A Large Multicenter Case-Control Study to Evaluate Association of Opium Use and Risk of Lung, Bladder, Head and Neck and Colorectal Cancers

Hypothesis / Specific Aim

  • To assess sensitivity and specificity of the questionnaire in measurement of opium use in Iranian population;
  • To determine association between opium use and lung, colorectal, bladder, and head and neck cancers;
  • To determine the role of duration, and dose of opium use in cancer risk;
  • To assess geographic variation in association of cancer and opium use;
  • To determine the role of route of opium consumption (inhalation, oral use, etc.) on risk of cancer;
  • To determine the association between opium metabolites and risk of cancer;

To determine interaction of opium and other established risk factors of cancer including tobacco.

Target sample size 3200 Cases and 3200 Controls
Enrollment update 2563 cases and 2557 controls
Website last update date  20-Nov-2018

  • Opium use and its side effects is an important health problem in Iran.
  • Several small studies found association between opium use and risk of cancer. However, there are some concerns on the validity of these findings and it is important to create valid reports about these associations.
  • Valid results about this issue will be used to communicate the results with policy makers for cancer prevention programs as well as with the general public for the public awareness programs.
  • We have set up a good national and international network to conduct well design study and answer an important public health questions.
  • In fact this is four projects and will answer this question about four common cancers which will be done as a package.
  • Three PhD students will use the data from this project for their thesis.
  • Our international collaborators have promised to use their capacity in their own country and rise further funding, in particular for molecular studies.
  • We also hope that we will use benefit from this network and provide an opportunity for our students to apply for international fellowship and experience research environment in the well-known universities in the world.
  • In addition to Opium use, we will analyses association of other risk factors like Hookah use, in which the epidemiological data is scarce.


Opium is a substance that extracted from the opium poppy. Derivatives of this substance have useful effect in medicine. For example, opioids drugs derived from this substance have an analgesic application reducing pain in chronic disease like cancer. Moreover, some opioids like codeine have an anti-cough effect [1, 2]. High prevalence of opium use was reported in the Near and Middle East/South-West Asia, primarily in Afghanistan and I.R of Iran [3]. Opium use is considered a criminal behavior and have stigma. In addition, there are laws against its use and distribution in I.R. of Iran. Despite this legislation, prevalence of opium use and other drugs has increased in European countries and was reported 8.7 per 1000 in 50 states of the USA and district of Colombian in 2002-2003 [4-6]. Prevalence of the opium use and its derivatives in Kerman province, which is located in the southern part of Iran, was 17.1% in 2005 [7]. Opium is used in different shapes including Teriak (crude opium), Shire (refined opium extract), and Sukhte (residual opium dross after smoking it) in different part of the Iran [8, 9]. Teriak and Shire can be ingested or smoked, while Sukhte is usually consumed orally [10].

Epidemiologic studies have reported significant associations between opium use and the risk of different cancers including: lung[10-12], bladder[13-19], oral cavity, larynx, pharynx [20, 21], stomach[22-24] and esophageal [22, 25, 26] cancers. In a recent systematic review, all studies about the association of opium use and cancer have been reviewed. This study reported that there is a significant association between opium use and risk of esophageal, stomach, larynx, and lung and bladder cancer. Interestingly, most of these studies were case-control and were published by Iranian researchers. Only two studies reported the cancer-opium association from other populations, one from Hong Kong [20] and one from Singapore [11]. Two cohort studies, one from northeast and one from northwest Iran, has so far reported an association between opium use and cancer risk. [27].
Two mechanisms have been suggested for carcinogenic effect of opium use, including the exposure to opium smoke and the alkaloid component of opium. First, opium users heat the opium to a high temperature and inhale the smoke through particular tube (pipe), when the opium contents starts to vaporize. The opium smoke contains polycyclic aromatic hydrocarbons which is a known carcinogen. In addition, the residual component in the pipe is called Sukhte and can be eaten without any changes or after refinement. Studies have shown that this residual substance have mutagenic role after metabolic activation in Salmonella Typhimurium [28]. This effect can also be caused by morphine and opium pyrolysates [29]. The main carcinogen component of Sukhte consist of all nitrogen containing heterocyclic components derived from pyrolysis of morphine[30]. In the second mechanism, opium contains alkaloid compounds that are absorbed in the body and lead to cancer.
Notwithstanding the several publication on association between opium use and cancer risk, they are usually performed in a small region and could not control for confounding variables properly, In addition, because of small power they could not investigate dose- response relationship, role of starting time of opium use, type and methods of consumption on the risk of cancer. Because opium use is not socially acceptable in Iranian population, the results of epidemiological studies is subject to the selection or measurement bias. However, most of the previous studies did not report response rates and sensitivity and specificity of their questionnaire for assessment of the opium use. Furthermore, available opium products have some additives such as lead, selenium, acetic anhydride, dried blood of animals and addicted persons. Type and amount of additives may vary from region to region. Therefore it is important to consider the role of opium additives in the cancer risk and compare the opium-cancer association between different regions.



1٫ Adcock, J., Peripheral opioid receptors and the cough reflex. Respiratory medicine, 1991. 85: p. 43-46.
2٫ Zeppetella, G., Opioids for the management of breakthrough cancer pain in adults: a systematic review undertaken as part of an EPCRC opioid guidelines project. Palliative medicine, 2011. 25(5): p. 516-524.

