Morphine pharmacokinetics and pain assessment in premature newborns

To determine morphine pharmacokinetics in premature neonates varying in postconceptional age (PCA) and evaluate behavioral pain response in relationship to serum morphine concentrations.

Applications of dihydroarenediols to chemoenzymatic synthesis : approaches to total synthesis of morphine alkaloids

The present studies describe, as a primary goal, our recent progess toward the synthesis of morphine alkaloids from aromatic precursors. Model substrates were synthesized which allowed investigation into Diels-Alder, radical cascade, and palladium-catalyzed bond-forming reactions as possible routes to the morphine alkaloid skeleton. As a secondary objective, three separate series of aromatic substrates were subjected to whole-cell oxidation with Escherichia coli JM 109 (pDTG601), a recombinant organism over-expressing the enzyme toluene dioxygenase. Included in this study were bromothioanisoles, dibromobenzenes, and cyclopropylbenzene derivatives. The products of oxidation were characterized by chemical conversion to known intermediates. The synthetic utility of one of these bacterial metabolites, derived from oxidation of o-dibromobenezene, was demonstrated by chemical conversion to (-)conduritol E.

Fungal biotransformation of morphine alkaloids

The purpose of the study was to determine the ability of certain fungi to biotransform morphine alkaloids into medicinally relevant intermediates. Fungal strains screened for their ability to affect biotransformation of morphine alkaloids include Cunninghamella echinulata, Helicostylum pirijorme, Pycnoporus sanguinea, Pycnoporus cinnabarina, Curvularia lunata and Sporotrichum sulfurescens. The research demonstrated that Cunninghamella echinulata N-demethylated thebaine, hydrocodone, codeine, oripavine and oxycodone into corresponding nor-compounds in varying yields. The study further focused on the characterization of the enzyme responsible for the biotransformation of thebaine into northebaine by Cunninghamella echinulata. The study clearly showed that incubation of the fungal culture with thebaine over a period of 48 hours was required to activate the biotransformation process. The biotransformation studies with [14C] labeled thebaine showed that Ndemethylation by Cunningham ella echinulata does not involve O-demethylation followed by methyl group transfer as suggested in previous studies.

Development of thermally stable versions of the Burgess Reagent : approaches to the chemoenzymatic total synthesis of morphine

The present studies describe our recent work on expanding the use of the Burgess reagent and its reaction with oxiranes. Several new variants of the Burgess reagent and its chiral auxiliary version were evaluated for their thermal stability by NMR spectroscopy. Three new versions of the reagent were synthesized and their stability was determined. The reactivity of all five Burgess reagents was compared in a dehydration reaction and reactions with epoxides and diols. Progress toward a chemoenzymatic synthesis of morphine is also included in this report. The synthesis began with the whole cell oxidation of bromobenzene by Escherichia coli JMI09(pDTG601). The preparation of several precursors for a key step involving the lohnson-Claisen rearrangement and progress toward the total synthesis are described.

Chemoenzymatic Total Synthesis of Morphine alkaloids: Synthesis of Dihydrocodeine and Hydrocodone via a Double Claisen Strategy and ent-Hydromorphone via an Oxidative Dearomatization/intramolecular [4+2] Cycloaddition

This thesis describes the chemoenzymatic synthesis of three morphine alkaloids. The total synthesis of dihydrocodeine and hydrocodone was accomplished starting from bromobenzene in 16 and 17 steps, respectively. The key steps included a microbial oxidation of bromobenzene by E. coli JM109 (pDTG601A), a Kazmaier-Claisen rearrangement of glycinate ester to generate C-9 and C-14 stereo centers, a Johnson-Claisen rearrangement to set the C-13 quaternary center, and a C-10/C-11 ring closure via a Friedel-Crafts reaction. In addition, the total synthesis of ent-hydromorphone starting from β-bromoethylbenzene in 12 steps is also described. The key reactions included the enzymatic dihydroxylation of β-bromoethylbenzene to the corresponding cis-cyclohexadienediol, a Mitsunobu reaction, and an oxidative dearomatization followed by an intramolecular [4+2] cycloaddition.

