Emergency. 2017; 5 (1): e69 OR I G I N A L RE S E A RC H Blood Lead Levels in Asymptomatic Opium Addict Pa- tients; a Case Control Study Kazem Ghaemi1,2, Atefeh Ghoreishi3, Navid Rabiee3, Samira Alinejad3, Esmaeil Farzaneh4, Alireza Amirabadi Zadeh3, Mohammad Abdollahi 5, Omid Mehrpour3∗ 1. Atherosclerosis and Coronary Artery Research Center, Birjand University of Medical Sciences, Birjand, Iran. 2. Department of Neurosurgery, Birjand University of Medical Sciences, Birjand, Iran. 3. Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sciences, Birjand, Iran. 4. Department of Internal Medicine, Ardabil University of Medical Sciences, Ardabil, Iran. 5. Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran. Received: March 2017; Accepted: June 2017; Published online: 15 June 2017 Abstract: Introduction: One of the newest non-occupational sources of lead contamination is drug addiction, which has recently been addressed as a major source of lead poisoning in some countries. The present study aimed to investigate the blood lead level (BLL) of asymptomatic opium addicts. Methods: This case-control study was conducted during a one-year period to compare BLL of three groups consisting of opium addicts, patients un- der methadone maintenance therapy (MMT), and healthy individuals. Results: 99 participants with the mean age of 55.43±12.83 years were studied in three groups of 33 cases (53.5% male). The mean lead level in opium addicts, MMT and control groups were 80.30 ± 6.03 µg/L, 67.94 ± 4.42 µg/L, and 57.30±4.77 µg/L, respectively (p=0.008). There was no significant difference in BLL between MMT and healthy individuals (p=0.433) and also between opium addicts and MMT individuals (p=0.271).Oral opium abusers had significantly higher lead levels (p = 0.036). There was a significant correlation between BLL and duration of drug abuse in opium addict cases (r=0.398, p=0.022). The odds ratio of having BLL ≥ 100 in oral opium users was 2.1 (95% CI: 0.92 - 4.61; p = 0.43). Conclusion: Based on the result of present study, when compared to healthy individuals, opium addicts, especially those who took substance orally had significantly higher levels of blood lead, and their odds of having BLL ≥ 100 was two times. Therefore, screening for BLL in opium addicts, particularly those with non-specific complaints, could be useful. Keywords: Lead; substance abuse treatment centers; methadone; opium; heroin; case-control studies © Copyright (2017) Shahid Beheshti University of Medical Sciences Cite this article as: Ghaemi k, Ghoreishi A, Rabiee N, Alinejad S, Farzaneh E, Amirabadi Zadeh A, Abdollahi M, Mehrpour O. Blood Lead Levels in Asymptomatic Opium Addict Patients; a Case Control Study. 2017; 5(1): e69. 1. Introduction L ead is a versatile metal, used in approximately 900 in- dustries (1). Due to its prevalence in various chemi- cal derivatives (2), lead poisoning is a common prob- lem particularly in developing countries. Lead, is easily ab- sorbed through skin, respiratory system, and gastrointesti- nal tract. It readily crosses the blood-brain barrier and pla- ∗Corresponding Author: Omid Mehrpour; Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sci- ences (BUMS), Moallem Avenue, Birjand, Iran, 9713643138. Email: Omid.mehrpour@yahoo.com.au Mobile Phone: +989155598571 centa after entering plasma and is spread in all soft and hard tissues. Abdominal pain, anemia, fatigue, joint pain, headache, memory impairment, ataxia, peripheral neuropa- thy, deafness, kidney disease, weakened immunity, reduced birth weight, abortion, and premature birth are some of the most important signs of lead poisoning (2-4). Although lead contamination usually occurs only when the individual has a history of contact with traditional sources of lead, new types of non-occupational poisoning have created some problems (5). One of the newest non-occupational sources of lead con- tamination is drug addiction, which has recently been ad- dressed as a major source of lead poisoning in some coun- tries, including Iran (6). Inorganic lead toxicity related to in- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com K. Ghaemi et al. 2 travenous injection or smoking of contaminated heroin has been reported since 1989 (7). Other instances include pro- cessed cannabis, methamphetamine, and Indian traditional herbal medicine (8-10). In Asia, opium and cannabis have been reported as the drugs abused most frequently in re- cent decades (11). Illicit opium may be adulterated with vari- ous materials like strychnine, paracetamol, and heavy metals such as lead and thallium (12). Salesmen and smugglers may add heavy metals to opium to raise its weight for more benefit (13, 14). Addition of lead into opium can cause an important health problem in Iran and growing reports of lead poisoning due to drug abuse are alarming. Based on above mentioned points, the present study was conducted to investigate blood lead level (BLL) in opium addicts and compare it with healthy individuals and individuals under methadone maintenance therapy (MMT). 