Subcutaneous Injection Of Morphine Research Articles

Current Status of Cognition and Clinical Practice of Refractory Cancer Pain in Shanghai: A Questionnaire Survey.

This study aimed to assess the current status of clinical practice of refractory cancer pain (RCP) among a sample of physicians specializing in cancer pain management in Shanghai. From 2019 to 2021, a questionnaire survey was conducted among physicians engaged in diagnosis and treatment of cancer pain through the questionnaire WJX network platform in Shanghai, China. A total of 238 responses participated in the survey. This survey reports physicians' understanding and incidence rate of breakthrough cancer pain (BTCP). The choice of analgesics and satisfaction of analgesic effect were investigated. We also investigated doctors' knowledge of the diagnostic criteria for RCP and their tendency to choose analgesics. Oral immediate-release morphine and intravenous or subcutaneous morphine injection have been the common treatment approach for transient cancer pain exacerbations. The main barriers to pain management are lack of standardized treatment methods for RCP, lack of knowledge related to RCP, and single drug dosage form. Doctors believe the most necessary measures to improve the current situation of poor cancer pain control include improving medical staff's understanding and treatment techniques for RCP, updating treatment techniques and methods, and improving the configuration of drug types in medical institutions. Clinicians expect to improve understanding and treatment techniques through systematic training. Despite multiple available analgesic measures, the treatment of RCP remains challenging. Improving the understanding of medical staff towards RCP, improving treatment techniques, and increasing the accessibility of multiple drug types are important ways to improve the satisfaction of cancer pain management in the future.

Repeated pre-exposure to morphine inhibited the amnesic effect of ethanol on spatial memory: Involvement of CaMKII and BDNF

Evidence has suggested that addiction and memory systems are related, but the signaling cascades underlying this interaction have not been completelyealed yet. The importance of calcium-calmodulin-dependent protein kinase II (CaMKII) and brain-derived neurotrophic factor (BDNF) in the memory processes and also in drug addiction has been previously established. In this present investigation, we examined the effects of repeated morphine pretreatment on impairment of spatial learning and memory acquisition induced by systemic ethanol administration in adult male rats. Also, we assessed how these drug exposures influence the expression level of CaMKII and BDNF in the hippocampus and amygdala. Animals were trained by a single training session of 8 trials, and a probe test containing a 60-s free-swim without a platform was administered 24 h later. Before training trials, rats were treated with a once-daily subcutaneous morphine injection for 3 days followed by a 5-day washout period. The results showed that pre-training ethanol (1 g/kg) impaired spatial learning and memory acquisition and down-regulated the mRNA expression of CaMKII and BDNF. The amnesic effect of ethanol was suppressed in morphine- (15 mg/kg/day) pretreated animals. Furthermore, the mRNA expression level of CaMKII and BDNF increased significantly following ethanol administration in morphine-pretreated rats. Conversely, this improvement in spatial memory acquisition was prevented by daily subcutaneous administration of naloxone (2 mg/kg) 15 min prior to morphine administration. Our findings suggest that sub-chronic morphine treatment reverses ethanol-induced spatial memory impairment, which could be explained by modulating CaMKII and BDNF mRNA expressions in the hippocampus and amygdala.

Surgical Determinants of Post Operative Pain in Patients Undergoing Laparoscopic Adnexectomy

Objective The objective of our study was to determine the main surgical factors associated with postoperative pains in patients undergoing adnexectomy. Material and Methods Patients that underwent adnexectomy in two French Gynecological centers between July, 2018 and March, 2020 were prospectively included and retrospectively analyzed. The main pre and per operative surgical factors were analyzed to assess their impact on immediate postoperative pain. Analgesic consumption was recorded for each patient and pain was evaluated using the validated numeric rating scale (ranging between 0 and 10). Results One hundred and seventeen patients underwent laparoscopic adnexectomy. Eighty-four patients (72%) experienced either no or minor postoperative pain (NRS ≤ 2). Seventeen patients (14.5%) required strong opioids (subcutaneous morphine injection) in the immediate postoperative period. The only two parameters that had a significant impact on immediate postoperative pain were the realization of a fascia closure and the duration of pneumoperitoneum longer than 60 minutes. Pneumoperitoneum pressure and size of ports were not significantly correlated with postoperative pain. Conclusion Fascia closure and increased surgical time were significantly associated with immediate postoperative pain and the need for strong opioids consumption. Surgical training to limit prolonged surgeries should be strongly emphasized to lower postoperative pain and limit opioids consumption.

