Morphine Content Research Articles

Effect of filtration on morphine and particle content of injections prepared from slow-release oral morphine tablets

BackgroundInjections of mixtures prepared from crushed tablets contain insoluble particles which can cause embolisms and other complications. Although many particles can be removed by filtration, many injecting drug users do not filter due to availability, cost or performance of filters, and also due to concerns that some of the dose will be lost.MethodsInjection solutions were prepared from slow-release morphine tablets (MS Contin®) replicating methods used by injecting drug users. Contaminating particles were counted by microscopy and morphine content analysed by liquid chromatography before and after filtration.ResultsUnfiltered tablet extracts contained tens of millions of particles with a range in sizes from < 5 μm to > 400 μm. Cigarette filters removed most of the larger particles (> 50 μm) but the smaller particles remained. Commercial syringe filters (0.45 and 0.22 μm) produced a dramatic reduction in particles but tended to block unless used after a cigarette filter. Morphine was retained by all filters but could be recovered by following the filtration with one or two 1 ml washes. The combined use of a cigarette filter then 0.22 μm filter, with rinses, enabled recovery of 90% of the extracted morphine in a solution which was essentially free of tablet-derived particles.ConclusionsApart from overdose and addiction itself, the harmful consequences of injecting morphine tablets come from the insoluble particles from the tablets and microbial contamination. These harmful components can be substantially reduced by passing the injection through a sterilizing (0.22 μm) filter. To prevent the filter from blocking, a preliminary coarse filter (such as a cigarette filter) should be used first. The filters retain some of the dose, but this can be recovered by following filtration with one or two rinses with 1 ml water. Although filtration can reduce the non-pharmacological harmful consequences of injecting tablets, this remains an unsafe practice due to skin and environmental contamination by particles and microorganisms, and the risks of blood-borne infections from sharing injecting equipment.

Effectiveness of Chemical Protection against Weeds Applied to Poppy (Papaver Somniferum L.)

Effectiveness of Chemical Protection against Weeds Applied to Poppy (Papaver Somniferum L.) The aim of the presented studies was to determine the effect of chemical weed control on the development and yield of native poppy cultivars. The results of presented experiment showed that the native poppy cultivars are more susceptible to herbicides than ‘Opal’ and ‘Lazur’ cultivars. The yield of ‘Michałko’ cultivar in all treatments of chemical protection was very low. It was proved that the suggestion of a necessary protection of ‘Mieszko’ cultivar against weeds with lower doses of herbicides than the doses applied in the cultures of cultivars with a high content of morphine is justified. ‘Mieszko’ cultivar gave the highest yield on plots protected after sowing with Lentipur Flo™ 500 SC (a.s. chlorotoluron) in the dose of 1.2 l/ha and in the growth stage of 4 leaves, when the treatment was carried out with Callisto™ 100 SC (a.s. mesotrione) in the dose of 0.4 l/ha. Positive results of weed control after the application of these herbicides indicate the possibility to initiate studies aiming at authorization to use these herbicides in growing of the native cultivars of poppy (minor crop).

The latex capacity of opium poppy capsules is fixed early in capsule development and is not a major determinant in morphine yield

AbstractThis study found that the latex capacity (mg latex mg−1 dry weight capsule) of opium poppy capsules is fixed early in capsule development. Latex capacity, which represents the proportion of the capsule wall allocated to laticifers (specialised cells for latex storage), had peaked in the capsule at 1 week after flowering. In contrast, the morphine content of capsules continued to increase with capsule development until commercial harvest. Morphine content was correlated with capsule mass and total latex mass, but there was no correlation between latex capacity and morphine yield. The most important morphological characteristic in terms of morphine end yield (commercial harvest stage) was capsule mass. The findings of this study demonstrate that although latex yield per plant is a highly heritable morphological characteristic, it may have limited potential for use in a breeding strategy aimed at increasing the morphine yield from capsules.

Morphine content variation in Papaver somniferum L. as affected by the presence of some isoquinoline alkaloids

The variation in morphine content has been investigated in some different varieties of Papaver somniferum, attention being paid to the presence of phtalide- and benzylisoquinoline alkaloids. Generally a higher morphine content was found in varieties where phtalideisoquinoline alkaloids were absent. The presence of benzylisoquinoline alkaloids exerted no influence on the morphine content. In the investigated varieties, of which the majority are used for morphine production, 75 per cent contained phtalideisoquinoline alkaloids. Thus, by excluding these alkaloids, further improvements of the morphine content are possible. Crosses between plants with and without noscapine resulted in a progeny lacking this alkaloid. On papaverine being investigated in a similar manner, the progeny was found to give an intermediary content.

