opium use and mortality: a prospective cohort of 50,000 adults in iran

Opium Use and Opium Use and Mortality: Mortality:

A Prospective Cohort of 50,000 A Prospective Cohort of 50,000 Adults in IranAdults in Iran

Farin KamangarFarin Kamangar

1

OutlineOutline Significance of the StudySignificance of the Study

ObjectivesObjectives

Golestan Cohort StudyGolestan Cohort Study

Statistical methodsStatistical methods

ResultsResults

DiscussionDiscussion Lessons learned and suggestions for further researchLessons learned and suggestions for further research

2





ResultsResults

DiscussionDiscussion Lessons learned and suggestions for further researchLessons learned and suggestions for further research3

Opium and Opioid UseOpium and Opioid Use Recreational and medicinal useRecreational and medicinal use

Long history Long history

13 – 22 million used opium or its derivatives in 2008 13 – 22 million used opium or its derivatives in 2008

Many areas of the worldMany areas of the world

4

Opium: Recreational Use Opium: Recreational Use (19(19thth Century) Century)

5

Opium: Medicinal UseOpium: Medicinal Use

6

Opium: Distributed and Opium: Distributed and Used WorldwideUsed Worldwide

7

Long History: Goddess of Long History: Goddess of OpiumOpium

8

Tintin and Opium UseTintin and Opium Use

9

Epidemiologic Studies of Epidemiologic Studies of Opium and HealthOpium and Health

Very few epidemiologic studies of chronic opium Very few epidemiologic studies of chronic opium use, despite such widespread use and long history use, despite such widespread use and long history

Only a few case-control studiesOnly a few case-control studies

10

Studies of Opium and Studies of Opium and HealthHealth

Increases the risk of esophageal cancer Increases the risk of esophageal cancer (Ghadirian 1985, (Ghadirian 1985, Nasrollahzadeh 2008)Nasrollahzadeh 2008)

Increases the risk of bladder cancer Increases the risk of bladder cancer (Behmard 1981, (Behmard 1981, Aliasgari 2004, Shakhssalim 2010, Hosseini 2010)Aliasgari 2004, Shakhssalim 2010, Hosseini 2010)

Increases the risk of laryngeal cancer Increases the risk of laryngeal cancer (Mousavi, 2003)(Mousavi, 2003)

Increases the risk of two other cancers Increases the risk of two other cancers (unpublished)(unpublished)

11

Studies of Opium and Studies of Opium and HealthHealth

Increases the risk of cardiovascular disease Increases the risk of cardiovascular disease (Sadeghian 2007, Sadeghian 2010, Masoomi 2010, Masoumi 2010)(Sadeghian 2007, Sadeghian 2010, Masoomi 2010, Masoumi 2010)

Increases the risk of deep vein thrombosis Increases the risk of deep vein thrombosis (Safaii 2010)(Safaii 2010)

Increases the risk of lung disease with chronic Increases the risk of lung disease with chronic obstruction obstruction (Da Costa 1971)(Da Costa 1971)

12

Research GapResearch Gap

No large-scale or long-term prospective No large-scale or long-term prospective cohort studies of opium and healthcohort studies of opium and health

13





ResultsResults


ObjectivesObjectivesUse data from Golestan Cohort StudyUse data from Golestan Cohort Study

To determine the effect of opium use on overall and To determine the effect of opium use on overall and cause-specific mortality cause-specific mortality

To determine this effect by type of opium useTo determine this effect by type of opium use TeriakTeriak Shireh Shireh Sukhteh Sukhteh HeroinHeroin

15





ResultsResults


Golestan CohortGolestan Cohort In Golestan Province, northeast of IranIn Golestan Province, northeast of Iran

50,045 adults, 40 to 75 years of age 50,045 adults, 40 to 75 years of age

Detailed questionnaire dataDetailed questionnaire data General QuestionnaireGeneral Questionnaire Food Frequency QuestionnaireFood Frequency Questionnaire

Biologic samplesBiologic samples BloodBlood UrineUrine Hair Hair NailNail 17

Very High Rates of Esophageal Cancer

Anecdotal reportsAnecdotal reports Reports from central institutions (Habibi 1965, Haghighi Reports from central institutions (Habibi 1965, Haghighi

1971)1971) Exploratory observations (Kmet 1966)Exploratory observations (Kmet 1966)

Cancer registry (1968 to 1971, Iran-IARC Cancer registry (1968 to 1971, Iran-IARC collaborations)collaborations)

20

Registry ResultsRegistry Results

The highest rates ever reported in the worldThe highest rates ever reported in the world

