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PubMed1990

Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide.

The pharmacokinetic parameters of morphine, morphine-6-glucuronide, and morphine-3-glucuronide were studied after single-dose morphine administration by five different routes. The quantitative significance of the active metabolite morphine-6-glucuronide was assessed, and the effects of novel dosing forms on morphine metabolism and distribution were examined. After administration of intravenous morphine the morphine-6-glucuronide plasma AUC exceeded that of morphine. After administration of oral morphine very low morphine levels were observed--the morphine-6-glucuronide plasma AUC exceeded that of morphine by a factor of 9:1. Sublingual, buccal, and sustained-release buccal morphine tablet administration resulted in delayed absorption, with attenuation and delay of peak morphine and metabolite levels. Morphine bioavailability and morphine glucuronide production were not altered.

Administration, Oral↗
PubMed1999

Determination of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in plasma after intravenous and intrathecal morphine administration using HPLC with electrospray ionization and tandem mass spectrometry.

High-performance liquid chromatography (HPLC) coupled to atmospheric pressure ionization (API) mass spectrometry (MS) has become a useful technique in the direct analysis of low concentrations of conjugated opiate metabolites. Previous methods using HPLC with traditional detection methods do not have the sensitivity to detect low concentrations of most conjugated drug metabolites. Methods using gas chromatography-mass spectrometry (GC-MS) require hydrolysis and derivatization of the sample followed by an indirect quantitation of conjugated metabolites. Recently, several reports have described direct analysis of opiates and their glucuronide conjugates by HPLC and API-MS. These methods report lower limits of detection than GC-MS methods and quantitation in the low nanogram-per-milliliter range for the glucuronide metabolites of morphine. This report describes an HPLC-electrospray-MS-MS method capable of detecting subnanogram concentrations of morphine (MOR) and its 3- and 6-glucuronide metabolites (M3G and M6G, respectively). The assay has a dynamic range of 250-10,000 pg/mL for M3G and M6G and 500-10,000 pg/mL for MOR. Inter- and intra-assay precision and accuracy varied by less than 8% for all analytes at 750-, 2500-, and 7500-pg/mL concentrations. This assay was used for the determination of MOR, M3G, and M6G in human plasma after intravenous (i.v.) and intrathecal (i.t.) administration of MOR and its effects on the ventilatory response to hypoxia. Peak plasma concentrations of MOR and M6G were measured 1 h after i.v. administration of MOR. Peak concentrations of M3G were measured 2 h after i.v. administration of MOR. After i.t. administration of MOR, peak concentrations of M3G were measured 8 h postdose. MOR was not detected in plasma of patients administered MOR i.t.. Subnanogram concentrations of M6G were measured in the plasma of five of nine patients administered MOR i.t..

Chromatography, High Pressure Liquid↗
PubMed1988

Effect of kappa-opioid receptor agonists on morphine analgesia in morphine-naive and morphine-tolerant rats.

The effect of i.p. administration of kappa-opioid receptor agonists, bremazocine, tifluadom and U-50,488H on morphine (8 mg/kg i.p.)-induced analgesia in morphine-naive and morphine tolerant male Sprague-Dawley rats was determined using the tail-flick test. The tolerance to morphine in the rats was induced by s.c., implantation of six morphine pellets during a 7-day period. Implantation of morphine pellets resulted in the development of tolerance as evidenced by the decrease in the analgesic response to morphine when compared to placebo pellets implanted rats. Bremazocine (0.3, 1.0 and 3.0 mg/kg) and U-50,488H (16 mg/kg) antagonized morphine-induced analgesia in morphine-naive rats while tifluadom (8 and 16 mg/kg) potentiated the effect. In morphine-tolerant rats, bremazocine (3 mg/kg) and U-50,488H (16 mg/kg) potentiated morphine-induced analgesia. Tifluadom at any of the doses had no effect on morphine-induced analgesia in morphine-tolerant rats. These results provide evidence that different kappa-opioid agonists modify morphine-induced analgesia differentially in morphine-naive and morphine-tolerant rats.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2002

Sex-specific differences in levels of morphine, morphine-3-glucuronide, and morphine antinociception in rats.

