At an important historical event , Carcinogenicity of Opium Consumption , the most prominent achievement of more than two decades of research efforts of Iranian scientists in the "Golestan Cohort Study " was confirmed by the International Agency for Research on Cancer of the World Health Organization (IARC / WHO) and it will be published in Volume 126 of the IARC Monographs.

According to the Digestive Diseases Research Institute (DDRI) of Tehran University of Medical Sciences (TUMS) Carcinogenicity of Opium Consumption in humans  was evaluated during the 126th series of the Monographs meetings held virtually from 11-20 September 2020 by IARC (due to The COVID-19 pandemic) with the participation of 16 expert scientists from 10 countries around the world. The results of these assessments were published October 8, 2020 in the Lancet Oncology.

 

The Golestan Cohort Study  is part of the Gastroesophageal Malignancy in North of Iran (GEMINI) study and one of the largest cohort studies in West Asia and North Africa that was initiated in 2004 by a team of scientists from the Digestive Diseases Research Institute (DDRI) of Tehran University of Medical Sciences (TUMS) led by Professor Reza Malekzadeh in collaboration with the Golestan University of Medical Sciences and scientists from  the International Agency for Research on Cancer of the World Health Organization (IARC / WHO),  the US National Cancer Institute (NCI / NIH), in Gonbad Kavus city and 326 villages of the Golestan province in Northeast Iran, with an initial aim of identifying the underlying causes of the high rates of esophageal cancer in this region. Since then, the Golestan Cohort Study has collaborated with many international academic and research institutes including  Cambridge University , Johns Hopkins University ,Harvard University, Icahn School of Medicine at Mount Sinai, Morgan State University, Karolinska University and University of Toronto.

During more than two decades of research efforts, the Golestan Cohort Study has made significant and unique contributions to the identification of causes of cancer and non-communicable diseases including cardiovascular and cerebrovascular diseases which led to the reception of the IARC Medal of Honor by the  founder and principal investigator of the Golestan Cohort Study, Profesor Reza Malekzadeh, in 2018 .

IARC: The evaluation applies only to opium

Monograph 126 evaluates the consumption of opium an addictive narcotic drug . Other opiates, such as heroin, morphine, and codeine, as well as synthetic opioids, such as fentanyl, are outside the scope of this evaluation.

Opium has a complex chemical composition consisting of at least 25 alkaloids

Opium has a complex chemical composition consisting of at least 25 alkaloids (Morphine is one of the most important alkaloids derived  from opium ( and other ingredients. The harvested latex of the poppy plant is typically processed by drying or boiling before consumption as opium. Forms of illicit opium that are commonly consumed include raw (or crude) opium, opium dross (tarry residues formed after smoking raw opium, called sukhteh in the Islamic Republic of Iran), and refined opium or opium sap (boiled opium dross with or without added raw opium). All three forms are typically smoked or ingested, and pyrolysis products may result from combustion (smoking) of any form of opium. Opium may be contaminated (or, in the case of illicit opium, adulterated) with lead, other heavy metals, and/or arsenic.

Classification of carcinogens in humans

The IARC Monographs identify environmental factors that have carcinogenic hazards to humans. These include chemicals, complex mixtures, occupational exposures, physical agents, biological agents, and lifestyle factors.

Since 1971, more than 1000 agents have been evaluated, of which more than 400 have been identified as Carcinogenic (Group 1) , Probably Carcinogenic (Group2A) ,Possibly Carcinogenic (Group 2B) and  Non Classiffiable (Group3) to humans.

The Monographs assess the strength of the available evidence that an agent can cause cancer in humans, based on three streams of evidence: on cancer in humans ,on cancer in experimental animals , and  on  mechanistic  evidence . In addition, the exposure to each  agent is characterized.

Among a variety of studies ,well conducted cohort and case–control studies provide most of the evidence of cancer  in  humans  evaluated  by  Working  Groups.

 

 
 

Classification of Opium Consumption as a Carcinogen

The working group of international experts that participated in the volume 126 of the IARC’S Monographs program, spent more than 17 months in reviewing in details all evidence on the carcinogenicity of opium consumption and then in 10 days discussed all the available evidence that originated from human studies and the mechanistic studies which are included :

-Opium Consumption is Carcinogenic to humans (Group1). The Group1 evaluation is based on sufficient evidence of cancer in human studies. This  sufficient  evidence determination applies to smoked and ingested routes of raw, dross, and sap opium consumption.

-Evidence in humans was sufficient for cancers of bladder, larynx, and lung.

-Evidence in humans was association for cancers of oesophagus, stomach, pancreas, and pharynx.

-There is strong evidence in experimental systems that opium (sukteh & opium pyrolysates) exhibits key characteristics of carcinogenicity (opium is genotoxic).

