Pharmacological Aspects of Over-the-Counter Opioid Drugs Misuse.

Several over-the-counter (OTC) drugs are known to be misused. Among them are opioids such as codeine, dihydrocodeine, and loperamide. This work elucidates their pharmacology, interactions, safety profiles, and how pharmacology is being manipulated to misuse these common medications, with the aim to expand on the subject outlined by the authors focusing on abuse prevention and prevalence rates. The reviewed literature was identified in several online databases through searches conducted with phrases created by combining the international non-proprietary names of the drugs with terms related to drug misuse. The results show that OTC opioids are misused as an alternative for illicit narcotics, or prescription-only opioids. The potency of codeine and loperamide is strongly dependent on the individual enzymatic activity of CYP2D6 and CYP3A4, as well as P-glycoprotein function. Codeine can also be utilized as a substrate for clandestine syntheses of more potent drugs of abuse, namely desomorphine ("Krokodil"), and morphine. The dangerous methods used to prepare these substances can result in poisoning from toxic chemicals and impurities originating from the synthesis procedure. OTC opioids are generally safe when consumed in accordance with medical guidelines. However, the intake of supratherapeutic amounts of these substances may reveal surprising traits of common medications.

Adult and infant pharmacokinetic profiling of dihydrocodeine using physiologically based pharmacokinetic modeling.

We previously analysed the serum concentrations of dihydrocodeine in a 1-month-old infant with respiratory depression after being prescribed dihydrocodeine phosphate 2.0 mg/day divided t.i.d. for 2 days. The purpose was to develop a full physiologically based pharmacokinetic (PBPK) model that could account for these and other drug monitoring results. Based on experiments in Caco-2 cell monolayers, the effective permeability of dihydrocodeine in human jejunum was established as 1.28 × 10-4 cm/s. The in vitro Vmax /Km values for dihydrocodeine demethylation mediated by recombinant cytochrome P450 2D6 and 3A4 were 0.19 and 0.066 µl/min/pmol, respectively, and for dihydrocodeine 6-O-glucuronidation mediated by recombinant UGT2B4 and 2B7, the Vmax /Km values were 0.14 and 0.22 µl/min/mg protein, respectively. Renal clearance was calculated as 5.37 L/h on the total clearance value multiplied by the fraction recovered in urine. The reported plasma concentration-time profiles of dihydrocodeine after intravenous administration in healthy volunteers were used to adjust the tissue partitioning ratios. The developed model simulated the pharmacokinetic profiles of dihydrocodeine after single and multiple oral administrations reasonably well in the same population. Subsequently, the validated model was used to simulate pharmacokinetic profiles for five pediatric cases, including the 1-month-old Japanese boy and a 14-year-old Japanese girl who took an overdose of dihydrocodeine phosphate (37 mg). The simulated pharmacokinetic profiles for five virtual pediatric subjects matching the age, gender, and P450 2D6 phenotype of each case approximately reflected the observed values. These results suggested that our dihydrocodeine PBPK model reproduced the results of clinical cases reasonably well for subjects.

Subcutaneous Dihydrocodeine Tartrate: Compatibility in a Syringe Pump With Other Drugs Frequently Prescribed for the Management of Symptoms Associated With Brain Tumors.

BACKGROUND: Dihydrocodeine can be more effective in the management of headache due to brain tumor than other opioids. It can be used as a subcutaneous infusion, but at present, there is little available data to support its use in combination with other medicines in a syringe pump. AIM: This project aimed to establish physical stability data for the use of dihydrocodeine with other drugs when combined in a syringe pump. Design: Dihydrocodeine was combined in a syringe pump with either cyclizine, midazolam, or hyoscine butylbromide at different doses chosen to represent routine clinical practice. Each drug combination was repeated twice-with 0.9% sodium chloride and with water for injections. Setting: The project was conducted in an independent hospice after seeking appropriate approvals to use the drugs for this purpose. RESULTS: Dihydrocodeine and midazolam appear compatible at when 0.9% sodium chloride is used as the diluent. Dihydrocodeine and cyclizine appeared compatible when either 0.9% saline or water for injections was used as the diluent. Dihydrocodeine and hyoscine butylbromide appeared compatible with either diluent at 24 hours. CONCLUSIONS: Physical stability data has been described that will support the use of dihydrocodeine and other drugs that are commonly used to manage symptoms due to brain tumors at the end of life. This information will benefit patients and ensure that one syringe pump can be used where possible. Future work could expand on this data and explore the physical stability of three drug combinations in each syringe.

