk of gastric-related mortality (HR = 1.22; 95% CI = 0.79 to 1.89).⁵⁷ In another case-control study in the Golestan Province of Iran, Shakeri et al evaluated 922 patients (309 cases of gastric adenocarcinoma) and demonstrated that opium consumption after the diagnosis of gastric cancer exhibited a significant rise in all types of gastric cancer (OR = 2.9; 95% CI = 1.7 to 4.8). Moreover, those with the highest cumulative opium consumption showed the strongest relationship (OR = 4.5; 95% CI = 2.3 to 8.5).⁵⁹ Sadjadi et al performed a cohort study on 928 Helicobacter-positive patients and observed that opium use was significantly associated with baseline antral and body intestinal metaplasia (OR = 3.2, 95% CI = 1.2 to 9.1; P = 0.022 and OR = 7.3, 95% CI = 2.5 to 21.5; P = 0.001, respectively). Opium use increased the prevalence of all gastric cancers (HR = 3.2; 95% CI = 1.4 to 7.7).⁶⁰ Sheikh et al performed another analysis from the Golestan Cohort Study to evaluate the association between opium consumption and developing gastric carcinoma. They found that the use of opium was associated with an increased risk of the development of gastric cancer (HR = 1.36, 95% CI = 1.03 to 1.79; P < 0.05).⁵⁴

Pancreatic Cancer

Shakeri and colleagues observed that after adjustment for potential confounding variables including age and the duration and cumulative use of opium, a relationship was observed between opium consumption and the risk of pancreatic cancer (OR = 1.91; 95% CI = 1.06 to 3.43) without a dose-response relationship.⁶¹ In an analysis of the Golestan Cohort Study, Moossavi and colleagues identified a greater effect of opium ingestion (HR = 2.38, 95% CI = 1.00 to 5.69; P =  0.05) in comparison to its inhalation (HR = 1.88; 95% CI = 0.91 to 3.89) on the incidence of pancreatic cancer. After adjustment for the cumulative dose of cigarette smoking, the authors also detected that high cumulative use of opium was significantly associated with the risk of pancreatic cancer (HR = 3.56, 95% CI = 1.49 to 8.50; P =  0.090).⁶²

Colorectal Carcinomas

A few studies have explored the association between opium consumption and colorectal carcinomas (CRCs), including colon, rectum, and anus cancers. Naghibzadeh-Tahami et alconducted a case-control study on 175 patients with CRC and 350 healthy individuals to observe any possible association between opium consumption and the incidence of CRCs. They demonstrated that opium and its derivatives were associated with an increased risk of all CRCs (OR = 4.5; 95% CI = 2.4 to 8.7) and colon cancers (OR = 5.7; 95% CI = 2.7 to 11.9). They observed strong relationships between the daily dose and the duration of opium consumption and CRCs and colon cancers.⁶³ Dianatinasab et alperformed a prospective cohort study on 220 patients with CRCs to determine their mortality rate. They demonstrated that opium consumption was significantly associated with a higher risk of CRC-related mortality (HR = 2.49, 95% CI = 1.41 to 4.42; P =  0.001).⁶⁴

Bladder Cancer

Sadeghi et alwere the first to perform a case-control study on 189 patients in Iran to demonstrate a correlation between opium addiction and bladder cancer.⁶⁵ Afterwards, many investigators reported such an association between opium consumption and bladder cancer^66-77 (Table 3). The dominant histological type was transitional-cell carcinoma in most of the studies. Akbari et alobserved a significant relationship between opium consumption and the prevalence of bladder cancer after adjustment for potential confounding variables including nutritional factors and tobacco use (OR = 3.9; 95% CI = 1.3 to 12.0). Additionally, they observed a significant dose-response relationship between opium use and bladder cancer (OR = 4.9; 95% CI = 1.1 to 21.9).⁷⁴ Opium has been demonstrated to have a deleterious effect on cell survival insofar as it increases the metastasis of cells in the urinary system. A systematic-review and meta-analysis was conducted by Afshari and colleagues to evaluate the association between opium consumption and the development of bladder cancer. The OR for the association between bladder cancer and opium use (without cigarette smoking) was 3.85 (95% CI = 3.05 to 4.87), which increased to 5.7 (95% CI = 1.9 to 16.3) when both opium use and cigarette smoking were examined.⁷³ Another analysis of the Golestan Cohort Study demonstrated a significant association between opium consumption and bladder cancer (HR = 2.86, 95% CI = 1.47 to 5.55; P <  0.05).⁵⁴

Other Types of Cancer

Razmpa and colleagues evaluated the connection between opium use and oral cavity cancer in 160 individuals (80 patients with oral cavity cancer). They demonstrated that opium consumption was significantly related to oral cavity cancer (OR = 4.0; 95% CI = 1.2 to 13.6).⁷⁶

The Shared Role of Opium in the Pathogenesis of ASCVD and Cancer

Inflammation

It is well known that chronic low-grade inflammation has a pivotal role in the formation of atherosclerotic plaques and their progression. Atherosclerotic plaques contain many pro-inflammatory cytokines such as C-reactive protein (CRP), interleukin-1 (IL-1), tumor necrosis factor-α, and interferon-γ (INF- γ)⁷⁷ that accelerate atherogenesis. This lipid-rich, inflamed microenvironment of plaques also contains reactive oxygen species (ROS) and oxidized low-density-lipoprotein cholesterol, causing increased inflammatory signaling, foam cell formation, and angiogenesis.

Rudolf Virchow in the 19th century claimed that there was a link between inflammation and cancer.⁷⁸ He found that several solid cancers were triggered by chronic inflammatory state, inflamed environments, and interactions of mediators.¹ Tumor growth depends on the activation of a wide range of pathways such as Janus-activated kinase, mitogen-activated protein kinase, and protein kinase B that can progress the carcinogenesis of affected cells and promote malignancy by the transcriptional activation of pro-inflammatory, pro-survival, and proteolytic programs via the signal transducer and activator of transcription, nuclear factor-kB, and hypoxia-inducible factor-1α.^78-82 Furthermore, ROS and subsequent reactive nitrogen species can stimulate DNA destruction and resultant mutations in oncogenes and tumor suppressor genes could result in carcinogenesis.^81,82

In conclusion, inflammation and oxidative stress have an important part in the pathogenesis of both CVD and cancer. Recent studies have shown that chronic exposure to opium enhances the levels of pro-inflammatory mediators including CRP, IL-17, IL-6, INF-γ, IL-1 receptor antagonist, and C3 and C4 complement factors and decreases the levels of cytokines like transforming growth factor-β.^83-85 Hence, chronic exposure to opium could initiate/accelerate atherogenesis and carcinogenesis by enhancing inflammation and oxidative stress.

