Arne Helland

Ethanol and drug findings in women consulting a sexual assault center: Associations with clinical characteristics and suspicions of drug-facilitated sexual assault

The purpose of the study was to describe toxicological findings among women seeking health care after sexual assault, and to assess the relationship with so-called proactive DFSA (drug facilitated sexual assault). We also explored associations between ethanol in blood/urine and background data, assault characteristics, and clinical findings. We conducted a retrospective, descriptive study of female patients ≥ 12 years of age consulting the Sexual Assault Center at St. Olavs University Hospital, Trondheim, Norway. They were examined between July 1, 2003 and December 31, 2010, and urine and/or blood were analyzed for ethanol and selected medicinal/recreational drugs. Among the 264 patients included, ethanol and/or drugs were detected in 155 (59%). Of the 50 patients (19%) testing positive for drugs other than ethanol, benzodiazepines/benzodiazepine-like drugs were found in 31, central stimulants in 14, cannabinoids in 13 and opioids in nine. None tested positive for gamma-hydroxybutyrate (GHB). In total, 57 patients (22%) suspected proactive DFSA, but only five had findings of sedative drugs that were not accounted for by self-reported voluntary intake. No cases could unequivocally be attributed to proactive DFSA. Among the 120 patients tested for ethanol within 12 h after the assault, 102 were positive. The median estimated blood alcohol concentration (BAC) at the time of assault was 1.87 g/L. Patients testing positive for ethanol more often reported a public place of assault and a stranger assailant. Higher estimated BAC at the time of assault was associated with higher frequency of suspecting proactive DFSA. Ethanol was the most prevalent toxicological finding in urine/blood from victims of sexual assault, and high ethanol concentrations were often detected. Among the patients suspecting proactive DFSA, very few had sedative drug findings not explained by voluntary intake. It seems like opportunistic DFSA, rather than proactive DFSA dominate among the sexually assaulted attending our SAC.

Investigation of morphine and morphine glucuronide levels and cytochrome P450 isoenzyme 2D6 genotype in codeine-related deaths

Compared to morphine and morphine-6-glucuronide (M6G), codeine and its other major metabolites codeine-6-glucuronide and norcodeine have weak affinity to opioid μ-receptors. Analgesic effects of codeine are thus largely dependent on metabolic conversion to morphine by the polymorphic cytochrome P450 isoenzyme 2D6 (CYP2D6). How this relates to toxicity and post-mortem whole blood levels is not known. This paper presents a case series of codeine-related deaths where concentrations of morphine, M6G and morphine-3-glucuronide (M3G), as well as CYP2D6 genotype, are taken into account. Post-mortem toxicological specimens from a total of 1444 consecutive forensic autopsy cases in Central Norway were analyzed. Among these, 111 cases with detectable amounts of codeine in femoral blood were identified, of which 34 had femoral blood concentrations exceeding the TIAFT toxicity threshold of 0.3mg/L. Autopsy records of these 34 cases were retrieved and reviewed. In the 34 reviewed cases, there was a large variability in individual morphine to codeine concentration ratios (M/C ratios), and morphine levels could not be predicted from codeine concentrations, even when CYP2D6 genotype was known. 13 cases had codeine concentrations exceeding the TIAFT threshold for possibly lethal serum concentrations (1.6 mg/L). Among these, 8 individuals had morphine concentrations below the toxic threshold according to TIAFT (0.15 mg/L). In one case, morphine as well as M6G and M3G concentrations were below the limit of detection. A comprehensive investigation of codeine-related fatalities should, in addition to a detailed case history, include quantification of morphine and morphine metabolites. CYP2D6 genotyping may be of interest in cases with unexpectedly high or low M/C ratios.

Driving simulator sickness: impact on driving performance, influence of blood alcohol concentration, and effect of repeated simulator exposures

Simulator sickness is a major obstacle to the use of driving simulators for research, training and driver assessment purposes. The purpose of the present study was to investigate the possible influence of simulator sickness on driving performance measures such as standard deviation of lateral position (SDLP), and the effect of alcohol or repeated simulator exposure on the degree of simulator sickness. Twenty healthy male volunteers underwent three simulated driving trials of 1hs duration with a curvy rural road scenario, and rated their degree of simulator sickness after each trial. Subjects drove sober and with blood alcohol concentrations (BAC) of approx. 0.5g/L and 0.9g/L in a randomized order. Simulator sickness score (SSS) did not influence the primary outcome measure SDLP. Higher SSS significantly predicted lower average speed and frequency of steering wheel reversals. These effects seemed to be mitigated by alcohol. Higher BAC significantly predicted lower SSS, suggesting that alcohol inebriation alleviates simulator sickness. The negative relation between the number of previous exposures to the simulator and SSS was not statistically significant, but is consistent with habituation to the sickness-inducing effects, as shown in other studies. Overall, the results suggest no influence of simulator sickness on SDLP or several other driving performance measures. However, simulator sickness seems to cause test subjects to drive more carefully, with lower average speed and fewer steering wheel reversals, hampering the interpretation of these outcomes as measures of driving impairment and safety. BAC and repeated simulator exposures may act as confounding variables by influencing the degree of simulator sickness in experimental studies.