Prolonged Codeine Administration Causes Degeneration of Myelinated Axons and Motor Dysfunction in Wistar Rats.

Purpose: Over-the-counter (OTC) anti-cough medications which contain codeine (an opioid) are extensively available in Nigeria, and hence prone to overuse or abuse. The study aimed to understand the effects of oral codeine administration on the integrity of neurons of the cerebral cortex and cerebellum and its behavioral implications in male Wistar rats. Methods: Thirty adult male Wistar rats of comparable weights were obtained and randomly allocated into 5 groups: A, B, C, D, and E (n = 6). Drugs used for the study were ArchilinTM with codeine and dihydrocodeine 30mg. Group A served as control and was administered 0.5mL/kg of normal saline. Groups B and C were treated with 1mg/kg and 2mg/kg of dihydrocodeine, respectively; Group D and E received 2mL/kg and 4mL/kg of ArchilinTM codeine syrup, respectively. The ArchilinTM codeine syrup and dihydrocodeine solutions were administered to the animals based on their body weight, orally and daily with the aid of oropharyngeal tubes for 21 days. The experimental animals were subjected to neurobehavioral studies using beam walk and open field. At the end of the treatment period, the animals were anesthetized with ketamine-hydrochloride intraperitoneally. The brains were quickly dissected out, rinsed with normal saline, and tissue processed for myelin studies. Results: The beam walking and open field result revealed that prolonged codeine administration interfered with motor function in the experimental animals. Sections of the prefrontal cortex and cerebellum of rats given normal saline showed normal myelin sheaths, whereas animals in the treatment group showed degenerating myelin compared to the control. Conclusion: Prolonged consumption of prescription codeine causes degeneration of the myelin sheaths and this may affect the conduction of electrical impulses in myelinated axons thus resulting in motor function insufficiency.

Highlighting the hidden dangers of a 'weak' opioid: Deaths following use of dihydrocodeine in England (2001-2020).

BACKGROUND: Dihydrocodeine (DHC) is considered a 'weak' opioid, but there is evidence of its increasing misuse in overdose deaths. This research aims to analyse trends in DHC-related deaths in England relevant to source and dose of DHC, and decedent demographics. METHODS: Cases from England reported to the National Programme on Substance Abuse Deaths (NPSAD) where DHC was identified at post-mortem and/or implicated in death between 2001 and 2020 were extracted for analysis. RESULTS: 2071 DHC-related deaths were identified. The greatest number of deaths involved illicitly obtained DHC and a significant increase in these deaths was recorded over time (r = 0.5, p = 0.03). However, there was a concurrent decline in the implication rate of DHC in causing death (r = -0.6, p < 0.01). Fatalities were primarily due to accidental overdose (64.8%) and misuse was highly prevalent in combination with additional central nervous system depressants (95.3%), namely illicit heroin/morphine and diazepam. In contrast, when DHC was obtained over-the-counter (OTC) suicide mortality accounted for almost half of the deaths (42.5%). Differences in polysubstance use were also identified, with less heroin/morphine and benzodiazepine co-detection, but increased OTC codeine co-detection. CONCLUSIONS: DHC misuse in England is increasing. The pharmacological consideration of DHC as a 'weak' opioid may be misinterpreted by users, leading to accidental overdosing. There is an urgent need to understand increasing polypharmacy in overdose deaths. Additionally, suicides involving DHC is a potential cause for concern and a review of OTC opioid-paracetamol preparations is necessary to determine whether the benefits of these medications continue to outweigh the risks of intentional overdose.