Plasminogen Activator Inhibitor-1

Plasminogen activator inhibitor-1 (PAI-1) accounts as an inhibitor of fibrinolysis.⁸⁶ There is accumulating evidence that PAI-1 is involved in atherogenesis; its activation promotes thrombus formation, stabilizes the fibrin matrix, and stimulates vascular smooth muscle cell proliferation and low-density lipoprotein uptake into the plaque.^87,88 Additionally, it has been shown that levels of PAI-1 are increased in individuals with various types of cancer^86,89-92 and predict worse prognoses.^93-95 Recent studies have demonstrated that levels of PAI-1 are higher in opium addicts than nonusers. More interestingly, there is evidence that opioid receptors are present on various cancer cell types and the main alkaloids of opium-like morphine could upregulate the expression of the PAI-1 gene and, therefore, increase the progression of tumor cells.⁹⁶ Hence, it could explain, at least in part, the increased risk of atherosclerosis and cancer in opium users.

Adipokine (Adiponectin)

Adiponectin is a unique adipokine which has beneficial metabolic properties including anti-inflammatory, anti-oxidant, anti- or pro-atherogenic, and insulin sensitizing effects. It is a potential prognostic biomarker and a therapeutic target for patients with CVD that have atherosclerosis, inflammation, and insulin resistance.⁹⁷ Moreover, evidence proposes that adiponectin may have connection with the pathogenesis of several malignancies and their poor prognoses.⁹⁸ Generally, serum adiponectin levels are reduced in various cancers, including breast,⁹⁹ endometrial,¹⁰⁰ CRC,¹⁰¹ hematologic,¹⁰² pancreatic,¹⁰³ lung,¹⁰⁴ prostate,¹⁰⁵ esophageal,¹⁰⁶ and gastric¹⁰⁶ cancer. A recent investigation has shown that the adiponectin level is lower in opium consumers than in no consumers.¹⁰⁷ The decreased levels of adiponectin could explain, at least in part, the increased risk of CVD occurrence and cancer in opium users.

Homocysteine

Hyperhomocysteinemia is known to be an independent risk factor for ASCVD.^108-112 Homocysteine can cause vascular lesion, atherogenesis, thrombogenesis, hyperplasia, endothelial dysfunction, decreased nitric oxide and stimulating vascular smooth muscle cell proliferation.^109,113 Recent studies have also proven that there is a close link between hyperhomocystinuria and cancer and it is a novel potential tumor biomarker.¹¹⁴ Moreover, several polymorphisms in the enzymes involved in the homocysteine detoxification pathways have close clinical ties to several cancer types, such as breast,¹¹⁵ CRC,¹¹⁶ acute lymphoblastic leukemia¹¹⁷ and prostate.¹¹⁸ Masoomi et al demonstrated that opium consumption was strongly accompanied by increased levels of homocysteine, which could explain the increased incidence of CVD and cancer in opium users.¹¹⁹

Fibrinogen

Fibrinogen is an independent risk factor for ASCVD.¹²⁰ Increased levels of fibrinogen are associated with the development of ASCVD through platelet aggregation, fibrin formation, atherosclerotic plaque evolution, and thrombus formation.^121-123 In a few recent studies, convincing evidence has been provided to demonstrate that plasma fibrinogen is associated with tumor progression and poor prognoses in lung,¹²⁴ breast,¹²⁵ gastric.¹²⁶ ovarian,¹²⁷ oral and oropharyngeal,¹²⁸ biliary tract,^129,130 and penile cancer. Fibrinogen/fibrin seems to simplify the microvascular entrapment necessary for metastasis and to contribute to the formation of the connective tissue (stroma) of some forms of solid tumor.^131,132 There is evidence that opium consumption is associated with increased levels of clotting factors such as fibrinogen, explaining partially the increased risk of cancer development and ASCVD in opium users.^133,134

HbA1c

HbA1c is a well-known marker of long-term glycemic control in patients with diabetes mellitus, and elevated HbA1c levels are correlated with an increased risk for future microvascular and macrovascular disease. A few studies have shown HbA1c to be predictive of CAD in nondiabetics and to be correlated with the severity of CAD.^135,136 Furthermore, evidence also suggests that elevated HbA1c is related with an increased risk of developing certain types of cancer compared with nondiabetics, with the strongest associations seen with hepatic, pancreatic, endometrial, renal, breast, esophageal, colorectal, and bladder cancer.¹³⁷ Recently, contrary to the traditional belief that opium consumption decreases blood glucose and insulin resistance, it has been found that HbA1c is higher in opium users than in nonusers.^11,16,133 Hence, it could also justify the increased risk of ASCVD and cancer in opium users.

Factor VII

Factor VII (FVII) contributes to the initiation of the extrinsic pathway by binding to tissue factor. Coagulation cascade and platelet activation and subsequent acute coronary events is led by the formation of the FVII complex.^138,139 Additionally, mounting evidence suggests that the tissue factor-FVII complex is involved in pathophysiological processes of cancer development, including angiogenesis, tumor migration and invasion, and cell survival.^138,140,141 Asgary et aldemonstrated that opium users had higher levels of FVII than nonusers, which could also explain the higher risk of ASCVD and cancer in opium users.¹³³

Limitations of Studies on the Association Between Opium and ASCVD and Cancer

As we reviewed in previous sections and summarized in tables, the majority of the studies evaluating the association between opium consumption and ASCVD and cancer have case-control or cross-sectional designs. Case-control studies are excellent for studying rare/non-prevalent diseases such as cancer; however, they carry some inherent limitations that call for attention when interpreting their results. Although case-control clinical studies have demonstrated the relationship between opium consumption CAD, stroke, and cancer, we cannot make a causative interpretation because the temporal relationship between opium consumption and ASCVD or cancer cannot be determined in these studies. Indeed, it is likely that some people with ASCVD, stroke, or cancer start consuming opium due to their symptoms/belief about the advantageous effects of opium use on ASCVD or cancer following the development of their disease. Thus, as we witness a higher prevalence of opium usage among patients with ASCVD or cancer than among normal controls, we cannot make a causal interpretation. Despite the high prevalence of opium consumption among Eastern people, opium carries a stigma for the individual and its reporting varies between patients and healthy individuals. It is expected that healthy individuals within the control group under-report their opium consumption that would result in the overestimation of the outcomes of opium consumption on the development of ASCVD or cancer. Nonetheless, cohort studies can overcome the limitation of temporality and unbalanced reporting of exposure to opium. Fortunately, almost all of the aforementioned concerns have been regarded and minimized thanks to the results of the Golestan Cohort Study.

In conclusion, although ASCVD and cancer are seemingly different types of disease, they have multiple shared pathogenesis mechanisms and lifestyle-related risk factors like smoking, unhealthy diet, excessive alcohol consumption, and inadequate physical activity. We believe that opium consumption should be added to the current list of the lifestyle-related shared risk factors of ASCVD and cancer and special strategies should be developed and conducted for more comprehensive joint preventive programs that target both top-ranking killers in the world.