A number of studies reported striking differences in antinociceptive responses to morphine as a function of sex. Although sex differences in the sensitivity to morphine are widely characterized in rodents, the underlying causes are not identified. Gonadal steroids are believed to contribute to sex differences in response to opioid-induced antinociception. In rats, morphine is metabolized by glucuronidation to morphine-3-glucuronide (M3G). M3G was found to be a functional antagonist of the actions of morphine. Knowledge about the role morphine glucuronides play in sex-specific responses to the antinociceptive effect of morphine may be useful in evaluating therapeutic outcomes of morphine treatment. The purpose of this project was to investigate the effects of sex on the systemic formation of M3G in rats and to correlate glucuronidation variability with differences in antinociceptive responses to morphine. Female rats showed significantly lower morphine-induced antinociception as compared to male rats; 4.6+/-0.5s vs. 11.7+/-2.2s, respectively. Female rats also demonstrated about three-fold higher maximum plasma levels of M3G compared with male rats; 6.2+/-2.2 microg/ml vs. 1.9+/-0.7 microg/ml, respectively. The M3G:morphine AUC ratio was 6.6:1 in female rats and 0.7:1 in male rats. Gonadectomy only partially eliminated sex differences in morphine antinociception and plasma levels of M3G. The results of this study demonstrate that sex and sex differences in the M3G:morphine plasma ratio may play a role in male-female differences observed in morphine antinociception.

Analgesics↗
PubMed1996

Concentrations of morphine and morphine metabolites in CSF and plasma during continuous subcutaneous morphine administration in cancer pain patients.

Plasma and cerebrospinal fluid (CSF) steady-state concentrations (Css) of morphine (M) and the main metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), were determined by high performance liquid chromatography (HPLC) in 21 cancer patients treated with chronic subcutaneous morphine infusion. There was a moderate, but statistically significant correlation between the daily dose of morphine and the concentrations of morphine, M3G and M6G in CSF. A poorer correlation to concentrations were seen in plasma. The mean +/- SEM CSF/plasma morphine concentration ratio was 0.36 +/- 0.07. In plasma and CSF, the mean steady state concentration of M3G but not M6G substantially exceeded that of morphine where the mean CSF M/M3G/M6G ratio was 1:15:0.5 (molar basis), and the mean plasma ratio was M/M3G/M6G 1:31:3 (molar basis). The mean M3G and M6G concentrations in CSF were approximately 8 and 10% of those found in plasma, but there was a wide interindividual variation. Plasma concentrations of both morphine glucuronides were positively correlated to serum creatinine. Neither pain intensity, evaluated by visual analogue scale (VAS), nor side effects showed any relationship to the CSF M3G concentrations, M3G/M or the M3G/M6G ratios. We conclude that during steady state subcutaneous administration of morphine, there is a large interindividual variation in plasma morphine with poor relationship to the daily administered dose. In CSF this correlation was more evident. Plasma and CSF concentrations of M3G and CSF concentrations of M6G correlated with administered morphine dose. There was an accumulation of both morphine glucuronides in patients with elevated serum creatinine. Measurements of morphine, M3G and M6G in CSF did not show any overt relationship to analgesia or side effects.

Aged↗
PubMed1992

Morphine 6-glucuronide: a metabolite of morphine with greater emetic potency than morphine in the ferret.