Post-mortem levels and tissue distribution of codeine, codeine-6-glucuronide, norcodeine, morphine and morphine glucuronides in a series of codeine-related deaths

This article presents levels and tissue distribution of codeine, codeine-6-glucuronide (C6G), norcodeine, morphine and the morphine metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in post-mortem blood (peripheral and heart blood), vitreous fluid, muscle, fat and brain tissue in a series of 23 codeine-related fatalities. CYP2D6 genotype is also determined and taken into account. Quantification of codeine, C6G, norcodeine, morphine, M3G and M6G was performed with a validated solid phase extraction LC-MS method. The series comprise 19 deaths (83%) attributed to mixed drug intoxication, 4 deaths (17%) attributed to other causes of death, and no cases of unambiguous monointoxication with codeine. The typical peripheral blood concentration pattern in individual cases was C6G≫codeine≫norcodeine>morphine, and M3G>M6G>morphine. In matrices other than blood, the concentration pattern was similar, although in a less systematic fashion. Measured concentrations were generally lower in matrices other than blood, especially in brain and fat, and in particular for the glucuronides (C6G, M3G and M6G) and, to some extent, morphine. In brain tissue, the presumed active moieties morphine and M6G were both below the LLOQ (0.0080mg/L and 0.058mg/L, respectively) in a majority of cases. In general, there was a large variability in both measured concentrations and calculated blood/tissue concentration ratios. There was also a large variability in calculated ratios of morphine to codeine, C6G to codeine and norcodeine to codeine in all matrices, and CYP2D6 genotype was not a reliable predictor of these ratios. The different blood/tissue concentration ratios showed no systematic relationship with the post-mortem interval. No coherent degradation or formation patterns for codeine, morphine, M3G and M6G were observed upon reanalysis in peripheral blood after storage.

Evaluation of measures of impairment in real and simulated driving: results from a randomized, placebo-controlled study

ABSTRACT Objective: Standard deviation of lateral position (SDLP) is often the primary outcome in experimental studies on impaired driving. However, other measures may be easier and more practical to obtain and reflect a broader range of driving-related behaviors. We wanted to assess the validity and sensitivity of a range of measures in a driving simulator as well as during real driving and compare these to SDLP. Methods: Twenty healthy male volunteers undertook 6 driving trials each, 3 in a regular car on a closed track resembling rural road conditions and 3 in a simulator with an identical driving scenario. Ethanol was used as impairing substance due to its well-characterized effects on driving. The subjects were tested sober and at blood alcohol concentrations (BAC) of approximately 0.5 and 0.9 g/L. We explored dose–response relationships between BAC and a range of driving-related measures, as well as their BAC-dependent effect sizes. Results: In simulator driving, ethanol intake increased steering wheel reversal frequency, steering wheel movement measures, average speed, standard deviation of speed, and pedal use frequency. At the test track, only steering wheel movement and standard deviation of speed were significantly correlated to BAC. Likewise, reaction to unexpected incidents and observance of red traffic lights were adversely affected by ethanol in the simulator but not at the test track. Whereas SDLP showed a relatively large effect size that was similar in simulated and real driving, all other measures demonstrated smaller effect sizes, with less pronounced BAC effects on the test track than in the simulator. Conclusions: The results suggest that the driving-related measures explored in this study are less sensitive to alcohol-mediated driving impairment than SDLP, especially during real (test track) driving. The discrepancy in effect sizes between simulated and real driving may imply low external validity of these measures in simulator studies.

Two Hospitalizations and One Death After Exposure to Ortho-Fluorofentanyl

Two young males were hospitalized with miosis and respiratory dysfunction after exposure to a white powder obtained from a foreign source by mail. A few days later, one of the males was found dead at his home. A serum sample from one of the hospitalized patients and a blood sample from the deceased contained ortho-fluorofentanyl in concentrations of 2.5 and 2.4 ng/mL, respectively. It was concluded that death was caused by ortho-fluorofentanyl.