Rates also very high in womenRates also very high in women

Large differences in rates in 500 kilometersLarge differences in rates in 500 kilometers

22

Ecologic Studies in the Ecologic Studies in the 1970s1970s

Differences in fauna and floraDifferences in fauna and flora

Differences in foods consumed (sheep’s milk, fruit Differences in foods consumed (sheep’s milk, fruit and vegetables, sesame oil, etc)and vegetables, sesame oil, etc)

Hot tea consumption in high quantitiesHot tea consumption in high quantities

Chewing of nass (a mixture of ash, lime, and Chewing of nass (a mixture of ash, lime, and tobacco) tobacco)

Opium use (up to 50% of both sexes over 35 years)Opium use (up to 50% of both sexes over 35 years)23

Case-Control StudyCase-Control Study(350 cases and 700 controls)(350 cases and 700 controls)

Not associated: Not associated: sheep’s milk, sesame oil, chewing sheep’s milk, sesame oil, chewing of nass, use of pregnancy diets, salting and sun-of nass, use of pregnancy diets, salting and sun-dryingdrying

Moderately associated: Moderately associated: cigarette smoking, drinking cigarette smoking, drinking hot tea, low intake of fresh fruits and vegetables, hot tea, low intake of fresh fruits and vegetables, low socio-economic statuslow socio-economic status

Not assessed:Not assessed: opium use opium use Cook-Cook-

Mozaffari, BJC 1979Mozaffari, BJC 197924

Opium: Further StudiesOpium: Further Studies Types:Types:

Crude opiumCrude opium Sukhteh (opium pipe residues): mutagen in Sukhteh (opium pipe residues): mutagen in

Ames test Ames test Shireh (refined opium extract)Shireh (refined opium extract)

Hewer , Lancet 1978Hewer , Lancet 1978 Case-control study of familiesCase-control study of families

A half-completed case-control study showed a A half-completed case-control study showed a non-significant two-fold risk associated with EC non-significant two-fold risk associated with EC risk risk

Ghadirian, IJC 1985 Ghadirian, IJC 1985 25

Summary Results from Summary Results from the 1970sthe 1970s

Northeastern Iran: a very high-risk area for ECNortheastern Iran: a very high-risk area for EC

Risk similar in men and womenRisk similar in men and women

Smoking a weak risk factor, and alcohol consumption Smoking a weak risk factor, and alcohol consumption very uncommonvery uncommon

Some risk factors suggested (low SES, low intake of Some risk factors suggested (low SES, low intake of fresh fruit and vegetables, hot tea intake, but none fresh fruit and vegetables, hot tea intake, but none striking) striking)

Opium: some suggestions, but studies incomplete Opium: some suggestions, but studies incomplete

27

Case-Control Study:Case-Control Study:Basic idea Basic idea

To re-evaluate the previous hypotheses for the very To re-evaluate the previous hypotheses for the very high incidence of esophageal cancer (e.g., opium high incidence of esophageal cancer (e.g., opium use, hot tea intake, low socioeconomic status, low use, hot tea intake, low socioeconomic status, low intake of fresh fruits and vegetables)intake of fresh fruits and vegetables)

To test new hypotheses (e.g., animal contact, oral To test new hypotheses (e.g., animal contact, oral hygiene, genetic studies)hygiene, genetic studies)

Use new technology (e.g., new genotyping Use new technology (e.g., new genotyping capabilities, proteomics)capabilities, proteomics)

31

Cases and controlsCases and controls

300 esophageal cancer cases (all squamous cell)300 esophageal cancer cases (all squamous cell)

600 neighborhood controls, matched for age, sex, 600 neighborhood controls, matched for age, sex, and neighborhood of residenceand neighborhood of residence

33

Data and samplesData and samples General questionnaireGeneral questionnaire

Food Frequency Questionnaire (validated against 24-Food Frequency Questionnaire (validated against 24-hour recalls)hour recalls)

Blood Blood

Hair and NailHair and Nail

Biopsy samplesBiopsy samples 35

General QuestionnaireGeneral Questionnaire Demographic characteristicsDemographic characteristics Residential historyResidential history Occupational historyOccupational history Family and SESFamily and SES Personal history of diseasePersonal history of disease Upper GI signs and symptomsUpper GI signs and symptoms Personal and family history of cancerPersonal and family history of cancer Tobacco and opium useTobacco and opium use Alcohol consumptionAlcohol consumption Medication historyMedication history Oral healthOral health Anthropometric indicesAnthropometric indices Animal contactAnimal contact Tea consumptionTea consumption Physical activityPhysical activity Methods of cooking and food preservation and water sourceMethods of cooking and food preservation and water source

36

Esophageal Cancer Lecture for Turkmen Doctors

41

Case-Control StudyCase-Control Study

Recruitment started in 2003 and was completed in Recruitment started in 2003 and was completed in 2007. 2007.