1. The emetic potencies of morphine and its metabolite morphine 6-glucuronide have been determined in the ferret by constructing dose-response curves for mean total retches and vomits for subcutaneous doses of 0.05 mg kg-1 to 5 mg kg-1. Morphine 6-glucuronide induced retching and vomiting at lower doses than morphine and at a maximal dose induced more retching and vomiting than morphine. 2. The emesis induced by both morphine and morphine 6-glucuronide was abolished by the preadministration of naloxone (0.5 mg kg-1 s.c.). 3. The 5-HT3 receptor antagonists granisetron and ondansetron (1 mg kg-1, s.c.) failed to abolish or reduce emesis induced by either compound. 4. At a high-dose (5 mg kg-1), morphine but not morphine 6-glucuronide failed to induce emesis and abolished the emesis induced by the cytotoxic drug, cyclophosphamide (200 mg kg-1, i.p.). 5. Preliminary pharmacokinetic studies of intravenous and subcutaneous morphine and morphine 6-glucuronide revealed that morphine 6-glucuronide accounts for less than 1% of the metabolic product of morphine in the ferret. Peak plasma levels of the two compounds after their subcutaneous administration were obtained within 10 min. The metabolic profile of morphine was not dose-dependent. There was no relationship between plasma level and emetic response for either compound.

Animals↗
PubMed1995

Plasma and cerebrospinal fluid concentrations of morphine and morphine glucuronides in rabbits receiving single and repeated doses of morphine.

The pharmacokinetics of morphine in plasma and the distribution of morphine and its glucuronidated metabolites within the cerebrospinal fluid were investigated in rabbits. After single morphine dosage, the plasma AUC ratio of morphine-3- glucuronide/morphine was 11.1 compared with 0.14 for morphine-6-glucuronide/morphine. The similar elimination half-lives of morphine (107 min), morphine-3-glucuronide (122 min), and morphine-6-glucuronide (105 min) suggested the glucuronidation to be the rate-limiting step, which was substantiated by the observation that morphine-3-glucuronide becomes eliminated four times faster when applied intravenously. Both after single and repeated morphine administration, the ratios of CSF and plasma levels of the parent drug were higher than those of morphine-3-glucuronide or morphine-6-glucuronide. These data demonstrate a poor penetration of the glucuronides across the blood-brain barrier and do not support the previously postulated accumulation of morphine-6-glucuronide in the central nervous system during chronic morphine treatment.

Animals↗
PubMed2005

Morphine preexposure facilitates morphine place preference and attenuates morphine taste aversion.

Repeated morphine preexposure has been reported to enhance measures of morphine reward (conditioned place preference; CPP) and attenuate measures of morphine aversion (conditioned taste aversion; CTA). These effects are generally independently assessed, limiting the ability to determine if the enhancing and attenuating effects of morphine exposure are mediated by a common factor. To assess any potential relationship between these two effects, the present study examined the impact of morphine preexposure on these motivational properties of morphine using a combined CTA/CPP procedure in which the same animals receive concurrent taste and place conditioning. Specifically, male Sprague-Dawley rats were preexposed to morphine [5 mg/kg; subcutaneously (sc)] or equivolume drug vehicle. Following preexposure, animals were given saccharin to drink and injected with morphine sulfate (1 or 5 mg/kg sc) or drug vehicle (CTA). Immediately thereafter, they were placed on one side of a two-compartment chamber (CPP). On the next day, they were given water followed by injections of the drug's vehicle and then placed in the other compartment. There were four such conditioning cycles after each of which a CTA and CPP test were given. While preexposure to morphine attenuated morphine-induced CTAs, morphine-induced CPPs were enhanced within the same animals. These effects of morphine preexposure were dose- and time-dependent and parallel. These data indicate that the attenuating and sensitizing effects of morphine preexposure on taste aversions and place preferences, respectively, could be mediated by a common mechanism, although other possibilities for these effects of morphine preexposure remain.

Animals↗
PubMed1996

Lack of morphine-6-glucuronide antinociception after morphine treatment. Is morphine-3-glucuronide involved?

