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 withdrawalsymptomatology during buprenorphine dose induction, maintenance treatment (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 administration 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.     

Sinonasal undifferentiated carcinoma. An aggressive neoplasm derived from schneiderian epithelium and distinct from olfactory neuroblastoma

Eight cases of a highly aggressive undifferentiated carcinoma of the nasal cavity and paranasal sinuses are described. The patients, who ranged in age from 30-77 years, had multiple sinonasal symptoms, and each had involvement of the nasal cavity, maxillary antrum, and ethmoid sinus. Six tumors extended into the orbital bones, and five penetrated the cranial cavity. Five patients died of disease from 1 to 41 months after diagnosis (median: 4 months), and three are alive with tumor less than 1 year following diagnosis. Microscopically, the neoplasms formed nests, trabeculae, and sheets containing medium-sized cells with small to moderate amounts of eosinophilic cytoplasm. A high mitotic rate, tumor necrosis, and prominent vascular permeation were characteristic. Seven neoplasms were immunoreactive for cytokeratin, five for epithelial membrane antigen, and four for neuron-specific enolase. Ultrastructurally, occasional small desmosomes and rare membrane-bound, dense-core granules were observed. Sinonasal undifferentiated carcinoma is a distinctive clinicopathologic entity that must be distinguished from other, less aggressive sinonasal neoplasms.     

Complications of surgical endoscopy

Background: This study examines the notion that gastrointestinal endoscopy performed by supervised surgical residents is safe. Methods: We reviewed all gastrointestinal endoscopic procedures performed by surgical residents with faculty supervision for complications and deaths occurring up to 30 days following the procedures. Results: The overall complication rate for 9,201 upper and lower endoscopy procedures was 1.4% and 0.42%, respectively. Overall mortality rate was 0.76% for upper endoscopy and 0.6% for lower endoscopy. No mortality was a direct result of a procedure-related complication. Intestinal perforation, drug overdose, bleeding, and aspiration were the most common procedure-related complications. Each resident completed an average of 75 upper endoscopies and 79 lower endoscopies during their training period. Conclusions: Gastrointestinal endoscopy can be performed safely by surgical residents with appropriate supervision. The higher morbidity and mortality of upper endoscopy are most likely related to the underlying disease rather than the procedure. Awareness of common complications and application of appropriate precautions and instruction are critical for minimizing complications. Received 25 March 1996/Accepted: 24 April 1996     

Metastatic thyroid carcinoma presenting as an expansile intraluminal esophageal mass

We report a patient with metastatic thyroid carcinoma invading the esophagus in whom barium and MR examinations revealed an expansile intraluminal mass indistinguishable from that of a primary esophageal malignancy. Metastatic thyroid carcinoma should therefore be included in the differential diagnosis of an expansile esophageal mass. As in our patient, MR imaging may be useful for showing that the mass originates in the thyroid gland.     

Skeletal effects of calcitonin in ovariectomized rats

Although calcitonin (CT) has been shown to be effective for the prevention of bone loss in early postmenopausal women, the skeletal effects of the hormone specifically during the early stages of estrogen deficiency have not been characterized histomorphometrically to date. The current study involves use of the ovariectomized (OVX) rat as an animal model for early postmenopausal bone loss to perform such a histomorphometric analysis. One group of OVX rats was injected sc with salmon CT on alternate days for a 6-week period. Additional groups of OVX and sham-operated control rats were treated with vehicle alone. In comparison to control rats, the proximal tibia of vehicle-treated OVX rats were characterized by a 3-fold decrease in cancellous bone volume and significant increases in osteoblast surface (+200%), osteoclast surface (+143%), mineralizing surface (+111%), mineral apposition rate (+36%), bone formation rate (+181%), and longitudinal bone growth (+38%). In contrast, treatment of OVX rats with CT normalized tibial cancellous bone volume and significantly decreased all of the above cellular- and fluorochrome-based indices of bone turnover to near control levels. The results indicate that CT treatment depresses bone turnover and prevents the development of osteopenia in OVX rats. These findings are consistent with the bone protective effect of CT in early postmenopausal women and further support the OVX rat as an animal model for the preclinical evaluation of prophylactic treatments for postmenopausal bone loss.     

Fatality resulting from methylphenidate overdose

A case involving an accidental overdose fatality resulting from an intravenous injection of crushed Ritalin (methylphenidate) tablets is presented. The drug was quantified by gas chromatography/nitrogen-phosphorus detection and confirmed by gas chromatography/mass spectrometry. Concentrations of drug were as follows: blood, 2.8 mg/L; bile, 5.7 mg/L; kidney, 3.0 mg/kg; liver, 2.1 mg/kg; and stomach contents, 1.6 mg total. Other drugs and volatile substances were not detected.