Tess Cramond

Morphine-3-glucuronide - a potent antagonist of morphine analgesia

Abstract In this study, morphine-3-glucuronide (M3G), the major plasma and urinary metabolite of morphine, was shown to be a potent antagonist of morphine analgesia when administered to rats by the intra-cerebroventricular (i.c.v.) route. The antagonism of morphine analgesia was observed irrespective of whether i.c.v. M3G (2.5 or 3.0μg) was administered 15 mins prior to or 15 mins after i.c.v. morphine (20μg). When M3G (10mg) was administered intraperitoneally (i.p.) to rats 30–40 mins prior to morphine (1.5mg i.p.), the analgesic response was significantly reduced compared to administration of morphine (1.5mg i.p.) alone. It was further demonstrated that i.c.v. M3G (2.0μg) antagonized the analgesic effects of subsequently administered i.c.v. morphine-6-glucuronide (0.25μg).

Single‐dose and steady‐state pharmacokinetics and pharmacodynamics of oxycodone in patients with cancer

The single‐dose and steady‐state pharmacokinetics and pharmacodynamics of oxycodone have been determined in patients with moderate to severe cancer pain. The mean ± SD elimination half‐life after single‐dose administration of intravenous (4.6 mg to 9.1 mg) and oral (9.1 mg) oxycodone was 3.01 ± 1.37 hours and 3.51 ± 1.43 hours, respectively. After intravenous administration, the mean ± SD volume of distribution was 211.9 ± 186.6 L, and the mean ± SD total plasma clearance was 48.6 ± 26.5 L/hr. The mean absolute oral bioavailability of oxycodone was 87%, and the mean ± SD volume of distribution after oral administration was 249.1 ± 204.3 L. When administered orally as 10 mg oxycodone hydrochloride every 4 hours, there was no accumulation of oxycodone at steady state and the mean ± SD steady‐state concentration was 34.6 ± 10.3 μg/L. Intravenous oxycodone produced a faster onset of pain relief than oxycodone tablets, but the duration of analgesia was approximately the same (4 hours). However, the incidence of side effects and their severity were significantly higher (p < 0.05) for intravenous oxycodone than for oxycodone tablets. The marked interindividual variation observed in the pharmacokinetics and pharmacodynamics of oxycodone in this study supports the need for individualized dosing regimens.

The excitatory effects of morphine-3-glucuronide are attenuated by LY274614, a competitive NMDA receptor antagonist, and by midazolam, an agonist at the benzodiazepine site on the GABAA receptor complex

Administration of morphine-3-glucuronide (M3G) by the intracerebroventricular (i.c.v.) route in doses of 2-8 micrograms produced a marked dose-dependent behavioural excitation in adult Sprague-Dawley rats. When LY274614 (1-50 ng i.c.v.) or midazolam maleate (25-50 micrograms i.c.v.) was administered 20 min prior to a maximal excitatory dose of M3G (7 micrograms), all excitatory behaviours were reduced. In contrast, when LY274614 (200 ng i.c.v.) was given after M3G (7 micrograms), it did not reduce all of the excitatory behaviours. Since we have also shown in in vitro binding studies that M3G has very low affinity for the known binding sites on the N-methyl-D-aspartate (NMDA) and the gamma-amino-butyric acid (GABAA) receptor complexes (1), the results of this study suggest that the anti-convulsant compounds, LY274614 and midazolam, are functional antagonists of the excitatory effects of M3G. LY274614 (1-50 ng i.c.v.) and midazolam (25-50 micrograms i.c.v.) did not produce significant behavioural excitation and phenyclidine (PCP)-type effects were not observed. This contrasts with the NMDA receptor antagonists CGS19755 and MK801, where PCP-type effects have been reported to interfere with behavioural assessment. Morphine hydrochloride in a maximal analgesic dose (50 micrograms i.c.v.), did not reduce the excitation score of a maximal excitatory dose of M3G (7 micrograms), lending support to the view that M3Gs excitatory effects are elicited through a non-opioid mechanism.

Pharmacokinetics and pharmacodynamics of oxycodone when given intravenously and rectally to adult patients with cancer pain.

The single-dose pharmacokinetics and pharmacodynamics of oxycodone administered by the intravenous and rectal routes were determined in 12 adult cancer patients with moderate to severe cancer pain (visual analog scale [VAS] score, approximately 5). Oxycodone was administered by the intravenous and rectal routes with open drug administration and a cross-over design. After single-dose intravenous administration (7.9 +/- 1.5 mg, mean +/- SD), the mean (+/- SD) terminal half-life was 3.4 h (+/- 1.1), the mean (+/- SD) plasma clearance was 45.4 L/h (+/- 10.1), and the mean (+/- SD) volume of distribution in the terminal phase was 3.0 L/kg (+/- 1.1). After rectal oxycodone (30 mg), the mean (+/- SD) absorption lag time was 0.52 h (+/- 0.29) and the mean (+/- SD) absolute bioavailability was 61.6% (+/- 30.2%). Intravenous oxycodone was associated with a rapid onset of pain relief (5-8 min) in contrast to the 0.5- to 1.0-h delay observed after rectal administration. However, rectal oxycodone provided analgesia of much longer duration (approximate equals 8-12 h) than did intravenous oxycodone (approximate equals 4 h). There were no significant differences (P > 0.05) in the incidence and severity of side effects between intravenous and rectal oxycodone. The marked interindividual variation observed in the pharmacokinetics and pharmacodynamics of oxycodone in this study emphasizes the need for individualized dosing regimens. (Anesth Analg 1995;80:296-302)