References

1. Koene RJ, Prizment AE, Blaes A, Konety SH. Shared risk factors in cardiovascular disease and cancer. Circulation 2016; 133(11):1104-14. doi: 10.1161/circulationaha.115.020406 [Crossref] [ Google Scholar]
2. World Health Organization. Global Status Report on Noncommunicable Diseases 2014. Available from: https://apps.who.int/iris/handle/10665/148114.
3. Meijers WC, de Boer RA. Common risk factors for heart failure and cancer. Cardiovasc Res 2019; 115(5):844-53. doi: 10.1093/cvr/cvz035 [Crossref] [ Google Scholar]
4. UN. General Assembly. Political Declaration of the High-Level Meeting of the General Assembly on the Prevention and Control of Non-Communicable Diseases. New York: United Nations; 2011.
5. World Health Organization. The World Health Report: 2002: Reducing Risks, Promoting Healthy Life. Available from: https://www.who.int/publications/i/item/9241562072.
6. Zand S, Shafiee A, Boroumand M, Jalali A, Nozari Y. Serum uric acid is not an independent risk factor for premature coronary artery disease. Cardiorenal Med 2013; 3(4):246-53. doi: 10.1159/000355484 [Crossref] [ Google Scholar]
7. Lee DK, Nathan Grantham R, Trachte AL, Mannion JD, Wilson CL. Activation of the canonical Wnt/beta-catenin pathway enhances monocyte adhesion to endothelial cells. Biochem Biophys Res Commun 2006; 347(1):109-16. doi: 10.1016/j.bbrc.2006.06.082 [Crossref] [ Google Scholar]
8. Masoudkabir F, Sarrafzadegan N, Gotay C, Ignaszewski A, Krahn AD, Davis MK. Cardiovascular disease and cancer: Evidence for shared disease pathways and pharmacologic prevention. Atherosclerosis 2017; 263:343-51. doi: 10.1016/j.atherosclerosis.2017.06.001 [Crossref] [ Google Scholar]
9. United Nations Office on Drugs and Crime. World Drug Report 2020. Available from: http://vngoc.org/wp-content/uploads/2020/07/wdr2020_Presentation-CSO_EN_27072020-rev.pdf.
10. Warnakulasuriya S, Cronin-Fenton D, Jinot J, Kamangar F, Malekzadeh R, Dar NA. Carcinogenicity of opium consumption. Lancet Oncol 2020; 21(11):1407-8. doi: 10.1016/s1470-2045(20)30611-2 [Crossref] [ Google Scholar]
11. Masoudkabir F, Sarrafzadegan N, Eisenberg MJ. Effects of opium consumption on cardiometabolic diseases. Nat Rev Cardiol 2013; 10(12):733-40. doi: 10.1038/nrcardio.2013.159 [Crossref] [ Google Scholar]
12. Karbakhsh M, Salehian Zandi N. Acute opiate overdose in Tehran: the forgotten role of opium. Addict Behav 2007; 32(9):1835-42. doi: 10.1016/j.addbeh.2006.12.014 [Crossref] [ Google Scholar]
13. Kulsudjarit K. Drug problem in southeast and southwest Asia. Ann N Y Acad Sci 2004; 1025:446-57. doi: 10.1196/annals.1316.055 [Crossref] [ Google Scholar]
14. Sadr-Bafghi SM, Rafiei M, Bahadorzadeh L, Namayeh SM, Soltani MH, Andishmand MM. Is opium addiction a risk factor for acute myocardial infarction?. Acta Med Iran 2005; 43(3):218-22. [ Google Scholar]
15. Farahani MA, Mohammadi E, Ahmadi F, Maleki M, Hajizadeh E. Cultural barriers in the education of cardiovascular disease patients in Iran. Int Nurs Rev 2008; 55(3):360-6. doi: 10.1111/j.1466-7657.2008.00635.x [Crossref] [ Google Scholar]
16. Asadikaram G, Reisi M, Alizadeh Kaseb A, Khaksari M, Mohammadi A, Mahmoodi M. Effects of opium addiction on some serum factors in addicts with non-insulin-dependent diabetes mellitus. Addict Biol 2004; 9(1):53-8. doi: 10.1080/13556210410001674095 [Crossref] [ Google Scholar]
17. Mohammadi A, Darabi M, Nasry M, Saabet-Jahromi MJ, Malek-Pour-Afshar R, Sheibani H. Effect of opium addiction on lipid profile and atherosclerosis formation in hypercholesterolemic rabbits. Exp Toxicol Pathol 2009; 61(2):145-9. doi: 10.1016/j.etp.2008.08.001 [Crossref] [ Google Scholar]
18. Asadikaram G, Vakili S, Akbari H, Kheirmand-Parizi M, Sadeghi E, Asiabanha M. Effects of opium addiction on some biochemical factors in diabetic rats. Addict Health 2018; 10(2):123-30. doi: 10.22122/ahj.v10i2.531 [Crossref] [ Google Scholar]
19. Najafipour H, Joukar S. Combination of opium smoking and hypercholesterolemia augments susceptibility for lethal cardiac arrhythmia and atherogenesis in rabbit. Environ Toxicol Pharmacol 2012; 34(2):154-9. doi: 10.1016/j.etap.2012.03.008 [Crossref] [ Google Scholar]
20. Najafipour H, Joukar S, Malekpour-Afshar R, Mirzaeipour F, Nasri HR. Passive opium smoking does not have beneficial effect on plasma lipids and cardiovascular indices in hypercholesterolemic rabbits with ischemic and non-ischemic hearts. J Ethnopharmacol 2010; 127(2):257-63. doi: 10.1016/j.jep.2009.11.011 [Crossref] [ Google Scholar]
21. Joukar S, Najafipour H, Malekpour-Afshar R, Mirzaeipour F, Nasri HR. The effect of passive opium smoking on cardiovascular indices of rabbits with normal and ischemic hearts. Open Cardiovasc Med J 2010; 4:1-6. doi: 10.2174/1874192401004010001 [Crossref] [ Google Scholar]
22. Sadeghian S, Darvish S, Davoodi G, Salarifar M, Mahmoodian M, Fallah N. The association of opium with coronary artery disease. Eur J Cardiovasc Prev Rehabil 2007; 14(5):715-7. doi: 10.1097/HJR.0b013e328045c4e9 [Crossref] [ Google Scholar]
23. Sadeghian S, Graili P, Salarifar M, Karimi AA, Darvish S, Abbasi SH. Opium consumption in men and diabetes mellitus in women are the most important risk factors of premature coronary artery disease in Iran. Int J Cardiol 2010; 141(1):116-8. doi: 10.1016/j.ijcard.2008.11.063 [Crossref] [ Google Scholar]
24. Hosseini SA, Abdollahi AA, Behnampour N, Salehi A. The relationship between coronary risk factors and coronary artery involvement based on angiogrpahy findings. Koomesh 2012;14(1):7-12. [Persian].