Breeding oil poppy (Papaver somniferum) for low content of morphine.

A method has been developed for breeding oil poppy for low content of morphine. The method allows determination of the morphine content in 60 plants a day. Morphine content in opium has been investigated in plants of the Swedish oil poppy variety Indra. Mean value of morphine in opium was 21% in this population. However, plants have been found with morphine content in opium of 1–2%.

Some varieties of Papaver somniferum L. with changed morphinane alkaloid content.

Plants with a genetically determined low morphine content have been studied. During two years one spontaneous mutant has produced a morphine content in opium of 2 per cent and 0.03 per cent in dry, ripe capsules. Other alkaloids are only found in trace amounts. At least 9 per cent cross pollination occurred in Papaver somniferum as a two year average. Another spontaneous mutant has been isolated with a low production of morphine and a high thebaine content. The fresh latex of this mutant shows a reddish colour.

Selection for high thebaine/low morphine content in Papaver somniferum L.

High contents of thebaine in the ripe capsules were observed in the L4 and I5 generations from a spontaneous mutant, similar to the observations in earlier generations. Outcrossings of plants with normal morphine contents still take place. Some correlation was found for ‘high thebaine content in mother capsule/high frequency of plants with thebaine as major alkaloid in progeny’ but no correlation was obtained for thebaine content and capsule size. Thebaine in these plants accumulates in a way similar to that of morphine in normal plants. Varying light intensities had no influence on the the-baine/morphine relationship in the plant. A retarded development in the pre-flowering period was observed in breeding lines with high frequencies of thebaine plants.

Alkaloid content in the F1 and F2 generations obtained from crosses between different chemoprovarieties in Papaver somniferum L.

The alkaloid pattern was investigated in the F, and F, generations obtained from crosses between different chemoprovarieties of Papaver somniferum L. The results indicate a monogenic recessive inheritance for the low alkaloid content obtained in a mutant. The block regulating this low content is probably situated in the protoalkaloidal biosynthetic pathways. Extremely low contents of morphine were obtained in the F3 generation from an interspecific hybrid between the low alkaloid mutant of P. somniferum and a P. setigerum variety. In a cross with a morphine-rich variety of P. somniferum and Sv. Indra, high contents of this alkaloid (up to 1.27 %) were achieved in the F2 generation.

Science in Drug Control: The Alkaloid Content of Afghan Opium

Opium samples from Afghanistan were analyzed by HPLC for their content of morphine and three further alkaloids (codeine, thebaine, and papaverine). To our knowledge, this is the largest set of authentic opium samples analyzed in one study until now. The purpose was to assess possible correlations between samples and selected external factors, such as region of origin within Afghanistan, year of harvest, or intra-batch variation. In the investigated samples, a trend towards higher morphine concentrations in opium from the North-Eastern parts of Afghanistan was observed in the period from 2003 to 2005. More than 75% of the samples contained above 10% of morphine, the overall average was 14.4%.

Determining Plasma Morphine Levels Using Gc-Ms After Solid Phase Extraction to Monitor Drug Levels in the Postoperative Period

OBJECTIVETo implement a selective and sensitive analytical method to quantify morphine in small volumes of plasma by gas-liquid chromatography-mass spectrometry (GC-MS), aimed at post-operatively monitoring the drug.METHODA gas-liquid chromatographic method with mass detection has been developed to determine morphine concentration in plasma after solid phase extraction. Morphine-d3 was used as an internal standard. Only 0.5 mL of plasma is required for the drug solid-phase extraction in the Bond Elut-Certify®, followed by the quantification of morphine derivative by GC-MS using a linear temperature program, a capillary fused silica column, and helium as the carrier and make-up gas. The method was applied to determine morphine content in plasma samples of four patients during the postoperative period of cardiac surgery. Patient-controlled analgesia with morphine was performed by a venous catheter, and a series of venous blood samples were collected. After the oro-tracheal extubation, morphine plasma levels were monitored for up to 36 hours.RESULTSThe run time was 16 minutes because morphine and the internal standard were eluted after 8.8 minutes. The GC-MS method had 0.5–1000 ng/mL linearity range (r2=0.9995), 0.1 ng/mL limit of detection, intraday and interday precision equivalent to 1.9% and 6.8%, and 0.1% and 0.8% systematic error (intraday and interday, respectively). The analytical method showed optimal absolute (98%) and relative (100.7%) recoveries. Morphine dose requirements and plasma levels are discussed.CONCLUSIONThe analytical gas-liquid chromatography-mass spectrometry method is selective and adequate for morphine measurements in plasma for applications in clinical studies.

