Injection Of Morphine Research Articles

Comparison of Divided Dose versus Bolus Administration Morphine Sulfate for Management of Acute Pain in Traumatic Fracture in Patients Admitted to Emergency Department

Introduction: Pain is one of the most common reasons that patients visit emergency departments. Morphine has been used extensively in pain management but there is no consensus about the effectiveness of method of administration. The aim of this study was to compare the divided dose vs bolus medication form of morphine sulfate for management of acute pain in traumatic fracture. Methods: we designed a randomized double-blind clinical trial. On basis of inclusion and exclusion criteria, 160 patients with acute traumatic fracture were enrolled to the study and randomly divided into two groups. The first group (bolus group) received 0.1mg/kg morphine and then 0.1mg/kg normal saline every 5 minutes. The second group (titration group) received 0.1mg/kg of morphine in divided doses every 5 minutes. All injections were intravenously. The primary outcome was pain and before of injection, 15 minutes and 60 minutes after injection were recorded. Data were analyzed using SPSS 19. Results: 77 patients included 49 (63.6%) male with mean age of 47.42 ± 13.15 years were in titration group and 83 patients included 47 males (56.6%) with mean age of 52.40 ± 15.62 years were in bolus group. The complication rate was significantly higher in bolus group (75.9% vs 53.2%, P <0.0001). The need to extra morphine injection in bolus and titration group were 62.7% and 28.6%, respectively (P <0.0001). The mean pain score before and at 15 and 60 minutes after injection were 9.56 ± 1.03, 6.61 ± 1.86 and 1.85 ± 1.13 in titration group and 9.76 ± 0.48, 6.53 ± 1.59 and 0.61 ± 0.46 in bolus group, respectively. The pain score was significantly lower in titration group at 60 minutes after injection (P <0.0001). Discussion: The results of this study showed that titration of morphine are a safe and effective method in compared with bolus administration to reducing acute pain in traumatic fracture.

The mitochondrial calcium uniporter contributes to morphine tolerance through pCREB and CPEB1 in rat spinal cord dorsal horn

BackgroundThe long-term use of opioid analgesics is limited by the development of unwanted side-effects, such as tolerance. The molecular mechanisms of morphine anti-nociceptive tolerance are still unclear. The mitochondrial calcium uniporter (MCU) is involved in painful hyperalgesia, but the role of MCU in morphine tolerance has not been uncharacterised. MethodsRats received intrathecal injection of morphine for 7 days to induce morphine tolerance. The mechanical withdrawal threshold was measured using von Frey filaments, and thermal latency using the hotplate test. The effects of an MCU inhibitor, antisense oligodeoxynucleotide against cyclic adenosine monophosphate response element (CRE)-binding protein (CREB) or cytoplasmic polyadenylation element-binding protein 1 (CPEB1) in morphine tolerance were examined. ResultsSpinal morphine tolerance was associated with an increased expression of neuronal MCU, phospho-CREB (pCREB), and CPEB1 in the spinal cord dorsal horn. MCU inhibition increased the mechanical threshold and thermal latency, and reduced the accumulation of mitochondrial calcium in morphine tolerance. Intrathecal antisense oligodeoxynucleotide against CREB or CPEB1 restored the anti-nociceptive effects of morphine compared with mismatch oligodeoxynucleotide in von Frey test and hotplate test. Chromatin immunoprecipitation with quantitative PCR assay showed that CREB knockdown reduced the interaction of pCREB with the ccdc109a gene (encoding MCU expression) promoter and decreased the MCU mRNA transcription. RNA immunoprecipitation assay suggested that CPEB1 binds to the MCU mRNA 3′ untranslated region. CPEB1 knockdown decreased the expression of MCU protein. ConclusionsThese findings suggest that spinal MCU is regulated by pCREB and CPEB1 in morphine tolerance, and that inhibition of MCU, pCREB, or CPEB1 may be useful in preventing the development of opioid tolerance.

Effect of sub-effective dose of GABA agonists on attenuation of morphine tolerance in rats: Behavioral and electrophysiological studies

GABAergic drugs can change analgesic effect of morphine. Wide dynamic range (WDR) neurons play an important role in pain transmission and may change behaviors in morphine tolerance. In this study WDR neuron behaviors in morphine tolerant rats and rats treated with GABA agonists, were recorded to elucidate the effect of morphine and GABA agonists on WDR behavioral changes. Rats were divided to 4 groups: 1. Control, 2. Morphine tolerance (MT), 3. MT+ muscimol, 4- MT+ baclofen. To induce morphine tolerance in rats, they received morphine sulfate 10 mg/kg intraperitoneally for 8 days. In treatment group, GABA agonists were injected on days 1, 3, 5 and 8 before injection of morphine. To confirm morphine tolerance induced, formalin test was used. Extracellular single unit recording was used to record spinal WDR neurons. Results showed that chronic administration of morphine failed to attenuate formalin pain but GABA agonists improved analgesic effect of morphine.

