Assessment of opioid partial agonist activity with a three-choice hydromorphone dose-discrimination procedure.
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The discriminative stimulus and subjective effects of opioid mixed agonist-antagonists were assessed in volunteer nondependent heroin users trained in a three-choice drug discrimination procedure to discriminate among the effects of i.m. administration of 2 ml of saline, 1 mg of hydromorphone, and 4 mg of hydromorphone (a morphine-like mu agonist). Other subjective, behavioral, and physiological measures were concurrently collected. The discrimination was readily learned by six of the eight subjects. After training, generalization curves were determined for the following i.m. drug conditions: hydromorphone (0.375-4.0 mg), pentazocine (7.5-60 mg), butorphanol (0.75-6 mg), nalbuphine (3-24 mg), and buprenorphine (0.075-0.6 mg). All five of the test drugs were discriminated significantly or showed trends toward being discriminated as hydromorphone 1 mg-like at one or more dose levels. Hydromorphone showed an inverted U-shaped dose-effect function on the hydromorphone 1 mg-like discrimination. Subjective effect measures produced clearer differentiation among the test drugs than did drug discrimination performance. The present results differ from those of a previous study that observed a close relationship between the results of the discrimination measure and subjective effect measures. The previous study used similar methods and test drugs but different training drugs (e.g., 3 mg of hydromorphone versus 6 mg of butorphanol versus saline). It appears that both the sensitivity of drug discrimination performance to between-drug differences and the relationship between discriminative and subjective effects depends upon the specific discrimination that is trained (e.g., two-choice or three-choice). The present high dose-low dose-saline discrimination procedure appears useful for assessing partial agonist activity. The present data are consistent with partial agonist activity for pentazocine, butorphanol, nalbuphine, and buprenorphine. (+info)
Subjective, psychomotor, and physiological effects of cumulative doses of opioid mu agonists in healthy volunteers.
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The subjective, psychomotor, and physiological effects of three opioid mu-receptor agonists were studied in healthy volunteers using a cumulative-dosing procedure. Sixteen volunteers with no history of drug abuse received i.v. injections of saline (SAL), morphine (MOR), hydromorphone (HM), or meperidine (MEP) in a randomized double-blind crossover design. Subjects received 1 injection/h for the first 4 h, and a 3-h recovery period followed. SAL was injected first during each session, then SAL or increasing doses of each drug were administered every hour for the next 3 h. The absolute doses per injection were MOR: 2.5, 5, and 10 mg/70 kg; HM: 0.33, 0.65, and 1.3 mg/70 kg; and MEP: 17.5, 35, and 70 mg/70 kg. These injections resulted in cumulative doses of MOR: 2.5, 7.5, and 17.5; HM: 0.33, 0.98, and 2.28; and MEP: 17.5, 52.5, and 122.5 mg/70 kg. Subjects completed mood forms and psychomotor tests, and physiological measures were recorded at various times after each injection and during recovery. MEP tended to produce the most intense effects immediately after drug injection, which dissipated rapidly. MOR produced the mildest effects but was associated with unpleasant side effects during recovery and after the session. HM's effects were stronger than MOR's, and the recovery from HM was slower than with MEP. None of the opioids produced consistent effects that are typically associated with abuse liability. Orderly dose-response functions suggested that our cumulative-dosing procedure is an efficient way of determining dose-response functions for multiple opioids within the same subjects within the same study. (+info)
GC-MS confirmation of codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, and oxymorphone in urine.
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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 relationship between the visual analog pain intensity and pain relief scale changes during analgesic drug studies in chronic pain patients.
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BACKGROUND: Most analgesic drug studies in humans quantify drug action based on verbal reports of pain intensity and pain relief. Although measures of pain intensity and pain relief show a good overall correlation, it is not known if they relate to each other consistently over time Such consistency is necessary if both measures are used to depict analgesic drug action versus time. This study examined in chronic pain patients if the relationship between visual analog pain intensity and pain relief scores was consistent during two analgesic drug studies. METHODS: Data from two independently performed analgesic drug studies were analyzed using linear regression. Data were split into pain intensity and pain relief scores recorded before and after patients' experience of maximum analgesia (>90% of maximum pain relief). The slopes of the linear regression line depicting pain intensity versus pain relief scores before and after maximum analgesia were statistically compared. RESULTS: The slope of the linear regression line before and after maximum analgesia was significantly different in both drug studies (nonoverlapping 95% confidence intervals), -2.16+/-0.57 versus -1.05+/-0.10 and -1.47+/-0.26 versus -1.09+/-0.07, respectively. These results are compatible with the observation that patients indicating the same pain intensity before and after maximum analgesia reported a different magnitude of pain relief. CONCLUSIONS: The relationship between visual analog pain intensity and pain relief scores changed systematically during both analgesic drug studies. The authors hypothesize that patients' interpretation of the pain relief scale had changed during the studies and therefore suggest using the pain intensity scale to quantify analgesic drug action over time. (+info)
Mechanistic studies of morphine dehydrogenase and stabilization against covalent inactivation.