Morphine, morphine-6-glucuronide (M6G) tolerance and cross-tolerance between morphine and M6G have been evaluated in mice. Daily administration of equipotent doses of M6G and morphine induced similar declines in antinociception over 9 days of treatment. However, a higher dose of M6G than morphine is required in tolerant animals to recover the initial response. In studies where daily morphine doses were substituted by M6G administration, on specific days, there was a significant fall in M6G antinociception on those days immediately following morphine administration, relative to the response to continued morphine (a decrease of 53.7% on day 2, P < 0.001 and a decrease of 62.5% on day 11, P < 0.05) and M6G (a decrease of 45.4% on day 2, P < 0.05) exposure. The decrease was independent of treatment duration and dosage. This decrease in the antinociceptive effect of M6G after morphine was avoided after clofibrate treatment, an inhibitor of (-)morphine metabolism. Determination of morphine and its metabolites in plasma revealed that morphine-3-glucuronide (M3G) concentration was significantly lower (P < 0.001) in animals treated with clofibrate (8.3 +/- 8.3 ng/ml) than in controls (422 +/- 80 ng/ml). The dose-response curve for M6G was shifted to the right by prior administration of M3G. These results suggest that during morphine treatment the antinociceptive effect of M6G may be antagonized by the other metabolite, M3G.

Analgesics, Opioid↗
PubMed1997

Morphine, morphine-3-glucuronide, morphine-6-glucuronide, and 6-monoacetylmorphine determined by means of atmospheric pressure chemical ionization-mass spectrometry-liquid chromatography in body fluids of heroin victims.

Morphine, morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), and 6-monoacetylmorphine (6-MAM) were isolated from body fluids using solid-phase extraction and determined by means of atmospheric pressure chemical ionization-mass spectrometry-liquid chromatography (APCI-LC-MS) in selected ion monitoring mode. The following ions were monitored: m/z 286 for morphine; m/z 286 and 462 for M3G and M6G; m/z 211, 268, and 328 for 6-MAM; and m/z 289 for morphine-d3 (internal standard). The recoveries ranged from 82 to 89% The limits of detection were as follows: 0.1 ng/mL (morphine), 0.5 ng/mL (6-MAM), and 1 ng/mL (M3G and M6G). The analytes were determined in samples taken from 21 heroin-overdose victims. Twenty-one blood samples, 11 cerebrospinal fluid (CSF) samples, 12 vitreous humor (VH) samples, and 6 urine samples were investigated. Blood concentrations (ng/mL) of morphine ranged from 8 to 1539, of M3G from 111 to 941, of M6G from 32 to 332, and of 6-MAM from 0 to 73. The levels of morphine were correlated with glucuronide values and with 6-MAM. The concentrations of morphine, M3G, and M6G in CSF were, as a rule, lower than in blood and lower in VH than in CSF. The concentrations of morphine and molar ratios of M6G-morphine in blood and CSF were correlated. Low ratios of M3G-morphine and M6G-morphine in blood of heroin-overdose victims indicated short survival time after drug intake.

Adolescent↗
PubMed1979

Pharmacokinetics of morphine and its surrogates. III: Morphine and morphine 3-monoglucuronide pharmacokinetics in the dog as a function of dose.

The pharmacokinetics of morphine and its derived metabolite, morphine 3-monoglucuronide, were studied in normal and bile-cannulated dogs. High doses (7.2-7.7 mg/kg iv) caused renal and biliary shutdowns and time lags in urinary drug and metabolite excretion and in biliary secretion of the hepatically formed conjugate. Intermediate doses (0.41-0.47 mg/kg iv) inhibited urine flow but not renal clearance. Low doses (0.019-0.07 mg/kg iv) had no apparent effect. Dose-related effects on the total, metabolic, and biliary clearances imply saturable enzymes and/or dose-inhibited hepatic flows, accounting for the major elimination half-lives of 83 +/- 8 and 37 +/- 13 min at the high and low doses, respectively. The slow terminal phase in plasma morphine and metabolite elimination and urinary accumulation is due apparently to the enterohepatic metabolite recirculation after biliary excretion, gastrointestinal hydrolysis, and hepatic first-pass reconjugation. Bile-cannulated dogs showed no fecal drug and no slow terminal plasma and urine elimination phases. Intravenous morphine 3-monoglucuronide was eliminated only renally and showed neither biliary excretion nor prolonged hepatically formed glucuronide elimination. Hepatic morphine clearances at normal therapeutic doses parallel hepatic blood flow and explain the lack of oral morphine bioavailability by anticipating complete first-pass liver metabolism. Renal morphine and morphine conjugate clearances were 85 (+/- 9 SEM) and 41 (+/- 4 SEM) ml/min, respectively, indicating glomerular filtration for the latter and glomerular filtration plus tubular secretion for the former. Urinary morphine and morphine conjugate excretion accounted for approximately to 83% of the dose. Biliary secretion accounted for 11-14% of the dose. Morphine showed dose-independent plasma protein binding of 36 (+/- 1 SEM) % and a red cell-plasma water partition coefficient of 1.11 +/- 0.04 SD. New equations were developed to model the discontinuous morphine and morphine metabolite pharmacokinetics.

