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Opium Use and Mortality: A Prospective Cohort of 50,000 Adults in Iran

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Title: Opium Use and Mortality: A Prospective Cohort of 50,000 Adults in Iran


1
Opium Use and Mortality A Prospective Cohort of
50,000 Adults in Iran
  • Farin Kamangar

2
Outline
  • Significance of the Study
  • Objectives
  • Golestan Cohort Study
  • Statistical methods
  • Results
  • Discussion
  • Lessons learned and suggestions for further
    research

3
Outline
  • Significance of the Study
  • Objectives
  • Golestan Cohort Study
  • Statistical methods
  • Results
  • Discussion
  • Lessons learned and suggestions for further
    research

4
Opium and Opioid Use
  • Recreational and medicinal use
  • Long history
  • 13 22 million used opium or its derivatives in
    2008
  • Many areas of the world

5
Opium Recreational Use (19th Century)
6
Opium Medicinal Use
7
Opium Distributed and Used Worldwide
8
Long History Goddess of Opium
9
Tintin and Opium Use
10
Epidemiologic Studies of Opium and Health
  • Very few epidemiologic studies of chronic opium
    use, despite such widespread use and long history
  • Only a few case-control studies

11
Studies of Opium and Health
  • Increases the risk of esophageal cancer
    (Ghadirian 1985, Nasrollahzadeh 2008)
  • Increases the risk of bladder cancer (Behmard
    1981, Aliasgari 2004, Shakhssalim 2010, Hosseini
    2010)
  • Increases the risk of laryngeal cancer (Mousavi,
    2003)
  • Increases the risk of two other cancers
    (unpublished)

12
Studies of Opium and Health
  • Increases the risk of cardiovascular disease
    (Sadeghian 2007, Sadeghian 2010, Masoomi 2010,
    Masoumi 2010)
  • Increases the risk of deep vein thrombosis
    (Safaii 2010)
  • Increases the risk of lung disease with chronic
    obstruction (Da Costa 1971)

13
Research Gap
  • No large-scale or long-term prospective cohort
    studies of opium and health

14
Outline
  • Significance of the Study
  • Objectives
  • Golestan Cohort Study
  • Statistical methods
  • Results
  • Discussion
  • Lessons learned and suggestions for further
    research

15
Objectives
  • Use data from Golestan Cohort Study
  • To determine the effect of opium use on overall
    and cause-specific mortality
  • To determine this effect by type of opium use
  • Teriak
  • Shireh
  • Sukhteh
  • Heroin

16
Outline
  • Significance of the Study
  • Objectives
  • Golestan Cohort Study
  • Statistical methods
  • Results
  • Discussion
  • Lessons learned and suggestions for further
    research

17
Golestan Cohort
  • In Golestan Province, northeast of Iran
  • 50,045 adults, 40 to 75 years of age
  • Detailed questionnaire data
  • General Questionnaire
  • Food Frequency Questionnaire
  • Biologic samples
  • Blood
  • Urine
  • Hair
  • Nail

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Very High Rates of Esophageal Cancer
  • Anecdotal reports
  • Reports from central institutions (Habibi 1965,
    Haghighi 1971)
  • Exploratory observations (Kmet 1966)
  • Cancer registry (1968 to 1971, Iran-IARC
    collaborations)

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Registry Results
  • The highest rates ever reported in the world
  • Rates also very high in women
  • Large differences in rates in 500 kilometers

23
Ecologic Studies in the 1970s
  • Differences in fauna and flora
  • Differences in foods consumed (sheeps milk,
    fruit and vegetables, sesame oil, etc)
  • Hot tea consumption in high quantities
  • Chewing of nass (a mixture of ash, lime, and
    tobacco)
  • Opium use (up to 50 of both sexes over 35 years)

24
Case-Control Study(350 cases and 700 controls)
  • Not associated sheeps milk, sesame oil, chewing
    of nass, use of pregnancy diets, salting and
    sun-drying
  • Moderately associated cigarette smoking,
    drinking hot tea, low intake of fresh fruits and
    vegetables, low socio-economic status
  • Not assessed opium use

  • Cook-Mozaffari, BJC 1979

25
Opium Further Studies
  • Types
  • Crude opium
  • Sukhteh (opium pipe residues) mutagen in Ames
    test
  • Shireh (refined opium extract)
  • Hewer , Lancet 1978
  • Case-control study of families
  • A half-completed case-control study showed a
    non-significant two-fold risk associated with EC
    risk
  • Ghadirian, IJC 1985

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Summary Results from the 1970s
  • Northeastern Iran a very high-risk area for EC
  • Risk similar in men and women
  • Smoking a weak risk factor, and alcohol
    consumption very uncommon
  • Some risk factors suggested (low SES, low intake
    of fresh fruit and vegetables, hot tea intake,
    but none striking)
  • Opium some suggestions, but studies incomplete