Genetics of Morphine and Seed-Related Traits in Opium Poppy

ABSTRACT Combining ability in opium poppy, Papaver somniferum L. was analyzed using a line × tester (L × T) design. A total of 15 diverse, inbred lines of opium poppy and three testers were selected on the basis of seed and straw yields and hybridized in L × T fashion to produce an F1 generation (4 & 5). The mean sum of squares due to lines, testers and lines × testers were significant for all the characteristics studied, suggesting the experimental material possessed considerable genetic variability. Estimates of general and specific combining ability variances for all of the characteristics were also significant, indicating both additive and nonadditive gene action in inheritance of these characteristics. The larger magnitude of specific combining ability (SCA) mean sum of squares suggested that the nonadditive gene action was predominant for capsules per plant, straw and seed yields per plant, and morphine content in straw. Conversely, the seed oil and seed protein content were governed by additive gene action. None of the inbred lines were observed to be good general combiners for all the studied traits. Among females, the economic parent Shubhra showed good general combining ability (GCA) for all traits. Interestingly, Shubhra was a parent in any of the crosses that showed high SCA, except for the characteristics of morphine content and seed oil content. Considerable amounts of economic heterosis were recorded for all of the traits, except for seed protein content and the morphine content of straw.

Gibberellic acid and triacontanol can ameliorate the opium yield and morphine production in opium poppy (Papaver somniferum L.)

A pot experiment was conducted during 2004–2005 on opium poppy (Papaver somniferum L.) and the influence of 10−6 M gibberellic acid (GA3) and 10−6 M triacontanol (TRIA) either alone or together, on the growth, yield, quality and morphine content. Among the treatments, foliar spray of GA3+TRIA significantly promoted the values of most of the physiological and biochemical parameters including the opium yield. The morphine content was also enhanced. The effects of GA3 and TRIA were similar when given individually, in general, while only TRIA induced branching in the plants. Another important finding of this experiment was that GA3+TRIA favoured the branching as well as the development of capsules at the same levels of height in all the branches. This influence will bring about a practical benefit by facilitating easier manual or mechanical lancing of the capsules, the collection of the latex and the harvesting of the opium poppies. Thus, we conclude that 10−6 M each of GA3 and TRIA given together may be used for maximizing the yield of opium and morphine.

Assessment of genotype × environment interactions for yield and morphine content in opium poppy ( Papaver somniferum L.)

The analysis of the genotype × environmental interaction, which indicates the stability of genotypes, has always been part of plant breeding programmes before the release of varieties for commercial cultivation. In the present investigation the stability of seed yield, opium yield and morphine content in 11 advanced breeding lines of opium poppy was evaluated over five years. Combined ANOVA showed that both the main effects and interactions were significant, indicating the presence of genotype × environment interactions. The average seed yield and opium yield ranged from 10.41–16.92 q/ha and 45.21–59.85 kg/ha, respectively. Stability analysis involving the parameters bi, S 2 di, λi, s 2 , δ 2 , Wi, r 2 and CV identified four genotypes (BR330, BR333, BR229 and BR243) as ideal and stable for the traits studied. The level of association among different parameters obtained using Spearman’s rank correlation showed that Eberhart and Russell’s deviation from regression (S 2 di) was significantly and positively associated with s 2 , λi, δ 2 i and CV and negatively with r 2 . The parameters λi, s 2 , δ 2 i and CV also showed positive mutual association.