Animals↗
PubMed2000

Pain relief after arthroscopic knee surgery: intravenous morphine, epidural morphine, and intra-articular morphine.

OBJECTIVE: The aim of this study was to compare the analgesic efficacy and side effects of intravenous (IV), epidural, and intra-articular (IA) morphine after arthroscopic knee surgery. DESIGN: Prospective, randomized, double-blind clinical investigation. SETTING: Medical center, university teaching hospital. PATIENTS: Inpatients with an American Society of Anesthesiologists physical status of I or II who were scheduled for elective arthroscopic knee surgery. INTERVENTIONS AND OUTCOME MEASURES: A total of 75 patients scheduled for arthroscopic knee surgery under epidural anesthesia were randomly divided into three groups (n = 25 in each group). At the end of surgery, patients in group 1 received 3 mg of IV morphine, patients in group 2 received 3 mg of epidural morphine, and patients in group 3 received 3 mg of IA morphine. Patients were then observed for 24 hours. During the observation period, the proportion of patients requiring rescue analgesia with intramuscular diclofenac in each group was calculated and the occurrence of morphine-related side effects was recorded. RESULTS: We found that patients who received IV morphine requested more rescue analgesia than those who received either epidural or IA morphine. The proportions of patients requiring rescue analgesia in the IV, epidural, and IA groups were 65%, 13%, and 9%, respectively (p < 0.01 in group 1 vs. group 2 and in group 1 vs. group 3). Epidural morphine was associated with higher incidences of nausea and vomiting, pruritus, and urinary retention than IA morphine (range, p < 0.05-0.01 in group 2 vs. group 3). CONCLUSIONS: Patients who received IA morphine consumed less rescue analgesia than those who received IV morphine. They also reported fewer side effects than those patients who received epidural morphine. Intra-articular morphine may be the method of choice for pain relief after arthroscopic knee surgery.

Arthroscopy↗
PubMed1996

Continuous co-administration of dextromethorphan or MK-801 with morphine: attenuation of morphine dependence and naloxone-reversible attenuation of morphine tolerance.

N-Methyl-D-aspartate (NMDA) receptor antagonists have been repeatedly shown to attenuate the development of opiate tolerance and dependence in rodents. In the present experiments, continuous subcutaneous infusion of either MK-801 (0.01 mg/kg/h but not 0.005 mg/kg/h) or DM (0.133, 0.67 and 1.33 mg/kg/h) reliably prolonged the antinociceptive effect of continuous subcutaneous infusion of morphine sulfate (2.0 mg/kg/h), indicating attenuation of the development of morphine tolerance. Furthermore, this prolonged antinociception was completely reversible by naloxone (10 mg/kg, i.p.). Doses of MK-801 and DM that were equipotent in attenuating morphine tolerance (0.01 mg/kg/h and 1.33 mg/kg/h, respectively) revealed different profiles of effects, however, on locomotor activity and naloxone-precipitated abstinence/withdrawal symptoms. With regard to locomotor activity, rats having received continuous (48 h) subcutaneous infusion of morphine sulfate and MK-801, but not rats having received morphine sulfate and DM, displayed a reliable and striking increase in locomotor activity as compared with rats having received morphine alone. With regard to naloxone-precipitated withdrawal symptoms, continuous (48 h) subcutaneous co-infusion of either MK-801 (0.01 mg/kg/h) or DM (1.33 mg/kg/h) with morphine attenuated naloxone-precipitated hyperalgesia as compared with rats infused with morphine alone. MK-801 (0.01 mg/kg/h) was more effective than DM (0.133, 0.67, or 1.33 mg/kg/h), however, in reducing other naloxone-precipitated withdrawal symptoms (teeth chattering, jumping and wet dog shakes). The effects of MK-801 on all withdrawal symptoms were confounded, however, by the appearance of flaccidity following naloxone administration to rats having received MK-801 and morphine. These results extend previous observations by showing that the prolonged antinociception observed following co-administration of morphine and an NMDA antagonist is completely naloxone-reversible, supporting the notion that this antinociception reflects prolongation of an opioid receptor-mediated effect. The different profiles of side effects associated with MK-801 and DM, however, suggest that (1) attenuation of naloxone-precipitated withdrawal symptoms by MK-801 may be an artifact of toxicity, and (2) DM may prove clinically useful for the prevention of morphine tolerance, given its lack of observable side effects when administered concurrently with morphine to rodents.

