Cardioprotection conferred by exercise training is blunted by blockade of the opioid system

OBJECTIVES:

To investigate the effect of opioid receptor blockade on the myocardial protection conferred by chronic exercise and to compare exercise training with different strategies of myocardial protection (opioid infusion and brief periods of ischemia-reperfusion) preceding irreversible left anterior descending coronary ligation.

INTRODUCTION:

The acute cardioprotective effects of exercise training are at least partly mediated through opioid receptor-dependent mechanisms in ischemia-reperfusion models.

METHODS:

Male Wistar rats (n = 76) were randomly assigned to 7 groups: (1) control; (2) exercise training; (3) morphine; (4) intermittent ischemia-reperfusion (three alternating periods of left anterior descending coronary occlusion and reperfusion); (5) exercise training+morphine; (6) naloxone (a non-selective opioid receptor blocker) plus morphine; (7) naloxone before each exercise-training session. Myocardial infarction was established in all groups by left anterior descending coronary ligation. Exercise training was performed on a treadmill for 60 minutes, 5 times/week, for 12 weeks, at 60% peak oxygen (peak VO₂). Infarct size was histologically evaluated.

RESULTS:

Exercise training significantly increased exercise capacity and ΔVO₂ (VO₂ peak − VO₂ rest) (p<0.01 vs. sedentary groups). Compared with control, all treatment groups except morphine plus naloxone and exercise training plus naloxone showed a smaller infarcted area (p<0.05). No additional decrease in infarct size occurred in the exercise training plus morphine group. No difference in myocardial capillary density (p = 0.88) was observed in any group.

CONCLUSIONS:

Exercise training, morphine, exercise training plus morphine and ischemia-reperfusion groups had a smaller infarcted area than the control group. The effect of chronic exercise training in decreasing infarct size seems to occur, at least in part, through the opioid receptor stimulus and not by increasing myocardial perfusion.     

Benzodiazepine Receptor Agonists Cause Drug-Specific and State-Specific Alterations in EEG Power and Acetylcholine Release in Rat Pontine Reticular Formation

Study Objectives:

Benzodiazepine (BDZ) and non-benzodiazepine (NBDZ) hypnotics enhance GABAergic transmission and are widely used for the treatment of insomnia. In the pontine reticular formation (PRF), GABA inhibits rapid eye movement (REM) sleep and acetylcholine (ACh) release. No previous studies have characterized the effects of BDZ and NBDZ hypnotics on ACh release in the PRF. This study tested 2 hypotheses: (1) that microdialysis delivery of zolpidem, eszopiclone, and diazepam to rat PRF alters ACh release in PRF and electroencephalographic (EEG) delta power and (2) that intravenous (IV) administration of eszopiclone to non-anesthetized rat alters ACh release in the PRF, sleep, and EEG delta power.

Design:

A within- and between-groups experimental design.

Setting:

University of Michigan.

Patients or Participants:

Adult male Crl:CD*(SD) (Sprague-Dawley) rats (n = 57).

Interventions:

In vivo microdialysis of the PRF in rats anesthetized with isoflurane was used to derive the concentration-response effects of zolpidem, eszopiclone, and diazepam on ACh release. Chronically instrumented rats were used to quantify the effects of eszopiclone (3 mg/kg, IV) on ACh release in the PRF, sleep-wake states, and cortical EEG power.

Measurements and Results:

ACh release was significantly increased by microdialysis delivery to the PRF of zolpidem and eszopiclone but not diazepam. EEG delta power was increased by zolpidem and diazepam but not by eszopiclone administered to the PRF. Eszopiclone (IV) decreased ACh release in the PRF of both anesthetized and non-anesthetized rats. Eszopiclone (IV) prevented REM sleep and increased EEG delta power.

Conclusion:

The concentration-response data provide the first functional evidence that multiple GABA_A receptor subtypes are present in rat PRF. Intravenously administered eszopiclone prevented REM sleep, decreased ACh release in the PRF, and increased EEG delta power. The effects of eszopiclone are consistent with evidence that ACh release in the PRF is lower during NREM sleep than during REM sleep, and with data showing that cholinergic stimulation of the PRF activates the cortical EEG.

Citation:

Hambrecht-Wiedbusch VS; Gauthier EA; Baghdoyan HA; Lydic R. Benzodiazepine receptor agonists cause drug-specific and state-specific alterations in EEG power and acetylcholine release in rat pontine reticular formation. SLEEP 2010;33(7):909-918.     

Effect of wound infiltration with bupivacaine on pulmonary function after elective lower abdominal operations

Background

Subcutaneous or intrafascial wound infiltration of local anaesthetic with systemic opioids has been shown to enhance patient comfort with improved analgesia and reduced opioid requirements.

