Papaver bracteatum is an important medicinal plant valued for its high content of thebaine and an alternative to P. somniferum for benzylisoquinoline alkaloid production. Salutaridinol 7-o-acetyltransferase (SalAT) is a key gene in morphinan alkaloids biosynthesis pathway. Over expression of SalAT gene was used for metabolic engineering in P. bracteatum hairy root cultures. Transcript level of the salutaridinol 7-o-acetyltransferase gene in transgenic hairy root lines increased up to 154 and 128 % in comparison with hairy roots without SalAT over expression and wild type roots, respectively. High performance liquid chromatography analysis showed that the transgenic hairy roots relatively improved levels of thebaine (1.28 % dry weight), codeine (0.02 % dry weight) and morphine (0.03 % dry weight) compared to those hairy roots without SalAT over expression. This suggests that P. bracteatum hairy roots expressing the SalAT gene could be potentially used for the production of valuable morphinan alkaloids.

PURPOSE:

Major spine surgery with multilevel instrumentation is followed by large amount of opioid consumption, significant pain and difficult mobilization in a population of predominantly chronic pain patients. This case-control study investigated if a standardized comprehensive pain and postoperative nausea and vomiting (PONV) treatment protocol would improve pain treatment in this population.

METHODS:

A new regimen with acetaminophen, NSAIDs, gabapentin, S-ketamine, dexamethasone, ondansetron and epidural local anesthetic infusion or patient controlled analgesia with morphine, was introduced in a post-intervention group of 41 consecutive patients undergoing multilevel (median 10) instrumented spinal fusions and compared with 44 patients in a pre-intervention group.

RESULTS:

Compared to patients in the pre-intervention group, patients treated according to the new protocol consumed less opioid on postoperative day (POD) 1 (P = 0.024) and 2 (P = 0.048), they were mobilized earlier from bed (P = 0.003) and ambulation was earlier both with and without a walking frame (P = 0.027 and P = 0.027, respectively). Finally, patients following the new protocol experienced low intensities of nausea, sedation and dizziness on POD 1-6.

CONCLUSIONS:

In this study of patients scheduled for multilevel spine surgery, it was demonstrated that compared to a historic group of patients receiving usual care, a comprehensive and standardized multimodal pain and PONV protocol significantly reduced opioid consumption, improved postoperative mobilization and presented concomitant low levels of nausea, sedation and dizziness.

BACKGROUND::

The authors tested the primary hypothesis that perioperative IV lidocaine administration during spine surgery (and in the postanesthesia care unit for no more than 8 h) decreases pain and/or opioid requirements in the initial 48 postoperative hours. Secondary outcomes included major complications, postoperative nausea and vomiting, duration of hospitalization, and quality of life.

METHODS::

One hundred sixteen adults having complex spine surgery were randomly assigned to perioperative IV lidocaine (2 mg·kg·h) or placebo during surgery and in the post-anesthesia care unit. Pain was evaluated with a verbal response scale. Quality of life at 1 and 3 months was assessed using the Acute Short-form (SF) 12 health survey. The authors initially evaluated multivariable bidirectional noninferiority on both outcomes; superiority on either outcome was then evaluated only if noninferiority was established.

RESULTS::

Adjusted mean pain scores were 4.4 (4.2-4.7) points on the verbal response scale for lidocaine and 5.3 (5.0-5.5) points for placebo (P < 0.001). Adjusted mean morphine equivalents were 55 (36-84) mg for lidocaine and 74 (49-111) mg for placebo (P = 0.12). Postoperative nausea and vomiting and the duration of hospitalization did not differ significantly. Patients given lidocaine had slightly fewer 30-day complications than patients given placebo (odds ratio [95% CI] of 0.91 [0.84-1.00]; P = 0.049). Patients given lidocaine had significantly greater SF-12 physical composite scores than placebo at 1 (38 [31-47] vs. 33 [27-42]; P = 0.002) and 3 (39 [31-49] vs. 34 [28-44]; P = 0.04) months, postoperatively.

CONCLUSION:

: IV lidocaine significantly improves postoperative pain after complex spine surgery.