Cell-type and region-specific nucleus accumbens AMPAR plasticity associated with morphine reward, reinstatement, and spontaneous withdrawal.

Despite evidence that morphine-related pathologies reflect adaptations in NAc glutamate signaling, substantial gaps in basic information remain. The current study examines the impact of non-contingent acute, repeated, and withdrawal-inducing morphine dosing regimens on glutamate transmission in D1- or D2-MSNs in the nucleus accumbens shell (NAcSh) and core (NAcC) sub-regions in hopes of identifying excitatory plasticity that may contribute tounique facets of opioid addiction-related behavior. Following an acute morphine injection (10mg/kg), average miniature excitatory postsynaptic current (mEPSC) amplitude mediated by AMPA-type glutamate receptors was increased at D1-MSNs in the both the NAcShl and NAcC, whereas only the frequency of events was elevated at D2-MSNs in the NAcSh. In contrast, spontaneoussomatic withdrawal induced by escalating dose of repeated morphine twice per day (20, 40, 60, 80, 100mg/kg) enhanced mEPSC frequency specifically atD2-MSNs in the NAcSh. Similar to previous findings, excitatory drive was elevated at NAcSh D1-MSNs after10-14dayshome cage abstinence. Following abstinence, an acute drug re-exposureproduced a rapid and enduring endocytosis of GluA2-containing AMPARs at D1-MSNs in the shell, that when blocked by an intra-NAc shell infusion of the Tat-GluA23Y peptide, increased reinstatement of morphine place preference-a phenomenon distinctly different than effects previously found with cocaine. The present study is the first to directly identify unique circuit specific adaptations in NAc glutamate synaptic transmission associated with morphine-related acute reward and somatic withdrawal as well as post-abstinence short-term plasticity. Moreover,while differing classes of abused drugs (i.e., psychostimulants and opioids) produce seemingly similar bidirectional plasticity in the NAc following drug re-exposure, our findings indicate this plasticity has distinct behavioral consequences.

Electroacupuncture alleviates morphine‑induced hyperalgesia by regulating spinal CB1�receptors and ERK1/2 activity

Electroacupuncture (EA), a traditional Chinese therapeutic technique, is considered an effective method for treating certain painful neuropathies induced by various neuropathological damage. The current study investigated the effect of EA on intrathecal (IT) morphine-induced hyperalgesia (MIH) and examined the hypothesis that activation of cannabinoid receptor 1 (CB1) could enhance the antinociceptive effect of EA on MIH via regulation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. Using a rat model of IT MIH, mechanical and thermal hyperalgesia were evaluated by an electronic von Frey filament and hotplate at baseline (1 day before IT administration) and at days 1, 3, 5 and 7 after IT administration. Rats received IT normal saline, IT morphine or IT morphine + EA at ST36-GB34. The protein levels of ERK1/2, phosphorylated (p)-ERK1/2 and CB1 in the spinal cord were assayed by western blotting. Furthermore, the effect of IT injection of the CB1 agonist WIN 55,212-2 and the CB1 antagonist SR141716 on the antinociceptive effect of EA in rats with MIH was investigated. Nociceptive behavior and ERK1/2, phosphorylated (p)-ERK1/2 and CB1 protein levels were evaluated as mentioned above. The results revealed that chronic IT injections of morphine induced a significant decrease in mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) accompanied with remarkable upregulation of p-ERK1/2 in the spinal cord, which could be attenuated by EA at the ST36-GB34 acupoints. In the rat model of MIH, IT injection of WIN 55,212-2 combined with EA induced a significant increase in MWT and TWL accompanied with a significant decrease in p-ERK1/2 and a significant increase in CB1 protein level compared with EA alone, while SR141716 induced the opposite results. The present study suggests that EA alleviates hyperalgesia induced by IT injection of morphine partially through the inhibition of ERK1/2 activation. Activation of the CB1 receptor enhances the antinociceptive effect of EA in rats with MIH partly through the regulation of the spinal CB1-ERK1/2 signaling pathway.

Anaesthetic management and complications of canine adrenalectomies: 41 cases (2007-2017).

Little information is available about the management of adrenalectomies in veterinary anaesthesia. The aim of this study was to describe the anaesthetic techniques, the complication rate and outcome of these cases. Data were collected retrospectively from patients' records. Descriptive statistics were performed with Student's t-tests and Chi-square tests where appropriate. Forty-one cases were included. The mean age was 124.7 ± 29.4 months and the median body weight was 23.1 kg (5.3-69 kg). Carcinoma was the most common diagnosis (34.1%). Premedication was most commonly achieved with methadone alone (70.7%) IV. Propofol was the most common induction agent (39%). An infusion of opioids (80.4%) and an epidural injection of morphine (70.7%) were the most common analgesic techniques. Hypotension was the most common complication observed (51.2%). The mortality rate was 14.6%. The lowest recorded oesophageal temperature was statistically associated with the incidence of haemorrhage (P = 0.025). The invasion of the vena cava (P = 0.001) was significantly associated with haemorrhagic complications. The survival rate was better when patients received hydrocortisone intra-operatively (P = 0.026). This study highlights some possible association between the anaesthetic management and the outcome of the procedure.