Comparative oxycodone, pharmacokinetics in humans after intravenous, oral, and rectal administration

The pharmacokinetics of oxycodone have been determined after single-dose administration by the intravenous (4.6–7.3 mg), oral (tablets, 9.1 mg and syrup, 9.1 mg), and rectal (30 mg) routes, in 48 patients undergoing minor surgery. There were no significant differences in the mean elimination half-lives between the intravenous (5.45 ± 1.43 h), oral tablets (5.65 ± 1.13 h), oral syrup (4.80 ± 1.13 h), and rectal suppository (5.40 ± 1.19 h) formulations of oxycodone. After intravenous administration, the mean plasma clearance of oxycodone was 25.5 ± 10.1 L/h and the mean volume of distribution at steady state was 2.5 ± 0.8 L/kg. The mean normalized area under the curve (AUC/D) obtained after intravenous dosing (48.2 ± 30.2 μg · h/L/mg) was more than twice the AUC/D values obtained after the administration of oxycodone tablets (19.8 ± 3.5 μg · h/L/mg), oxycodone syrup (17.5 ± 5.3 μg · h/L/mg), and rectal suppository (20.3 ± 5.1 μg · h/L/mg), indicating that the amount of oxycodone reaching the systemic circulation after the extravascular routes of administration was <50% of that obtained after intravenous dosing. The mean absorption lag times after oxycodone tablets (0.52 ± 0.33 h), oxycodone syrup (0.48 ± 0.40 h), and rectal suppository (0.76 ± 0.47 h) were consistent with the onset of pharmacological effects reported by the patients.

Quantitation of Morphine, Morphine-3-Glucuronide, and Morphine-6-Glucuronide in Plasma and Cerebrospinal-Fluid Using Solid-Phase Extraction and High-Performance Liquid-Chromatography with Electrochemical Detection

An original, sensitive, and specific high-performance liquid chromatographic (HPLC) assay was developed for the quantitation of morphine and its two major metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), in human plasma and cerebrospinal fluid (CSF) and in rat plasma, using hydromorphone as the internal standard. Solid-phase extraction was used to separate morphine and its glucuronide metabolites from plasma constituents. Extraction efficiencies of morphine, M3G, and M6G from human plasma samples (0.5 ml) were 84, 87, and 88%, respectively. Extraction efficiencies of morphine, M3G, and M6G did not differ significantly (p > 0.05) between human plasma and CSF or rat plasma. Morphine, M3G, M6G, and hydromorphone were separated on a 10 μ C8 Resolve radially compressed cartridge using a mobile phase comprising methanol:acetonitrile:phosphate buffer, (0.0125M pH 7.5; 10:10:80), in which 11 mg/L of cetyltrimethylammo-nium bromide (cetrimide) was dissolved. Quantitation was achieved using a single electrochemical detector at ambient temperature (23°C). Standard curves were linear over the ranges 0.020–2.190, 0.027–2.709, and 0.027–0.542 μ for morphine, M3G, and M6G, respectively. Lower limits of detection for morphine, M3G, and M6G in human plasma and CSF samples (0.5 ml) were 0.020, 0.027, and 0.027 μM, respectively. Corresponding lower limits of detection in rat plasma (0.1 ml) were 0.102, 0.135, and 0.135 μM, respectively. Intraassay precision for low and high concentrations of morphine, M3G, and M6G were <23 and <8% respectively. Similarly, interassay accuracy for low and medium concentrations of morphine, M3G, and M6G were <17% and were <9% for high concentrations.

Self-report and pain behavior among patients with chronic pain

Objectives: To determine the relationship between pain behaviors and self-report of pain and disability in patients with chronic pain. Methods: Thirty-nine patients (59% women), aged 19 to 79 years, admitted to a Multidisciplinary Pain Center with chronic noncancer pain, were assessed on the following: 1) pain intensity using a 0 to 10 Numerical Graphic Rating Scale; 2) the Pain Disability Index; 3) the Pain Self-Efficacy Questionnaire; 4) a 10-minute videotaped session involving sitting, standing, walking, and reclining, after which pain behaviors were coded using a standardized observational protocol. Results: Interrelationships among pain intensity, pain disability, self-efficacy, and pain behavior were tested using the Pearson product-moment correlations. Significant relationships were found between pain behavior frequencies and self-reported pain intensity (r = 0.29, P < 0.05), self-reported pain disability (r = 0.54, P < 0.0005), and reported self-efficacy (r = −0.42, P < 0.005). Multiple regression analyses were performed to further investigate these interrelationships. Only the Pain Disability Index score was found to make a significant unique contribution (semipartial correlation of 15%, P < 0.008) to the prediction of total pain behavior score. Discussion: Findings suggest that pain behavior observation is a valid and reliable assessment tool for use with a heterogeneous chronic pain population. Significant associations were found between pain behaviors and self-report measures of pain intensity, pain disability, and self-efficacy; pain intensity scores displayed a weak relationship; and pain disability scores the strongest relationship with pain behavior. Viewed with previous research, the results of this study indicate the value of a multimodal, cognitive-behavioral approach to assessing patients with chronic pain.