Objective

To demonstrate improved pulmonary function when postoperative analgesia was provided by combined bupivacaine wound infiltration and systemic opioid.

Methods

In a prospective, randomized, placebo-controlled study, 46 patients (23 per group) scheduled for elective gynaecological surgery under general anaesthesia had subcutaneous and intrafascial wound infiltration of 40 ml, 0.25% bupivacaine (study patients) or 40 ml 0.9% saline (control) just before the end of surgery. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and peak expiratory flow rate (PEFR) were done before surgery and at 6, 12 and 24 hours postoperatively. Student''s T and chi-square tests were used for tests of significance set at P < 0.05.Postoperative analgesia was provided with intramuscular morphine 0.15mg/kg 4hourly and 10mg/kg of intravenous paracetamol as rescue analgesia.

Results

PEFR, FVC and FEV1 were reduced in both the control and study groups but the reduction was greater in the control group.

Conclusion

Bupivacaine wound infiltration produced statistically significant elevations in pulmonary function tests results at all assessment periods.     

Opioid-prescribing Practices in Chronic Cancer Pain in a Tertiary Care Pain Clinic

Introduction:

Under treatment of pain is a recognized global issue. Opioid analgesic medication is the mainstay of treatment in cancer patients as per the World Health Organization (WHO) pain relief ladder, yet 50% of cancer patients worldwide do not receive adequate pain relief or are undertreated.

Aim:

The aim of this study was to audit the ongoing opioid-prescribing practices in our tertiary cancer pain clinic during January–June 2010.

Materials & Methods:

The prescribed type of opioid, dose, dosing interval, and laxatives details were analyzed.

Results:

Five hundred pain files were reviewed and 435 were found complete for audit. Three hundred forty-eight (80%) patients were prescribed opioids. Two hundred fifty-nine (74.4%) received weak opioids while 118 (33.9%) received strong opioids. A total of 195 (45%) patients had moderate and 184 (42%) had severe pain. Ninety-three (26.7%) patients received morphine; however, only 31.5% (58 of 184) in severe pain received morphine as per the WHO pain ladder. Only 73 of 93 (78.4%) patients received an adequate dose of morphine with an adequate dosing interval and only 27 (29%) were prescribed laxatives with morphine.

Conclusion:

This study shows that the under treatment of pain and under dosing of opioids coupled with improper side effect management are major issues.     

Deep vein thromboses in users of opioid drugs: incidence, prevalence, and risk factors

Background

Users of illicit opioids are at increased risk of hospital admission for deep vein thromboses (DVTs); however, the community prevalence, risk factors, and complications of DVTs in this group are poorly understood.

Aim

This study aimed to describe the prevalence of previous DVT for users of opioids in primary care; provide age- and sex-adjusted annual incidence rates of DVT; and explore factors associated with DVT, concordance with subsequent treatment, and complications.

Design

A retrospective analysis of DVT prevalence and incidence, and analysis of risk factors for DVT using Poisson regression of incidence rates.

Method

A review of 734 patients in treatment for opioid addiction, who were registered to a single, specialised primary care practice in Middlesbrough, England.

Results

The prevalence of previous DVT in users of opioids was 13.9% (95% confidence interval [CI] = 11.5 to 16.6) with an annual incidence rate of 3.2% (95% CI = 2.6 to 3.7). The incidence rate increased with age and for female users; an exploration of risk factors suggests that rising age, female sex, sex-worker status, and intravenous delivery all independently increase the risk of DVT. Concordance with treatment appeared reasonable and, compared with DVT in groups of people who do not use drugs, there was no evidence of increased risk of pulmonary embolism. Participants with previous DVT reported lower health and wellbeing scores.

Conclusion

Primary care providers should be aware of the considerably increased risk of DVT and its sequelae in users of intravenous drugs. Evidence for effective primary care prevention and the effective management of DVT complications is lacking; until this emerges, vigilance on the part of clinicians may help to minimise harm.     

Analgesic mechanism of electroacupuncture in an arthritic pain model of rats: a neurotransmitter study

Purpose

We investigated what kinds of neurotransmitters are related with electroacupuncture (EA) analgesia in an arthritic pain model of rats.

Materials and Methods

One hundred rats were assigned to six groups: control, EA, opioid, adrenergic, serotonin and dopamine group. A standardized model of inflammatory arthritis was produced by injecting 2% carrageenan into the knee joint cavity. EA was applied to an acupoint for 30 min in all groups except fo the control group. In the opioid, adrenergic, serotonin and dopamine groups, each receptor antagonist was injected intraperitoneally to their respective group before initiating EA.