 

 

Opium Consumption is Carcinogenic to humans

According to the International Agency for Research on Cancer (IARC) there is sufficient evidence in humans for the carcinogenicity of opium consumption and this “sufficient” evidence determination applies to smoked and ingested routes of raw, dross, and sap opium consumption. Therefore, Opium Consumption is Carcinogenic to humans.

The main evidences of opium monograph were from Golestan Cohort Study

Two cohort studies and more than two dozen case-control studies (most hospital-based) carried out across diverse regions and populations of Iran have investigated the association between opium consumption and incident cancers of various sites but the most informative was the Golestan Cohort Study (GCS).

According to the Digestive Diseases Research Institute (DDRI) of Tehran University of Medical Sciences (TUMS) The Golestan Cohort Study, included 50,045  participants, aged 40-75 year old, of whom 17% (8,487 people) reported regular use of different types of minimally processed opium (Raw opium, Shireh and Sukhteh). Over a decade of follow-up , around 8,000 deaths were recorded  up to 2019 among the participants, of which 1570 were due to cancer and more than 54% of these cancer deaths were caused by gastrointestinal cancers.

The International Agency for Research on Cancer has described The Golestan Cohort  as a study that used a structured questionnaire (validated with urinary levels of opium metabolites), which incorporated questions on opium type mode of consumption, temporality of exposure, duration, intensity and cumulative exposure. The prospective cohort design minimizes concerns regarding selection bias and reverse causation.

The detailed assessment of demographic, socioeconomic, and lifestyle factors addressed concerns regarding major potential confounders, including tobacco smoking. Several unrelated case-control studies also used the GCS questionnaire, while others used different questionnaires, interviews, or patient records to evaluate opium exposure. The amount of detail and quality of exposure information varied considerably across the epidemiological studies.

While individually each study has its limitations, the Working Group concluded that collectively these studies provide a basis to rule out chance, bias, and confounding as alternative explanations for the positive association between opium use and cancers of bladder, larynx, and lung with reasonable certainty; thus, there was suffficient evidence of human arcinogenicity for these three cancer types.  Additionally, evidence  was deemed to be limited that opium consumption causes cancers of oesophagus, stomach, pancreas, and pharynx.

 According to  the International Agency for Research on Cancer of the World Health Organization (IARC / WHO) ,in human opium metabolites have been detected in urine, hair, and blood following ingestion or smoking of opium. there was strong evidence in experimental systems that opium, specifically sukhteh and opium pyrolysates, exhibits key characteristics of carcinogens .These opium metabolites are genotoxic.
 


Opium is illicitly produced in some 50 countries worldwide

Professor Reza Malekzadeh ,founder and the lead investigator of  the  Golestan Cohort  Study  said: Although the production and distribution of opium has been under control since 1961, it has increased over the past decade. Opium is illicitly produced in some 50 countries worldwide. Over 80% of the world’s illicit opium comes from Afghanistan. The number of opium users in the world has increased from 20 million in 2007 to 42.5 million in 2018 .Also 76% of the total 1,100 tons of opium consumed in 2017 were consumed in Asia.

20% of all opium produced is consumed raw

Distinguished professor of Tehran University of Medical Sciences (TUMS) added:  Of the total opium produced, 15-20% is used as raw or minimally processed opium; the rest is processed into other opiates, mainly heroin. While opium is used across the spectrum of society , sex, age, socioeconomic status, and tobacco use are strong determinants of opium consumption. Legal forms of opium (e.g., opium tincture and syrup) make up a small proportion of the global opium production, and no epidemiologic studies were found of consumers of these products.

Iran is one of the highest consumer of raw opium in the world

Founder and the lead investigator of  the  Golestan Cohort  Study said : Iran is one  of the highest consumer of opium in the world  for historical, cultural and geographical reasons (being neighbor to Afghanistan as the largest poppy cultivator). In 2009, Iran was estimated to be the world’s largest per capita consumer of raw or minimally processed opium, accounting for 42% (450 tons ) of global consumption, followed by Afghanistan and Pakistan (7%  /80 tons).

According to the  Director of the Digestive Diseases Research Institute of Tehran University of Medical Sciences, about 10 % of Iranians over the age of 40 use opium in three forms of recreational, entertainment, and permanent. Opium alone accounts for 69% of all illicite drugs used in Iran. The Percentage of opium users in different provinces of iran varies from 7% to 17.5% .  Golestan and Kerman provinces are the highest opium consumer among other provinces in Iran."