2. Methods 2.1. Study design and setting This case-control study was conducted during June to De- cember 2014 to compare the BLL of three groups, consist- ing of opium addicts (hospitalized in Vali-e-Asr Hospital, Bir- jand, Iran), MMT cases (from the MMT clinic of Imam Reza Hospital, Mashhad, Iran), and healthy companions of the pa- tients as control group. The participants were enrolled only if they provided direct informed consent to participate in the study. The study protocol was reviewed and approved by ethics review committee of the Birjand University of Medical Sciences under the code number 631. Researchers adhered to confidentiality of patients’ information and declarations of Helsinki. 2.2. Participants Opium addicts were selected randomly from asymptomatic patients hospitalized in ophthalmology ward with other common diagnoses like cataract, glaucoma, etc. and pa- tients under MMT were selected randomly from patients of the MMT clinic. Control group consisted of patients’ non- addict family members in order to reduce the selection bias. Case and control groups were matched based on age, sex and region. Opium addicts were enrolled in this study only if they fulfilled DSM IV criteria for substance dependence. Inclusion criterion for patients under MMT was its duration of more than six months. Control group was selected from individu- als who had no history of opioid exposure. Suspected passive smoking (especially in control group), history of lead poison- ing, known occupational contact with lead (e.g., plumbing, pottery, solder, battery making, and painting) and presence of an underlying systemic disease were considered as exclu- sion criteria. There was not any sex and age limitation. 2.3. Data collection A checklist consisting of age, sex, type and duration of drug abuse, route of administration, duration of MMT, as well as BLL was developed and filled for the participants. Two mL of venous blood was collected from all participants in com- plete blood count (CBC) vials, stored at 4◦C and transferred to the Toxicology Laboratory of Imam Reza Hospital, Mash- had, Iran, in ice-containing flasks for measurement of lead level. BLL was measured by flame atomic absorption spec- trophotometry (FAAS) method (Perkin Elmer 3030, USA). Re- sults were expressed in µg/L. 3 trained medical students were responsible for data gathering. Laboratory technician was blind to the patients’ information. 2.4. Statistical Analysis Sample size was determined based on study of Khatibi. et al. (6) considering α=0.05, β=0.1 (power:0.9) and d= 1.72 (n=33 for each group). Statistical analysis was performed using SPSS software 19. Findings were reported as mean ± standard deviation or standard error and frequency (percent- age). Student t test for parametric and Man Whitney U-test for nonparametric variables were used for two group com- parison. Since BLL had a normal distribution in each group, inter-group comparison was done by a parametric test (one way ANOVA). The U.S. Department of Health and Human Services recommends that BLLs among all adults be reduced to <100 (15). Therefor 100 µg/L was considered as a cut point for determining at risk individuals. P-value less than 0.05 was considered statistically significant. 3. Results 3.1. Baseline characteristics 99 participants with the mean age of 55.43±12.83 years (25- 86) were studied in three groups of 33 cases (53.5% male). There was no significant age (p = 0.13) and sex (p = 0.07) dif- ference between the groups. The route of opium adminis- tration in addict patients was ingestion in 16 (48.4%) cases, inhalation in 8 (24.2%), and mixed in 9 (27.3%). 15 (45.5%) cases used opium, 14 (42.4%) cases opium residue (Shireh), 2 (6.0%) cases heroin, and 2 (6.0%) Iranian Crystal (Heroin base). Duration of drug abuse was 18.21 ± 2.47 (1 - 50) years among the opium addicted. Duration of MMT was 21.39 ± 3.13 (0.5- 60) months in MMT group and they had previous drug abuse duration of 10.88 ± 1.76 years. 