Results

In the opioid receptor antagonist group, adrenergic receptor antagonist group, serotonin receptor antagonist group, dopamine receptor antagonist group and the control group weight-bearing force decreased significantly from 30 min to 180 min after EA in comparison with the EA group.

Conclusion

The analgesic effects of EA are related to opioid, adrenergic, serotonin and dopamine receptors in an arthritic pain model of rats.     

Dexamethasone versus a combination of dexamethasone and ondansetron as prophylactic antiemetic in patients receiving intrathecal morphine for caesarean section

Background

Intrathecal morphine for caesarean delivery provides excellent postoperative analgesia but it is commonly associated with nausea and vomiting. This prospective, randomized, double blind study was carried out to compare the effectiveness of a combination of dexamethasone and ondansetron with dexamethasone alone for prevention of postoperative nausea and vomiting (PONV) following intrathecal morphine injection for caesarean section.

Methods

A total of 108 parturients aged 18–40 years for elective caesarean section were randomized into 2 groups (n=54) to receive either intravenous dexamethasone 8mg (Group A) or a combination of intravenous dexamethasone 8mg and ondansetron 4mg (group B). The study drug for each group consisted of 0.5% hyperbaric bupivacaine and 0.2mg morphine. The primary outcome variables were postoperative nausea and vomiting (PONV) which were assessed for a period of 24 hours. The patient''s vital signs were monitored and documented.

Results

The incidence of nausea and vomiting was significantly reduced in patients who received a combination of dexamethasone and ondansetron compared with dexamethasone alone (9.3% Vs 37%, respectively, P = 0.003).

Conclusion

This study showed that a combination of dexamethasone and ondansetron administered prophylactically significantly reduced the incidence of PONV in pregnant women on intrathecal morphine for caesarean section.     

Intrathecal Morphine Plus General Anesthesia in Cardiac Surgery: Effects on Pulmonary Function, Postoperative Analgesia, and Plasma Morphine Concentration

OBJECTIVES:

To evaluate the effects of intrathecal morphine on pulmonary function, analgesia, and morphine plasma concentrations after cardiac surgery.

INTRODUCTION:

Lung dysfunction increases morbidity and mortality after cardiac surgery. Regional analgesia may improve pulmonary outcomes by reducing pain, but the occurrence of this benefit remains controversial.

METHODS:

Forty-two patients were randomized for general anesthesia (control group n=22) or 400 μg of intrathecal morphine followed by general anesthesia (morphine group n=20). Postoperative analgesia was accomplished with an intravenous, patient-controlled morphine pump. Blood gas measurements, forced vital capacity (FVC), forced expiratory volume (FEV), and FVC/FEV ratio were obtained preoperatively, as well as on the first and second postoperative days. Pain at rest, profound inspiration, amount of coughing, morphine solicitation, consumption, and plasma morphine concentration were evaluated for 36 hours postoperatively. Statistical analyses were performed using the repeated measures ANOVA or Mann-Whiney tests (*p<0.05).

RESULTS:

Both groups experienced reduced FVC postoperatively (3.24 L to 1.38 L in control group; 2.72 L to 1.18 L in morphine FEV₁ (p=0.085), group), with no significant decreases observed between groups. The two groups also exhibited similar results for FEV₁/FVC (p=0.68) and PaO₂/FiO₂ ratio (p=0.08). The morphine group reported less pain intensity (evaluated using a visual numeric scale), especially when coughing (18 hours postoperatively: control group= 4.73 and morphine group= 1.80, p=0.001). Cumulative morphine consumption was reduced after 18 hours in the morphine group (control group= 20.14 and morphine group= 14.20 mg, p=0.037). The plasma morphine concentration was also reduced in the morphine group 24 hours after surgery (control group= 15.87 ng.mL⁻¹ and morphine group= 4.08 ng.mL⁻¹, p=0.029).

CONCLUSIONS:

Intrathecal morphine administration did not significantly alter pulmonary function; however, it improved patient analgesia and reduced morphine consumption and morphine plasma concentration.     

The Impact of High Sensitivity C-Reactive Protein Level on Coronary Artery Spasm as Assessed by Intracoronary Acetylcholine Provocation Test

Purpose

High sensitive C-reactive protein (hs CRP) is well known as a strong risk factor of cardiovascular disease (CVD). The aim of this study is to evaluate the impact of elevated hs CRP on coronary artery spasm (CAS) as assessed by intracoronary acetylcholine (ACh) provocation test.