Aims Cocaine and heroin are frequently co-abused in a combination known as speedball. Despite the relevance of the liver in the metabolism and detoxification of these drugs, little is known about the impact of speedball on liver function. Main methods In this work, we evaluated the effects of cocaine, morphine and morphine+cocaine (Mor+Coc) combination (1:1) in isolated rat liver mitochondria, upon glutamate/malate or succinate energization, in mitochondrial bioenergetics and oxidative stress-related parameters by using Clark O2, Ca(2+), TPP(+) and pH electrodes and by measuring thiobarbituric acid reactive substances (TBARS) and H2O2 production. Key findings Cocaine and Mor+Coc at the higher concentrations (1mM) similarly increased O2 consumption at state 2, state 4 and state oligomycin. In these conditions, maximum respiration was decreased only upon glutamate/malate energization, suggesting an involvement of complex I. Morphine (1mM) only increased state 2 respiration. Cocaine and Mor+Coc induced a similar decrease in maximum mitochondrial membrane potential and in ADP-induced depolarization, whereas morphine had no effect. The drugs and their combination similarly decreased mitochondrial ATPase activity and had no effect on Ca(2+)-induced permeability transition. Morphine and Mor+Coc prevented lipid peroxidation, since in these conditions there was a decrease in O2 consumption and in TBARS upon ADP/Fe(2+) stimulus, and a decrease in H2O2 formation, suggesting an antioxidant effect. Interestingly, heroin did not share morphine antioxidant properties. Significance Our results show that the sequential direct exposure of liver mitochondria to morphine and cocaine does not alter the effects observed in the presence of each drug alone.

BACKGROUND:

Teas from the husk fiber of Cocos nucifera are used in the folk medicine to treat arthritis and other inflammatory processes. Some works show that some varieties have biological activities. However, one of the main variety of the species, C. nucifera var. typica, known in Brazil as "gigante", was not studied yet. Thus, this study evaluates if this variety has the anti-inflammatory and antimicrobial activities already reported in other varieties.

METHODS:

C. nucifera aqueous crude extract (10, 50, and 100 mg/kg) and the reference drugs morphine (1 mg/kg) and acetylsalicylic acid (100 mg/kg) were evaluated in models of inflammation (formalin-induced licking and subcutaneous air pouch). The antioxidant activity was evaluated by 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) photometric assay and compared with those of the standards (quercetin, rutin, and ascorbic acid). The extract was also screened against Candida albicans, Escherichia coli, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus (MRSA), in the agar diffusion method. The minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) were determined by the broth micro-dilution assay. Activities of combinations of the extract and antibiotics (methicillin or vancomycin) against MRSA were evaluated using checkerboard assays.

RESULTS:

The extract significantly inhibited the time that the animals spent licking the formalin-injected paws (second phase). The extract also inhibited the inflammatory process induced by subcutaneous carrageenan injection by reducing cell migration, protein extravasation, and TNF-alpha production. Additionally, the extract showed an antioxidant potential in vitro as good as standards in their antioxidant activity. The extract was active only against S. aureus and MRSA. MIC and the bactericidal concentrations were identical (1,024 mug/ml). The extract and methicillin acted synergistically against the clinical MRSA isolate, whereas an indifferent effect was detected when the extract was combined with vancomycin.

CONCLUSIONS:

The extract exhibits anti-inflammatory activity through the inhibition of the cell migration. The mixture of extract constituents and methicillin could lead to the development of a new combination antibiotic against MRSA infections.

To examine the effects of an intensive 2-day course on physicians' prescribing of opioids.Population-based retrospective observational study.College of Physicians and Surgeons of Ontario (CPSO) in Toronto.Ontario physicians who took the course between April 1, 2000, and May 30, 2008.A 2-day opioid-prescribing course with a maximum of 12 physician participants. Educational methods included didactic presentations, case discussions, and standardized patients. A detailed syllabus and office materials were provided.Participants were matched with control physicians using specific variables. The primary outcome was the rate of opioid prescribing, expressed as milligrams of morphine equivalent per quarter.One hundred thirty-eight course participants (120 family physicians, 15 specialists, and 3 physicians whose status was uncertain) were eligible for analysis. Of these, 68.1% were self-referred and 31.9% were referred by the CPSO. Overall, among physicians referred by the CPSO, the rate of opioid prescribing decreased dramatically in the year before course participation compared with matched control physicians. The course had no added effect on the rate of physicians' opioid prescribing in the subsequent 2 years. There was no statistically significant effect on the rate of opioid prescribing observed among the self-referred physicians. Among 15 of the self-referred physicians who, owing to the high quantities of opioids they prescribed, were not matched with control physicians, the rate of opioid prescribing decreased by 43.9% in the year following course completion.Physicians markedly reduced the quantities of opioids they prescribed after medical regulators referred them to an opioid-prescribing course. The course itself did not lead to significant additional reductions; however, a subgroup of physicians who prescribed high quantities of opioids might have responded to what was taught in the course.