Effects of systemic and neuraxial morphine on the immune system.

In the study, we tried to evaluate the effects of morphine injected through the systemic or neuraxial route on immune cell function and cytokine production in healthy women.In total, 29 paired samples of fresh peripheral blood were collected from healthy women who had been administered morphine for anesthetic analgesia through intravenous (IV), epidural, or spinal route postpartum. Their isolated peripheral blood mononuclear cells were mitogen-activated and stained with fluorochrome-conjugated anti-CD4, anti-CD8, anti-interleukin (IL)-2, and anti-interferon (IFN)-γ antibodies for flow cytometry, and the plasma levels of cytokines, including IL-6, IFN-α2, IL-10, IL-8, GM-CSF, and monocyte chemoattractant protein (MCP)-1, were measured through enzyme-linked immunosorbent assay.The results demonstrated that regardless of the administration route, morphine delivery slightly reduced IL-2 expression in CD4 cells after activation, and the same effect was not noted for CD8 cells. Intravenous or epidural morphine tended to reduce IFN-γ expression in CD8 cells. Spinal and IV morphine substantially increased IL-6 production, whereas epidural morphine hindered IL-10 and GM-CSF production. IV morphine injection reduced MCP-1 production in plasma. Compared with spinal morphine, IV or epidural morphine may more effectively inhibit the expression of various cytokines and thus affect immune response.All 3 routes of morphine injection tended to decrease IL-2 production by CD4 cells, whereas IV or epidural morphine injection showed lower IFN-γ production by CD8 cells. However, additional large-scale studies with longer follow-up durations are warranted.

Suppression of neuropathic pain by selective silencing of dorsal root ganglion ectopia using nonblocking concentrations of lidocaine.

Neuropathic pain is frequently driven by ectopic impulse discharge (ectopia) generated in injured peripheral afferent neurons. Observations in the spinal nerve ligation (SNL) model in rats suggest that cell bodies in the dorsal root ganglion (DRG) contribute 3 times more to the ectopic barrage than the site of nerve injury (neuroma). The DRG is therefore a prime interventional target for pain control. Since DRG ectopia is selectively suppressed with lidocaine at concentrations too low to block axonal impulse propagation, we asked whether targeted delivery of dilute lidocaine to the L5 DRG can relieve L5 SNL-induced tactile allodynia without blocking normal sensation or motor function. Results showed that intraforaminal injection of 10-µL bolus doses of 0.2% lidocaine suppressed allodynia transiently, while sustained infusion over 2 weeks using osmotic minipumps suppressed it for the duration of the infusion. Bolus injections of morphine or fentanyl were ineffective. Lidocaine applied to the cut spinal nerve end or the L4 DRG did not affect allodynia, suggesting that discharge originating in the neuroma and in neighboring "uninjured" afferents makes at best a minor contribution. Spike electrogenesis in the DRG is apparently the primary driver of tactile allodynia in the SNL model of neuropathic pain, and it can be controlled selectively by superfusing the relevant DRG(s) with nonblocking concentrations of lidocaine. This approach has potential clinical application in conditions such as postherpetic neuralgia and phantom limb pain in which one or only a few identifiable ganglia are implicated as pain drivers.

Pain Relief in the Sickle-Cell Crisis: Intravenous Morphine Versus Ketorolac; A Double-Blind, Randomized Clinical Trial

Background: Sickle cell disease (SCD) is a congenital hemoglobinopathy. A low Hb level and high hemoglobin-to-hematocrit ratio may lead to the vaso-occlusive crisis in patients, for the management of which hyperbaric oxygen, hydration, and pain relief therapy are proposed. Objectives: In this study, we sought to compare the effects of morphine and ketorolac on relieving painful sickle cell crisis. Methods: In this double-blind, randomized clinical trial, we recruited 92 SCD patients who referred to the Emergency Department of a university-affiliated hospital, in Mashhad, Iran, from December 2016 to May 2017. The patients were randomly assigned to two groups of ketorolac and morphine injections for relieving pain crisis according to the clinical conditions of the patients. Pain severity was measured by the visual analogue scale before and after the intervention. Data were analyzed using SPSS software. Results: A total of 92 SCD patients were evaluated, while, 19 (21%) were female and 73 (79%) were male, with the mean age of 20.77 ± 8.6 years. At the pre-injection phase, the mean pain scores were 9.1 ± 0.4 and 9.1 ± 0.7 in the ketorolac and morphine groups, respectively. After the intervention, the mean pain scores were 3.7 ± 1.2 and 4.9 ± 2.1 in the ketorolac and morphine groups, respectively. A significant association was found between the pain score after drug injection and the administered drug (P = 0.006). Conclusions: The management of pain crisis with ketorolac injection yielded the same results as the morphine injection in SCD patients. However, ketorolac was found to be associated with fewer side effects than morphine; thus, it can be beneficial for managing SCD patients suffering pain crisis.