Materials and Methods

A total of 1729 consecutive patients without significant CVD who underwent coronary angiography and intracoronary ACh test between November 2004 and August 2010 were analyzed. The patients were divided into five groups according to quintiles of hs CRP levels.

Results

At baseline, the prevalence of elderly, hypertension, diabetes mellitus, current smoking, and lipid levels were higher in patients with higher hs CRP. During ACh test, the incidences of significant CAS, ischemic electrocardiography (EKG) change, multivessel, and diffuse CAS were higher in patients with higher hs CRP. Multivariate analysis showed that the old age (OR=1.01, CI; 1.0-1.02, p=0.0226), myocardial bridge (OR=3.34, CI; 2.16-5.17, p<0.001), and highest quintile hs CRP (OR=1.54, CI; 1.12-2.18, p=0.008) were independent predictors of ACh induced CAS. However, there was no difference in clinical outcomes up to 12 months.

Conclusion

In conclusion, higher hs CRP was associated with higher incidence of CAS, worse angiographic characteristics and ischemic EKG change, but was not associated with clinical outcomes.     

Comparative study of fentanyl and morphine in addition to hyperbaric or isobaric bupivacaine in combined spinal anaesthesia for caesarean section

Introduction

The aim of our study was to compare the effects of isobaric and hyperbaric bupivacaine combined with morphine or fentanyl in patients undergoing caesarean section. We assessed quality and spread of analgesia and anaesthesia, postoperative analgesic requirement and side effects.

Material and methods

Hundred patients with American Society of Anesthesiologists physical status (ASA) I-II, age 18 to 40 years, were randomized to 4 groups. The intrathecal solutions were isobaric bupivacaine + morphine (group A), isobaric bupivacaine + fentanyl (group B), heavy bupivacaine + + morphine (group C) and heavy bupivacaine + fentanyl (group D). Mean arterial pressure, heart rate, oxygen saturation, ephedrine consumption, analgesic requirement time and additional analgesic needs were recorded.

Results

The 1^st min value of mean arterial pressure was the lowest one in all groups. Heart rate decreased significantly in group A at the 10^th min but not in the other groups. The decrease of visual analogue scale (VAS) pain scores began in the groups after the 4^th postoperative h (p < 0.05) and the VAS value of group B at the 8^th h was significantly higher than the other groups. The first analgesic requirement time in the postoperative period was longer in patients who had intrathecal morphine than those who had fentanyl. The duration of analgesia with isobaric bupivacaine and morphine was the longest one.

Conclusions

We concluded that intrathecal morphine provides a long duration of postoperative analgesia but the duration gets longer when it is combined with plain bupivacaine instead of heavy bupivacaine.     

The influence of pre-emptive analgesia on postoperative analgesia and its objective evaluation

Introduction

The evaluation of pain intensity is still a subject of research. Mostly psychological evaluations are used. We started to conduct biochemical evaluation in animal experiments. Now we present biochemical evaluation in postoperative pain in man.

Material and methods

In 67 patients herniotomy was done. For pre-emptive analgesia morphine and pethidine were used and the following indicators were measured: visual analogue scale (VAS), measurement of lipid spectra, saccharides and proteins, thioredoxin, super-oxide dismutase (SOD), glutathione peroxidase (GPx) and NAD(P)H-oxidase (NOX), and free radicals using electron paramagnetic resonance (EPR). Blood samples were taken and tested: before pre-medication and intervention, 4 h after and 24 h after intervention.

Results

Free radicals (FR) increased in individual samples during the postoperative course in pethidine and without pre-medication. After application of morphine the FR were insignificantly reduced. Statistically significant differences were found in albumin, prealbumin, apolipoprotein A, total cholesterol, atherosclerotic index, CRP, glucose, and thioredoxin (p ≤ 0.001). A greater difference was seen in VAS values between morphine and pethidine premedications (p ≤ 0.001).

Conclusions

It was proved that the biochemical markers of lipid, protein and saccharide metabolisms and free radicals as well as singlet oxygen can serve as very good indicators of the intensity of pain and nociception. In patients it was proved that pre-emptive analgesia plays an important role in reducing the intensity of postoperative pain. From the three modalities of pre-emptive analgesia morphine represents the best solution.     

Changes in Dynamic Pedobarography after Extensive Plantarmedial Release for Paralytic Pes Cavovarus

Purpose

Plantarmedial release and first ray extension osteotomy are often combined to treat paralytic cavovarus foot deformity. The purpose of this study is to evaluate the effect of additional first ray extension osteotomy in terms of dynamic pedobarography.

