Opium, Street Opium, and Cancer Risk.

Opium is defined as the air-dried latex obtained by incision from the unripe capsules of Papaver somniferum L. Opium is a complex mixture that contains approximately 10% morphine and 2% codeine. It is commonly used to prepare opium tinctures for people with chronic diarrhea. Morphine and related opioids are powerful but highly addictive analgesics; designing less addictive opioids is an active area of pharmaceutical research that may lead to significant improvements in chronic pain management. Recently, the International Agency for Research on Cancer (IARC) has classified opium consumption as carcinogenic to humans (Group 1) based on sufficient evidence of carcinogenicity in human studies. However, all human studies analyzed by the IARC Working Group included participants who consumed opium that was mixed, adulterated, and/or contaminated with known and probable human carcinogens (e.g., tarry residues of combusted opium, arsenic, lead, and chromium). The working group considered that these carcinogens were part of the complex mixture that opium is, rather than co-exposure or confounders. No evidence of carcinogenicity was available for pure opium in human, animal, or mechanistic studies. To avoid confusion and concern among health professionals and patients using medicinal opium preparations and in scientists involved in the design and development of new opium derivatives, opium should be classified in Group 3 (not classifiable as to its carcinogenicity to humans). The term 'street opium' could be used to refer to opium that probably contains human carcinogens not present in pure opium and should remain in Group 1 (carcinogenic to humans).

Carbon and nitrogen isotopic analysis of morphine from opium and heroin samples originating in the four major heroin producing regions.

The forensic analysis of stable isotopes is a valuable tool to geo-source natural or semisynthetic drugs such as cocaine and heroin. The present study describes a novel methodology to isolate morphine from opium for isotopic analysis. Furthermore, this isotopic data from regional sources is corroborated with morphine data obtained from seized heroin (deacetylated to morphine) from the same regions. All five primary alkaloids of opium, namely, morphine, codeine, thebaine, noscapine, and papaverine, were quantified using high performance liquid chromatography with photodiode array (PDA) detector before the preparative experiment to gather a complete major alkaloidal profile. Morphine fractions of authentic opium submissions from Mexico, South America, Southwest Asia, and Southeast Asia were isolated and collected using preparative high performance liquid chromatography, and the collected morphine samples were subsequently analyzed by isotope ratio mass spectrometry. Carbon and nitrogen isotope data are presented. The data demonstrate that nitrogen ratios are capable of differentiating samples from Mexico and South America while carbon ratios are able to distinguish Southwest Asian samples from other source regions. Analogous results have routinely been observed (as part of Heroin Signature Program analysis) for morphine obtained from deacetylated authentic heroin samples from the same source regions. The results suggest that the poppy growing region has a greater influence on the carbon and nitrogen isotope values than the heroin manufacturing processes employed. When utilized in conjunction with existing signature methodologies, carbon and nitrogen isotope ratio data can enhance the ability to geo-source heroin.

Blood lead concentration among oral/inhaled opium users: systematic review and meta-analysis.

Lead is a poisonous heavy metal with various known side effects. The effect of opium on raising blood lead concentration (BLC) has been investigated with no general agreement. In Iran, the number of lead poisoning cases has raised among the opium-addicted population. This systematic review and meta-analysis aim to combine the results of previous studies with the Iranian population to investigate the effect of opium on BLC. In this systematic review, PubMed/Medline, Web of Sciences, Embase, and Scopus were searched for studies using the Iranian population to compare the BLC of opium-addicted cases and non-addicted controls till January 2020. A random-effects model was used to pool the results. I-square test was used to assess the heterogeneity of the studies. The effect sizes were standardized mean differences (proxied by Hedges' g) followed by a 95% confidence interval. Of 417 initial articles, 13 studies met the inclusion criteria to be considered in the meta-analysis. The sample size of eligible studies ranged from 40 to 131 (mean 81.83, SD 27.6). All studies were focused on adults with mean age ranged from 33.5 to 65.15 years old (overall mean 49.0, SD 7.66). There were 13 studies included with 18 Hedges' g effect sizes. Using a random effect model, the pooled effect size was gw = 2.48 (95% CI: 1.58-3.39) and statistically significant in favor of opium-addicted participants. Moreover, heterogeneity was 96.6% (I2=96.6, Q(17) = 504.95, p < 0.001). For studies with large Hedges' g effect sizes (> 4) identified as outliers and removed from meta-analysis. The pooled Hedges' g effect size reduced to 1.39 (95% CI: 0.94-1.85), still highly significant in favor of higher levels of lead in the opium-addicted group. The funnel plot appeared symmetrical confirmed by Egger's test (t = 1.87, p = 0.088), indicating no publication bias present.