Spontaneous Cingulate High-Current Spikes Signal Normal and Pathological Pain States.

Prominent 7-12 Hz oscillations in frontal cortical networks in rats have been reported. However, the mechanism of generation and the physiological function of this brain rhythm have not yet been clarified. Multichannel extracellular field potentials of the ACC were recorded and analyzed using the current source density method in halothane-anesthetized rats. Spontaneous high-current spikes (HCSs) were localized in the deep part of layer II/III and upper part of layer V of the ACC. The frequency of HCSs in the ACC was 7-12 Hz, with an amplitude of 6.5 ± 0.76 mV/mm2 and duration of 55.24 ± 2.43 ms. The power density significantly decreased (84.56 ± 6.93%, p < 0.05, t test) after pinching the hindpaw and significantly increased (149.28 ± 15.96%) after treatment with morphine. The suppressive effect of pinching was reversed by naloxone (0.7 mg/kg, i.p.). HCSs coincided with initiation of the depolarization of cingulate neurons and remained in a depolarized upstate. The occurrence of cingulate HCSs was persistently preceded by a hyperpolarization phase and a burst of multiunit spike activity in the medial dorsal thalamic nucleus. Spontaneous field-potential oscillations changed from 10 Hz to a lower band (i.e., ∼7.5 Hz) when a central poststroke pain condition was induced. The central poststroke pain group had a higher average coherence coefficient compared with the control group. Our results indicate that spontaneous cingulate cortical HCSs could be initiated by thalamocortical synaptic inputs from the medial dorsal thalamic nucleus and maintained by intracortical neuronal upstate mechanisms in physiological and pathological pain states.SIGNIFICANCE STATEMENT This study elucidated the mechanism of generation and physiological function of prominent 7-12 Hz frequency oscillations in frontal cortical networks in rats. Spontaneous cingulate cortical high-current spikes in anesthetized rats could be initiated by thalamocortical synaptic inputs from the medial dorsal thalamic nucleus and maintained by intracortical neuronal upstate mechanisms. Suppression of the anterior cingulate cortex-filtered EEG during noxious stimulation may have resulted from the desynchronization of high-current spikes in the ACC. The enhancement of fast Fourier transform power after a systemic morphine injection suggested that the opioid system may play an important role in synchronizing cingulate cortical neuronal networks. Spontaneous cingulate high-current spikes may also play an important role in thalamocortical dysrhythmia in central poststroke pain.

Activation of spinal Extacellular Signal‐Regulated Kinases and c‐jun N‐terminal kinase signaling pathways contributes to morphine‐induced acute and chronic hyperalgesia in mice

This study investigated the activation of mitogen-activated protein kinases in the spinal dorsal horn to explore the mechanisms underlying morphine-induced acute and chronic hyperalgesia in mice. Male adult mice were given a single subcutaneous injection (SC) of morphine (1 μg/kg) or twice-daily administration of morphine (10 mg/kg/day) for 8 days. Thermal hyperalgesia and mechanical allodynia were assessed using the radiant heat and von Frey filament test. Levels of phospho (p)-extracellular signal-regulated kinases (p-ERK), p-c-Jun N-terminal kinase (p-JNK), p-p38, p-PKCγ, N-methyl-d-aspartate receptor (NMDAr), and c-Fos protein in the spinal dorsal horn were examined by Western blot assays. A single ultra-low dose or repeated administration of morphine induced hyperalgesia in mice and caused a significant increase in the levels of p-ERK and p-JNK, but not p-p38, in the spinal dorsal horn. The level of c-Fos protein was significantly elevated following administration of morphine. The protein levels of p-PKCγ and NMDAr subunits (NR2B and NR2A) were also altered. Pretreatment with the NMDAr antagonist MK-801 or the protein kinase C (PKC) inhibitor calphostin C (CC) suppressed the morphine-induced increase in p-ERK, p-JNK, and c-Fos. Administration of MK-801 and CC also relieved morphine-induced hyperalgesia. These findings suggest that activation of the spinal ERK and JNK signaling pathways contribute to morphine-induced acute and chronic hyperalgesia in mice.

Evaluation of the Antinociceptive Effect of Maropitant, a Neurokinin-1 Receptor Antagonist, in Cats Undergoing Ovariohysterectomy.