Materials and Methods

We reviewed findings of pre- and postoperative plain radiography and dynamic pedobarography for 25 patients in whom the flexibility of the hindfoot was confirmed by the Coleman block test. The results of treatment by extensive plantar medial release with first ray osteotomy (group I) were compared with the results of treatment by extensive plantar medial release alone (group II).

Results

Plain radiographs obtained pre- and postoperatively showed no statistically significant improvement in each group. Only in group I, peak forces at the 1st metatarsal head, 2nd metatarsal head and medial calcaneus were increased after operation.

Conclusion

In paralytic hindfoot flexible cavovarus, extensive plantarmedial release with first ray osteotomy improve foot pressure distribution more than extensive plantarmedial release alone.     

Microdialysis delivery of morphine to the hypoglossal nucleus of Wistar rat increases hypoglossal acetylcholine release

STUDY OBJECTIVES: The medullary hypoglossal nucleus (XII) innervates the genioglossal muscles of the tongue, and opioid-induced alterations in tongue muscle tone contribute to airway obstruction. Previous studies have shown that morphine causes a significant decrease in acetylcholine (ACh) release in some brain regions, but the effects of morphine on ACh release in XII have not been quantified. DESIGN: A within-subjects design was used to test the hypothesis that morphine alters ACh release in XII of anesthetized Wistar rat. ACh release during microdialysis with Ringer's solution (control) was compared to ACh release during dialysis delivery of opioids. SETTING: University of Michigan. PATIENTS OR PARTICIPANTS: N/A. INTERVENTIONS: Microdialysis delivery of opioids to XII. MEASUREMENTS AND RESULTS: Morphine caused a statistically significant, concentration-dependent increase in XII ACh release. The increase in XII ACh release caused by 10 microM morphine was blocked by the mu opioid antagonist naloxone and not blocked by the kappa opioid antagonist norbinaltorphimine. CONCLUSIONS: The data comprise the first direct measures of ACh release in XII and support the conclusion that morphine depresses hypoglossal nerve activity, in part, by increasing ACh release in XII. Activation of mu opioid receptors on inhibitory neurons within XII likely disinhibits cholinergic terminals, causing increased ACh release. The results are consistent with previous studies showing that blocking the enzymatic degradation of ACh in XII significantly inhibited tongue muscle activity.     

Obstructive Apneas Induce Early Release of Mesenchymal Stem Cells into Circulating Blood

Study Objectives:

To investigate whether noninvasive application of recurrent airway obstructions induces early release of mesenchymal stem cells into the circulating blood in a rat model of obstructive sleep apnea.

Design:

Prospective controlled animal study.

Setting:

University laboratory.

Patients or Participants:

Twenty male Sprague-Dawley rats (250–300 g).

Interventions:

A specially designed nasal mask was applied to the anesthetized rats. Ten rats were subjected to a pattern of recurrent obstructive apneas (60 per hour, lasting 15 seconds each) for 5 hours. Ten anesthetized rats were used as controls.

Measurements and Results:

Mesenchymal stem cells from the blood and bone marrow samples were isolated and cultured to count the total number of colony-forming unit fibroblasts (CFU-F) of adherent cells after 9 days in culture. The number of CFU-F from circulating blood was significantly (P = 0.02) higher in the rats subjected to recurrent obstructive apneas (5.00 ± 1.16; mean ± SEM) than in controls (1.70 ± 0.72). No significant (P = 0.54) differences were observed in CFU-F from bone marrow.

Conclusions:

Application of a pattern of airway obstructions similar to those experienced by patients with sleep apnea induced an early mobilization of mesenchymal stem cells into circulating blood.

Citation:

Carreras A; Almendros I; Acerbi I; Montserrat JM; Navajas D; Farré R. Obstructive apneas induce early release of mesenchymal stem cells into circulating blood. SLEEP 2009;32(1):117-119.     

Chronic alcohol exposure increases ganglia endogenous morphine levels

Introduction

We have previously demonstrated that alcohol has the ability to release low levels of endogenously expressed, chemically authentic, morphine from neural tissues.

Material and methods

Presently, we demonstrate that chronic exposure of Mytilus edulis pedal ganglia tissues maintained in organotypic culture to very concentrations of 1 mM and 10 mM ethanol induces a time dependent increase in both endogenous morphine and dopamine (DA) levels.

Results

Chronic incubation of M. edulis pedal ganglia with 3 concentrations of DA resulted in statistically significant elevations of cellular morphine levels, thereby confirming previous studies from our laboratory establishing DA as an essential precursor in the morphine biosynthetic pathway.

Conclusions

By understanding multiple debilitating effects of alcohol on “morphinergic” signaling, we may understand the ravages of neural processes associated with alcohol abuse and how its treatment may be made more effective.