25. Rahimi Darabad B, Vatandust J, Pourmousavi Khoshknab MM, Hajahmadi Poorrafsanjani M. Survey of the effect of opioid abuse on the extent of coronary artery diseases. Glob J Health Sci 2014; 6(7 Spec No):83-91. doi: 10.5539/gjhs.v6n7p83 [Crossref] [ Google Scholar]
26. Esmaeili Nadimi A, Pour Amiri F, Sheikh Fathollahi M, Hassanshahi G, Ahmadi Z, Sayadi AR. Opium addiction as an independent risk factor for coronary microvascular dysfunction: a case-control study of 250 consecutive patients with slow-flow angina. Int J Cardiol 2016; 219:301-7. doi: 10.1016/j.ijcard.2016.06.034 [Crossref] [ Google Scholar]
27. Masoumi M, Ramezani MA, Karimzadeh H. The relationship of opium addiction with coronary artery disease. Int J Prev Med 2010; 1(3):182-6. [ Google Scholar]
28. Masoumi M, Shahesmaeili A, Mirzazadeh A, Tavakoli M, Zia Ali A. Opium addiction and severity of coronary artery disease: a case-control study. J Res Med Sci 2010; 15(1):27-32. [ Google Scholar]
29. Hosseini SK, Masoudkabir F, Vasheghani-Farahani A, Alipour-Parsa S, Sheikh Fathollahi M, Rahimi-Foroushani A. Opium consumption and coronary atherosclerosis in diabetic patients: a propensity score-matched study. Planta Med 2011; 77(17):1870-5. doi: 10.1055/s-0031-1280017 [Crossref] [ Google Scholar]
30. Khademi H, Malekzadeh R, Pourshams A, Jafari E, Salahi R, Semnani S. Opium use and mortality in Golestan Cohort Study: prospective cohort study of 50,000 adults in Iran. BMJ 2012; 344:e2502. doi: 10.1136/bmj.e2502 [Crossref] [ Google Scholar]
31. Rezvani MR, Ghandehari K. Is opium addiction a risk factor for ischemic heart disease and ischemic stroke?. J Res Med Sci 2012; 17(10):958-61. [ Google Scholar]
32. Nakhaee S, Amirabadizadeh A, Qorbani M, Lamarine RJ, Mehrpour O. Opium use and cardiovascular diseases: a systematic review and meta-analysis. Crit Rev Toxicol 2020; 50(3):201-12. doi: 10.1080/10408444.2020.1740972 [Crossref] [ Google Scholar]
33. Roohafza H, Talaei M, Sadeghi M, Haghani P, Shokouh P, Sarrafzadegan N. Opium decreases the age at myocardial infarction and sudden cardiac death: a long- and short-term outcome evaluation. Arch Iran Med 2013; 16(3):154-60. [ Google Scholar]
34. Harati H, Shamsi A, Firouzkouhi Moghadam M, Seyed Zadeh FS, Ghazi A. The mortality rate of myocardial infraction patients with and without opium dependen. Int J High Risk Behav Addict 2015; 4(3):e22576. doi: 10.5812/ijhrba.22576 [Crossref] [ Google Scholar]
35. Masoomi M, Zare J, Nasri H, Mirzazadeh A, Sheikhvatan M. Abrupt opium discontinuation has no significant triggering effect on acute myocardial infarction. J Cardiovasc Med (Hagerstown) 2011; 12(4):234-8. doi: 10.2459/JCM.0b013e328343d5b7 [Crossref] [ Google Scholar]
36. Dehghani F, Masoomi M, Haghdoost AA. Relation of opium addiction with the severity and extension of myocardial infarction and its related mortality. Addict Health 2013; 5(1-2):35-42. [ Google Scholar]
37. Azimzade-Sarwar B, Yousefzade G, Narooey S. A case-control study of effect of opium addiction on myocardial infarction. Am J Appl Sci 2005; 2(7):1134-5. [ Google Scholar]
38. Davoodi G, Sadeghian S, Akhondzadeh S, Darvish S, Alidoosti M, Amirzadegan A. Comparison of specifications, short term outcome and prognosis of acute myocardial infarction in opium dependent patients and nondependents. J Tehran Heart Cent 2006; 1(1):48-53. [ Google Scholar]
39. Javadi HR, Allami A, Mohammadi N, Alauddin R. Opium dependency and in-hospital outcome of acute myocardial infarction. Med J Islam Repub Iran 2014; 28:122. [ Google Scholar]
40. Mirzaiepour F, Dadras M, Forood A, Najafipour H, Shokoohi M. The effect of opium addiction on arrhythmia following acute myocardial infarction. Acta Med Iran 2012; 50(10):670-5. [ Google Scholar]
41. Khosoosi Niaki MR, Hamid M, Farshidi F, Mohammadpour M, Salehi Omran MT. Evaluation of the role of opium addiction in acute myocardial infarction as a risk factor. Caspian J Intern Med 2013; 4(1):585-9. [ Google Scholar]
42. Najafi M, Jahangiry L, Mortazavi SH, Jalali A, Karimi A, Bozorgi A. Outcomes and long-term survival of coronary artery surgery: the controversial role of opium as risk marker. World J Cardiol 2016; 8(11):676-83. doi: 10.4330/wjc.v8.i11.676 [Crossref] [ Google Scholar]
43. Najafi M, Sheikhvatan M. Does analgesic effect of opium hamper the adverse effects of severe coronary artery disease on quality of life in addicted patients?. Anesth Pain Med 2012; 2(1):22-7. doi: 10.5812/aapm.5139 [Crossref] [ Google Scholar]
44. Sharafi A, Pour Hosseini HR, Jalali A, Salarifar M, Nematipour E, Shojanasab M. Opium consumption and mid-term outcome of percutaneous coronary intervention in men. J Tehran Heart Cent 2014; 9(3):115-9. [ Google Scholar]
45. Hamzei-Moghaddam A, Shafa MA, Khanjani N, Farahat R. Frequency of opium addiction in patients with ischemic stroke and comparing their cerebrovascular doppler ultrasound changes to non-addicts. Addict Health 2013; 5(3-4):95-101. [ Google Scholar]
46. Ebrahimi H, Haghjoo Javanmard S, Asgary S, Dehghani L, Amiri M, Saadatnia M. Opium addiction and ischemic stroke in Isfahan, Iran: a case-control study. Eur Neurol 2018; 79(1-2):82-5. doi: 10.1159/000485098 [Crossref] [ Google Scholar]
47. Shirani S, Shakiba M, Soleymanzadeh M, Esfandbod M. Can opium abuse be a risk factor for carotid stenosis in patients who are candidates for coronary artery bypass grafting?. Cardiol J 2010; 17(3):254-8. [ Google Scholar]