The efficacy and safety of DW1601 in patients with acute bronchitis: a multi-center, randomized, double-blind, phase III clinical trial.

BACKGROUND/AIMS: DW1601, an oral fixed dose combination syrup composed of DW16011 and Pelargonium sidoides, was developed to enhance the symptom relief effect in patients with acute bronchitis. We evaluated the efficacy and safety of DW1601 compared to DW16011 or P. sidoides for treatment of acute bronchitis using a randomized, double-blind, placebocontrolled, multi-centre trial design. METHODS: A total of 204 patients with acute bronchitis was randomized 1:1:1 to receive DW1601 (n = 67), DW16011 (n = 70), or P. sidoides (n = 64) for 7 days. The primary outcome was efficacy of DW1601 compared to DW16011 or P. sidoides in reducing the total bronchitis severity score (BSS) at day 4 of treatment. Secondary endpoints were changes in total and symptomspecific BSS, response rate and patient satisfaction rate. Safety analysis was assessed at day 7. RESULTS: At 4 days after medication, decrease of total BSS from baseline was significantly greater in the DW1601 group than in the DW16011 group (-3.51 ± 0.18 vs. -2.65 ± 0.18, p = 0.001) or P. sidoides group (-3.56 ± 0.18 vs. -2.64 ± 0.19, p < 0.001). In addition, the BSS total score at day 7 and the BSS cough and sputum component scores at days 4 and 7 were significantly more improved with DW1601 treatment compared with the DW16011 group or P. sidoides group. Participants treated with DW1601 showed higher rates of response and satisfaction than control groups (response rate, DW1601, 100% vs. DW16011, 85.7% vs. P. sidoides, 85.9%; satisfaction rate, DW1601, 92.6% vs. DW16011, 82.9% vs. P. sidoides, 81.2%). Significant adverse events were not observed in the DW1601 group. CONCLUSION: DW1601 is superior to DW16011 or P. sidoides in improving symptoms of acute bronchitis.

A retrospective analysis of the effects of different analgesics on the pain of patients with traumatic thoracolumbar fractures in the peri-treatment period.

OBJECTIVE: To analyze and compare the effects of peri-treatment analgesics on acute and chronic pain and postoperative functional recovery of patients with thoracolumbar fractures, so as to guide the clinical drug use. METHODS: Seven hundred nineteen patients with thoracolumbar fractures were collected and divided into acetaminophen dihydrocodeine, celecoxib, and etoricoxib groups. The main indicators were the degree of postoperative pain (visual analog scale (VAS)), the incidence of chronic pain and postoperative functional recovery (Oswestry dysfunction index (ODI) and Japanese Orthopedics Association score (JOA)), which were continuously tracked through long-term telephone follow-up. The correlation analysis of ODI-pain score, peri-treatment VAS score, and ODI index was performed, and bivariate regression analysis was conducted to understand the risk factors for chronic pain. RESULTS: Regression analysis showed that severe spinal cord injury and peri-treatment use of acetaminophen dihydrocodeine were both one of the risk factors for postoperative chronic pain. But there were no statistically conspicuous differences in basic characteristics, preoperative injury, and intraoperative conditions. Compared with the other two groups, patients in the acetaminophen dihydrocodeine group had longer peri-therapeutic analgesic use, higher pain-related scores (VAS 1 day preoperatively, VAS 1 month postoperatively, and ODI-pain 1 year postoperatively), higher VAS variation, higher incidence of chronic pain 1 year after surgery, and higher ODI index. And other ODI items and JOA assessments showed no statistically significant differences. In addition, the correlation analysis showed that the peri-treatment pain score was correlated with the severity of postoperative chronic pain. CONCLUSION: Although the peri-treatment analgesic effect of acetaminophen dihydrocodeine is good, it is still necessary to combine analgesics with different mechanisms of action for patients with severe preoperative pain of thoracolumbar fracture, so as to inhibit the incidence of postoperative chronic pain and improve the quality of postoperative rehabilitation.