Maropitant is a neurokinin-1 (NK1) receptor antagonist that can be used for pain management. The objective of this study was to evaluate the effect of continuous infusion of two doses of maropitant on cardiorespiratory parameters and its postoperative analgesic effect in cats undergoing ovariohysterectomy. Thirty cats were randomly assigned to one of three groups (10 cats each group): the control group (CG) received a continuous infusion of 10 ml/kg/h Ringer's lactate; GM30 and GM100 first received an intravenous (IV) bolus of 1 mg/kg maropitant; GM30 then received continuous infusion of 30 μg/kg/h maropitant; and GM100 then received continuous infusion of 100 μg/kg/h maropitant. The maropitant was diluted into Ringer's lactate and the GM30 and GM100 also received fluids intraoperatively. In all groups, premedication included intramuscular injections of morphine and acepromazine, followed by induction with propofol and maintenance with isoflurane. Temperature, heart rate (HR), Doppler blood pressure (DBP), respiratory rate, oxygen saturation, and measuring the end-tidal carbon dioxide and isoflurane were monitored. Postoperative pain was evaluated using a visual analog scale and the UNESP-Botucatu multidimensional composite pain scale in cats; morphine was used for analgesic rescue. During the surgical procedure, cats in GM100 demonstrated lower HR and DBP than those in CG. With regard to the evaluation of postoperative pain, GM100 required the least frequent morphine rescue and less rescue analgesia compared with CG. In conclusion, cats in GM100 maintained lower DBP and HR and required lower analgesic rescue during the postoperative period. The results suggested that animals receiving maropitant bolus (1 mg/kg) plus (100 μg/kg/h) experienced greater postoperative comfort, reflected by the lesser need for analgesic rescue. The use of maropitant in surgical procedures in cats contributes to postoperative comfort.

DNMT3a in the hippocampal CA1 is crucial in the acquisition of morphine self-administration in rats.

Drug-reinforced excessive operant responding is one fundamental feature of long-lasting addiction-like behaviors and relapse in animals. However, the transcriptional regulatory mechanisms responsible for the persistent drug-specific (not natural rewards) operant behavior are not entirely clear. In this study, we demonstrate a key role for one of the de novo DNA methyltransferase, DNMT3a, in the acquisition of morphine self-administration (SA) in rats. The expression of DNMT3a in the hippocampal CA1 region but not in the nucleus accumbens shell was significantly up-regulated after 1- and 7-day morphine SA (0.3mg/kg/infusion) but not after the yoked morphine injection. On the other hand, saccharin SA did not affect the expression of DNMT3a or DNMT3b. DNMT inhibitor 5-aza-2-deoxycytidine (5-aza) microinjected into the hippocampal CA1 significantly attenuated the acquisition of morphine SA. Knockdown of DNMT3a also impaired the ability to acquire the morphine SA. Overall, these findings suggest that DNMT3a in the hippocampus plays an important role in the acquisition of morphine SA and may be a valid target to prevent the development of morphine addiction.

In vivo Dependence Liability Assessment of Novel Fentanyl Analogues: Science to Guide drug Policy

The emergence of fentanyl analogues as drugs of abuse raises concern regarding their dependence liability. Following prolonged opioid administration, physical dependence leads to increased use, which facilitates the development of tolerance and the dangers of overdose. In animal models, opioid dependence can be inferred by assessing signs of withdrawal, with vertical jumping being the most sensitive and easily quantified in the mouse. In this study, we aimed to characterize the dependence liability of fentanyl, morphine, and six fentanyl analogues by assessing antinociception and withdrawal signs elicited by each compound in the mouse. First, to determine antinociceptive effects, we used a warm‐water tail withdrawal procedure using both 50°C and 55°C water. Latencies until mice removed their tails from the water were recorded, and fully effective doses were determined using a 10 second cut‐off to prevent tissue damage. Dose effect‐curves were generated to determine the potency (ED50) of each compound for eliciting antinociception. All analogues were less potent than fentanyl but more potent than morphine. Additionally, all test compounds were fully effective in both 50°C and 55°C water. Next, to assess withdrawal, we treated animals with 3 injections of morphine, fentanyl or the various fentanyl analogues spaced 12 hours apart. Following the first two injections on day 1, we precipitated withdrawal on day 2, 3 hours after the final injection of agonist, using the nonselective opioid antagonist naloxone. Withdrawal sessions lasted 20 minutes and the number of vertical jumps were recorded for each session. Antagonist dose‐effect curves for withdrawal jumps were generated first using an agonist dose one‐log unit higher than the fully effective antinociceptive dose and precipitating withdrawal with 3, 10, and 30 mg/kg of naloxone. Next, we used 30 mg/kg of naloxone to precipitate withdrawal using increasing unit doses of each test compoewund since maximal jumping was elicited using 30 mg/kg of naloxone. Agonist dose‐effect curves were generated starting with the lowest fully effective antinociceptive dose and increasing in half‐log units. Our results indicate that all of these fentanyl derivatives are capable of eliciting dependence and offer valuable insight into their abuse potential.Support or Funding InformationThese studies supported in part by DEA/NCTR (224‐16‐0505R),) and the University of Arkansas for Medical ScienVA (D‐15‐OD‐002cesThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Ginger Extract Reduces Chronic Morphine-Induced Neuroinflammation and Glial Activation in Nucleus Accumbens of Rats.