48. Jafarian A, Elyasinia F, Keramati MR, Ahmadi F, Parsaei R. Surgical infrainguinal revascularization for peripheral arterial disease: factors affecting patency rate. Med J Islam Repub Iran 2015; 29:278. [ Google Scholar]
49. Pourshams A, Khademi H, Malekshah AF, Islami F, Nouraei M, Sadjadi AR. Cohort Profile: The Golestan Cohort Study-- a prospective study of oesophageal cancer in northern Iran. Int J Epidemiol 2010; 39(1):52-9. doi: 10.1093/ije/dyp161 [Crossref] [ Google Scholar]
50. Nalini M, Shakeri R, Poustchi H, Pourshams A, Etemadi A, Islami F. Long-term opiate use and risk of cardiovascular mortality: results from the Golestan Cohort Study. Eur J Prev Cardiol 2021; 28(1):98-106. doi: 10.1093/eurjpc/zwaa006 [Crossref] [ Google Scholar]
51. Ahmadi Mousavi MR, Damghani MA, Haghdoust AA, Khamesipour A. Opium and risk of laryngeal cancer. Laryngoscope 2003; 113(11):1939-43. doi: 10.1097/00005537-200311000-00016 [Crossref] [ Google Scholar]
52. Rahmati A, Shakeri R, Khademi H, Poutschi H, Pourshams A, Etemadi A. Mortality from respiratory diseases associated with opium use: a population-based cohort study. Thorax 2017; 72(11):1028-34. doi: 10.1136/thoraxjnl-2015-208251 [Crossref] [ Google Scholar]
53. Bakhshaee M, Raziee HR, Afshari R, Amali A, Roopoosh M, Lotfizadeh A. Opium addiction and risk of laryngeal and esophageal carcinoma. Iran J Otorhinolaryngol 2017; 29(90):19-22. [ Google Scholar]
54. Sheikh M, Shakeri R, Poustchi H, Pourshams A, Etemadi A, Islami F. Opium use and subsequent incidence of cancer: results from the Golestan Cohort Study. Lancet Glob Health 2020; 8(5):e649-e60. doi: 10.1016/s2214-109x(20)30059-0 [Crossref] [ Google Scholar]
55. Ghadirian P, Stein GF, Gorodetzky C, Roberfroid MB, Mahon GA, Bartsch H. Oesophageal cancer studies in the Caspian littoral of Iran: some residual results, including opium use as a risk factor. Int J Cancer 1985; 35(5):593-7. doi: 10.1002/ijc.2910350505 [Crossref] [ Google Scholar]
56. Nasrollahzadeh D, Kamangar F, Aghcheli K, Sotoudeh M, Islami F, Abnet CC. Opium, tobacco, and alcohol use in relation to oesophageal squamous cell carcinoma in a high-risk area of Iran. Br J Cancer 2008; 98(11):1857-63. doi: 10.1038/sj.bjc.6604369 [Crossref] [ Google Scholar]
57. Malekzadeh MM, Khademi H, Pourshams A, Etemadi A, Poustchi H, Bagheri M. Opium use and risk of mortality from digestive diseases: a prospective cohort study. Am J Gastroenterol 2013; 108(11):1757-65. doi: 10.1038/ajg.2013.336 [Crossref] [ Google Scholar]
58. Sheikh M, Poustchi H, Pourshams A, Etemadi A, Islami F, Khoshnia M. Individual and combined effects of environmental risk factors for esophageal cancer based on results from the Golestan Cohort Study. Gastroenterology 2019; 156(5):1416-27. doi: 10.1053/j.gastro.2018.12.024 [Crossref] [ Google Scholar]
59. Shakeri R, Malekzadeh R, Etemadi A, Nasrollahzadeh D, Aghcheli K, Sotoudeh M. Opium: an emerging risk factor for gastric adenocarcinoma. Int J Cancer 2013; 133(2):455-61. doi: 10.1002/ijc.28018 [Crossref] [ Google Scholar]
60. Sadjadi A, Derakhshan MH, Yazdanbod A, Boreiri M, Parsaeian M, Babaei M. Neglected role of hookah and opium in gastric carcinogenesis: a cohort study on risk factors and attributable fractions. Int J Cancer 2014; 134(1):181-8. doi: 10.1002/ijc.28344 [Crossref] [ Google Scholar]
61. Shakeri R, Kamangar F, Mohamadnejad M, Tabrizi R, Zamani F, Mohamadkhani A. Opium use, cigarette smoking, and alcohol consumption in relation to pancreatic cancer. Medicine (Baltimore) 2016; 95(28):e3922. doi: 10.1097/md.0000000000003922 [Crossref] [ Google Scholar]
62. Moossavi S, Mohamadnejad M, Pourshams A, Poustchi H, Islami F, Sharafkhah M. Opium use and risk of pancreatic cancer: a prospective cohort study. Cancer Epidemiol Biomarkers Prev 2018; 27(3):268-73. doi: 10.1158/1055-9965.epi-17-0592 [Crossref] [ Google Scholar]
63. Naghibzadeh-Tahami A, Yazdi Feyzabadi V, Khanjani N, Ashrafi-Asgarabad A, Alizaeh H, Borhaninejad VR. Can opium use contribute to a higher risk of colorectal cancers? a matched case-control study in Iran. Iran J Public Health 2016; 45(10):1322-31. [ Google Scholar]
64. Dianatinasab M, Ghaem H, Rezaianzadeh A, Hosseini SV, Khazraei H. Colorectal cancer mortality in Shiraz, Iran. Asian Pac J Cancer Prev 2016; 17(8):4101-5. [ Google Scholar]
65. Sadeghi A, Behmard S, Vesselinovitch SD. Opium: a potential urinary bladder carcinogen in man. Cancer 1979; 43(6):2315-21. doi: 10.1002/1097-0142(197906)43:6<2315::aidcncr2820430622>3.0.co;2-j [Crossref] [ Google Scholar]
66. Aliasgari MA, Kaviani A, Gachkar L, Hosseini-Nassab SR. Is bladder cancer more common among opium addicts?. Urol J 2004; 1(4):253-5. [ Google Scholar]
67. Ketabchi A, Gharaei M, Ahmadinezhad M, Mirshekari T. Evaluation of bladder cancer in opium addicted patients in the Kerman province, Iran, from 1999 to 2003. J Res Med Sci 2005; 10(6):355-7. [ Google Scholar]
68. Nourbakhsh A, Mohseni NG, Hatmi ZN. Opium use in transitional cell carcinoma of the urinary bladder. Acta Med Iran 2006; 44(4):263-8. [ Google Scholar]
69. Shakhssalim N, Hosseini SY, Basiri A, Eshrati B, Mazaheri M, Soleimanirahbar A. Prominent bladder cancer risk factors in Iran. Asian Pac J Cancer Prev 2010; 11(3):601-6. [ Google Scholar]
70. Hosseini SY, Safarinejad MR, Amini E, Hooshyar H. Opium consumption and risk of bladder cancer: a case-control analysis. Urol Oncol 2010; 28(6):610-6. doi: 10.1016/j.urolonc.2008.10.016 [Crossref] [ Google Scholar]