A total of 300 cases and 571 matched controls were A total of 300 cases and 571 matched controls were recruited. recruited.

Several papers have been published. Several papers have been published.

44

Opium and Tobacco Use Opium and Tobacco Use in Relation to in Relation to

Esophageal CancerEsophageal Cancer Tobacco and/or opiumTobacco and/or opium

NeitherNeither 1.001.00 Tobacco onlyTobacco only 1.70 (1.05 – 2.73)1.70 (1.05 – 2.73) Opium onlyOpium only 2.12 (1.21 – 3.74)2.12 (1.21 – 3.74) Both Both 2.35 (1.50 – 3.67)2.35 (1.50 – 3.67)

Some 30% of all cases can be attributed to these two Some 30% of all cases can be attributed to these two factors. factors.

Nasrollahzadeh et al. BJC Nasrollahzadeh et al. BJC

45

Cohort StudyCohort Study

47

Cohort StudyCohort Study This cohort study was designed to enroll 50,000 This cohort study was designed to enroll 50,000

subjects from the eastern part of Golestan Province, subjects from the eastern part of Golestan Province, with objectives similar to the case-control study. with objectives similar to the case-control study.

Design was very similar to the case-control study. Design was very similar to the case-control study. General questionnaireGeneral questionnaire Dietary questionnaireDietary questionnaire BloodBlood Hair and nailHair and nail Urine Urine

48

Cohort StudyCohort Study Plasma (x8), RBC (x2), and buffy coat (x4) are stored Plasma (x8), RBC (x2), and buffy coat (x4) are stored

in bar-coded straws and kept in – 80 freezers or in bar-coded straws and kept in – 80 freezers or nitrogen tanks.nitrogen tanks.

Urine samples (used for PAH and opium assays) are Urine samples (used for PAH and opium assays) are also stored in -20 freezers or nitrogen tanks. also stored in -20 freezers or nitrogen tanks.

Half the samples in Iran and half in IARC. Half the samples in Iran and half in IARC.

49

Cohort StudyCohort Study Outcomes:Outcomes:

Death (from any cause)Death (from any cause) Incident cancer (any site)Incident cancer (any site) Esophageal and gastric cancers (emphasis)Esophageal and gastric cancers (emphasis)

Outcome assessment:Outcome assessment: All relevant data are collected from hospitals and All relevant data are collected from hospitals and

clinicsclinics Two internists assign codes; may be a third one Two internists assign codes; may be a third one For EC and GC: an international panel of expertsFor EC and GC: an international panel of experts

51

Cohort StudyCohort Study

Recruitment started in 2004 and was completed in Recruitment started in 2004 and was completed in May 2008. May 2008.

Follow-up continues to dateFollow-up continues to date

52

Cohort Study Follow-UpCohort Study Follow-Up Annual follow-up: Annual follow-up:

Private phone (available to 98% of the participants)Private phone (available to 98% of the participants) Phone numbers from relatives and friendsPhone numbers from relatives and friends Home visitsHome visits In rural areas: the Behvarz (local health person)In rural areas: the Behvarz (local health person)

Follow-up through May 2011: Follow-up through May 2011: 234,928 person-years234,928 person-years > 99% success rate> 99% success rate 2,145 deaths (130 due to esophageal cancer)2,145 deaths (130 due to esophageal cancer)

53

Case-controlCase-control

GEMINIGEMINICohortCohort

54





ResultsResults


Regression modelRegression model Cox proportional hazards models to estimate the Cox proportional hazards models to estimate the

hazard ratios and 95% confidence intervalshazard ratios and 95% confidence intervals

Adjustment for potential confoundersAdjustment for potential confounders

Assessment of interactionsAssessment of interactions

Sensitivity analysesSensitivity analyses

56

Exposure and Outcome Exposure and Outcome VariablesVariables

Exposure: Opium useExposure: Opium use Type (teriak, shireh, sukhteh, heroin)Type (teriak, shireh, sukhteh, heroin) Typical amount of use in nokhod (~ 0.2 g)Typical amount of use in nokhod (~ 0.2 g) Duration of useDuration of use Frequency of useFrequency of use

Outcome: DeathOutcome: Death OverallOverall Cause-specificCause-specific

57

Other VariablesOther Variables Potential confounders and effect modifiersPotential confounders and effect modifiers