Epidural analgesia with morphine or buprenorphine in ponies with lipopolysaccharide (LPS)-induced carpal synovitis

This study evaluated the analgesia effects of the epidural administration of 0.1 mg/kg bodyweight (BW) of morphine or 5 mu g/kg BW of buprenorphine in ponies with radiocarpal joint synovitis. Six ponies were submitted to 3 epidural treatments: the control group (C) received 0.15 mL/kg BW of a 0.9% sodium chloride (NaCl) solution; group M was administered 0.1 mg/kg BW of morphine; and group B was administered 5 mu g/kg BW of buprenorphine, both diluted in 0.9% NaCl to a total volume of 0.15 mL/kg BW administered epidurally at 10 s/mL. The synovitis model was induced by injecting 0.5 ng of lipopolysaccharide (LPS) in the left or right radiocarpal joint. An epidural catheter was later introduced in the lumbosacral space and advanced up to the thoracolumbar level. The treatment started 6 h after synovitis induction. Lameness, maximum angle of carpal flexion, heart rate, systolic arterial pressure, respiratory rate, temperature, and intestinal motility were evaluated before LPS injection (baseline), 6 h after LPS injection (time 0), and 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 h after treatments. Although the model of synovitis produced clear clinical signs of inflammation, the lameness scores in group C were different from the baseline for only up to 12 h. Both morphine and buprenorphine showed a reduction in the degree of lameness starting at 0.5 and 6 h, respectively. Reduced intestinal motility was observed at 0.5 h in group M and at 0.5 to 1 h in group B. Epidural morphine was a more effective analgesic that lasted for more than 12 h and without side effects. It was concluded that morphine would be a valuable analgesic option to alleviate joint pain in the thoracic limbs in ponies.

Morphine treatment during pregnancy modulates behavioral selection in lactating rats

Previous studies have demonstrated that treatment of postpartum female rats with morphine inhibits maternal behavior and stimulates foraging. Exposure to drugs of abuse may result in a progressive enhancement of their reinforcing effects. Puerperal treatment with morphine leads to reverse tolerance to this drug. The present study investigated whether repeated morphine treatment during late pregnancy may influence the effects of different morphine dosages on behavioral selection in lactating rats. Females were simultaneously exposed to pups and insects, and the choice between taking care of the pups and hunting insects was observed. Female Wistar rats were treated with morphine (3.5 mg/kg/day, subcutaneous [s.c.]) or saline for 5 days beginning on pregnancy day 17. On day 5 of lactation, animals were acutely challenged with morphine (0.5, 1.0, or 1.5 mg/kg, s.c.; MM0.5, MM1.0, and MM1.5 groups, respectively) or saline (MS group) and tested for predatory hunting and maternal behavior. Control groups were pretreated with saline and challenged with morphine (SM0.5, SM1.0, and SM1.5 groups) or saline (SS group). Animals treated with morphine during late pregnancy and acutely challenged with 1.0 mg/kg morphine (MM1.0 group) exhibited significantly decreased maternal behavior and enhanced hunting. This effect was not evident with the 0.5 mg/kg dose. The 1.5 mg/kg morphine dose decreased maternal behavior and increased hunting in both the MM1.5 group and in animals challenged with morphine after previous saline treatment (SM1.5 group). These results provide evidence of plasticity of the opioidergic role in behavioral selection during lactation. (C) 2010 Elsevier Inc. All rights reserved.

Morphine peripheral analgesia depends on activation of the PI3K gamma/AKT/nNOS/NO/K(ATP) signaling pathway

Morphine is one of the most prescribed and effective drugs used for the treatment of acute and chronic pain conditions. In addition to its central effects, morphine can also produce peripheral analgesia. However, the mechanisms underlying this peripheral action of morphine have not yet been fully elucidated. Here, we show that the peripheral antinociceptive effect of morphine is lost in neuronal nitric-oxide synthase null mice and that morphine induces the production of nitric oxide in primary nociceptive neurons. The activation of the nitric-oxide pathway by morphine was dependent on an initial stimulation of PI3K gamma/AKT protein kinase B (AKT) and culminated in increasedactivation of K(ATP) channels. In the latter, this intracellular signaling pathway might cause a hyperpolarization of nociceptive neurons, and it is fundamental for the direct blockade of inflammatory pain by morphine. This understanding offers new targets for analgesic drug development.

