Nitrocinnamoyl and chlorocinnamoyl derivatives of dihydrocodeinone: in vivo and in vitro characterization of mu-selective agonist and antagonist activity. (1/55)

Two 14beta-p-nitrocinnamoyl derivatives of dihydrocodeinone, 14beta-(p-nitrocinnamoylamino)-7,8-dihydrocodeinone (CACO) and N-cyclopropylmethylnor-14beta-(p-nitrocinnamoylamino)- 7, 8-dihydrocodeinone (N-CPM-CACO), and the corresponding chlorocinnamoylamino analogs, 14beta-(p-chlorocinnamoylamino)-7, 8-dihydrocodeinone (CAM) and N-cyclopropylmethylnor-14beta-(p-chlorocinnamoylamino) -7, 8-dihydrocodeinone (MC-CAM), were tested in opioid receptor binding assays and the mouse tail-flick test to characterize the opioid affinity, selectivity, and antinociceptive properties of these compounds. In competition binding assays, all four compounds bound to the mu opioid receptor with high affinity. When bovine striatal membranes were incubated with any of the four dihydrocodeinones, binding to the mu receptor was inhibited in a concentration-dependent, wash-resistant manner. Saturation binding experiments demonstrated that the wash-resistant inhibition of mu binding was due to a decrease in the Bmax value for the binding of the mu-selective peptide [3H][D-Ala2, MePhe4,Gly(ol)5] enkephalin and not a change in the Kd value, suggesting an irreversible interaction of the compounds with the mu receptor. In the mouse 55 degrees C warm water tail-flick test, both CACO and N-CPM-CACO acted as short-term mu-selective agonists when administered by i. c.v. injection, whereas CAM and MC-CAM produced no measurable antinociception at doses up to 30 nmol. Pretreatment of mice for 24 h with any of the four dihydrocodeinone derivatives produced a dose-dependent antagonism of antinociception mediated by the mu but not the delta or kappa receptors. Long-term antagonism of morphine-induced antinociception lasted for at least 48 h after i.c. v. administration. Finally, shifts in the morphine dose-response lines after 24-h pretreatment with the four dihydrocodeinone compounds suggest that the nitrocinnamoylamino derivatives may produce a greater magnitude long-term antagonism of morphine-induced antinociception than the chlorocinnamoylamino analogs.  (+info)

GC-MS confirmation of codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, and oxymorphone in urine. (2/55)

A procedure for the simultaneous confirmation of codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, and oxymorphone in urine specimens by gas chromatography-mass spectrometry (GC-MS) is described. After the addition of nalorphine and naltrexone as the two internal standards, the urine is hydrolyzed overnight with beta-glucuronidase from E. coli. The urine is adjusted to pH 9 and extracted with 8% trifluoroethanol in methylene dichloride. After evaporating the organic, the residue is sequentially derivatized with 2% methoxyamine in pyridine, then with propionic anhydride. The ketone groups on hydrocodone, hydromorphone, oxycodone, oxymorphone, and naltrexone are converted to their respective methoximes. Available hydroxyl groups on the O3 and O6 positions are converted to propionic esters. After a brief purification step, the extracts are analyzed by GC-MS using full scan electron impact ionization. Nalorphine is used as the internal standard for codeine, morphine, and 6-acetylmorphine; naltrexone is used as the internal standard for the 6-keto-opioids. The method is linear to 2000 ng/mL for the 6-keto-opioids and to 5000 ng/mL for the others. The limit of quantitation is 25 ng/mL in hydrolyzed urine. Day-to-day precision at 300 and 1500 ng/mL ranged between 6 and 10.9%. The coefficients of variation for 6-acetylmorphine were 12% at both 30 and 150 ng/mL. A list of 38 other basic drugs or metabolites detected by this method is tabulated.  (+info)

The antitussive activity of delta-opioid receptor stimulation in guinea pigs. (3/55)

In this study, the activity of the delta-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor.  (+info)

Identification of hydrocodone in human urine following controlled codeine administration. (4/55)