A Rapid Mercury Droplet Electrode Polarography Method for Determination of Blood Lead Level in Lead Poisoned People.

BACKGROUND: Lead is a hazardous heavy metal, which causes many problems in the human body. Unfortunately, recent reports showed that smugglers and opium sellers add lead to drugs during the production procedure in order to increase its weight and cost. PURPOSE: The aim of this study was development of a rapid and accurate method for measurement of blood lead levels (BLL) in the oral and inhaled opiate abuser people. METHODS: BLL in samples obtained from the oral and inhaled opium addicted patients referring to Sina Hospital in Tabriz, Iran, during 2017 was compared with healthy control group (N=15). The wet digestion method was used to prepare whole blood and Mercury Droplet Electrode Polarography (MDEP) method was utilized for measurement of the lead content of digested samples. RESULTS: Results showed that there were significant differences between the BLL of samples obtained from oral (17.12±74.61 µg/dL, p<0.0003) and inhaled (19.33±2.257 µg/dL, p<0.0001) opium addicted groups in comparison with healthy control group (4.669±0.3367 µg/dL). CONCLUSION: Based on the results of this study it was observed that BLL in opium addicted people needs to be measured as soon as possible. Furthermore, screening of blood lead concentrations in opium-addicted people with a rapid and accurate MDEP method is very necessary and important.

Encephalopathy following ingestion of Lead-contaminated opium; magnetic resonance imaging findings.

BACKGROUND: Encephalopathy is an uncommon but serious presentation of lead toxicity. OBJECTIVE: We aimed to determine and follow-up the brain magnetic resonance imaging (MRI) abnormalities in the patients with lead encephalopathy due to ingestion of lead contaminated opium. METHODS: In a cross-sectional study during lead-contaminated opium outbreak, all lead-poisoned patients with any signs/symptoms of encephalopathy were included. RESULTS: Of 19 patients with lead encephalopathy, five died early and other five could not be sent to MRI during their hospitalization period. Mean age was 51 ± 11 years and males were dominant (89%). Median [IQR] blood lead level (BLL) was 101 [81, 108] µg/dL (range; 50 to 200 µg/dL). There was no correlation between MRI findings and signs/symptoms. MRI was normal in six and abnormal in three. Bilateral symmetric involvement of parieto-occipital lobes was observed. Gray matter, gray-white matter junction, and subcortical white matter were also affected. Follow-up MRI was performed in two with abnormal MRI which showed complete and near complete resolution of the abnormalities after cessation of opium use and treatment. CONCLUSION: There was no correlation between MRI findings and BLL. Complete recovery of brain MRI lesions was detected after cessation of opium use.

Lead poisoning due to ingestion of lead-contaminated opium: A diagnostic study on patients' imaging findings.