[Message from the President of the Japanese Society for the Study of Xenobiotics].

The Japanese Society for the Study of Xenobiotics has focused on drug development and clinical pharmacotherapy by applying cutting-edge technology and reviewing drugs. One specific area of focus has been the reverse-translational approach. This approach uses data from the investigation of clinical problems and from the detailed revisiting of preclinical studies to discover new pharmacotherapies and new methods to prevent drug-induced side effects. In 2017, the U.S. Food and Drug Administration restricted the use of prescription codeine cough-and-cold medicines in children. This decision was based on concerns about the effects of the extensive metabolite morphine in cytochrome P450 2D6 ultra-rapid metabolizers. However, there are few reports on the side effects of dihydrocodeine in Japanese children. Our laboratory measured serum concentrations of dihydrocodeine in a 1-month-old infant with respiratory depression who was given dihydrocodeine phosphate in a suspected case of overdosing. Levels of dihydrocodeine and its primary metabolite, dihydromorphine, were high in this infant. However, the molar ratios of glucuronide conjugates of dihydrocodeine and dihydromorphine were lower than those found in a 3-year-old and a 6-year-old child used as references. To support and facilitate reverse-translational research, the elimination of regional differences in the methodologies used for liquid chromatography to measure drug concentrations and for the genotyping of drug-metabolizing enzymes should become the focus in hospitals, laboratories, and doctoral programs.

Time course detection of dihydrocodeine in body hair after a single dose.

BACKGROUND: When head hair is not suitable or not available, body hair, such as leg or beard hair might be the most suitable sample for drug hair analysis. Information about the time course of drugs in hair, from the different anatomical body sites, should still be well documented. AIM: The aim of this study was to determine and compare (a) the detection window of dihydrocodeine in frequently shaved legs and beard, (b) in unshaved hair from head hair, chest hair, leg hair, and/or arm hair, and (c) the distribution concentrations over the scalp, after a single dihydrocodeine intake. METHOD: Before a single intake of 12 mg dihydrocodeine by subject 1 (woman), both legs hair were shaved in the morning. The subject 2 (man) shaved his beard in the morning and 30 min later he had a dose of 10 mg of dihydrocodeine. The samples were washed with water and shampoo, dried and collected as follows: Subject 1: every 3-days shaved leg hair (n = 9) and 1-month-later head hair (n = 1). Subject 2: daily shaved beard hair (n = 15), 2 months later head hair (n = 145), and every 20 days unshaved arm, leg and chest hair (from different areas) (n = 4/area). The samples were analysed for dihydrocodeine using a validated liquid chromatography-tandem mass spectrometry method with a limit of quantification (LOQ) of 15.6 pg/mg for dihydrocodeine. About 20 mg of hair samples were weighted, washed with dichloromethane, centrifuged, dried, and pulverized in the same disposable tubes. Then the samples were incubated with methanol (under sonication at 45 °C) during 4 h. After centrifugation, the supernatant was evaporated and a cation exchange solid phase extraction followed by separation and quantification using ultra performance liquid chromatography-tandem mass spectrometry (ULC-MS/MS) was carried out. Chromatographic separation was achieved using a BEH phenyl column eluted with 0.1% formic acid: methanol (0.1% formic acid). The UPLC-MS/MS method was validated and used in routine for drug hair analysis for already several years. RESULTS AND DISCUSSION: In the present study leg hair was collected every 3 days, as an average of frequent shaved hair in western woman population. Shaved leg hair was very limited and only one hair sample was available per analysis. Beard was collected daily and in a higher amount. Dihydrocodeine was detected in leg hair from the first sample (3 days after the intake). Maximum concentration at 68 pg/mg for the single intake was obtained after 15 days (±2 days), decreasing later to the LOQ from the 21th day. Beard hair was positive from the first day sample, and the maximum concentration was observed at 66 pg/mg, 6 days after the intake, decreasing later to the LOQ from day 13. This may be explained by growth rate and the amount of growing hairs, in anagen phase. In other body hair samples, dihydrocodeine was negative or detected from 1 month after the intake. No significant differences in dihydrocodeine concentrations over the scalp in the different regions were observed (p > 0.05). CONCLUSION: Body hair presents different time course window detection due to the different growth rates. Frequently shaved leg and beard hair may be suitable samples for recent single dihydrocodeine dose detection from the first days up to 2-3 weeks after the intake, respectively, when a LOQ of 15.6 pg/mg is applied.