Guidelines for reduction of morphine in poppy seed intended for food purposes

Due to major concerns about morphine present in poppy seed intended for use in food, the establishment of maximum limits is currently discussed and options to reduce its content are searched. With the aim to propose guidelines for consumers and bakeries about minimization of the morphine content in poppy seed, the kinetics of morphine degradation during grinding as well as the possibility to reduce the morphine content by washing steps are evaluated in this study. A significant reduction of morphine by grinding using standard poppy seed mills was ascertained. The degradation occurs directly at grinding and does not continue during subsequent storage. Washing the poppy seed with hot water (60 °C) is an effective way to reduce the morphine content by approx. 70%. The optimal treatment of poppy seed consists of washing, drying, and grinding. This process significantly reduces the morphine content and simultaneously improves the organoleptical quality of the product.

Optimized LC/MS/MS Analysis of Morphine and Codeine in Poppy Seed and Evaluation of Their Fate during Food Processing as a Basis for Risk Analysis

The opiate alkaloids present in poppy seed intended for use in food recently have raised major concerns. An efficient method for routine analysis of morphine and codeine using liquid chromatography in combination with tandem mass spectrometry on a triple quadrupole instrument (LC/MS/MS) was therefore developed. The optimal sample preparation was found to be cold extraction of 10 g of unground poppy seed with 30 mL of methanol containing 0.1% acetic acid for 60 min shaken at 250 rpm. The fate of morphine during food processing was also studied. All experiments led to a significant reduction of morphine and codeine. For poppy cake only 16-50% of the morphine was recovered, and in poppy buns at the highest temperature (220 degrees C) only 3% of the original morphine content was found. Ground poppy seed showed significantly lower recoveries than untreated seed. Morphine elimination during food processing has to be taken into account in the current discussion about its maximum limits in poppy seed.

Genetic Variability and Interrelationship Among Opium and its Alkaloids in Opium Poppy (Papaver Somniferum L.)

The plant species Papaver somniferum L. (opium poppy) is grown commercially in several countries under secure area to produce opium and its major alkaloids i.e. morphine, codeine, thebaine, narcotine and papaverine for pharmaceutical industries. In recent years the global demand for these alkaloids and its derivatives are growing. Seeing the global demand there is urgent need to develop high opium yielding varieties integrated with high specific alkaloids. However, a breeding programme focused on developing improved varieties requires knowledge about the genetic variability for the concern traits. Therefore the present investigation was undertaken to examine phenotypic and genotypic variability, broad sense heritability, genetic advance under selection and interrelationship of traits. A total of 122 accessions were found to be highly variables for all the traits studied. Broad sense heritability ranged from 74.18% (for opium yield/plant) to 99.00% (for papaverine content). Expected genetic advance was varied between 33.91% (for morphine content) and 257.46% (for papaverine content). Genetic correlation analysis revealed that opium yield is negatively correlated with morphine and papaverine content. Among alkaloids codeine, thebaine, narcotine and papaverine showed positive correlation among themselves. The correlations among alklaloids were justified based on the biosynthetic pathway of opium alkaloids.

Alkaloid Spectrum of Different Germplasm Lines in Opium Poppy (Papaver somniferum L.)

The opium latex of 1470 individual plant samples of 98 germplasm lines were screened for five major economic alkaloids. The alkaloids profile showed that morphine content ranged from 9.20–20.86% with an average of 15.00 ± 0.267. Codeine ranged from 1.69–6.48% with arithmetic mean of 3.35 ± 0.091, thebaine from 0.52–7.95% with an average of 2.27 ± 0.116. Narcotine ranged from 8.79–17.97% with an average 8.79 ± 0.266 and papaverine content ranged from 0.00–6.07% with an average 1.18 ± 0.167 in over all the germplasm lines. The content of different alkaloids categorized into class interval which exhibited that maximum number of plants and accessions for morphine content fall in group of 10–15% followed by 15–20%, for codeine content in group of 2–4% followed by 4–6%, for thebaine content in 1–2% followed by 2–4%, for narcotine in 5–10% followed by 10–15% and for papaverine content 0–2%. 24 germplasm lines had morphine content above 16.0%. Similarly, 37 germplasm lines for codeine and 13 for thebaine showed consistently high content, i.e., above 3%. 33 germplasm lines had narcotine content above 9% and 20 lines exhibited papaverine content above 2%. Line BR 316 was found unique having thebaine content 6.27–9.33%. The probable reasons of increase or decrease of different alkaloids based on their biosynthetic pathway has been discussed in detail.