OBJECTIVES: Our study attempts to determine if for patients following ingestion of lead-contaminated opium, radiographs [plain X-ray (KUB)] or unenhanced computed tomography (CT scan) of the abdomen may be predictive of lead poisoning. METHODS: Our study is concerned with patients of >21 years with elevated lead concentrations, who had undergone KUB or CT. Patients with other toxicities who had undergone similar imaging profiles but who had low blood lead level (BLL) were enrolled as controls. RESULTS: We evaluated a total of 79 cases and 79 controls with median [IQR] BLLs of 126 [97.4, 160] µg/dL and 8.7 [5.5, 15] µg/dL. All cases and eleven controls (13.9%) were addicted to oral opium, and of these cases, anemia (94.9%) and abdominal pain (92.4%) were the two most common clinical manifestations. Two radiologists reviewed the X-ray and non-contrast CTs. Fifty (63.3%) and 53 (67.1%) cases and controls underwent CT scanning with 34 (68%) vs. 6 (11.3%) positive CTs (P < 0.001) while 43 (54.4%) and 39 (43.3%) underwent X-rays with 21 (48.8%) vs. 4 (11.8%) positive X-rays, respectively (P < 0.001). Positive CT is associated with BLL between 10 and 45 µg/dL with a specificity of 96.9%, 88.7% and positive predictive value of 97.5% and 85% respectively. CONCLUSIONS: In suspected cases of lead exposure due to ingested opium, and if BLL is not readily available, a positive imaging result may guide radiologists and physicians to consider lead poisoning.

UHPLC-MS/MS quantitation of porphyroxine in opium and application of porphyroxine-acetylated products as signature markers for heroin.

Porphyroxine, a trace alkaloid in opium, was identified in the early 1800s and isolated/characterized in the 1960s. Recently, two significant porphyroxine-related byproducts found in the acidic and neutral extracts of illicit heroin were characterized by this laboratory as the N-acetyl-O14 -desmethyl-epi-porphyroxine (B) and N,O8 -diacetyl-O14 -desmethyl-epi-porphyroxine (C). The prevalence of the B and C compounds has been consistent in the following order of abundance for the thousands of authentic heroin samples analyzed: Southwest Asia (SWA) > South America (SA) > Southeast Asia (SEA) > Mexico (MEX). In this research, a rapid and efficient ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed to determine the content of porphyroxine and five primary alkaloids (morphine, codeine, thebaine, noscapine, and papaverine) in opium after extraction with methanol/water (50/50). The method was validated in terms of linearity, accuracy, recovery, and precision for porphyroxine. The limit of quantitation (LOQ) for porphyroxine was 2.5 ng/mL. The developed method was successfully applied to a total of 114 authentic opium samples from the major poppy-growing regions. The amount of porphyroxine was determined at the level of part per thousand (‰) and the relative concentrations to morphine were in the range of 1x10-4 and 1x10-2 with an order of SWA > SEA, SA > MEX for its average abundance, which is consistent with the order of the average abundance of its acetylated products (B, C) in illicit heroin. This study reveals the significance of porphyroxine and its acylated compounds in classifying heroin and opium samples to major geographical regions of production.

DARK Classics in Chemical Neuroscience: Opium, a Historical Perspective.

Opium is the latex from the opium poppy Papaver somniferum L., which humankind has utilized since ancient Mesopotamia all the way to modern times. Opium used to be surrounded in divine mystery or magic-like abilities and was given to cure a wide variety of diseases until its analgesic, antitussive, and antidiarrheal properties were understood, the resulting alkaloids were isolated, and their structure and properties unmasked. Opium went from being sold in any store front in the form of pills or tinctures with no prescription necessary for purchase or smoked in an opium den down the street, to then bringing about consumer advocacy and the right to know what is in a medication. Legislation was created to limit the prescribing and selling of medications to doctors and pharmacists as well as outlawing opium dens and smoking opium. This review focuses primarily on the uses of opium throughout history, the isolation of the principle alkaloids, and their structure elucidation.

Oxidative stress in opium users after using lead-adulterated opium: The role of genetic polymorphism.

Use of lead-adulterated opium has become one of the major sources of lead poisoning in Iran. This study was designed to assess clinical effects and oxidative stress and its association with GSTM1, GSTT1, NQO1, and ALAD genes polymorphisms and blood lead level (BLL) in lead-adulterated opium users. The oxidative stress status in 192 opium users with lead poisoning symptoms measured and compared with 102 healthy individuals. Gluthatione S-transferase (GST)-M1 and -T1 genes deletion, NQO1 rs1800566, and δ-aminolevulinic acid dehydratase (ALAD) rs1800435 polymorphisms were determined using PCR and PCR-RFLP. The relation between the polymorphisms, BLL, and oxidative stress parameters were analysed using multivariate linear regressions. The common symptoms of lead toxicity were gastrointestinal and neurologic complications. Oxidative stress was significantly higher in opium addicts and lipid peroxidation significantly correlated with BLL. There was significant association between ALAD rs1800435 and BLL, and the BLL was significantly lower in the patients with ALAD 1-2 genotype. Use of lead-adulterated opium causes high frequency of lead toxicity symptoms, hematological and biochemical abnormalities, and oxidative stress which are associated with BLL. Route of opioid use and the polymorphism of rs1800435 in ALAD gene are the major determinants of BLL in lead-adulterated opium users.

