Relationship of plasma buprenorphine and norbuprenorphine to withdrawal symptoms during dose induction, maintenance and withdrawal from sublingual buprenorphine.

AIMS: Examine the relationship between buprenorphine and norbuprenorphine plasma concentrations with subject-reported withdrawal symptomatology during buprenorphine dose induction, maintenance treatments (daily and alternate-day dosing) and withdrawal. DESIGN: Two groups of randomly assigned subjects inducted onto buprenorphine and maintained on 8 mg daily by the sublingual route for 18 days. Group 1 continued to receive daily buprenorphine to day 36. Group 2 subjects received alternate-day dosing of buprenorphine and placebo on days 19 to 36. Both groups received placebo on days 37 to 52. SETTING: Inpatient facilities at the Addiction Research Center, Intramural Research Center, NIDA, Baltimore, MD. PARTICIPANTS: Eleven male, heroin-dependent volunteers participating in a research study. INTERVENTION: Medications for treatment of withdrawal symptoms were prescribed as needed after day 39 (72 hours after the last dose of buprenorphine). MEASUREMENTS: Plasma concentrations of buprenorphine and norbuprenorphine, withdrawal symptomatology and pupil diameter. FINDINGS: The mean steady-state buprenorphine plasma concentration (24 hours) after daily administrations of sublingual buprenorphine for study days 21-35 was 0.80 ng/ml, and the mean alternate day steady-state buprenorphine plasma concentration (24 hours) was 0.77 ng/ml. Daily and alternate day steady-state norbuprenorphine plasma concentrations were 1.10 and 0.90 ng/ml, respectively. Predicted alternate day steady-state buprenorphine and norbuprenorphine plasma concentrations at 48 hours were 0.49 ng/ml and 0.57 ng/ml, respectively. Withdrawal scores varied inversely with plasma concentration. There were no significant differences between Groups 1 and 2 during steady-state (days 21-35) with regard to withdrawal scale scores or pupillary diameter. The overall, mean terminal elimination half-lives for buprenorphine and norbuprenorphine were 42 and 57 hours, respectively. CONCLUSIONS: during daily buprenorphine maintenance, plasma concentrations greater than 0.7 ng/ml of buprenorphine and norbuprenorphine were associated with minimal withdrawal symptoms. The long elimination half-life of buprenorphine suggested that increasing the buprenorphine dose with alternate-day administration may provide an effective, flexible therapy regimen for the treatment of opioid dependence.

MDA-MDMA concentrations in urine specimens.

Urine specimens collected from active-duty U.S. Army personnel were submitted for analysis to the Tripler Army Medical Center, Forensic Toxicology Drug Testing Laboratory as part of the random drug testing program. During an 18-month drug-screening period, 34 specimens tested positive for amphetamines with the Roche Abuscreen Radioimmunoassay for Methamphetamine (High Specificity); based on gas chromatographic-mass spectrometric (GC-MS) analysis, the presence of 3,4-methylenedioxymethamphetamine (MDMA) was suspected. These samples were subsequently submitted to the Division of Forensic Toxicology, Office of the Armed Forces Medical Examiner, Armed Forces Institute of Pathology for further testing. All 34 samples screened positive using both the Abbott TDx Amphetamine/ Methamphetamine II assay and the Amphetamine class assay. Confirmation and quantitation by GC-MS revealed the presence of both MDMA and 3,4-methylenedioxyamphetamine (MDA) in all samples. The MDMA concentrations ranged from 0.38 to 96.2 mg/L (mean, 13.4 mg/L) and the MDA concentrations ranged from 0.15 to 8.6 mg/L (mean, 1.6 mg/L). The mean ratio of MDA, the N-demethylation metabolite of MDMA, to MDMA was 0.15, similar to the ratio of amphetamine, the N-demethylation metabolite of methamphetamine, to methamphetamine of 0.10. The presence of MDA in urine specimens at a concentration approximately 10-15% that of the MDMA present is consistent with MDMA metabolism, which may be indicative of the use of MDMA only, as compared with the combined use of both drugs.

Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine.

Buprenorphine is a potent opioid analgesic used in the treatment of moderate to severe pain. At higher doses, it has demonstrated potential for treating heroin dependence. This study was undertaken to investigate buprenorphine pharmacokinetics by different routes of administration at dosages approximating those used in opioid-dependence studies. Six healthy men who were nondependent but who had a history of heroin use were administered buprenorphine in a crossover design study by intravenous (1.2 mg), sublingual (4.0 mg), and buccal (4.0 mg) routes of administration. Plasma samples were collected up to 96 h and assayed for buprenorphine and norbuprenorphine by negative chemical ionization tandem mass spectrometry. Plasma concentrations of buprenorphine and norbuprenorphine were analyzed by nonlinear regression analysis with standard noncompartmental methods. Buprenorphine biovailability by the sublingual and buccal routes was estimated as 51.4% and 27.8%, respectively, although there was considerable interindividual variability by both routes of administration. The terminal elimination half-lives were longer for the sublingual and buccal routes than for the intravenous route. The extended elimination half-lives may be due to a shallow depot effect involving sequestration of buprenorphine in the oral mucosa. Norbuprenorphine mean peak plasma concentrations were less than 1 ng/mL and were highly variable among different routes of administration and individuals. The terminal elimination half-life of norbuprenorphine was longer than buprenorphine.