71. Aliramaji A, Kaseean A, Yousefnia Pasha YR, Shafi H, Kamali S, Safari M. Age distribution types of bladder cancers and their relationship with opium consumption and smoking. Caspian J Intern Med 2015; 6(2):82-6. [ Google Scholar]
72. Ghadimi T, Gheitasi B, Nili S, Karimi M, Ghaderi E. Occupation, smoking, opium, and bladder cancer: a case-control study. South Asian J Cancer 2015; 4(3):111-4. doi: 10.4103/2278-330x.173174 [Crossref] [ Google Scholar]
73. Afshari M, Janbabaei G, Bahrami MA, Moosazadeh M. Opium and bladder cancer: a systematic review and meta-analysis of the odds ratios for opium use and the risk of bladder cancer. PLoS One 2017; 12(6):e0178527. doi: 10.1371/journal.pone.0178527 [Crossref] [ Google Scholar]
74. Akbari M, Naghibzadeh-Tahami A, Khanjani N, Baneshi MR, Kamali E, Hesampour M. Opium as a risk factor for bladder cancer: a population-based case-control study in Iran. Arch Iran Med 2015; 18(9):567-71. [ Google Scholar]
75. Lotfi MH, Farzaneh F, Mehrparvar AH, Fallahzadeh H, Sadeghian MR. The effect of smoking and opium on bladder cancer in Yazd province: a case-control study. J Community Health Res 2016; 5(2):98-109. [ Google Scholar]
76. Razmpa E, Saedi B, Motiee-Langroudi M, Garajei A, Hoseinpor S, Kalantar Motamedi MH. Opium usage as an etiologic factor of oral cavity cancer. J Craniofac Surg 2014; 25(5):e505-7. doi: 10.1097/scs.0000000000001089 [Crossref] [ Google Scholar]
77. Plutzky J. Inflammatory pathways in atherosclerosis and acute coronary syndromes. Am J Cardiol 2001; 88(8A):10K-5K. doi: 10.1016/s0002-9149(01)01924-5 [Crossref] [ Google Scholar]
78. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow?. Lancet 2001; 357(9255):539-45. doi: 10.1016/s0140-6736(00)04046-0 [Crossref] [ Google Scholar]
79. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 2009; 30(7):1073-81. doi: 10.1093/carcin/bgp127 [Crossref] [ Google Scholar]
80. Lu H, Ouyang W, Huang C. Inflammation, a key event in cancer development. Mol Cancer Res 2006; 4(4):221-33. doi: 10.1158/1541-7786.mcr-05-0261 [Crossref] [ Google Scholar]
81. Kundu JK, Surh YJ. Emerging avenues linking inflammation and cancer. Free Radic Biol Med 2012; 52(9):2013-37. doi: 10.1016/j.freeradbiomed.2012.02.035 [Crossref] [ Google Scholar]
82. Wu Y, Antony S, Meitzler JL, Doroshow JH. Molecular mechanisms underlying chronic inflammation-associated cancers. Cancer Lett 2014; 345(2):164-73. doi: 10.1016/j.canlet.2013.08.014 [Crossref] [ Google Scholar]
83. Lashkarizadeh MR, Garshasbi M, Shabani M, Dabiri S, Hadavi H, Manafi-Anari H. Impact of opium addiction on levels of pro- and anti-inflammatory cytokines after surgery. Addict Health 2016; 8(1):9-15. [ Google Scholar]
84. Ghazavi A, Solhi H, Moazzeni SM, Rafiei M, Mosayebi G. Cytokine profiles in long-term smokers of opium (Taryak). J Addict Med 2013; 7(3):200-3. doi: 10.1097/ADM.0b013e31828baede [Crossref] [ Google Scholar]
85. Nabati S, Asadikaram G, Kazemi Arababadi M, Shahabinejad G, Rezaeian M, Mahmoodi M. The plasma levels of the cytokines in opium-addicts and the effects of opium on the cytokines secretion by their lymphocytes. Immunol Lett 2013; 152(1):42-6. doi: 10.1016/j.imlet.2013.04.003 [Crossref] [ Google Scholar]
86. Forood A, Malekpour-Afshar R, Mahdavi A. Serum level of plasminogen activator inhibitor type-1 in addicted patients with coronary artery disease. Addict Health 2014; 6(3-4):119-26. [ Google Scholar]
87. Ploplis VA. Effects of altered plasminogen activator inhibitor-1 expression on cardiovascular disease. Curr Drug Targets 2011; 12(12):1782-9. doi: 10.2174/138945011797635803 [Crossref] [ Google Scholar]
88. Liu CC, Prior J, Piwnica-Worms D, Bu G. LRP6 overexpression defines a class of breast cancer subtype and is a target for therapy. Proc Natl Acad Sci U S A 2010; 107(11):5136-41. doi: 10.1073/pnas.0911220107 [Crossref] [ Google Scholar]
89. Fang H, Placencio VR, DeClerck YA. Protumorigenic activity of plasminogen activator inhibitor-1 through an antiapoptotic function. J Natl Cancer Inst 2012; 104(19):1470-84. doi: 10.1093/jnci/djs377 [Crossref] [ Google Scholar]
90. Nordt TK, Lohrmann J, Bode C. Regulation of PAI-1 expression by genetic polymorphisms. Impact on atherogenesis. Thromb Res 2001; 103 Suppl 1:S1-5. doi: 10.1016/s0049-3848(01)00292-4 [Crossref] [ Google Scholar]
91. Iwaki T, Urano T, Umemura K. PAI-1, progress in understanding the clinical problem and its aetiology. Br J Haematol 2012; 157(3):291-8. doi: 10.1111/j.1365-2141.2012.09074.x [Crossref] [ Google Scholar]
92. Hursting SD, Hursting MJ. Growth signals, inflammation, and vascular perturbations: mechanistic links between obesity, metabolic syndrome, and cancer. Arterioscler Thromb Vasc Biol 2012; 32(8):1766-70. doi: 10.1161/atvbaha.111.241927 [Crossref] [ Google Scholar]
93. Bajou K, Noël A, Gerard RD, Masson V, Brunner N, Holst-Hansen C. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 1998; 4(8):923-8. doi: 10.1038/nm0898-923 [Crossref] [ Google Scholar]
94. Duffy MJ. Urokinase-type plasminogen activator: a potent marker of metastatic potential in human cancers. Biochem Soc Trans 2002; 30(2):207-10. [ Google Scholar]
95. Nekarda H, Schmitt M, Ulm K, Wenninger A, Vogelsang H, Becker K. Prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in completely resected gastric cancer. Cancer Res 1994; 54(11):2900-7. [ Google Scholar]