BackgroundChronic usage of morphine elicits the production of inflammatory factors by glial cells and induces neuroinflammation. Ginger (Zingiber Officinale Roscoe) is a medicinal herb that has anti-inflammatory properties. It has been reported that ginger shows anti-addictive effects against chronic usage of morphine; however, its influence on morphine-induced neuroinflammation has not yet been clarified.MethodsMorphine (12 mg/kg) was administrated intraperitoneally for 6 consecutive days. To evaluate the effect of ginger on morphine-induced neuroinflammation, ginger extract (100 mg/kg) was given orally 30 minutes before morphine. Glial fibrillary acidic protein (GFAP) and p38 mitogen-activated protein kinase (p38 MAPK) levels were assayed by immunoblotting in the rat nucleus accumbens (NAcc).FindingsThe injection of chronic morphine increased the levels of proteins involved in neuroinflammation (p38 MAPK and GFAP) in NAcc. Furthermore, the levels of p38 MAPK and GFAP significantly returned to the control levels by ginger extract.ConclusionThe results suggest that the ginger extract can reduce morphine-induced neuroinflammation in NAcc.

PATIENT SATISFACTION AND COST ANALYSIS OF ANALGESIA MANAGEMENT FOR POST-OPERATIVE PROCEDURES IN HTAA: PCA VS. CONVENTIONAL METHOD

Acute pain service (APS) offer several techniques to the post-operative patient in controlling and relieving the pain such as intravenous infusion, patient-controlled analgesia, epidural infusion, subcutaneous or intramuscular injection and intrathecal administration. The effectiveness of and satisfaction towards APS is not clearly defined. Therefore, the aim of this study is to conduct the cost analysis and comparison between these techniques and patient satisfaction. The study design for cost analysis was retrospective study. The means of the data were calculated based on Integration Store of Hospital Tengku Ampuan Afzan records. In addition, the evaluation of patient’s satisfaction was conducted by using a cross-sectional study design. The mean of the data was calculated and analysed by using Chi-square test. The total cost required to prepare PCA for post-operative patient was the highest with RM 8810.98. Meanwhile, the cost for subcutaneous morphine injection, epidural infusion and peripheral block injection were RM 2.11, RM 5323.95 and RM 4.95 respectively. However, when taking into the aspect of patient’s satisfaction, PCA has the highest level of excellent performance with 54.6% compare to EDA (33%) and BLOCK (12.4%) with the p-value is less than 0.05. In conclusion, every drug has its own side effects. As the healthcare provider, it is a need to ensure drugs that were given to the patients are at the very minimum risk of having the side effects. Based on the findings of this study, it could be said that both drugs have lower percentage of people experienced the side effect after treated with the drugs. Therefore, the future study should be more focusing on the side effect of the drugs used. In terms of cost spent for the methods, the PCA regimen is more likely expensive compared to the conventional methods. However, based on survey among the patients, PCA-treated patients expressed higher satisfaction compared to the conventional regimen of pain management.

To observe the clinical efficacy of Huajian-Badu membrane in the treatment of moderate and severe cancer pain

Objective To observe the clinical efficacy of Huajian-Badu membrane in the treatment of moderate and severe cancer pain. Methods The 80 malignant tumor patients with moderate to severe cancer pain from January 2016 to June 2017 in Tianjin University of Traditional Chinese Medicine First Teaching Hospital were recruited and randomly divided into the observation group and the control group, each of 40 cases. The control group were treated with Oxycodone Hydrochloride Prolonged-release Tablets, while the treatment group were treated with Huajian-Badu membrane on the basis of the treatment in control group. The pain relief, pain frequency, morphine consumption and quality of life (Karnofsky score), adverse reaction were evaluated between two groups before and after treatment. Results Compared with the control group, the total efficiency in the observation group was significantly higher (95.0% vs. 80.0%, χ2=4.114, P=0.043). The frequency of breakthrough pain of two groups increased on the seventh and fourteenth treatment days(0.3 ± 0.6 times vs. 0.8 ± 0.7 times, t=-3.430 and 0.4 ± 0.6 times vs. 0.9 ± 0.8 times, t=-3.162), but the number of outbreaks of pain in the observation group significantly less than the control group (P<0.05 or P<0.01). The morphine injection dosage increased on the seventh and fourteenth treatment days (3.01 ± 4.28 g vs. 5.62 ± 6.37 g, t=-2.151 and 3.21 ± 4.32 g vs. 7.84 ± 7.76 g, t=-3.297), but the amount of the observtation group was significantly lower than that of control group (P<0.05 or P<0.01). The KPS score in the observation group increased significantly, and significantly higher than the control group on the seventh and fourteenth treatment days (73.0 ± 15.0 vs. 66.0 ± 12.0, t=2.305 and 77.0 ± 13.0 vs. 70.0 ± 15.0, t=2.230, P<0.05). The adverse reaction rate of the control group was 25%, while the the observation group was 20%. The difference between two groups was significant (χ2=0.287, P=0.592). Conclusions The Huajian-Badu membrane combined Oxycodone Hydrochloride Prolonged-release Tablets can improve the total effective rate of pain relief, reduce the number of outbreaks, reduce morphine consumption, improve patient KPS score of the patients with cancer pain. Key words: Cancer pain; Huajian-Badu membrane; Oxycodone Hydrochloride Prolonged-release tablets; Morphine; Analgesics (TCD); Drug-related side effects and adverse reactions