3.2. Lead Levels The mean lead level in opium addicts, MMT and control groups were 80.30 ± 6.03 µg/L, 67.94 ± 4.42 µg/L, and 57.30±4.77 µg/L, respectively (p=0.008). There was no sig- nificant difference in BLL between MMT and healthy indi- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com 3 Emergency. 2017; 5 (1): e69 viduals (p=0.433) and also between opium addicts and MMT individuals (p=0.271). Table 1 compares the blood lead levels of opium addicts based on sex, age, route of administration and type of drug. Oral opium abusers had significantly higher lead levels (p = 0.036). There was a significant correlation be- tween BLL and duration of drug abuse in opium addict cases (r=0.398, p=0.022). Table 2 shows the distribution of BLL below and over 100 µg/L in the studied groups. The odds ratio of having BLL ≥ 100 in oral opium users was 2.1 (95% CI: 0.92 - 4.61; p = 0.43). 4. Discussion Based on the result of present study, when compared to healthy individuals, opium addicts, especially those who took substance orally had significantly higher levels of blood lead, and their odds of having BLL ≥ 100 was two times. MMT group also had a higher BLL in comparison with healthy in- dividuals but the difference was not significant. Iran’s shared border with Afghanistan (the world’s largest drug manufac- turer) has turned it into one of the main routes of trafficking drugs into Europe. Therefore, Iran could potentially be in- fluenced by complications caused by drug abuse (16). Tra- ditional opioids (opium and its extract) were the most fre- quently used drugs by the opium addicts in our study, which is consistent with other studies (17-19). 9.1% of healthy indi- viduals had BLL over 100 µg/L, which is considered accept- able for Birjand city region in comparison with the result of a study conducted on healthy individual in Arak, Iran. They re- ported 40.5% of participants, had BLL more than 10 µg /dl (20). U.S. Department of Health and Human Services has designated 100 Âţg/L of whole blood as the reference BLL for adults (15). Thus, the most recent guidelines for the manage- ment of lead-exposed adults carried out by the medical com- munity at the current center of disease control (CDC/NIOSH) reference BLL of 100 µg/L (3). Salehi et al. demonstrated that 40% of the studied opium addicts had a BLL over 250 µg/L (21). In addition, in a study by Shiri et al. three inpatients with lead poisoning symptoms had a mean BLL of 820 µg/L (22). The disagreement of the findings between other studies and the present study could be due to the particular method used for BLL measurement. In the cited studies, BLL was measured in symptomatic patients with confirmed diagnosis of lead poisoning, while only five of 33 (less than 5%) hospi- talized patients in the present study had some degree of ab- dominal pain, and none of them were diagnosed as poisoned with lead. In this study, mean BLL in opium addicts was sig- nificantly higher than in controls, which is consistent with re- sults described by Salehi et al., Farzin et al., Abbasi et al. and Khatibi-Moghadam et al. (6,21,23-24). Increased BLL in the opium addicts could be attributed to lead contamination due to opiate abuse. The mean BLL measured in opium addicts ingesting the drug was significantly higher than other route of administration. These findings are in line with the results of Hashemi Domeneh et al. who found a significantly higher level of lead in drug abusers who prefer the oral route of in- gestion (25). Previous studies demonstrated that the heat as- sociated with smoking opium may affect the amount of lead absorbed into the blood. On the contrary, the lead is not af- fected in oral routes of ingestion, leading to higher levels of absorption into the blood, leading to higher BLLs (25). BLL was higher in MMT group in comparison to healthy controls which was predictable because patients under MMT were used to opium abuse and therefore, had lead exposure, which has a long half-life in the body reported to be up to 20 years. Besides, our findings demonstrated a lower BLL in patients under MMT than opium addicts, which could represent a decreased risk of lead poisoning after withdrawal, however, the difference in BLL between the patients under methadone therapy and the opium addicts was not significant. Currently, opium addiction has become a major problem in some coun- tries and has increased the rate of lead poisoning that is al- most hidden for the physicians and they do not have enough training on how to treat those cases. Warning the health pro- fessionals about toxicological aspects of this issue is very im- portant. Therefore, screening for BLL in opium addicts, par- ticularly those with non-specific complaints, could be use- ful. This is the first study in this regard, describing this phe- nomenon in the South Khorasan Province. The results pre- sented here are initial findings and can be expanded in future studies employing larger sample sizes, which are more likely to be representative of the whole population. 