 

Completely false beliefs about the therapeutic effects of opium

He added:  one of the root and historical reasons for overuse of opium in Iran is totally false myths about the therapeutic effect of this drug. even physicians in the distant past were among the advertisers of opium use:  Gallon and Osler, famous physicians, have introduced opium as a useful medicine. Ibn Sina's book "The Law" mentions the usefulness of opium for the treatment of disease. Currently, some traditional practitioners in Iran are encouraging patients to use opium to relieve pain.

The use of morphine in modern medicine is allowed for some patients

International cancer researcher reminded: Currently, morphine  which is the most important alkaloid derived from opium is used as a very useful drug to relieve pain in people with heart attacks and advanced cancers in Iran and the world. in today Clinical practice, the use of morphine once or more per week is allowed for patients with severe pain, especially patients with very advanced cancers who have a short survival.

Consumption of raw opium in any amount, any type , any form is carcinogenic   

Lead investigator of  the  Golestan Cohort  Study  emphasized  : The important point is that long-term use of opium in any type (raw, sukhteh and pyrolysates), in any form (smoky and  ingesting) and in any amount (even  0.5g per day) causes cardiovascular disease, heart attacks  and cancers . Physicians should refrain from prescribing long-term opium use to patients and explain the  Irreversible effects of long-term opium use to patients.

High opium consumption in the world and Lack of population-based and prospective studies

Despite the long history of opium use in the world, no serious scientific and prospective study was conducted on the effect of this drug on the incidence of chronic and common diseases such as cancers and cardiovascular diseases up to two decades ago. However, three retrospective epidemiologic studies have shown the effect of opium use on a two-fold increased risk of cancer.

Distinguished professor of Tehran University of Medical Sciences added: " Despite the lack of valid scientific and reliable data on the impact of long-term opium use on the incidence of cancer and cardiovascular diseases, the Golestan Cohort Study in Iran, as the most important and largest study in the world in this field (due to being prospective, having 50,000 participants aged 40 to 75 years and 8,000 opium users who had consumed it for a long time) was able to present accurate and reliable population-based data on the effects of opium.

 

 


The most important results of the Golestan Cohort Study on the effect of Opium Consumption

The most important results of the Golestan Cohort Study on the effect of long-term use  of opium on the incidence of cancers and cardiovascular diseases, as follows:

-Opium use doubles the risk of cancer in humans.

-Opium use is effective in the development of seven types of cancer of  bladder, larynx, lung oesophagus, stomach, pancreas, and pharynx.

-The carcinogen substance of opium is precisely found in pure opium, and the notion that pure opium is not carcinogenic is completely false.

-The concentration of the hazardous substance, PAH, in cancerous tissues was higher than in other body tissues, and it was 25 times higher in the cancerous tissues of opium users.

-Opium metabolites have been detected in urine, hair, and blood following ingestion or smoking of opium. There was “strong” evidence in experimental systems that opium, specifically sukhteh and opium pyrolysates (solid residues of combusted opium), exhibits key characteristics of carcinogens; these opium metabolite are genotoxic.

-Opium is a much more potent substance than smoking in cancer and its mortality, and the effect of opium in the development of several cancer is even greater than smoking.

- Long-term use of opium was associated with increased CVD mortality .

-Long-term opium use doubles the chance of stroke and heart attacks.

-Long-term use of opium increases the risk of death from cardiovascular diseases, cancers and respiratory diseases by up to 86%.

-Opium use increases the risk of premature death in diabetic patients by 30%. Also, the concomitant of diabetes and opium use increases the risk to 2.76 times compared to non-diabetic non-opium users.

-Opium ever-use was associated with an increased risk of cirrhosis related death with a hazard ratio of 2.74 .

IARC History

The International Agency for Research on Cancer (IARC)  was founded as a specialized cancer organization on May 20, 1965. IARC was the outcome of an initiative by a group of leading French public figures, who succeeded in persuading President de Gaulle to adopt a project to lighten humanity’s ever-growing burden of cancer.

IARC was created on 20 May 1965, by a resolution of the World Health Assembly, as the specialized cancer agency of the World Health Organization. The Agency’s headquarters building was provided by its host in Lyon, France.

IARC has its own Governing Council, and in 1965 the first members were the Federal Republic of Germany, France, Italy, the United Kingdom, and the United States of America. Today, IARC’s membership has grown to 26 countries.

France, Germany, Italy, the United Kingdom and the United States of America are the founders of this organization and the headquarters office for the Agency is located in Lyon, France. There are currently 26 countries that are permanent members of the IARC: France, Germany, Italy, the United Kingdom, the United States, Australia, Austria, Belgium, Brazil, Canada, Denmark, Finland, the Netherlands, Ireland, Japan, Morocco, Norway, Qatar, Korea, Russia, Spain, Sweden, Switzerland, Turkey, Argentina and Iran.

 Writer : Fereshteh Hashemi

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