96. Gach K, Szemraj J, Fichna J, Piestrzeniewicz M, Delbro DS, Janecka A. The influence of opioids on urokinase plasminogen activator on protein and mRNA level in MCF-7 breast cancer cell line. Chem Biol Drug Des 2009; 74(4):390-6. doi: 10.1111/j.1747-0285.2009.00875.x [Crossref] [ Google Scholar]
97. Katsiki N, Mantzoros C, Mikhailidis DP. Adiponectin, lipids and atherosclerosis. Curr Opin Lipidol 2017; 28(4):347-54. doi: 10.1097/mol.0000000000000431 [Crossref] [ Google Scholar]
98. Katira A, Tan PH. Evolving role of adiponectin in cancer-controversies and update. Cancer Biol Med 2016; 13(1):101-19. doi: 10.28092/j.issn.2095-3941.2015.0092 [Crossref] [ Google Scholar]
99. Mantzoros C, Petridou E, Dessypris N, Chavelas C, Dalamaga M, Alexe DM. Adiponectin and breast cancer risk. J Clin Endocrinol Metab 2004; 89(3):1102-7. doi: 10.1210/jc.2003-031804 [Crossref] [ Google Scholar]
100. Zheng Q, Wu H, Cao J. Circulating adiponectin and risk of endometrial cancer. PLoS One 2015; 10(6):e0129824. doi: 10.1371/journal.pone.0129824 [Crossref] [ Google Scholar]
101. Joshi RK, Kim WJ, Lee SA. Association between obesity-related adipokines and colorectal cancer: a case-control study and meta-analysis. World J Gastroenterol 2014; 20(24):7941-9. doi: 10.3748/wjg.v20.i24.7941 [Crossref] [ Google Scholar]
102. Aref S, Ibrahim L, Azmy E, Al Ashary R. Impact of serum adiponectin and leptin levels in acute leukemia. Hematology 2013; 18(4):198-203. doi: 10.1179/1607845412y.0000000059 [Crossref] [ Google Scholar]
103. Bao Y, Giovannucci EL, Kraft P, Stampfer MJ, Ogino S, Ma J. A prospective study of plasma adiponectin and pancreatic cancer risk in five US cohorts. J Natl Cancer Inst 2013; 105(2):95-103. doi: 10.1093/jnci/djs474 [Crossref] [ Google Scholar]
104. Arisan ED, Arisan S, Atis G, Palavan-Unsal N, Ergenekon E. Serum adipocytokine levels in prostate cancer patients. Urol Int 2009; 82(2):203-8. doi: 10.1159/000200801 [Crossref] [ Google Scholar]
105. Yildirim A, Bilici M, Cayir K, Yanmaz V, Yildirim S, Tekin SB. Serum adiponectin levels in patients with esophageal cancer. Jpn J Clin Oncol 2009; 39(2):92-6. doi: 10.1093/jjco/hyn143 [Crossref] [ Google Scholar]
106. Ishikawa M, Kitayama J, Kazama S, Hiramatsu T, Hatano K, Nagawa H. Plasma adiponectin and gastric cancer. Clin Cancer Res 2005; 11(2 Pt 1):466-72. [ Google Scholar]
107. Shahouzehi B, Shokoohi M, Najafipour H. The effect of opium addiction on serum adiponectin and leptin levels in male subjects: a case control study from Kerman Coronary Artery Disease Risk Factors Study (KERCADRS). EXCLI J 2013; 12:916-23. [ Google Scholar]
108. Raina JK, Sharma M, Panjaliya RK, Bhagat M, Sharma R, Bakaya A. Methylenetetrahydrofolate reductase C677T and methionine synthase A2756G gene polymorphisms and associated risk of cardiovascular diseases: a study from Jammu region. Indian Heart J 2016; 68(3):421-30. doi: 10.1016/j.ihj.2016.02.009 [Crossref] [ Google Scholar]
109. Bennouar N, Allami A, Azeddoug H, Bendris A, Laraqui A, El Jaffali A. Thermolabile methylenetetrahydrofolate reductase C677T polymorphism and homocysteine are risk factors for coronary artery disease in Moroccan population. J Biomed Biotechnol 2007; 2007(1):80687. doi: 10.1155/2007/80687 [Crossref] [ Google Scholar]
110. Li YY. Methylenetetrahydrofolate reductase C677T gene polymorphism and coronary artery disease in a Chinese Han population: a meta-analysis. Metabolism 2012; 61(6):846-52. doi: 10.1016/j.metabol.2011.10.013 [Crossref] [ Google Scholar]
111. Hou X, Chen X, Shi J. Genetic polymorphism of MTHFR C677T and premature coronary artery disease susceptibility: a meta-analysis. Gene 2015; 565(1):39-44. doi: 10.1016/j.gene.2015.03.062 [Crossref] [ Google Scholar]
112. Xuan C, Bai XY, Gao G, Yang Q, He GW. Association between polymorphism of methylenetetrahydrofolate reductase (MTHFR) C677T and risk of myocardial infarction: a meta-analysis for 8,140 cases and 10,522 controls. Arch Med Res 2011; 42(8):677-85. doi: 10.1016/j.arcmed.2011.11.009 [Crossref] [ Google Scholar]
113. Thambyrajah J, Townend JN. Homocysteine and atherothrombosis--mechanisms for injury. Eur Heart J 2000; 21(12):967-74. doi: 10.1053/euhj.1999.1914 [Crossref] [ Google Scholar]
114. Hasan T, Arora R, Bansal AK, Bhattacharya R, Sharma GS, Singh LR. Disturbed homocysteine metabolism is associated with cancer. Exp Mol Med 2019; 51(2):1-13. doi: 10.1038/s12276-019-0216-4 [Crossref] [ Google Scholar]
115. Bravatà V. Controversial roles of methylenetetrahydrofolate reductase polymorphisms and folate in breast cancer disease. Int J Food Sci Nutr 2015; 66(1):43-9. doi: 10.3109/09637486.2014.959896 [Crossref] [ Google Scholar]
116. Matsuo K, Hamajima N, Hirai T, Kato T, Inoue M, Takezaki T. Methionine synthase reductase gene A66G polymorphism is associated with risk of colorectal cancer. Asian Pac J Cancer Prev 2002; 3(4):353-9. [ Google Scholar]
117. Krajinovic M, Lamothe S, Labuda D, Lemieux-Blanchard E, Theoret Y, Moghrabi A. Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia. Blood 2004; 103(1):252-7. doi: 10.1182/blood-2003-06-1794 [Crossref] [ Google Scholar]
118. Singal R, Ferdinand L, Das PM, Reis IM, Schlesselman JJ. Polymorphisms in the methylenetetrahydrofolate reductase gene and prostate cancer risk. Int J Oncol 2004; 25(5):1465-71. [ Google Scholar]
119. Masoomi M, Azdaki N, Shahouzehi B. Elevated plasma homocysteine concentration in opium-addicted individuals. Addict Health 2015; 7(3-4):149-56. [ Google Scholar]