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Morphine dehydrogenase (MDH) of Pseudomonas putida M10 catalyses the NADP(+)-dependent oxidation of morphine and codeine to morphinone and codeinone. This enzyme forms the basis of a sensitive detection and assay method for heroin metabolites and a biotransformation process for production of hydromorphone and hydrocodone. To improve these processes we have undertaken a thorough examination of the kinetic mechanism of MDH. Sequence comparisons indicated that MDH belongs within the aldose reductase enzyme family. MDH was shown to be specific for the pro-R hydrogen of NADPH. In steady-state kinetic studies, product inhibition patterns suggested that MDH follows a Theorell-Chance mechanism for codeinone reduction at pH 7, and a non-Theorell-Chance sequential ordered mechanism for codeine oxidation at pH 9.5. Residues corresponding to the catalytically important Tyr-48, Lys-77 and Asp-43 of aldose reductase were modified by site-directed mutagenesis, resulting in substantial loss of activity consistent with a catalytic role for these residues. Loss of activity of MDH in the presence of the reaction product morphinone was found to be due to the formation of a covalent adduct with Cys-80; alteration of Cys-80 to serine resulted in an enzyme with greatly enhanced stability. (+info)
Effects of agonist-antagonist opioids in humans trained in a hydromorphone/not hydromorphone discrimination.
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The purpose of this study was to examine the discrimination of agonist-antagonist opioids in humans trained in a two-choice hydromorphone/not hydromorphone discrimination. Eight adult male volunteers with histories of opioid abuse who were not currently physically dependent were trained to discriminate the mu receptor agonist hydromorphone (3 mg/70 kg, i.m.) ("Drug A") from a "Not Drug A" training condition (saline placebo). Volunteers received financial reinforcement for correct responses. After training, generalization dose-effect curves for hydromorphone, butorphanol, pentazocine, nalbuphine, and buprenorphine were determined. Other subjective, behavioral, and physiological measures were concurrently collected in all sessions. In generalization testing hydromorphone and buprenorphine produced dose-related increases in hydromorphone-appropriate responses. Pentazocine produced an inverted U-shaped dose-response curve with complete substitution at 32 mg/70 kg but not at 64 mg/70 kg. Butorphanol and nalbuphine did not completely substitute for hydromorphone at any dose tested. These results differ from an earlier two-choice, Drug A versus Drug B (hydromorphone/saline) discrimination study. After Drug/Not Drug instructions the behavioral discriminations of agonist-antagonist opioids were more consistent with their putative agonist activities at the mu opioid receptor and with their subjective effects profiles than was the case after Drug A versus Drug B instructions. These results suggest that instructions are an important factor in the outcome of human drug discrimination studies. (+info)
Cofactor regeneration by a soluble pyridine nucleotide transhydrogenase for biological production of hydromorphone.
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We have applied the soluble pyridine nucleotide transhydrogenase of Pseudomonas fluorescens to a cell-free system for the regeneration of the nicotinamide cofactors NAD and NADP in the biological production of the important semisynthetic opiate drug hydromorphone. The original recombinant whole-cell system suffered from cofactor depletion resulting from the action of an NADP(+)-dependent morphine dehydrogenase and an NADH-dependent morphinone reductase. By applying a soluble pyridine nucleotide transhydrogenase, which can transfer reducing equivalents between NAD and NADP, we demonstrate with a cell-free system that efficient cofactor cycling in the presence of catalytic amounts of cofactors occurs, resulting in high yields of hydromorphone. The ratio of morphine dehydrogenase, morphinone reductase, and soluble pyridine nucleotide transhydrogenase is critical for diminishing the production of the unwanted by-product dihydromorphine and for optimum hydromorphone yields. Application of the soluble pyridine nucleotide transhydrogenase to the whole-cell system resulted in an improved biocatalyst with an extended lifetime. These results demonstrate the usefulness of the soluble pyridine nucleotide transhydrogenase and its wider application as a tool in metabolic engineering and biocatalysis. (+info)
Pharmacodynamics of orally administered sustained- release hydromorphone in humans.
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BACKGROUND: The disposition kinetics of hydromorphone generally necessitates oral administration every 4 h of the conventional immediate-release tablet to provide sustained pain relief. This trial examined time course and magnitude of analgesia to experimental pain after administration of sustained-release hydromorphone as compared with that after immediate-release hydromorphone or placebo. METHODS: Using a 4 x 4 Latin square double-blind design, 12 subjects were randomized to receive a single dose of 8, 16, and 32 mg sustained-release hydromorphone and placebo. The same subjects had received 8 mg immediate-release hydromorphone before this study. Using an electrical experimental pain paradigm, analgesic effects were assessed for up to 30 h after administration, and venous hydromorphone plasma concentrations were measured at corresponding times. RESULTS: The hydromorphone plasma concentration peaked significantly later (12.0 h [12.0--18.0] vs. 0.8 h [0.8--1.0]; median and interquartile range) but was maintained significantly longer at greater than 50% of peak concentration (22.7 +/- 8.2 h vs. 1.1 +/- 0.7 h; mean +/- SD) after sustained-release than after immediate-release hydromorphone. Similarly, sustained-release hydromorphone produced analgesic effects that peaked significantly later (9.0 h [9.0--12.0] vs. 1.5 h [1.0--2.0]) but were maintained significantly longer at greater than 50% of peak analgesic effect (13.3 +/- 6.3 h vs. 3.6 +/- 1.7 h). A statistically significant linear relation between the hydromorphone plasma concentration and the analgesic effect on painful stimuli existed. CONCLUSION: A single oral dose of a new sustained-release formulation of hydromorphone provided analgesia to experimental pain beyond 24 h of its administration. (+info)