A Randomized Clinical Trial Comparing the Effects of Antitussive Agents on Respiratory Center Output in Patients With Chronic Cough.

BACKGROUND: Cough is produced by the same neuronal pool implicated in respiratory rhythm generation, and antitussive drugs acting at the central level, such as opioids, may depress ventilation. Levodropropizine is classified as a nonopioid peripherally acting antitussive drug that acts at the level of airway sensory nerves. However, the lack of a central action by levodropropizine remains to be fully established. We set out to compare the effects of levodropropizine and the opioid antitussive agent dihydrocodeine on the respiratory responses to a conventional CO2 rebreathing test in patients with chronic cough of any origin. METHODS: Twenty-four outpatients (aged 39-70 years) with chronic cough were studied. On separate runs, each patient was randomly administered 60 mg levodropropizine, 15 mg dihydrocodeine, or a matching placebo. Subsequently, patients breathed a mixture of 93% oxygen and 7% CO2 for 5 min. Fractional end-tidal CO2 (Fetco2) and inspiratory minute ventilation (V˙i) were continuously monitored. Changes in breathing pattern variables were also assessed. RESULTS: At variance with dihydrocodeine, levodropropizine and placebo did not affect respiratory responses to hypercapnia (P < .01). The ventilatory increases by hypercapnia were mainly accounted for by a rise in the volume components of the breathing pattern. CONCLUSIONS: The results are consistent with a peripheral action by levodropropizine; the assessment of ventilatory responses to CO2 may represent a useful tool to investigate the central respiratory effects of antitussive agents. TRIAL REGISTRY: European Union Clinical Trials Register (EudraCT No.: 2013-004735-68); URL: https://www.clinicaltrialsregister.eu/.

Systematic Reviews Published in the Cochrane Library January-March 2017.

The Cochrane Library of Systematic Reviews is now only published monthly online ( http://www.thecochranelibrary.com ). The methods for searching have changed and are in flux. This report attempted to identify all relevant reviews published in the last 3 months to March 30, 2017. The current version contains 7243 complete reviews and 2544 protocols for reviews in production. In addition, there are citations of 1,036,153 randomized controlled trials (first time passing the million mark) and 15,700 cited papers in the Cochrane Methodology Register. The Health Technology Assessment database contains some 17,000 citations. Six reviews have been identified that have potential relevance for practitioners in pain and palliative medicine. The impact factor of the Cochrane Library stands at 6.1. Readers are encouraged to access the full report for any articles of interest, as only a brief commentary is provided.

Dihydrocodeine: safety concerns.

Dihydrocodeine (DHC) is a semi-synthetic analogue of codeine, which was formed by the hydrogenation of the double tie in the main chain of the codeine molecule - instead of a double bond between carbons 7 and 8 DHC possesses a single bond. DHC is used as an analgesic and antitussive agent and for the management of dyspnea and opioid addiction. Limited data is available on the potency of DHC to other opioids. The analgesic effect of DHC is similar to codeine and approximately twice as potent as tramadol for an oral route. In contrast to codeine and tramadol, DHC analgesia seem to be irrespective of CYP2D6 activity due to parent compound analgesic effects, multiple metabolic pathways and limited role of dihydromorphine in DHC analgesia. As the drug is commonly available appropriate titration and dosing and knowledge of its metabolism and possible adverse effects are important for safe prescription of DHC.

Simultaneous determination of acetaminophen and dihydrocodeine in human plasma by UPLC-MS/MS: Its pharmacokinetic application.

An ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine acetaminophen (AAP) and dihydrocodeine (DHC) in human plasma simultaneously. Plasma samples were prepared using protein precipitation with acetonitrile, the two analytes and the internal standard midazolam were separated on an Acquity UPLC BEH C18 column and mass spectrometric analysis was performed using a QTrap5500 mass spectrometer coupled with an electro-spray ionization (ESI) source in the positive ion mode. The MRM transitions of m/z 151.2→110.0 and m/z 302.3→199.2 were used to quantify for AAP and DHC, respectively. The linearity of this method was found to be within the concentration range of 50-10000ng/mL for AAP, and 1-100ng/mL for DHC in human plasma, respectively. The lower limit of quantification (LLOQ) was 50ng/mL and 1ng/mL for AAP and DHC in human plasma, respectively. The relative standard deviations (RSD) of intra and inter precision were less than 10% for both AAP and DHC. The analysis time of per sample was 1.0min. The developed and validated method was successfully applied to a pharmacokinetic study of AAP (500mg) with DHC (20mg) capsule in Chinese healthy volunteers (N=20).

Hair analysis to demonstrate administration of amitriptyline, temazepam, tramadol and dihydrocodeine to a child in a case of kidnap and false imprisonment.

Amitriptyline, temazepam, tramadol and dihydrocodeine are prescription-only-medications that are rarely prescribed to children. Each of these drugs has a sedative effect on the central nervous system; their combined use could cause an exacerbation of the sedative effects. Amitriptyline (a tricyclic antidepressant) can be prescribed to treat nocturnal enuresis; temazepam (a hypnotic) can be used as a premedicant in inpatient and day-case surgery; tramadol (a synthetic opioid analgesic) is used to treat moderate or severe pain, though it is not recommended for children under the age of 12 years and dihydrocodeine (opioid analgesic), which is available in combination with acetaminophen (Co-dydramol), is not recommended for children under the age of 4 years; in children over 4 years, a reduced dose is necessary. The North West Forensic Science Service Laboratory, Euxton, Lancashire, was asked by a British police force to analyze three separate hair samples, which had been collected from a young child following their discovery as a result of a large scale kidnap and false imprisonment investigation. After decontamination and segmentation (20 x 1-cm section), two of the three hair specimens were analyzed by liquid chromatography coupled with tandem mass spectrometry after alkaline (pH 9.5) extraction using methylene chloride/isopropanol/n-heptane (25:10:65, v/v/v). The entire length of each hair specimen tested positive for amitriptyline and nortriptyline (7-314 pg/mg amitriptyline; 7-318 pg/mg nortriptyline), temazepam (2-29 pg/mg), tramadol (60-2000 pg/mg) and dihydrocodeine (10-90 pg/mg) demonstrating that the child had ingested these drugs on more than one occasion prior to the kidnap. In this case, the child's mother and the mothers' partner were found guilty of kidnap, false imprisonment and perverting the course of justice. There are very few studies citing the concentrations of these drugs in children - especially children's hair samples. This case demonstrates the added value of hair testing and emphasizes the importance of using hair samples to complement conventional analysis.

A randomized, double-blind, double-dummy comparison of short- and long-acting dihydrocodeine in chronic non-malignant pain.

Guidelines for opioid treatment of chronic non-malignant pain recommend long-acting over short-acting opioid formulations. The evidence for this recommendation is weak. This study is a randomized, double-blind, double-dummy, 8-week comparison of long-acting dihydrocodeine tablets (DHC-Continus) with short-acting dihydrocodeine tablets in 60 patients with chronic non-malignant pain who were referred to a multidisciplinary pain clinic. All patients used codeine-paracetamol tablets before the trial, and paracetamol was added in both groups during the trial. The primary outcome was stability in pain intensity, measured as the difference between the highest and least pain intensity reported on an 11-point numerical rating scale in a 7-day diary. The secondary outcomes were differences in quality of life, quality of sleep, depression, and episodes of breakthrough pain between the 2 formulations. Spontaneously reported adverse events were recorded. In all, 38 patients completed the trial, and 22 withdrew before the end. The reasons for withdrawal were adverse events, lack of efficacy, or both, and were similar between the groups. There were no significant differences in stability of pain intensity between groups. There were no significant differences between groups in quality of sleep, depression, health-related quality of life, or adverse events. Breakthrough pain was experienced in both groups during the trial. Long-acting dihydrocodeine was not observed to be superior for any of the outcomes in this trial. The results of this study do not support current guidelines recommending long-acting opioids.