5. Limitation One of the limitations of our study was the use of matched controls. Matching was done just based on age, sex and re- gion. In this regard, duration of drug abuse in the groups was not completely matched so conclusion regarding influ- ence of MMT on BLL should be considered with caution. There was no evidence regarding the use (current or past) of opium, or other exposures that might contribute to elevated blood lead measurements in our control individuals. There- fore, we had to rely on their self-stated history. Moreover, due to lower socio-cultural status of opium addicts, expla- nation of the simplest objectives of the study was quite dif- ficult. Besides, we have just evaluated BLL in opium addicts while other contaminations could be present in opium that need further study. Another limitation of our study was lack of confirmation of absence of lead contamination of blood by other sources. However, a history of lead poisoning and known occupational contact with lead (e.g., plumbing, pot- tery, solder, battery making, and painting) were considered This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com K. Ghaemi et al. 4 Table 1: Blood lead levels of opium addicts based on sex, age, route of administration and type of drug Variable N (%) Lead level (µg/L) P value Sex Male 36 83.75±5.43 0.01 Female 27 64.00±4.80 Age (year) 25-40 15 61.73±7.67 40-65 54 69.20±4.21 0.63 >65 30 70.67±5.62 Route of administration Ingestion 16 (48.48) 96.94 ± 8.56 Inhalation 8 (24.24) 65.63 ± 12.36 0.036 Mix 9 (24.27) 66.56 ± 8.58 Type of drug Heroin 2 (6.06) 49.50 ± 1.49 Opium 15 (45.45) 79.67± 8.60 0.607 Opium residue (Shireh) 14 (42.42) 85.57± 10.08 Iranian Crystal (Heroin based) 2 (6.06) 108.00 ± 9.37 Data were presented as mean ± standard error. Table 2: Distribution of BLL ≥ 100 Îijg/L between the studied groups Groups N (%) BLL < 100 N (%) BLL ≥ 100 P value Opium addicts 23 (9.7) 62.61 ± 4.63 10 (30.3) 121.00 ± 6.16 Methadone users 29 (87.9) 60.76 ± 3.09 4 (12.1) 120.00 ± 6.33 0.047 Methadone users 29 (87.9) 60.76 ± 3.09 4 (12.1) 120.00 ± 6.33 Healthy Controls 30 (90.9) 51.40 ± 3.70 3 (9.1) 116.33 ± 9.86 Data were presented as mean ± standard error. as the exclusion criteria. Moreover, it is possible that the el- evated BLLs reported in this study were the result of patient exposure to a wide range of potential lead sources that were impossible to control for such as food, air pollution to lead, etc. Unfortunately, opium used by addicts was not accessible and we couldn’t analyze them for lead to ascertain the con- clusion. 6. Conclusion Based on the result of present study, when compared to healthy individuals, opium addicts, especially those who took substance orally had significantly higher levels of blood lead, and their odds of having BLL ≥ 100 was two times. Therefore, screening for BLL in opium addicts, particularly those with non-specific complaints, could be useful. 7. Appendix 7.1. Acknowledgements The authors would like to acknowledge the support of Medi- cal Toxicology and Drug Abuse Research Center (MTDRC) in Birjand University of Medical Sciences. 7.2. Author contribution Kazem Ghaemi, Omid Mehrpour and Mohammad Abdol- lahi were responsible for study conception and design; Ate- feh Ghoreishi, Navid Rabiee and Samira Alinejad performed sampling and data collection. Alireza Amirabadizadeh and Esmaeil Farzaneh performed data analysis. Atefeh Ghoreishi, Navid Rabiee and Samira Alinejad prepared the draft of the manuscript. Kazem Ghaemi and Mohammad Abdollahi as- sisted in English editing. 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Hashemi Domeneh B, Tavakoli N, Jafari N. Blood lead level in opium dependents and its association with ane- mia: A cross-sectional study from the capital of Iran. 2014. 2014;19(10). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com Introduction Methods Results Discussion Limitation Conclusion Appendix References