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Study Design

  • Methods:
    We are conducting a large multicenter case-control study to investigate the association between opium use and risk of different type of cancer including lung, Head and Neck, Colorectal, Bladder.
    Permission to participate in the study was obtained from seven provinces located in different part of Iran (Tehran, Fars, Kerman, Golestan, Mashhad, Khorasan, Kermanshah and Mazandaran Provinces) .In overall, we will recruit 3200 cases and 3200 healthy controls matched for age, sex, and residential place 800 cases and 800 controls for each cancer type. Controls will be selected from healthy people who visit general hospital.
  • Phases/steps of the research:
    Study designed in different steps including validation study, pilot study, and main study. First and second steps completed and we are conducting the main study. The data from participants consecutively are collecting from 17 hospitals in seven provinces. We enrolled 1452 cases and 1321 controls up to 3 February 2018.
    In order to manage the quality of data we visit each center two times each year. In addition, based on quality control protocol for monitor the data collection accuracy and precision all data were assessed by consecutive manager in each province and also in main center.
  • Biological Measurements:
    We are collecting 12 ml venous blood for each patient and control. 6 ml will be kept in a Vacationer tube with EDTA anticoagulant for DNA extraction and 3 mm of it for RNA extraction, 3 ml in a Vacationer tube without anticoagulant. In addition to blood sample, we are collecting the saliva sample from head and neck cancer cases and controls to evaluate the HPV infection.
  • Data:
    – Completed questionnaire (about …. Variables, demographic and clinical) based on face to face interviews.- Photographs of the oral lesions.
Collaborative Centers

– Kerman Pr. –  Bahonar H.
–  Afzalipoor H.
–  Jawad Alaemah H.
–  Shafa H.
– Fars Pr. –  Namazi H.
–  Saadi H.
– Golestan Pr. –  Sayad Sh H.
–  5th Azar H.
  –  Taleghani H.
  –  Payambar Azam H.
– Tehran Pr. –  Imam Khomeini H.
–   Masih Daneshvari H.
– Mazandaran Pr. –  Imam Khomeini H.
– Mashhad Pr. –  Imam Reza H.
–  Hasheminejad H.
–  Omid H.
– Kermanshah Pr. –  Ayatollah Taleghani H.
–  Imam Khomeini H.
–  Imam Reza H.
– Hormozgan Pr. Omid Radiation & Chemotherapy Center
Shahid Mohammadi H.
Imam Reza H.
– Boushehr Pr. Khalije Fars H.
Social Security H.
– Sistan & Baluchestan Pr. Ali Ebne Abitaleb H.
Khatamolanbia H.



دکتر کاظم زنده دل

Kazem Zendehdel 

MD, PhD Epidemiology

(Principal Investigator)

Reza Malekzadeh 

MD, Gastroentrology


Farin Kamangar 

MD, PhD Epidemiology


 Akbar Haghdoost

PhD Epidemiology


Paolo Boffetta

MD, MPH ,Oncology


Elisabete Weiderpass Vainio

MD, PhD Epidemiology


Abbas Rezaianzadeh

MD, PhD, Epidemiology


Abdolvahab  Moradi

PhD, Virology


Technical Consultants

Afarin Rahimi Movaghar

MD, Psychiatry

Reza Shirkoohi

MD, PhD, Genetics

Hossein Poustchi

MD, PhD Clinical Epidemiology

Hossein Daneshvar

PhD, Microbiology

Reza Ghiasvand

PhD Epidemiology

Sareh Eghtesad

MSc, Nutrition Science

Hamideh Rashidian

PhD, Epidemiology

Project Manager


Maryam Hadji

MSc, Epidemiology

Nutritional Status Investigator

Monireh Sadat Seyed Salehi

Job Exposure Analyst

Bayan Hosseini

DNA Extraction

Elmira Ebrihimi

Biobank Manager

Vahideh Peighambari

Collaborative Centers

Tehran Pr.

Focal points in the study centers

Kazem Zendehdel

MD, PhD, Epidemiology

Executive Managers

Elham Mohebi

DVM, MPH, PhD Student


Mina Khaki

Fars Pr.

Abbas Rezaianzadeh

MD, PhD, Epidemiology

Maryam Marzban

PhD, Epidemiology

Mahin Shiri

Marziyeh Dehghani

Zeinab Malekzadeh

Golestan Pr.

Abdolvahab  Moradi

PhD, Virology

Mahin Gholipour

MD, MPH, PhD Student, Molecular Medicine

Aysan Gharanjik

Fatemeh Shadfar

Fariba Khedrzadeh Guglani

Maida Saberi

Kerman Pr.

Akbar Haghdoost

PhD, Epidemiology

Ahmad Naghibzadeh Tahami

PhD Student, Epidemiology

Behnaz Karimpour

Samira Siamaki

Kermanshah Pr.

Dr Farid Najafi

MD, PhD, Epidemiology

Roya Safari

Bahare Safari

Mona Abdi

Mazandaran Pr.

Dr Reza Alizadeh

MD, PhD in Biomedical Sciences

Fatemeh Jabbari

Varsa Omrani


Dr Soudabeh Shahid Sales

M.D. Specialist in Oncology

Saide Ahmadi Simab


Narges Arabzadeh


Alireza Ansari Moghadam

PhD, Epidemiology

Mahdieh Bakhshi

Mahbubeh Bakhshi


Abdol Azim Nejatizadeh

Fellowship in clinical molecular genetics

Masumeh Mahmudi

Foruzan Nematzadeh

Organization Chart

Financial Support and Grant

It is hard to think about such a study in Iran without a large grant from government.
Fortunately after our application, NIMAD grant organization accepted to help us to reach our important objectives.

Timeline / Schedule

4 years_ Starting time, started in 2016