The Effect of Alpha-Tocopherol on Morphine Tolerance-induced Expression of c-fos Proto-oncogene from a Biotechnological Perspective.

The increase of oxidant compounds is the most well-known reasons for the tolerance to the analgesic properties of Morphine. Additionally, the production of proxy-nitrite impairs receptors, proteins and enzymes involved in the signaling pathways of analgesia, apoptosis and necrosis. Also, we revised all patents relating to opioid tolerance control methods. The aim of this study was to assess the effects of Alpha-tocopherol as an anti-oxidant agent to reduce Morphine tolerance. Forty male rats randomly divided into four groups. 10 mg/kg of morphine was injected subcutaneously to create the desired level of tolerance. After modeling, 70 mg/kg Alpha- Tocopherol was injected intraperitoneal. Also, the hot plate recorded pain threshold alterations was used to evaluate the behavioral test. All tissue samples were extracted from the spinal cord, thalamus and frontal cortex for molecular and gene expression evaluations. Also, the effect of Alpha- Tocopherol on the apoptosis and necrosis parameters was analyzed using nissl staining and tunel test. The time latency results showed that there were no significant differences in the different days in groups treated with Morphine plus Alpha-Tocopherol. However, our data highlighted that the pain threshold and their time latency in respond to it had substantially increased in comparison with the control group. Furthermore, we found that the Alpha-Tocopherol obviously decreased c-fos gene expression, especially in the spinal cord. Thus, co-administration of Alpha-Tocopherol with Morphine can decrease the adverse effects of nitrite proxy, which is released due to repeated injections of Morphine.

Electroacupuncture intervention relieves pain possibly by promoting MOR endocytosis in locus coeruleus in bone cancer pain rats with morphine tolerance

To observe the effect of electroacupuncture (EA) on pain behavior and expression of µ-opioid receptor (MOR) and Rab5 (an important protein molecule for internalization of MOR) in the locus coeruleus (LC) region in bone cancer pain (BCP) rats with morphine tolerance (MT), so as to explore its mechanisms underlying improvement of BCP and MT. The present study included two parts. In the first part, 23 female SD rats were randomized into sham BCP (n＝6), BCP (n＝9) and BCP＋MT (n＝8) groups, and in the second part, 61 female SD rats were randomized into 5 groups: sham BCP (n＝11), BCP (n＝11), BCP＋MT (n＝13), BCP＋MT＋EA (n＝13) and BCP＋MT＋sham EA (n＝13). The BCP morphine tolerance (BCP＋MT) model was established by injection of 10 µL of human Walker 256 breast cancer cells (MRMT-1 breast cancer cells, 1 x104 cells/µL) into the bone marrow cavity at the upper part of the left tibia and intraperitoneal injection of morphine hydrochloride (10 mg/kg, once per 12 h, for 11 successive days). On day 21 after inoculation, EA (2 Hz/100 Hz, 0.5－1.5 mA, increasing 0.5 mA every 10 min) was began to applied to bilateral "Zusanli" (ST30) and "Kunlun" (BL60) immediately after the first intraperitoneal injection of morphine. The treatment was performed for 30 min every time, once daily for 7 successive days. The paw withdrawal threshold (PWT) was detected before and 10, 11, 21, 22, 24, 26 and 28 days after inoculation. The immunoactivity of MOR and Rab5 proteins in the LC region was detected by immunofluorescence histochemistry. In the first part of the study, at the 10th day after inoculation of cancer cells, the PWT of the BCP and BCP＋MT groups was significantly lower than that of the sham BCP group (P<0.05), suggesting a success of BCP model. From day 11 to 19 after inoculation (during injection of morphine), the PWTs of the BCP＋MT group were significantly higher than those of the BCP group (P<0.01), and on day 21, the PWT of the BCP＋MT group was similar to that of the BCP group (P>0.05) but significantly lower than that of the sham BCP group (P<0.01), suggesting a success of MT. H．E. staining showed a large quantity of MRMT-1 cancer cells in the bone marrow cavity in both BCP and BCP＋MT groups. In the second part of the study, the decreased PWTs from 10th to 28th day after inoculation were significantly increased on day 22, 24, 26 and 28 in the BCP＋MT＋EA group relevant to the BCP, BCP＋MT and BCP＋MT＋sham EA groups (P<0.01). The ratios of MOR and Rab5 positive (＋) cells and MOR＋/Rab5＋ of the left LC region were significantly lower in the BCP and BCP＋MT groups than those of the sham BCP group (P<0.01), but were considerably higher in the BCP＋MT＋EA group than those in the BCP, BCP＋MT and BCP＋MT＋sham EA groups (P<0.01). The ratios of Rab5＋ and MOR＋/Rab5＋ cells of the BCP＋MT group were significantly lower than those of the BCP group (P<0.05). No significant changes were found in the ratios of MOR＋ and Rab5＋ cells and MOR＋/Rab5＋ cells after BCP＋MT＋sham EA in comparison with the BCP＋MT group (P>0.05). EA intervention can relieve pain and MT in bone cancer pain rats with MT, which may be related to its effects in increasing MOR expression and promoting endocytosis of MOR in LC region.