Allegations of illicit hydrocodone use have been made against individuals who were taking physician-prescribed oral codeine but denied hydrocodone use. Drug detection was based on positive urine opiate immunoassay results with subsequent confirmation of hydrocodone by gas chromatography-mass spectrometry (GC-MS). In these cases, low concentrations of hydrocodone (approximately 100 ng/mL) were detected in urine specimens containing high concentrations of codeine (> 5000 ng/mL). Although hydrocodone has been reported to be a minor metabolite of codeine in humans, there has been little study of this unusual metabolic pathway. We investigated the occurrence of hydrocodone excretion in urine specimens of subjects who were administered codeine. In a controlled study, two African-American and three Caucasian male subjects were orally administered 60 mg/70 kg/day and 120 mg/70 kg/day of codeine sulfate on separate days. Urine specimens were collected prior to and for approximately 30-40 h following drug administration. In a second case study, a postoperative patient self-administered 960 mg/day (240 mg four times per day) of physician-prescribed oral codeine phosphate, and urine specimens were collected on the third day of the dosing regimen. Samples from both studies were extracted on copolymeric solid-phase columns and analyzed by GC-MS. In the controlled study, codeine was detected in the first post-drug-administration specimen from all subjects. Peak concentrations appeared at 2-5 h and ranged from 1475 to 61,695 ng/mL. Codeine was detected at concentrations above the 10-ng/mL limit of quantitation for the assay throughout the 40-h collection period. Hydrocodone was initially detected at 6-11 h following codeine administration and peaked at 10-18 h (32-135 ng/mL). Detection times for hydrocodone following oral codeine administration ranged from 6 h to the end of the collection period. Confirmation of hydrocodone in a urine specimen was always accompanied by codeine detection. Codeine and hydrocodone were detected in all specimens collected from the postoperative patient, and concentrations ranged from 2099 to 4020 and 47 to 129 ng/mL, respectively. Analyses of the codeine formulations administered to subjects revealed no hydrocodone present at the limit of detection of the assay (10 ng/mL). These data confirm that hydrocodone can be produced as a minor metabolite of codeine in humans and may be excreted in urine at concentrations as high as 11% of parent drug concentration. Consequently, the detection of minor amounts of hydrocodone in urine containing high concentrations of codeine should not be interpreted as evidence of hydrocodone abuse.  (+info)

Do gender and race affect decisions about pain management? (5/55)

OBJECTIVE: To determine if patient gender and race affect decisions about pain management. DESIGN, SETTING, AND PARTICIPANTS: Experimental design using medical vignettes to evaluate treatment decisions. A convenience sample of 111 primary care physicians (61 men, 50 women) in the Northeast was asked to treat 3 hypothetical patients with pain (kidney stone, back pain) or a control condition (sinusitis). Symptom presentation and severity were held constant, but patient gender and race were varied. MEASUREMENTS AND MAIN RESULTS: The maximum permitted doses of narcotic analgesics (hydrocodone) prescribed at initial and return visits were calculated by multiplying mg per pill x number of pills per day x number of days x number of refills. No overall differences with respect to patient gender or race were found in decisions to treat or in the maximum permitted doses. However, for renal colic, male physicians prescribed higher doses of hydrocodone to white patients versus black patients (426 mg vs 238 mg), while female physicians prescribed higher doses to blacks (335 mg vs 161 mg, F1,85 = 9.65, P =.003). This pattern was repeated for persistent kidney stone pain. For persistent back pain, male physicians prescribed higher doses of hydrocodone to males than to females (406 mg vs 201 mg), but female physicians prescribed higher doses to females (327 mg v. 163 mg, F1,28 = 5.50, P =.03). CONCLUSION: When treating pain, gender and racial differences were evident only when the role of physician gender was examined, suggesting that male and female physicians may react differently to gender and/or racial cues.  (+info)

The simultaneous determination of codeine, morphine, hydrocodone, hydromorphone, 6-acetylmorphine, and oxycodone in hair and oral fluid. (6/55)

Recently, the abuse of prescription opiates as alternatives to heroin has become a national concern. The determination of a six-drug opiate panel, codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, and oxycodone, in hair and oral fluid using solid-phase extraction and capillary gas chromatography-mass spectrometry (GC-MS) is described. Oral fluid was obtained from the donor by insertion of absorptive collectors into the mouth. Hair was collected from the patient and powdered using stainless steel ball bearings in a mini bead-beater apparatus. Opiates present in the samples were extracted from a buffered, aqueous matrix using a solid-phase cartridge. The extracts were concentrated and the methoxime/BSTFA derivatives prepared in order to eliminate interference from the keto-opiates. The extracts were separated by GC-MS in electron impact mode. By utilizing methoxyamine, we were able to produce the methoxime derivatives required for single derivative production and chromatographically separate all six opiates. The routine analysis of these opiates in hair and oral fluid using GC-MS is described for the first time.  (+info)

CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. (7/55)

AIM: To determine the Michaelis-Menten kinetics of hydrocodone metabolism to its O- and N-demethylated products, hydromorphone and norhydrocodone, to determine the individual cytochrome p450 enzymes involved, and to predict the in vivo hepatic intrinsic clearance of hydrocodone via these pathways. METHODS: Liver microsomes from six CYP2D6 extensive metabolizers (EM) and one CYP2D6 poor metabolizer (PM) were used to determine the kinetics of hydromorphone and norhydrocodone formation. Chemical and antibody inhibitors were used to identify the cytochrome p450 isoforms catalyzing these pathways. Expressed recombinant cytochrome p450 enzymes were used to characterize further the metabolism of hydrocodone. RESULTS: Hydromorphone formation in liver microsomes from CYP2D6 EMs was dependent on a high affinity enzyme (Km = 26 microm) contributing 95%, and to a lesser degree a low affinity enzyme (Km = 3.4 mm). In contrast, only a low affinity enzyme (Km = 8.5 mm) formed this metabolite in the liver from the CYP2D6 PM, with significantly decreased hydromorphone formation compared with the livers from the EMs. Norhydrocodone was formed by a single low affinity enzyme (Km = 5.1 mm) in livers from both CYP2D6 EM and PM. Recombinant CYP2D6 and CYP3A4 formed only hydromorphone and only norhydrocodone, respectively. Hydromorphone formation was inhibited by quinidine (a selective inhibitor of CYP2D6 activity), and monoclonal antibodies specific to CYP2D6. Troleandomycin, ketoconazole (both CYP3A4 inhibitors) and monoclonal antibodies specific for CYP3A4 inhibited norhydrocodone formation. Extrapolation of in vitro to in vivo data resulted in a predicted total hepatic clearance of 227 ml x h-1 x kg-1 and 124 ml x h-1 x kg-1 for CYP2D6 EM and PM, respectively. CONCLUSIONS: The O-demethylation of hydrocodone is predominantly catalyzed by CYP2D6 and to a lesser extent by an unknown low affinity cytochrome p450 enzyme. Norhydrocodone formation was attributed to CYP3A4. Comparison of recalculated published clearance data for hydrocodone, with those predicted in the present work, indicate that about 40% of the clearance of hydrocodone is via non-CYP pathways. Our data also suggest that the genetic polymorphisms of CYP2D6 may influence hydrocodone metabolism and its therapeutic efficacy.  (+info)

Cough suppression during flexible bronchoscopy using combined sedation with midazolam and hydrocodone: a randomised, double blind, placebo controlled trial. (8/55)

BACKGROUND: Current British Thoracic Society guidelines do not recommend routinely the combined use of a benzodiazepine and opiate during flexible bronchoscopy (FB). A randomised, placebo controlled, double blind study was undertaken to determine whether hydrocodone in combination with midazolan improves cough suppression during FB without increasing the risk of desaturation. METHODS: 120 patients were randomised to receive midazolam and 5 mg i.v. hydrocodone or midazolam and placebo with topical anaesthesia. Pulse oximetry was recorded continuously during FB. Bronchoscopists and nurses charted their perception of cough and the patients rated their discomfort during the procedure on a 10 cm visual analogue scale (VAS). RESULTS: There was no significant difference between the two groups with regard to the indication for FB, duration of procedure (21 (11) min v 22 (10) min, p = 0.570), doses of supplemental lignocaine (171 (60) mg v 173 (66) mg, p = 0.766) and midazolam (4.5 (2.3) mg v 4.9 (2.7) mg, p = 0.309), lowest oxygen saturation (94.8 (2.7) v 94.9 (2.7), p = 0.433), and desaturations < or =90%. Perception of cough by both the bronchoscopist and the nurse was significantly lower in the hydrocodone group (3 (0-10) and 3 (0-10)) than in the placebo group (6 (0-10) and 6 (0-10)), respectively (p = 0.001). According to the VAS scale, patients' tolerance was also significantly better with hydrocodone than with placebo (2 (0-8) v 3 (0-9), p = 0.043). CONCLUSION: The combination of midazolam and hydrocodone markedly reduces cough during FB without causing significant desaturation, especially when invasive diagnostic procedures are performed.  (+info)