Migraine is a highly prevalent, disabling and complex episodic brain disorder whose pathogenesis is poorly understood, due in part to the lack of valid animal models. Here we report behavioral evidence of hallmark migraine features, photophobia and unilateral head pain, in transgenic knock-in mice bearing human familial hemiplegic migraine, type 1 (FHM-1) gain-of-function missense mutations (R192Q or S218L) in the Cacna1a gene encoding the CaV2.1 calcium channel α1 subunit. Photophobia was demonstrated using a modified elevated plus maze in which the safe closed arms were brightly illuminated; mutant mice avoided the light despite showing no differences in the standard (anxiety) version of the test. Multiple behavioral measures suggestive of spontaneous head pain were found in 192Q mutants subjected to novelty and/or restraint stress. These behaviors were: (1) more frequent in mutant versus wildtype mice; (2) lateralized in mutant but not in wildtype mice; (3) more frequent in females versus males; and (4) dose-dependently normalized by systemic administration of 2 different acute analgesics, rizatriptan and morphine. Furthermore, some of these behaviors were found to be more frequent and severe in 218L compared to 192Q mutants, consistent with the clinical presentation in humans. We suggest that Cacna1a transgenic mice can experience migraine-related head pain and can thus serve as unique tools to study the pathogenesis of migraine and test novel antimigraine agents.

Opiate addiction remains intractable in a large percentage of patients, and relapse is the biggest hurdle to recovery. Many studies have identified a central role of the nucleus accumbens (NAc) in addiction. Deep brain stimulation (DBS) has the advantages of being reversible, adjustable, and minimally invasive, and it has become a potential neurobiological intervention for addiction. The purpose of our study was to investigate whether high-frequency DBS in the NAc effectively attenuates the reinstatement of morphine seeking in morphine-primed rats.A morphine-dependent group of rats was given increasing doses of morphine during conditioned place preference training. A control group of rats was given equal volumes of saline. After the establishment of this model, withdrawal syndromes were precipitated in these two groups by administering naloxone, and the differences in withdrawal symptoms between the groups were analyzed. Electrodes for DBS were implanted in the bilateral shell of the NAc in the experimental group. The rats were stimulated daily in the NAc for 5 hours per day over 30 days. Changes in the conditioned place preference test and withdrawal symptoms in the rats were investigated and place navigation studies were performed using the Morris water maze. The data were assessed statistically with one-way analysis of variance (ANOVA) followed by Tukey's tests for multiple post hoc comparisons.High-frequency stimulation of the bilateral NAc prevented the morphine-induced reinstatement of morphine seeking in the conditioned place preference test. The time spent in the white compartment by rats following 30 days of DBS ((268.25 ± 25.07) seconds) was not significantly different compared with the time spent in the white compartment after relapse was induced by morphine administration ((303.29 ± 34.22) seconds). High-frequency stimulation of the bilateral NAc accelerated the innate decay of drug craving in morphine-dependent rats without significantly influencing learning and memory.Bilateral high-frequency stimulation of the shell of the NAc may be useful as a novel therapeutic modality for the treatment of severe morphine addiction.

Purpose:

To evaluate the safety and efficacy of spinal anesthesia comparing to general anesthesia in patients who underwent percutaneous nephrolithotomy (PCNL). Material and Method: 100 patients with American Anethesiological association (ASA) score < 3 were randomly divided into two groups according to the type of anesthesia. Spinal anesthesia was done using injection of 0.25 mg/kg bupivacaine 0.5% in intrathecal space and no opium (fentanyl) agent was used. All procedures were done in prone position. Stone access was made by using fluoroscopic guidance and tract dilated using single-stage technique. All patients received a solution including 1 mg/kg morphine in every 100 cc normal saline through the volumetric pump during three hours post-PCNL period in the recovery room. Afterwards, morphine (0.05 mg/kg) was injected only according to the verbal rating scale (VRS) greater than 3 after discharge of recovery room until 24 hours after surgery.

Results:

The two groups were matched by mean age, distribution of stone location and stone burden. Mean operative time, hospital stay, stone free rate and mean hemoglobin drop were comparable between two groups. The rate of complications according to Clavien grading system was nearly similar in both groups. Mean analgesic requirement during 24 hours after PCNL was 6.8 mg in spinal group and 13.2 mg in general group (p value < 0.001).

Conclusion:

It seems that using spinal anesthesia by intrathecal injection of local anesthetic solutions vs. general anesthesia has comparable surgical outcomes and reduces requirement to analgesia after PCNL in the early postoperative period.