Expression of matrix metalloproteinases, type IV collagen, and interleukin-10 in rabbits treated with morphine after lamellar keratectomy

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Comparison of analgesia provided by lidocaine, lidocaine-morphine or lidocaine-tramadol delivered epidurally in dogs following orchiectomy

ObjectiveTo evaluate and compare the postoperative analgesia provided by epidural lidocaine, lidocaine/morphine or lidocaine/tramadol in dogs following elective orchiectomy.Study designProspective experimental trial.AnimalsThirty-six mongrel dogs aged 2-8 years old, weighing 6.6-22 kg.MethodsThe dogs received 6.0 mg kg-1 of lidocaine combined with 1.0 mg kg-1 of tramadol, 0.1 mg kg-1 of morphine or 0.01 mL kg-1 of 0.9% NaCl epidurally. Analgesia was assessed at 4, 8, 12, 18 and 24 hours (T4, T8, T12 and T24) after the offset of lidocaine using a scale composed of physiologic and behavioral parameters. Rescue analgesia with morphine (0.2 mg kg-1, IM) was performed if the evaluation score exceeded 10 during the postoperative period. The scores over time were analyzed using the Friedman's two-way analysis of variance and the comparison between groups was made by the Kruskal-Wallis test with statistical significances accepted if p < 0.05.ResultsThere were no differences in the pain scores between the morphine and tramadol groups over time and no rescue analgesia was administered. In the NaCl group, rescue analgesia was needed at T4, T8 and T12. Within this group, the final evaluation times (T18 and T24) had lower pain scores than at T4, T8 and T12.Conclusions and clinical relevanceEpidural lidocaine/tramadol provided an analgesic effect comparable to that of epidural lidocaine/morphine during the first 12 hours after surgical castration without substantial side effects, suggesting that tramadol may be an effective postoperative analgesic in dogs submitted to this surgical procedure.

Postoperative analgesic effects of epidural administration of neostigmine alone or in combination with morphine in ovariohysterectomized dogs

Objective-To evaluate analgesic effects of epidurally administered neostigmine alone or in combination with morphine in dogs after ovariohysterectomy.Animals-40 healthy bitches.Procedures-After acepromazine premedication, anesthesia was induced. Dogs randomly received 1 of the following 4 epidural treatments 30 minutes before ovariohysterectomy (n = 10/group): saline (0.9% NaCl) solution (control), morphine (0.1 mg/kg), neostigmine (10 pg/kg), or morphine-neostigmine (0.1 mg/kg and 10 pg/kg, respectively). Analgesia was assessed for 24 hours after surgery by use of a visual analogue.scale (VAS; scale of 0 to 10) or numeric descriptive scale (NDS; scale of 0 to 24) and by the need for supplemental analgesia (morphine [0.5 mg/kg, IM] administered when VAS was >= 4 or NDS was >= 8).Results-Significantly more control dogs (n = 8) received supplemental analgesia, compared with the number of neostigmine-treated dogs (1); no dogs in the remaining groups received supplemental analgesia. Compared with values for the control dogs, the NDS scores were lower for morphine-neostigmine-treated dogs (from 2 to 6 hours and at 12 hours) and for morphine-treated dogs (all time points). The NDS scores were lower for morphine-treated dogs at 3, 12, and 24 hours, compared with values for neostigmine-treated dogs. The VAS was less sensitive than the NDS for detecting differences among groups.Conclusions and Clinical Relevance-Epidurally administered neostigmine reduced the use of supplemental analgesia after ovariohysterectorny in dogs. However, analgesic effects were less pronounced than for epidurally administered morphine or morphine-neostigmine. Adding neostigmine to epidurally administered morphine did not potentiate opioid-induced analgesia.