120. Salomaa V, Rasi V, Kulathinal S, Vahtera E, Jauhiainen M, Ehnholm C. Hemostatic factors as predictors of coronary events and total mortality: the FINRISK ‘92 Hemostasis Study. Arterioscler Thromb Vasc Biol 2002; 22(2):353-8. doi: 10.1161/hq0202.104078 [Crossref] [ Google Scholar]
121. De Luca G, Verdoia M, Cassetti E, Schaffer A, Cavallino C, Bolzani V. High fibrinogen level is an independent predictor of presence and extent of coronary artery disease among Italian population. J Thromb Thrombolysis 2011; 31(4):458-63. doi: 10.1007/s11239-010-0531-z [Crossref] [ Google Scholar]
122. Devendra GP, Hart SA, Whitney EJ, Krasuski RA. Impact of fibrinogen levels on angiographic progression and 12-year survival in the armed forces regression study. Angiology 2010; 61(4):333-7. doi: 10.1177/0003319709360525 [Crossref] [ Google Scholar]
123. Folsom AR, Aleksic N, Park E, Salomaa V, Juneja H, Wu KK. Prospective study of fibrinolytic factors and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb Vasc Biol 2001; 21(4):611-7. doi: 10.1161/01.atv.21.4.611 [Crossref] [ Google Scholar]
124. Jiang HG, Li J, Shi SB, Chen P, Ge LP, Jiang Q. Value of fibrinogen and D-dimer in predicting recurrence and metastasis after radical surgery for non-small cell lung cancer. Med Oncol 2014; 31(7):22. doi: 10.1007/s12032-014-0022-8 [Crossref] [ Google Scholar]
125. Wen J, Yang Y, Ye F, Huang X, Li S, Wang Q. The preoperative plasma fibrinogen level is an independent prognostic factor for overall survival of breast cancer patients who underwent surgical treatment. Breast 2015; 24(6):745-50. doi: 10.1016/j.breast.2015.09.007 [Crossref] [ Google Scholar]
126. Yu X, Hu F, Yao Q, Li C, Zhang H, Xue Y. Serum fibrinogen levels are positively correlated with advanced tumor stage and poor survival in patients with gastric cancer undergoing gastrectomy: a large cohort retrospective study. BMC Cancer 2016; 16:480. doi: 10.1186/s12885-016-2510-z [Crossref] [ Google Scholar]
127. Polterauer S, Grimm C, Seebacher V, Concin N, Marth C, Tomovski C. Plasma fibrinogen levels and prognosis in patients with ovarian cancer: a multicenter study. Oncologist 2009; 14(10):979-85. doi: 10.1634/theoncologist.2009-0079 [Crossref] [ Google Scholar]
128. Holzinger D, Danilovic I, Seemann R, Kornek G, Engelmann J, Pillerstorff R. Prognostic impact of pretreatment plasma fibrinogen in patients with locally advanced oral and oropharyngeal cancer. PLoS One 2016; 11(6):e0158697. doi: 10.1371/journal.pone.0158697 [Crossref] [ Google Scholar]
129. Li H, Zhao T, Ji X, Liang S, Wang Z, Yang Y. Hyperfibrinogenemia predicts poor prognosis in patients with advanced biliary tract cancer. Tumour Biol 2016; 37(3):3535-42. doi: 10.1007/s13277-015-4184-6 [Crossref] [ Google Scholar]
130. Ma C, Zhou Y, Zhou S, Zhao K, Lu B, Sun E. Preoperative peripheral plasma fibrinogen level is an independent prognostic marker in penile cancer. Oncotarget 2017; 8(7):12355-63. doi: 10.18632/oncotarget.12563 [Crossref] [ Google Scholar]
131. Dvorak HF, Senger DR, Dvorak AM. Fibrin as a component of the tumor stroma: origins and biological significance. Cancer Metastasis Rev 1983; 2(1):41-73. doi: 10.1007/bf00046905 [Crossref] [ Google Scholar]
132. Lu DY, Chen XL, Ding J. Treatment of solid tumors and metastases by fibrinogen-targeted anticancer drug therapy. Med Hypotheses 2007; 68(1):188-93. doi: 10.1016/j.mehy.2006.06.045 [Crossref] [ Google Scholar]
133. Asgary S, Sarrafzadegan N, Naderi GA, Rozbehani R. Effect of opium addiction on new and traditional cardiovascular risk factors: do duration of addiction and route of administration matter?. Lipids Health Dis 2008; 7:42. doi: 10.1186/1476-511x-7-42 [Crossref] [ Google Scholar]
134. Masoumi M, Nasri HR, Farajpour F. Comparison of plasma fibrinogen level in opium addict men with non-addict men. J Kerman Univ Med Sci 2002;9(1):27-31. [Persian].
135. Dutta B, Neginhal M, Iqbal F. Glycated hemoglobin (HbA1c) correlation with severity of coronary artery disease in non-diabetic patients-a hospital based study from North-Eastern India. J Clin Diagn Res 2016; 10(9):OC20-OC3. doi: 10.7860/jcdr/2016/22378.8525 [Crossref] [ Google Scholar]
136. Jia EZ, An FH, Chen ZH, Li LH, Mao HW, Li ZY. Hemoglobin A1c risk score for the prediction of coronary artery disease in subjects with angiographically diagnosed coronary atherosclerosis. Cell Physiol Biochem 2014; 34(3):672-80. doi: 10.1159/000363032 [Crossref] [ Google Scholar]
137. de Beer JC, Liebenberg L. Does cancer risk increase with HbA1c, independent of diabetes?. Br J Cancer 2014; 110(9):2361-8. doi: 10.1038/bjc.2014.150 [Crossref] [ Google Scholar]
138. Tsai MC, Chen KD, Wang CC, Huang KT, Wu CH, Kuo IY. Factor VII promotes hepatocellular carcinoma progression through ERK-TSC signaling. Cell Death Discov 2015; 1:15051. doi: 10.1038/cddiscovery.2015.51 [Crossref] [ Google Scholar]
139. Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342(8879):1076-9. doi: 10.1016/0140-6736(93)92062-x [Crossref] [ Google Scholar]
140. Hembrough TA, Swartz GM, Papathanassiu A, Vlasuk GP, Rote WE, Green SJ. Tissue factor/factor VIIa inhibitors block angiogenesis and tumor growth through a nonhemostatic mechanism. Cancer Res 2003; 63(11):2997-3000. [ Google Scholar]
141. Versteeg HH, Spek CA, Richel DJ, Peppelenbosch MP. Coagulation factors VIIa and Xa inhibit apoptosis and anoikis. Oncogene 2004; 23(2):410-7. doi: 10.1038/sj.onc.1207066 [Crossref] [ Google Scholar]