(251) A Time Course of the Development of Hyperalgesia during Spontaneous Withdrawal in NIH Swiss Mice

Pain patients may experience heightened sensitivity to pain while trying to discontinue opioid use which may contribute to resumption of opioid use in order to avoid more pain. However, most studies in animals that investigate hyperalgesia during opioid withdrawal focus on hyperalgesia during precipitated opioid withdrawal and include only male animals. The present study was conducted to assess hyperalgesia during a protracted withdrawal state in female and male NIH Swiss mice. Mice were rendered opioid-dependent by twice daily s.c. injections of morphine in escalating doses (50-125 mg/kg) or saline vehicle for four consecutive days; there was a final dose of morphine on day 5. Body weight was taken prior to injections as well as mornings and evenings prior to testing. Paw withdrawal thresholds to increasing paw pressures were recorded prior to the first injection and at 5, 10, 24, 34, 48, 58, 72, 82, 96 and 106 h after the final injection. Mice consistently lost weight during morphine administration; however, both sexes gained weight immediately following cessation of drug treatment. Morphine-dependent animals exhibited pronounced hyperalgesia starting at 10 h after the final morphine injection and subsiding at roughly 58 h for females and 82 h for males. A main effect of morphine administration showed that animals that received morphine had significantly reduced paw withdrawal thresholds in percentage of baseline. A main effect of sex indicates that males had generally lower scores over time than females in hyperalgesia data. These results indicate that spontaneous withdrawal causes hyperalgesia in NIH Swiss mice. This is significant because while it is known that withdrawal can cause hyperalgesia, most animal models that investigate this phenomenon use a precipitated withdrawal model, while our study demonstrated hyperalgesia also occurs in a spontaneous withdrawal model. This research was supported in part by State of Washington Initiative Measure 171. Pain patients may experience heightened sensitivity to pain while trying to discontinue opioid use which may contribute to resumption of opioid use in order to avoid more pain. However, most studies in animals that investigate hyperalgesia during opioid withdrawal focus on hyperalgesia during precipitated opioid withdrawal and include only male animals. The present study was conducted to assess hyperalgesia during a protracted withdrawal state in female and male NIH Swiss mice. Mice were rendered opioid-dependent by twice daily s.c. injections of morphine in escalating doses (50-125 mg/kg) or saline vehicle for four consecutive days; there was a final dose of morphine on day 5. Body weight was taken prior to injections as well as mornings and evenings prior to testing. Paw withdrawal thresholds to increasing paw pressures were recorded prior to the first injection and at 5, 10, 24, 34, 48, 58, 72, 82, 96 and 106 h after the final injection. Mice consistently lost weight during morphine administration; however, both sexes gained weight immediately following cessation of drug treatment. Morphine-dependent animals exhibited pronounced hyperalgesia starting at 10 h after the final morphine injection and subsiding at roughly 58 h for females and 82 h for males. A main effect of morphine administration showed that animals that received morphine had significantly reduced paw withdrawal thresholds in percentage of baseline. A main effect of sex indicates that males had generally lower scores over time than females in hyperalgesia data. These results indicate that spontaneous withdrawal causes hyperalgesia in NIH Swiss mice. This is significant because while it is known that withdrawal can cause hyperalgesia, most animal models that investigate this phenomenon use a precipitated withdrawal model, while our study demonstrated hyperalgesia also occurs in a spontaneous withdrawal model. This research was supported in part by State of Washington Initiative Measure 171.