Animals↗
PubMed1995

Plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide after intravenous and oral administration to healthy volunteers: relationship to nonanalgesic actions.

Healthy volunteers were given morphine as an i.v. infusion (10 mg), immediate release (IR) tablets (3 x 10 mg), and as a new controlled release (CR) tablet (30 mg) on separate occasions. Venous blood samples were analyzed for morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) using high-performance liquid chromatography (HPLC). Pupil size, salivation, and central nervous system (CNS) effects were evaluated serially. Pharmacokinetic parameters, calculated using a two-compartment model, were in accordance with previous results for i.v. administration of morphine. The absolute bioavailability of morphine in both IR and in CR tablets was, 32%, and the relative bioavailability of the CR tablet versus the IR tablets was 103% (91-115%, 95% confidence interval). Pupil size and unstimulated saliva production were significantly reduced and CNS effects most pronounced following i.v. infusion of morphine, but were only moderately affected after oral administration with IR or CR tablets. Miosis and reduction of salivation were observed at moderate concentrations of morphine and M6G. A pharmacokinetic/pharmacodynamic model based on previous studies of receptor binding and potency of morphine and its metabolites was used to assess the concentration-effect relationships. According to this model, M6G was four and eight times more potent than morphine in producing miosis and reduction of saliva production, respectively. The same model indicated that intrinsic activities of M6G and morphine were similar for both effect parameters, whereas M3G was either inactive or even opposed the effects of morphine and M6G.

Administration, Oral↗
PubMed2003

Plasma concentrations of morphine, morphine-6-glucuronide and morphine-3-glucuronide and their relationship with analgesia and side effects in patients with cancer-related pain.

Morphine, the recommended drug for the management of moderate to severe cancer pain, is metabolized predominantly to the glucuronides morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). The quantitative clinical importance of these metabolites following the administration of oral morphine is unclear. This study investigates the relationship between plasma concentrations of morphine (M), M6G, M3G and clinical effects in patients receiving sustained release oral morphine for cancer-related pain. Peak and trough plasma concentrations of morphine and its metabolites were determined by high-performance liquid chromatography (HPLC). At corresponding time points, pain [Visual Analogue Scales (VAS), Verbal Rating Scales (VRS), Pain Relief Scores (PRS)] and toxicity (VAS and VRS) were assessed. Renal and liver function tests were performed. Forty-six patients were included in the study. There was a significant correlation between dose and both peak and trough plasma M, M6G and M3G (r > 0.60, P < 0.001 for each). Differences between peak and trough M, M6G, M3G, M+M6G, M6G:M, M3G:M and M3G:M6G were all significant (P < 0.001 for each). Pain was generally well controlled in the group, with a median VAS of 15 mm at the peak blood sampling time point. The differences between peak and trough values for VAS pain, VAS nausea and VAS drowsiness were not statistically significant (P = 0.078, 0.45 and 0.099, respectively). There were no differences in peak or trough morphine and metabolite concentrations or ratios between patients with low (< median) or high pain scores. Similarly, there was no significant relationship between high and low plasma concentrations and clinical effect. This study did not identify a simple relationship between plasma concentrations of morphine, morphine metabolites or metabolite ratios and clinical effects in patients with cancer and pain who were receiving chronic oral morphine therapy. Although overall pain control was good, there was marked interpatient variability in the dose of morphine and the plasma concentrations necessary to achieve this degree of analgesia.