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31
Case-Control StudyBasic idea
  • To re-evaluate the previous hypotheses for the
    very high incidence of esophageal cancer (e.g.,
    opium use, hot tea intake, low socioeconomic
    status, low intake of fresh fruits and
    vegetables)
  • To test new hypotheses (e.g., animal contact,
    oral hygiene, genetic studies)
  • Use new technology (e.g., new genotyping
    capabilities, proteomics)

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33
Cases and controls
  • 300 esophageal cancer cases (all squamous cell)
  • 600 neighborhood controls, matched for age, sex,
    and neighborhood of residence

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35
Data and samples
  • General questionnaire
  • Food Frequency Questionnaire (validated against
    24-hour recalls)
  • Blood
  • Hair and Nail
  • Biopsy samples

36
General Questionnaire
  • Demographic characteristics
  • Residential history
  • Occupational history
  • Family and SES
  • Personal history of disease
  • Upper GI signs and symptoms
  • Personal and family history of cancer
  • Tobacco and opium use
  • Alcohol consumption
  • Medication history
  • Oral health
  • Anthropometric indices
  • Animal contact
  • Tea consumption
  • Physical activity
  • Methods of cooking and food preservation and
    water source

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41
Esophageal Cancer Lecture for Turkmen Doctors
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44
Case-Control Study
  • Recruitment started in 2003 and was completed in
    2007.
  • A total of 300 cases and 571 matched controls
    were recruited.
  • Several papers have been published.

45
Opium and Tobacco Use in Relation to Esophageal
Cancer
  • Tobacco and/or opium
  • Neither 1.00
  • Tobacco only 1.70 (1.05 2.73)
  • Opium only 2.12 (1.21 3.74)
  • Both 2.35 (1.50 3.67)
  • Some 30 of all cases can be attributed to these
    two factors.
  • Nasrollahzadeh et al. BJC

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  • Cohort Study

48
Cohort Study
  • This cohort study was designed to enroll 50,000
    subjects from the eastern part of Golestan
    Province, with objectives similar to the
    case-control study.
  • Design was very similar to the case-control
    study.
  • General questionnaire
  • Dietary questionnaire
  • Blood
  • Hair and nail
  • Urine

49
Cohort Study
  • Plasma (x8), RBC (x2), and buffy coat (x4) are
    stored in bar-coded straws and kept in 80
    freezers or nitrogen tanks.
  • Urine samples (used for PAH and opium assays) are
    also stored in -20 freezers or nitrogen tanks.
  • Half the samples in Iran and half in IARC.

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Cohort Study
  • Outcomes
  • Death (from any cause)
  • Incident cancer (any site)
  • Esophageal and gastric cancers (emphasis)
  • Outcome assessment
  • All relevant data are collected from hospitals
    and clinics
  • Two internists assign codes may be a third one
  • For EC and GC an international panel of experts

52
Cohort Study
  • Recruitment started in 2004 and was completed in
    May 2008.
  • Follow-up continues to date

53
Cohort Study Follow-Up
  • Annual follow-up
  • Private phone (available to 98 of the
    participants)
  • Phone numbers from relatives and friends
  • Home visits
  • In rural areas the Behvarz (local health person)
  • Follow-up through May 2011
  • 234,928 person-years
  • gt 99 success rate
  • 2,145 deaths (130 due to esophageal cancer)

54
  • Case-control
  • GEMINI Cohort

55
Outline
  • Significance of the Study
  • Objectives
  • Golestan Cohort Study
  • Statistical methods
  • Results
  • Discussion
  • Lessons learned and suggestions for further
    research

56
Regression model
  • Cox proportional hazards models to estimate the
    hazard ratios and 95 confidence intervals
  • Adjustment for potential confounders
  • Assessment of interactions
  • Sensitivity analyses

57
Exposure and Outcome Variables
  • Exposure Opium use
  • Type (teriak, shireh, sukhteh, heroin)
  • Typical amount of use in nokhod ( 0.2 g)
  • Duration of use
  • Frequency of use
  • Outcome Death
  • Overall
  • Cause-specific

58
Other Variables
  • Potential confounders and effect modifiers
  • Age
  • Sex
  • Place of residence
  • Ethnicity
  • Marital Status
  • Highest educational level
  • Cigarette smoking
  • Body mass index
  • Height
  • Consumption of fruit and vegetables
  • Socioeconomic status indicators

59
Pilot Studies
  • Reliability and validity of opiate use
    self-report in a population at high risk for
    esophageal cancer in Golestan, Iran. (Cancer
    Epidemiol Biomarkers Prev. 2004)
  • Golestan cohort study of oesophageal cancer
    feasibility and first results. (Br J Cancer.
    2005)
  • Validity and reliability of a new food frequency
    questionnaire compared to 24 h recalls and
    biochemical measurements pilot phase of Golestan
    cohort study of esophageal cancer. (Eur J Clin
    Nutr. 2006)