AgeAge SexSex Place of residencePlace of residence EthnicityEthnicity Marital StatusMarital Status Highest educational levelHighest educational level Cigarette smokingCigarette smoking Body mass indexBody mass index HeightHeight Consumption of fruit and vegetablesConsumption of fruit and vegetables Socioeconomic status indicatorsSocioeconomic status indicators

58

Pilot StudiesPilot Studies Reliability and validity of opiate use self-report in a Reliability and validity of opiate use self-report in a

population at high risk for esophageal cancer in population at high risk for esophageal cancer in Golestan, Iran. Golestan, Iran. (Cancer Epidemiol Biomarkers Prev. 2004) (Cancer Epidemiol Biomarkers Prev. 2004)

Golestan cohort study of oesophageal cancer: Golestan cohort study of oesophageal cancer: feasibility and first results. feasibility and first results. (Br J Cancer. 2005) (Br J Cancer. 2005)

Validity and reliability of a new food frequency Validity and reliability of a new food frequency questionnaire compared to 24 h recalls and questionnaire compared to 24 h recalls and biochemical measurements: pilot phase of Golestan biochemical measurements: pilot phase of Golestan cohort study of esophageal cancer. cohort study of esophageal cancer. (Eur J Clin Nutr. 2006)(Eur J Clin Nutr. 2006)

59





ResultsResults


Study PopulationStudy Population 50,045 participants50,045 participants 234,928 person-years of follow-up234,928 person-years of follow-up Median follow-up = 4.7 yearsMedian follow-up = 4.7 years

Mean age at enrollment = 52 yearsMean age at enrollment = 52 years 58% women58% women 74% of Turkmen ethnicity74% of Turkmen ethnicity 70% no formal education70% no formal education 17% smokers17% smokers 17% opium users17% opium users

61

Opium Distribution Opium Distribution RoutesRoutes

62

Global Opium Global Opium Consumption Consumption

63

All-Cause Mortality All-Cause Mortality HR (95% CI)HR (95% CI)

Unadjusted = 2.26 (2.06 – 2.47)Unadjusted = 2.26 (2.06 – 2.47) Adjusted = 1.86 (1.68 – 2.06)Adjusted = 1.86 (1.68 – 2.06)

Almost doubling the riskAlmost doubling the risk

Much stronger than cigarette smokingMuch stronger than cigarette smoking

(Khademi, BMJ 2012)(Khademi, BMJ 2012)

65

Opium and MortalityOpium and MortalityAdjusted HR (95% CI)Adjusted HR (95% CI)

All Causes (n = 2145)All Causes (n = 2145) 1.86 (1.68 – 2.06)1.86 (1.68 – 2.06)

Circulatory (n = 1073)Circulatory (n = 1073) 1.81 (1.56 – 2.09)1.81 (1.56 – 2.09) CancerCancer (n = 449)(n = 449) 1.61 (1.28 – 2.03)1.61 (1.28 – 2.03) Respiratory (n = 95)Respiratory (n = 95) 3.78 (2.36 – 6.04)3.78 (2.36 – 6.04) Digestive (n = 69)Digestive (n = 69) 3.12 (1.82 – 5.37)3.12 (1.82 – 5.37) Infectious (n = 51)Infectious (n = 51) 5.47 (2.87 – 10.4)5.47 (2.87 – 10.4) External (n = 135)External (n = 135) 0.86 (0.54 – 0.35)0.86 (0.54 – 0.35) Other (n = 150)Other (n = 150) 1.66 (1.11 – 2.48)1.66 (1.11 – 2.48) Unknown (n = 123)Unknown (n = 123) 2.42 (1.59 – 3.67)2.42 (1.59 – 3.67)

66

By Duration of UseBy Duration of Use(only in those who used it before diagnosis of (only in those who used it before diagnosis of

major diseases)major diseases) Never usersNever users 1.001.00 Former usersFormer users 1.27 1.27 Current usersCurrent users 1.70 1.70

≤ ≤ 3 years3 years 1.621.62 4 to 7 years4 to 7 years 1.391.39 8 to 12 years8 to 12 years 2.002.00 13 to 20 years13 to 20 years 1.791.79 ≥ ≥ 21 years21 years 1.901.90 p for trend < 0.001p for trend < 0.001

67

By time since last usedBy time since last used

68

Subtype Analyses & Subtype Analyses & Sensitivity AnalysesSensitivity Analyses

Teriak, shireh, and heroin all increased risk Teriak, shireh, and heroin all increased risk

Both smoking and ingesting opium increased riskBoth smoking and ingesting opium increased risk