Dihydrocodeine/Agonists for alcohol dependents.

OBJECTIVE: Alcohol addiction too often remains insufficiently treated. It shows the same profile as severe chronic diseases, but no comparable, effective basic treatment has been established up to now. Especially patients with repeated relapses, despite all therapeutic approaches, and patients who are not able to attain an essential abstinence to alcohol, need a basic medication. It seems necessary to acknowledge that parts of them need any agonistic substance, for years, possibly lifelong. For >14 years, we have prescribed such substances with own addictive character for these patients. METHODS: We present a documented best possible practice, no designed study. Since 1997, we prescribed Dihydrocodeine (DHC) to 102 heavily alcohol addicted patients, later, also Buprenorphine, Clomethiazole (>6 weeks), Baclofen, and in one case Amphetamine, each on individual indication. This paper focuses on the data with DHC, especially. The Clomethiazole-data has been submitted to a German journal. The number of treatments with the other substances is still low. RESULTS: The 102 patients with the DHC treatment had 1367 medically assisted detoxifications and specialized therapies before! The 4 years-retention rate was 26.4%, including 2.8% successfully terminated treatments. In our 12-steps scale on clinical impression, we noticed a significant improvement from mean 3.7 to 8.4 after 2 years. The demand for medically assisted detoxifications in the 2 years remaining patients was reduced by 65.5%. Mean GGT improved from 206.6 U/l at baseline to 66.8 U/l after 2 years. Experiences with the other substances are similar but different in details. CONCLUSION: Similar to the Italian studies with GHB and Baclofen, we present a new approach, not only with new substances, but also with a new setting and much more trusting attitude. We observe a huge improvement, reaching an almost optimal, stable, long term status in around 1/4 of the patients already. Many further optimizations are possible.

Mass Spectra and Cross-Contribution of Ion Intensity Between Drug Analytes and Their Isotopically Labelled Analogs - Common Opioids and Their Derivatives.

For the quantitation of most drugs and their metabolites, GC-MS is currently the preferred method and isotopically labeled analogs of the analytes are the internal standards (ISs) of choice. Under this analytical setting, chemical derivatization (CD) plays a critical role in the sample preparation process. In addition to meeting the conventional objectives of CD, products derived from the selected CD method must generate ions suitable for designating the analyte and the IS; these ions cannot have significant cross-contribution (CC), i.e., contribution to the intensity of the ions designating the analyte by the IS, and vice versa. With this in mind, the authors have reviewed literature and information provided by manufacturers, searching for suitable CD reagents, CD methods, and isotopically labeled analogs of the analytes related to the following 11 opioids: heroin, 6-acetylmorphine, morphine, hydromorphone, oxymorphone, 6-acetylcodeine, codeine, hydrocodone, dihydrocodeine, oxycodone, and noroxycodone. These analytes and ISs were derivatized with various derivatization groups, followed by GCMS analysis. The resulting MS data are systematically presented in two forms: (a) full-scan mass spectra; and (b) CC data of ion-pairs with potential for designating the analytes and their respective ISs. Many (if not most) of these full-scan mass spectra are not yet available in the literature and should be of reference value to laboratories engaged in the analysis of these drugs/metabolites. Full-scan MS data were further used to select ion-pairs with potential for designating the analytes and ISs in quantitative analysis protocols. The CC data of these ion-pairs were evaluated using data collected in selected ion monitoring mode and systematically tabulated, readily available for analysts searching for this important analytical parameter.