60
Outline
  • Significance of the Study
  • Objectives
  • Golestan Cohort Study
  • Statistical methods
  • Results
  • Discussion
  • Lessons learned and suggestions for further
    research

61
Study Population
  • 50,045 participants
  • 234,928 person-years of follow-up
  • Median follow-up 4.7 years
  • Mean age at enrollment 52 years
  • 58 women
  • 74 of Turkmen ethnicity
  • 70 no formal education
  • 17 smokers
  • 17 opium users

62
Opium Distribution Routes
63
Global Opium Consumption
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All-Cause Mortality
  • HR (95 CI)
  • Unadjusted 2.26 (2.06 2.47)
  • Adjusted 1.86 (1.68 2.06)
  • Almost doubling the risk
  • Much stronger than cigarette smoking
  • (Khademi, BMJ 2012)

66
Opium and MortalityAdjusted HR (95 CI)
  • All Causes (n 2145) 1.86 (1.68 2.06)
  • Circulatory (n 1073) 1.81 (1.56 2.09)
  • Cancer (n 449) 1.61 (1.28 2.03)
  • Respiratory (n 95) 3.78 (2.36 6.04)
  • Digestive (n 69) 3.12 (1.82 5.37)
  • Infectious (n 51) 5.47 (2.87 10.4)
  • External (n 135) 0.86 (0.54 0.35)
  • Other (n 150) 1.66 (1.11 2.48)
  • Unknown (n 123) 2.42 (1.59 3.67)

67
By Duration of Use(only in those who used it
before diagnosis of major diseases)
  • Never users 1.00
  • Former users 1.27
  • Current users 1.70
  • 3 years 1.62
  • 4 to 7 years 1.39
  • 8 to 12 years 2.00
  • 13 to 20 years 1.79
  • 21 years 1.90

  • p for trend lt 0.001

68
By time since last used
69
Subtype Analyses Sensitivity Analyses
  • Teriak, shireh, and heroin all increased risk
  • Both smoking and ingesting opium increased risk
  • Excluding deaths that occurred in the first 6,
    12, 18, and 24 months of follow-up had little
    effect on the results
  • Further adjustment didnt change the results
  • Results remained unchanged in a healthy
    subcohort analysis

70
Outline
  • Significance of the Study
  • Objectives
  • Golestan Cohort Study
  • Statistical methods
  • Results
  • Discussion
  • Lessons learned and suggestions for further
    research

71
Evidence for Causality (1)
  • Consistent with results of case-control studies
    of cancer and cardiovascular diseases
  • Relatively strong association (hazard ratio of
    2), stronger than tobacco use in this population
  • Dose-response association with duration of use
  • Risk reduction after cessation of exposure

72
Evidence for Causality (2)
  • Adjusting for multiple confounders (age, sex,
    ethnic group, place of residence, tobacco
    smoking, education, intake of fruit and
    vegetables, )
  • Measures taken to study reverse causality
  • Excluding those who started opium use after
    diagnosis of major diseases
  • Excluding outcomes within 24 months from the
    initiation of the cohort

73
Evidence for Causality (3)
  • Biologic plausibility Much to be learned, but
    alkaloid and non-alkaloid components have a
    number of systemic effects. Examples
  • Lung and Bronchi
  • Activation of opioid receptors in medulla,
    resulting in reduced breathing frequency and
    tidal volume
  • Upper airway constriction
  • Cancers
  • Activating angiogenesis and neovascularization
  • PAHs due to smoking
  • Liver
  • Perivenular and focal hepatocelluar necrosis

74
Evidence for Causality (4)
  • Opium users in this cohort use very low amounts
    of opium (average of 0.6 g/day), are at very low
    risk of overdose, and are NOT very different from
    other study participants for most other studied
    variables.
  • Results mostly reflect long-term effects of low
    amounts of use

75
Implications
  • Opium and opioids are widely used. Death due to
    opium use is not limited to overdose.
  • This study may (and only may) have implications
    for long-term use of opioids in medicine.

76
Outline
  • Significance of the Study
  • Objectives
  • Golestan Cohort Study
  • Statistical methods
  • Results
  • Discussion
  • Lessons learned and suggestions for further
    research

77
Further Research
  • Case-control studies of various outcomes in
    relation to opium use (keep in mind reverse
    causality)
  • Studies of the biologic effects of opium and
    opioid use
  • Investigating long-term effects of opioid
    analgesics

78
Lessons Learned
  • Just do it!
  • There is a story and a rationale behind every
    study but things take you where you dont
    necessarily expect.
  • For more cohorts, try to find a few unique
    things.
  • Leadership, collaborations, and patience All
    very important.

79
Further Reading
  • Khademi et al. Opium use and mortality in
    Golestan Cohort Study. BMJ, 2012
  • Pourshams et al. Cohort Profile The Golestan
    Cohort Study. Int J Epidemiol, 2010.
  • Kamangar et al. Esophageal cancer in Iran. Arch
    Iran Med, 2007.

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