Urinary Excretion of Morphine and Codeine Following the Administration of Single and Multiple Doses of Opium Preparations Prescribed in Taiwan as "Brown Mixture"

Parallel to the "poppy-seed defense" strategy commonly reported in the United States, donors of urine samples tested positive for opiates in Taiwan often claimed the consumption of Brown Mixture (BM) as the source of the observed morphine and codeine. Because BM contains opium powder (10.0-10.5% morphine), opium tincture (0.9-1.1% morphine), or camphorated opium tincture (0.045-0.055% morphine) and is a popular remedy, and heroin use is considered a serious criminal act, the claim of BM use has to be adequately addressed. In this study, BM from seven different manufacturers (5 tablets and 2 solutions) and urine samples from alleged heroin users and volunteers with various ingestion patterns and were analyzed for their morphine and codeine contents. The analytical procedure included hydrolysis, trimethylsilylation, and gas chromatography-mass spectrometry analysis. The contents of morphine and codeine in the tablets were found to be very consistent, but with significant differences in the two BM solutions. Morphine concentrations found in urine specimens collected from volunteers ingesting BM tablets (or solutions) were always < 4000 ng/mL. The following morphine-to-codeine ([M]/[C]) ratios were observed for urine specimens with morphine concentration > or = 300 ng/mL: (A) < 3.0 for volunteers ingesting BM solution and (B) > 3.0 (mostly > 5.0) for volunteers ingesting BM tablets and alleged heroin users. It appeared that (A) BM ingestion (tablet or solution) was unlikely to result in a morphine concentration > 4000 ng/mL; and (B) [M]/[C] ratio might not be an effective parameter to differentiate heroin use from BM tablet ingestion.

Paradoxical Results in Urine Drug Testing for 6-Acetylmorphine and Total Opiates: Implications for Best Analytical Strategy

A major task in urine drug testing is to detect heroin intake. The most common way of doing this is by using morphine as the analytical target in opiate immunoassay screening. However, this strategy sometimes leads to false-positive results because morphine is not a metabolite unique to heroin. The objective of this study was to evaluate the usefulness of the unique heroin metabolite 6-acetylmorphine (6-AM) as the primary analytical target in combination with morphine in the screening assay. A total number of 3521 randomly collected urine samples from 707 patients undergoing heroin substitution treatment were investigated for 6-AM and opiates by CEDIA (cloned enzyme donor immunoassay) and for opiates by DRI immunoassays and by gas chromatography-mass spectrometry (free 6-AM, free morphine, total morphine, and total codeine). The rate of positive outcome in the screening for 6-AM was 9.1% (cutoff 10 microg/L), and for opiates, it was 22.6% (cutoff 300 microg/L), which is in accordance with a known shorter detection time for 6-AM following heroin intake. However, by comparing 6-AM and opiate screening results at different cutoff levels, it was observed that 7-8% of the samples and 12.5% of the patients with detectable 6-AM had an unexpected low content of free and total morphine in the urine. This study confirms earlier observations that certain individuals may escape detection in urine drug testing when morphine is being utilized for the detection of heroin intake. The underlying mechanism for this may be a metabolic defect and/or interaction. It is concluded that 6-AM is a valuable target analyte in the screening of drugs of abuse in urine and may be used in combination with opiate screening in clinical testing.

Genetic parameters and correlations of collar rot resistance with important biochemical and yield traits in opium poppy (Papaver somniferum L.)

Collar rot, caused by Rhizoctonia solani Kühn, is one of the most severe fungal diseases of opium poppy. In this study, heritability, genetic advance and correlation for 10 agronomic, 1 physiological, 3 biochemical and 1 chemical traits with disease severity index (DSI) for collar rot were assessed in 35 accessions of opium poppy. Most of the economically important characters, like seed and capsule straw yield per plant, oil and protein content of seeds, peroxidase activity in leaves, morphine content of capsule straw and DSI for collar rot showed high heritability as well as genetic advance. Highly significant negative correlation between DSI and seed yield clearly shows that as the disease progresses in plants, seed yield declines, chiefly due to premature death of infected plants as well as low seed and capsule setting in the survived population of susceptible plants. Similarly, a highly significant negative correlation between peroxidase activity and DSI indicated that marker-assisted selection of disease-resistant plants based on high peroxidase activity would be effective and survived susceptible plants could be removed from the population to stop further spread.