Characterization of non-conventional opioid binding sites in rat and human lung.

Indirect evidence suggests that nebulized morphine relieves dyspnoea and bronchoconstriction via opioid receptors within the lung. This study used equilibrium binding studies to characterize opioid binding sites in lung membrane preparations. [3H]Morphine and [3H]naloxone were incubated separately with homogenates of Wistar rat brain and lung, and human lung. Binding affinities for both morphine and naloxone in rat and human lung were two orders of magnitude lower than those in brain. However, opioid binding site densities in lung were up to 100 times greater than that in brain. The addition of Na+ or GTP to lung homogenate preparations caused atypical effects on opioid binding. Na+ (50 mM) decreased the specific binding of [3H]naloxone 50% viz-à-vis a 20% increase in binding in the brain. GTP (100 microM) caused a 200% increase in the apparent capacity of morphine binding in the lung compared with a marked decrease in binding in the brain.

Pregabalin in severe burn injury pain: A double-blind, randomised placebo-controlled trial

&NA; This randomised, double‐blind, placebo‐controlled trial assessed the efficacy and tolerability of pregabalin to alleviate the neuropathic component of moderate to severe burn pain. Patients aged 18 to 65 years admitted to a burns unit with a 5% or greater total body surface area burn injury were screened to participate in the trial. Using the Neuropathic Pain Scale (NPS), patients scoring 4 or higher on ‘hot’ pain or ‘sharp’ pain were invited to participate. Consenting patients were randomly assigned to receive pregabalin or placebo for 28 days with individual dose titration commencing at 75 mg twice daily to a maximum pregabalin dose of 300 mg twice daily. The primary outcome measure was the patients’ daily response to the sharp and hot pain of the NPS. Secondary outcome measures included the remaining elements of the NPS, daily opioid requirement, length of hospital stay, pain at 6 months, and side effects of nausea, vomiting, drowsiness and giddiness. For patients administered pregabalin, the primary outcome measures hot (P = .01) and sharp (P = .04) pain were significantly reduced compared with those in patients administered placebo. Secondary outcome measures of itch, unpleasantness, surface pain, and procedural pain were significantly lower (P < .05) in the pregabalin group. Adverse effects were uncommon, with no difference between the treatment groups. There was no significant difference between the pregabalin and placebo treatment groups with respect to opioid consumption, duration of hospital stay, or pain at 6 months. Pregabalin was efficacious and well tolerated in patients after severe burn injury and whose pain was characterised by features of acute neuropathic pain. In this study, pregabalin was well tolerated and significantly reduced several elements of the neuropathic pain scale including hot pain, unpleasantness of the pain, surface pain, and itch, and also significantly reduced procedural pain.

Determination of the Serum-Protein Binding of Oxycodone and Morphine Using Ultrafiltration

Protein binding of oxycodone and morphine in human serum was determined in vitro using ultrafiltration. Binding studies were also performed using both purified human serum albumin and human α1-acid glycoprotein (AAG). Albumin was found to be the major binding protein for both oxycodone and morphine. The serum protein binding of both oxycodone and morphine was independent of drug concentration in the therapeutic range (5–100 ng/ml), but was dependent on protein concentration. In addition, bound fractions of oxycodone and morphine increased with increasing concentrations of both albumin and A AG. At physiological pH and temperature, the mean (± SD) serum protein binding of oxycodone was 45.1% (± 0.4%) and that of morphine was 35.3% (± 0.2%) A decrease in temperature from 37 to 23°C significantly increased the serum protein binding of oxycodone and morphine by 8–9% (p < 0.0001) and 7–10% (p < 0.0001), respectively, indicating the importance of maintaining the temperature at 37° C during protein binding experiments. A reduction in pH from 7.75–8.85 to 7.4 significantly reduced serum protein binding of both oxycodone and morphine by 4–5% (p < 0.0001) and 4–7% (p < 0.0001), respectively. Serum samples, to which known concentrations of oxycodone had been added and which were stored at −20° C, showing a gradual but significant decline (p < 0.0001) in serum protein binding of oxycodone from –45 to 39% during the 4-week storage period. Although serum protein binding of oxycodone and morphine is dependent on protein concentration and pH – factors that may vary in different disease states–any changes in the binding of oxycodone or morphine are unlikely to alter the pharmacological effects of these drugs because of their normally low extent of binding (45 and 35%, respectively).