Excluding deaths that occurred in the first 6, 12, 18, and Excluding deaths that occurred in the first 6, 12, 18, and 24 months of follow-up had little effect on the results24 months of follow-up had little effect on the results

Further adjustment didn’t change the resultsFurther adjustment didn’t change the results

Results remained unchanged in a “healthy” subcohort Results remained unchanged in a “healthy” subcohort analysisanalysis

69





ResultsResults


Evidence for Causality Evidence for Causality (1)(1)

Consistent with results of case-control studies of Consistent with results of case-control studies of cancer and cardiovascular diseases cancer and cardiovascular diseases

Relatively strong association (hazard ratio of ~ 2), Relatively strong association (hazard ratio of ~ 2), stronger than tobacco use in this populationstronger than tobacco use in this population

Dose-response association with duration of useDose-response association with duration of use

Risk reduction after cessation of exposureRisk reduction after cessation of exposure

71


Adjusting for multiple confounders (age, sex, ethnic Adjusting for multiple confounders (age, sex, ethnic group, place of residence, tobacco smoking, group, place of residence, tobacco smoking, education, intake of fruit and vegetables, …)education, intake of fruit and vegetables, …)

Measures taken to study reverse causalityMeasures taken to study reverse causality Excluding those who started opium use after Excluding those who started opium use after

diagnosis of major diseasesdiagnosis of major diseases Excluding outcomes within 24 months from the Excluding outcomes within 24 months from the

initiation of the cohortinitiation of the cohort

72


Biologic plausibility: Much to be learned, but alkaloid Biologic plausibility: Much to be learned, but alkaloid and non-alkaloid components have a number of and non-alkaloid components have a number of systemic effects. Examples: systemic effects. Examples: Lung and BronchiLung and Bronchi

Activation of opioid receptors in medulla, resulting in Activation of opioid receptors in medulla, resulting in reduced breathing frequency and tidal volumereduced breathing frequency and tidal volume

Upper airway constrictionUpper airway constriction CancersCancers

Activating angiogenesis and neovascularizationActivating angiogenesis and neovascularization PAHs due to smokingPAHs due to smoking

LiverLiver Perivenular and focal hepatocelluar necrosisPerivenular and focal hepatocelluar necrosis

73


Opium users in this cohort use very low amounts of Opium users in this cohort use very low amounts of opium (average of 0.6 g/day), are at very low risk of opium (average of 0.6 g/day), are at very low risk of overdose, and are NOT very different from other overdose, and are NOT very different from other study participants for most other studied variables.study participants for most other studied variables.

Results mostly reflect long-term effects of low Results mostly reflect long-term effects of low amounts of useamounts of use

74

ImplicationsImplications

Opium and opioids are widely used. Death due to Opium and opioids are widely used. Death due to opium use is not limited to overdose. opium use is not limited to overdose.

This study may (and only may) have implications for This study may (and only may) have implications for long-term use of opioids in medicine. long-term use of opioids in medicine.

75





ResultsResults


Further ResearchFurther Research

Case-control studies of various outcomes in relation Case-control studies of various outcomes in relation to opium use (keep in mind reverse causality)to opium use (keep in mind reverse causality)

Studies of the biologic effects of opium and opioid Studies of the biologic effects of opium and opioid useuse

Investigating long-term effects of opioid analgesicsInvestigating long-term effects of opioid analgesics

77

Lessons LearnedLessons Learned Just do it! Just do it!

There is a story and a rationale behind every study There is a story and a rationale behind every study but things take you where you don’t necessarily but things take you where you don’t necessarily expect. expect.

For more cohorts, try to find a few unique things.For more cohorts, try to find a few unique things.

Leadership, collaborations, and patience: All very Leadership, collaborations, and patience: All very important. important.

78

Further ReadingFurther Reading

Khademi et al. Opium use and mortality in Golestan Khademi et al. Opium use and mortality in Golestan Cohort Study. BMJ, 2012Cohort Study. BMJ, 2012

Pourshams et al. Cohort Profile: The Golestan Pourshams et al. Cohort Profile: The Golestan Cohort Study. Int J Epidemiol, 2010. Cohort Study. Int J Epidemiol, 2010.

Kamangar et al. Esophageal cancer in Iran. Arch Kamangar et al. Esophageal cancer in Iran. Arch Iran Med, 2007. Iran Med, 2007.

79

opium use and mortality: a prospective cohort of 50,000 adults in iran

Documents

used opium

effect of opium use

goddess of opium

tobacco opium

epidemiologic studies

crude opium sukhteh

opium use cookmozaffari

widespread use