Enantiomeric separation and quantification of R/S-amphetamine in urine by ultra-high performance supercritical fluid chromatography tandem mass spectrometry

To distinguish between legal and illegal consumption of amphetamine reliable analytical methods for chiral separation of the R- and S-enantiomers of amphetamine in biological specimens are required. In this regard, supercritical fluid chromatography (SFC) has several potential advantages over liquid chromatography, including rapid separation of enantiomers due to low viscosity and high diffusivity of supercritical carbon dioxide, the main component in the SFC mobile phase. A method for enantiomeric separation and quantification of R- and S-amphetamine in urine was developed and validated using ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MS/MS). Sample preparation prior to UHPSFC-MS/MS analysis was a semi-automatic solid phase extraction method. The UHPSFC-MS/MS method used a Chiralpak AD-3 column with a mobile phase consisting of CO2 and 0.2% cyclohexylamine in 2-propanol. The injection volume was 2 μL and run-time was 6 min. MS/MS detection was performed with positive electrospray ionization and two multiple reaction monitoring transitions (m/z 136.1 > 119.0 and m/z 136.1 > 91.0). The calibration range was 50-10,000 ng/mL for each enantiomer. The between-assay relative standard deviations were in the range of 3.7-7.6%. Recovery was 92-93% and matrix effects ranged from 100 to 104% corrected with internal standard. After development and validation, the method has been successfully implemented in routine use at our laboratory for both separation and quantification of R/S-amphetamine, and has proved to be a reliable and useful tool for distinguishing intake of R- and S-amphetamine in authentic patient samples.

Enantiomeric separation and quantification of citalopram in serum by ultra-high performance supercritical fluid chromatography-tandem mass spectrometry

A method for enantiomeric separation and quantification of R/S-citalopram in serum was developed and validated using ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MS/MS). Sample preparation prior to UHPSFC-MS/MS analysis consisted of protein precipitation with acidic acetonitrile and filtration through a phospholipid removal plate. The UHPSFC-MS/MS method used an UPC2 Trefoil CEL2 column with a mobile phase consisting of CO2 and methanol/acetonitrile (70:30, v/v) with 10mM ammonium acetate. The injection volume was 1μL and run time was 4min. MS/MS detection was performed with positive electrospray ionization and two multiple reaction monitoring transitions (m/z 325.1>262.0 and m/z 325.1>109.0). The calibration range was 5-500nM for each analyte. The between-assay relative standard deviations were in the range of 3.4-4.5%. Recovery was 81-91% and matrix effects ranged from 96 to 101% (corrected with internal standard). After development and initial testing, the method has been successfully implemented in routine use in our laboratory for both separation and quantification of R/S-citalopram in more than 250 serum samples for therapeutic drug monitoring.

Prolonged elimination of paliperidone after administration of paliperidone palmitate depot injections.

To the Editors: Paliperidone (9-hydroxy-risperidone), which is the pharmacologically active main metabolite of risperidone, has recently been approved for use as an antipsychotic agent on its own, both for oral (Invega) and intramuscular depot (Invega Sustenna, Xeplion) administration. In the depot formulation, paliperidone is bound to palmitic acid, resulting in high lipid solubility. After intramuscular administration, the drug is slowly dissolved and hydrolyzed to active paliperidone by a first-order process, after which it is absorbed into the circulation. The apparent elimination half-life is determined by the absorption rate from the administration site and is approximately 1 month (25Y49 days), allowing for once-monthly administration. To rapidly achieve therapeutic serum concentrations, higher andmore frequent dosing is recommended initially. If a procedure with loading doses is not followed, steady state may not be reached until 4 to 5 months after treatment initiation. Correspondingly, after withdrawal of treatment, pharmacologically active serum concentrations should be expected to linger for as long as 4 to 5 months. In the treatment of chronic psychotic disorders such as schizophrenia, intramuscular depot antipsychotics may offer an advantage over oral antipsychotics in terms of treatment adherence and thus improve outcomes, especially in patients with limited insight into their own condition and the necessity of treatment. The protracted elimination of depot injections provides long-term protection against psychotic breaks, even beyond the designated dosing intervals, thus providing a more robust pharmacological treatment and giving health care personnel more leeway time in cases of nonadherence. However, the long elimination time may also have some drawbacks, such as protracted adverse effects (eg, metabolic disturbances) or drug interactions (eg, with other QT-prolonging medications). Clinicians may not be aware that clinically significant plasma concentrations may be present several months after the end of intramuscular therapy. We present a patient with an exceptionally long detection time of paliperidone in serum after the cessation of intramuscular administration. Possible explanations to the prolonged elimination are discussed.

Quetiapine and the potential for abuse

Quetiapine is an atypical antipsychotic licensed for the treatment of schizophrenia and bipolar disorder and as an adjunctive for patients with unipolar depression. Case reports suggest a potential for drug abuse, especially among individuals with prior or current abuse of other substances.