Simultaneous assay of buprenorphine and norbuprenorphine by negative chemical ionization tandem mass spectrometry.

A method for the simultaneous measurement of buprenorphine and its N-dealkylated metabolite, norbuprenorphine, in human plasma was developed with negative chemical ionization tandem mass spectrometry. Buprenorphine and norbuprenorphine were extracted from biological fluids by solid-phase extraction. The samples were derivatized with heptafluorobutyric anhydride and measured with negative chemical ionization tandem mass spectrometry. Buprenorphine formed a heptafluorobutyryl derivative and norbuprenorphine formed a bis-heptafluorobutyryl derivative; consequently, the sensitivity of norbuprenorphine was substantially higher than buprenorphine. The limit of quantitation (LOQ) for buprenorphine was 0.20 ng/mL, and the LOQ for norbuprenorphine was 0.03 ng/mL. Daily calibration curves were prepared. Buprenorphine was linear from 0.15 ng/mL to 20 ng/mL, and norbuprenorphine was linear between 0.016 ng/mL and 5 ng/mL. Between-run and within-run precision for buprenorphine at 0.5 ng/mL were 13.8% and 9.8%, respectively. Between-run and within-run precision for norbuprenorphine at 0.5 ng/mL were 23.1% and 17.9%, respectively. The molecular anion for buprenorphine was used as a precursor ion, whereas the [M-197]- was used as a precursor ion for norbuprenorphine in tandem mass spectrometry. Product ion spectra from collision-induced dissociation resulted principally from dissociations of the heptafluorobutyryl group. Monitoring select precursor to product ion reactions and using qualifier ion ratios increased the method's sensitivity and selectivity. The method was applied to samples collected from a patient who received oral and subcutaneous buprenorphine. Buprenorphine plasma concentrations ranged from less than 0.20 ng/mL to 8.7 ng/mL.

Two deaths involving isoflurane abuse.

Two deaths due to isoflurane abuse are reported. One case was a suicide and the other a multiple drug death including isoflurane. A simple headspace gas chromatographic method was used for isoflurane quantitation. A review of the literature did not reveal blood and tissue concentrations of isoflurane. Drug tissue distributions and a discussion of the toxicological findings are presented.

Measurement of azacyclonol in urine and serum of humans following terfenadine (Seldane) administration using gas chromatography-mass spectrometry.

A gas chromatographic-mass spectrometric (GC-MS) method is presented for the analysis of azacyclonol (AZA), a metabolite of terfenadine in serum and urine specimens. Following an alkaline extraction, AZA and an internal standard were derivatized using heptafluorobutyric anhydride. Fourier transform infrared spectrometry suggested that two sites on the AZA molecule were derivatized. GC-MS of the extracts had a limit of quantitation (LOQ) of 1 ng/ml and linear range of 1-1000 ng/ml in urine. Four volunteers were administered a therapeutic regimen of terfenadine followed by urine and serum specimen collection(s) during the next seven days. The results indicated that following a 60-mg dose of terfenadine each 12 h for five days, (1) AZA appears in urine within 2 h, (2) urine AZA concentrations were above the LOQ 72 h following the last dose, (3) peak urine concentrations were as high as 19,000 ng/ml, and (4) mean serum concentration following the ninth dose was 59 ng/ml.

Chloroquine distribution in postmortem cases.

Chloroquine concentrations in blood and tissues were examined in overdose and non-overdose cases to determine appropriate ranges for interpretation. Twenty-nine literature overdose cases and 8 non-overdose literature cases were compared with this laboratory's findings. The results indicate significant postmortem redistribution of chloroquine. Combining this laboratory's results and the literature results indicates that using a liver concentration of 150 mg/kg as a cutoff between overdose and non-overdose concentrations properly identified 30 of the 34 published cases containing liver chloroquine and 19 of the 20 presented cases.

Toxicological findings in Federal Aviation Administration general aviation accidents.

Blood, urine, and tissue specimens were received from 377 Federal Aviation Administration (FAA) aviation fatalities during fiscal year 1989. Carbon monoxide at less than 10% saturation was found in 94% of the cases, and cyanide at less than 0.5 mg/L was found in 96% of the cases. Ethanol at greater than 10 mg/dL was found in 14.8% of the cases, but only 4.5% were determined to be due to ethanol ingestion from toxicological findings. Excluding nicotine and ethanol, 12.6% of the cases were positive for one or more drugs. Acetaminophen and salicylate were the most frequently found drugs. Cannabinoids were found in 1.3% of the cases and benzoylecgonine in 1.6%. There was minimal use of therapeutic drugs that cause central nervous system depression or stimulation. These results show no consistent pattern of drug involvement in civilian aviation fatalities.