Effect of intravenous alizapride on spinal morphine-induced pruritus

Background. This double-blind study was undertaken to determine whether alizapride inhibits spinal morphine-induced pruritus.Methods. Eighty-four patients undergoing Caesarean section under spinal anaesthesia (100 mg of hyperbaric lidocaine 5% plus morphine 0.2 mg) were randomly allocated to one of two groups. just after birth, alizapride-50 mg (alizapride group) or metoclopramide 10 mg (metoclopramide group) were injected i.v. Patients were assessed after surgery for pruritus (absent, mild, moderate or severe) or other untoward symptoms.Results. In the metoclopramide group, pruritus was absent in 5 (12%) patients, mild in 23 (55%), moderate in 11 (26%), and severe in 3 (7%), while in the alizapride group, these incidences were, respectively, 5 (12%), 33 (79%), 4 (10%), and 0 (P=0.045, chi(2)-test). There was no difference in the incidence of side-effects, which were all minor.Conclusions. Alizapride reduced the severity of morphine-induced pruritus.

Effects of subcutaneous methadone, morphine, buprenorphine or saline on thermal and pressure thresholds in cats

This study compared pressure and thermal thresholds after administration of three opioids in eight cats. Pressure stimulation was performed via a bracelet taped around the forearm. Three ball-bearings were advanced against the forearm by inflation of a modified blood pressure bladder. Pressure in the cuff was recorded at the end point (leg shake and head turn). Thermal threshold was tested as previously reported using a heated probe held against the thorax [Dixon et al. (2002) Research in Veterinary Science, 72, 205]. After baseline recordings, each cat received subcutaneous methadone 0.2 mg/kg, morphine 0.2 mg/kg, buprenorphine 0.02 mg/kg or saline 0.3 mL in a four period cross-over study. Measurements were made at 15, 30, 45 min and 1, 2, 3, 4, 8, 12 and 24 h after the injection. Data were analysed by ANOVA (P < 0.05). There were no significant changes in thresholds after saline. Thermal threshold increased at 45 min after buprenorphine (maximum 2.8 +/- 3 degrees C), 1-3 h after methadone (maximum 3.4 +/- 1.9 degrees C) and 45 min to 1 h (maximum 3.4 +/- 2 degrees C) after morphine. Pressure threshold increased 30-45 min (maximum 238 +/- 206 mmHg) after buprenorphine, 45-60 min after methadone (maximum 255 +/- 232 mmHg) and 45-60 min and 3-6 h (maximum 255 +/- 232 mmHg) after morphine. Morphine provided the best analgesia, and methadone appears a promising alternative. Buprenorphines limited effect was probably related to the subcutaneous route of administration. Previously, buprenorphine has produced much greater effects when given by other routes.

Comparative study on the sedative effects of morphine, methadone, butorphanol or tramadol, in combination with acepromazine, in dogs

To compare the effects of morphine (MOR), methadone (MET), butorphanol (BUT) and tramadol (TRA), in combination with acepromazine, on sedation, cardiorespiratory variables, body temperature and incidence of emesis in dogs.Prospective randomized, blinded, experimental trial.Six adult mixed-breed male dogs weighing 12.0 +/- 4.3 kg.Dogs received intravenous administration (IV) of acepromazine (0.05 mg kg(-1)) and 15 minutes later, one of four opioids was randomly administered IV in a cross-over design, with at least 1-week intervals. Dogs then received MOR 0.5 mg kg(-1); MET 0.5 mg kg(-1); BUT 0.15 mg kg(-1); or TRA 2.0 mg kg(-1). Indirect systolic arterial pressure (SAP), heart rate (HR), respiratory rate (f(R)), rectal temperature, pedal withdrawal reflex and sedation were evaluated at regular intervals for 90 minutes.Acepromazine administration decreased SAP, HR and temperature and produced mild sedation. All opioids further decreased temperature and MOR, BUT and TRA were associated with further decreases in HR. Tramadol decreased SAP whereas BUT decreased f(R) compared with values before opioid administration. Retching was observed in five of six dogs and vomiting occurred in one dog in MOR, but not in any dog in the remaining treatments. Sedation scores were greater in MET followed by MOR and BUT. Tramadol was associated with minor changes in sedation produced by acepromazine alone.When used with acepromazine, MET appears to provide better sedation than MOR, BUT and TRA. If vomiting is to be avoided, MET, BUT and TRA may be better options than MOR.