Occurrence of bacterial and toxic metals contamination in illegal opioid-like drugs in Iran: a significant health challenge in drug abusers.

BACKGROUND: The toxic metals and/or bacterial contaminants in illicit drugs are the main health problems in drug users worldwide. Hence, the potential risks of these contaminants were evaluated in some of the illicit drugs during 2015 and 2016. METHODS: The metals analysis were performed using graphite furnace atomic absorption spectrophotometry. In addition, all microbiological analysis stages, including handling procedures, dilution, and culture media, were conducted in accordance with the US Pharmacopeia (USP) which are harmonized with the European Pharmacopoeia (EP). RESULTS: In the present study, the highest lead (Pb; 138.10 ± 75.01 µg/g) and chromium (Cr; 447.38 ± 20.27 µg/g) levels were detected in opium samples. In addition, the highest prevalence of microbial contamination was observed in opium samples, and the lowest was recorded in heroin samples. Clostridium tetani, with about 50% of contaminant, was the most common bacteria in the analyzed samples. CONCLUSIONS: Our results indicate that Pb exposure as well as bacterial contamination could be the major threats for drug users. Graphical Abstract ᅟ.

Gas chromatographic-mass spectrometric characterization of thebaol, an opium constituent, and its structural analogs.

A GC-MS method is described for the characterization of thebaol, a component of opium poppy. The method includes preliminary sample derivatization to TMS, TBDMS, TFA, PFP and HFB substituted products. Fragmentation of resulting derivatives is unique under electron ionization, and proceeds via consecutive loss of two radicals that violate the "even-electron rule". Peaks of [M-2CH3]+. and [M-C4H9-CH3]+. ions show maximum intensities in the spectra of trimethyl- and tert-butyldimethylsilyl-thebaols. Elimination of perfluoroalkyl and methyl radicals from M+. is characteristic for TFA, PFP and HFB thebaols. The same fragmentation peculiarity is characteristic for derivatives prepared from related natural compounds containing vicinal 2-methoxyphenol moieties. The unique fragmentation of trialkylsilyl and perfluoroacyl derivatives of thebaol can be successfully used for thebaol determination within complex mixtures. This is part 4 from the series "Analytical derivatives in mass spectrometry", parts 1, 2 and 3 see [1-3].

Membrane integrated process for advanced treatment of high strength Opium Alkaloid wastewaters.

In this study, an integrated aerobic membrane bioreactor (MBR)-nanofiltration (NF) system has been applied for advanced treatment of Opium processing wastewaters to comply with strict discharge limits. Aerobic MBR treatment was successfully applied to high strength industrial wastewater. In aerobic MBR treatment, a non-fouling unique slot aeration system was designed using computational fluid dynamics techniques. The MBR was used to separate treated effluent from dispersed and non-settleable biomass. Respirometric modeling using MBR sludge indicated that the biomass exhibited similar kinetic parameters to that of municipal activated sludge systems. Aerobic MBR/NF treatment reduced chemical oxygen demand (COD) from 32,000 down to 2,500 and 130 mg/L, respectively. The MBR system provided complete removal of total inorganic nitrogen; however, nearly 50 mgN/L organic nitrogen remained in the permeate. Post NF treatment after MBR permeate reduced nitrogen below 20 mgN/L, providing nearly total color removal. In addition, a 90% removal in the conductivity parameter was reached with an integrated MBR/NF system. Finally, post NF application to MBR permeate was found not to be practical at higher pH due to low flux (3-4 L/m2/hour) with low recovery rates (30-40%). As the permeate pH lowered to 5.5, 75% of NF recovery was achieved at a flux of 15 L/m2/hour.