Administration, Oral↗
PubMed2003

Routine drug monitoring of serum concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide do not predict clinical observations in cancer patients.

The clinical importance of routine drug monitoring of serum concentrations of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) during chronic morphine therapy is not established. We measured morphine, M6G and M3G serum concentrations in cancer pain patients receiving oral (n = 263, median dose 80 mg/24 hours) or subcutaneous (sc) (n = 35, median dose 110 mg/24 hours) morphine. Regression analyses were performed to investigate if serum concentrations of morphine, M3G and M6G predicted pain intensity (Brief Pain Inventory), health-related quality-of-life variables (EORTC QLQ-C30) and cognitive function (Mini-Mental Score). Serum concentrations were also compared in patients categorized as morphine 'treatment successes' and 'treatment failures'. We observed that serum concentrations of morphine, M6G or M3G did not predict pain intensity, cognitive function, nausea or tiredness. 'Treatment failures' caused by nausea, tiredness, cognitive failure or constipation did not have statistically significant different morphine, M6G and M3G serum concentrations than patients classified as 'treatment successes'. In conclusion, this study did not observe any concentration-effect relationships of morphine, M3G or M6G with pain intensity, nausea, constipation, tiredness or cognitive failure in blood samples obtained during routine clinical drug monitoring in cancer patients. This result suggests that therapeutic drug monitoring as a routine tool during chronic morphine treatment has limited value for clinical decision making.

Administration, Oral↗
PubMed1984

Morphine effects on spontaneous, nociceptive, antinociceptive and sensory evoked responses of parafasciculus thalami units in morphine naive and morphine dependent rats.

The present experiments used freely behaving animals previously implanted with permanent recording electrodes within the parafasciculus thalami (PF) and stimulation electrodes in nociceptive and antinociceptive areas. The spontaneous and the evoked activity in PF neurons following nociceptive, antinociceptive and sensory stimulation, as well as the effects of morphine and its antagonist naloxone on these inputs in morphine naive and morphine dependent animals, were investigated. The observations demonstrated that the spontaneous activity of PF neurons exhibits variable spontaneous firing rates which are affected by acute and chronic morphine treatment. The PF neuronal population exhibits neurophysiological activity characteristic of morphine dependence, tolerance and withdrawal from morphine. The PF receives mono-, oligo- and polysynaptic inputs from multiple sources, including regions associated with pain pathways which converge on PF cells, as well as from sites involved in pain suppression mechanisms, which supports the hypothesis of a role of the PF as a modulator of pain input. The nociceptive, antinociceptive and sensory inputs are not modified by chronic morphine treatment, but single doses of morphine have remarkable effects on those inputs in morphine naive and morphine dependent animals; naloxone reversed the morphine effects on the evoked activity.

Action Potentials↗
PubMed1993

Intrathecal morphine-3-glucuronide does not antagonize spinal antinociception by morphine or morphine-6-glucuronide in rats.

Morphine or morphine-6-glucuronide either alone or in combination with morphine-3-glucuronide was administered intrathecally to rats. Antinociceptive effects were evaluated with the tail flick and the hot plate tests. Motor function was tested using the rotarod test. Estimated ED50 from the dose-response curves for morphine and morphine-6-glucuronide showed about a 30 times more potent antinociceptive effect of morphine-6-glucuronide compared with morphine. Morphine-3-glucuronide had no antinociceptive effect. Simultaneous administration of morphine-3-glucuronide 5.0 micrograms did not show any significant effect on antinociception induced by morphine 1.0 microgram or morphine-6-glucuronide 0.05 microgram.

Analgesics↗