Clinical Aspects of Opium Adulterated with Lead in Iran: A Review.

Adulteration of drugs with poisonous substances during production or consumption has caused numerous health problems. Among contaminants that have the potential of producing poisonous effects are the heavy metals lead, arsenic and thallium that make up an important group of toxic substances. The emergence of these new health problems related to opioid abuse has precipitated this MiniReview on the status of the most hazardous and common opioid adulterants. In fact, adulterated opium is a major public health problem and can threaten the health of users. In this study, we searched for information on opium, opiates, lead poisoning, toxicity, intoxication, Iran and heavy metals in the TUMS Digital Library, PubMed, Scopus, EMBASE and Google Scholar bibliographical databases. This MiniReview primarily included articles on lead poisoning, signs and symptoms, and management in opioid-dependent individuals. Exclusion criteria were articles dealing with animal studies, specific paediatric studies, adulterants other than heavy metals and substances other than opioids. Adulterated opium is one of the new sources of exposure to lead and has precipitated an increase in lead-poisoned cases owing to the widespread use of opium. The toxicology of lead and general guidelines on diagnosis and treatment of lead poisoning is briefly reviewed. The symptoms of lead toxicity mimic several diseases often leading to unnecessary diagnostic methods, misdiagnoses and even surgery. Finally, owing to the fact that lead toxicity shows non-specific signs and symptoms, screening for this disease, by taking blood samples and assessing blood lead levels in high-risk people, should be given an utmost priority. It is recommended that screening tests are adopted and applied for any drug-abusing patient with non-specific subacute signs and symptoms like abdominal pain, constipation and anaemia.

Response surface methodology based on central composite design accompanied by multivariate curve resolution to model gradient hydrophilic interaction liquid chromatography: Prediction of separation for five major opium alkaloids.

Hydrophilic interaction liquid chromatography on bare silica presents some benefits for analysis and purification of ionizable basic alkaloids. This mode was used to separate five major opium alkaloids: morphine, codeine, thebaine, papaverine, and noscapine. Central composite design based on response surface methodology was applied for experimental design, modeling, and optimization in a single-step gradient method. The main effects and their interactions (initial percentage of modifier, changing range of modifier in run time, pH of buffer, and its concentration) were investigated in 30 experiments. Multivariate curve resolution-alternating least squares, by resolving overlapped curves, helped in the accurate calculation of baseline resolution factors to be modeled and optimized more accurately. Then three crucial resolution factors besides elution time were modeled in quadratic and cubic equations and optimized. In addition to the four factors, five extra logarithmic, and nonlogarithmic factors extracted from the four factors to give nine factors overall were inspected on mechanism of retention. It was shown that a linear combination consist of four independence variables successfully describes morphinans retentivity in a single-step gradient method.

Evaluation of hydrophilic interaction liquid chromatography stationary phases for analysis of opium alkaloids.

The separation of a mixture containing five major opium alkaloids, namely morphine, codeine, thebaine, noscapine and papaverine has been investigated in hydrophilic interaction liquid chromatography (HILIC) mode using five different stationary phases: bare silica, zwitterion, aminopropyl, diol and cyanopropyl. In order to propose the appropriate column for separation and purification, retention behaviors of the five natural opioids have been studied on mentioned HILIC stationary phases. The mechanism of separation in diverse HILIC media, based on the formation of water-rich layer on surface of the HILIC stationary phases and the physicochemical properties of opium alkaloids, such as pKa (acidic pK) and the octanol-water distribution coefficient (log Do/w) are discussed. Chromatographic responses including modified limit of detection LODm, signal to noise ratio (S/N)m, and defined modified RSm have considered for suggestion of the suitable column for quantitative/qualitative and preparative purposes. According to the obtained results, diol stationary phase is best suited for analytical chromatography, whereas bare silica and zwitterionic stationary phases are appropriate for preparative applications.