Effects of dezocine on morphine tolerance and opioid receptor expression in a rat model of bone cancer pain

BackgroundClinically, the coadministration of opioids to enhance antinociception and decrease tolerance has attracted increasing research attention. We investigated the effects of dezocine, a mu- and kappa-opioid receptor agonist/antagonist, on morphine tolerance and explored the involvement of opioid receptor expression in a rat model of bone cancer pain.MethodsThermal nociceptive thresholds were measured after the subcutaneous injection of morphine (10 mg/kg) alone or combined with dezocine (10 or 1 mg/kg) for 7 consecutive days. Real-time PCR and western blot analysis were used to examine opioid receptor expression in the periaqueductal gray (PAG) and spinal cord.ResultsThe analgesic effect was significantly decreased after 4 days of morphine administration. We observed that low-dose dezocine significantly attenuated morphine tolerance without reducing the analgesic effect of morphine. Low-dose dezocine coadministration significantly reversed the downregulated expression of mu (MOR) and delta (DOR) opioid receptors in the PAG and the upregulated expression of kappa (KOR) and DOR in the spinal cord induced by morphine. Moreover, low-dose dezocine coadministered with morphine significantly inhibited KOR expression in both the PAG and spinal cord.ConclusionsThe combination of low-dose dezocine with morphine may prevent or delay the development of morphine tolerance in a rat model of bone cancer pain. The regulation of opioid receptor expression in the PAG and spinal cord may be part of the mechanism.

Cardiorespiratory anomalies and increased brainstem microglia in a rat model of neonatal opioid withdrawal syndrome

Infants born with neonatal opioid withdrawal syndrome (NOWS) can display abnormal cardiorespiratory patterns including tachypnea, tachycardia, and impaired ventilatory responses to hypoxia (HVR) and hypercapnia (HCVR). Chronic morphine exposure is associated with increased midbrain microglial expression. Using a rat model of pre- and post-natal morphine exposure, we assessed cardiorespiratory features of NOWS (resting tachycardia and tachypnea) including the attenuated HVR and HCVR and whether they are associated with increased brainstem microglia expression. Pregnant rats (dams) received twice-daily subcutaneous injections of morphine (5 mg/kg) during the third (last) week of pregnancy to simulate 3rd trimester in utero opioid exposure. Offspring then received once-daily subcutaneous injections of morphine (0.5 mg/kg) until postnatal (P) day P10 days of age to simulate postnatal morphine therapy. Cardiorespiratory responses were assessed 24 h later (P11 days) following spontaneous withdrawal. Compared to saline-treated pups, morphine-exposed offspring exhibited tachycardia and tachypnea as well as an attenuated HVR and HCVR. Microglial cell counts were increased in the nucleus tractus solitarius (nTS), dorsal motor nucleus of the vagus (DMNV) and nucleus ambiguous (NAamb), but not the retrapezoid nucleus (RTN) or the non-cardiorespriatory region, the cuneate nucleus (CN). These data suggest that the cardiorespiratory features and autonomic dysregulation in NOWS infants may be associated with altered microglial function in specific brainstem cardiorespiratory control regions.

Blockade of orexin receptors in the hippocampal dentate gyrus reduced the extinction latency of morphine-induced place preference in male rats

Relapse to drugs such as opioids is a major challenge in addiction therapy. It has been known that the orexinergic system has a significant role in mediating reward processing and addiction, as shown by the conditioned place preference (CPP). The dentate gyrus (DG) of the hippocampus receives orexinergic projections from the lateral hypothalamus that has been approved as a critical area arbitrating the maintenance of drug-seeking behavior following the extinction. The present study aimed to investigate the effects of intra-DG administration of the orexin-1 receptor (OX1R) and orexin-2 receptor (OX2R) antagonists on the extinction of morphine-induced CPP in male rats. Animals received different doses of SB334867 (as OX1R antagonist) or TCS OX2 29 (as OX2R antagonist) (0.5, 2.5, and 12.5 nM/0.5 μl DMSO 12 %) bilaterally into the DG during the extinction phase, after CPP had been induced by subcutaneous injection of morphine (5 mg/kg) during a 3-day conditioning phase. The conditioning scores were recorded during the test. The results demonstrated that intra-DG administration of the highest dose of OX1R antagonist (12.5 nM/0.5 μl DMSO 12 %) shortened the extinction latency of morphine-CPP compared to the DMSO group, while the OX2R antagonist did not significantly alter the latency. Findings imply that the blockade of OX1R, but not OX2R, within the DG facilitates the extinction of morphine-induced reward. In conclusion, the OX1R antagonist might be kept in mind as a convenient therapeutic factor in repressing drug-seeking behaviors in an optimum amount of treatment considering the low dose-treatments applied.

Increased brainstem microglia is associated with an attenuated hypercarbic ventilatory response in a rat model of neonatal opioid withdrawal syndrome

Background Infants born with neonatal opioid withdrawal syndrome (NOWS) display abnormal respiratory patterns including tachypnea, apnea and impaired ventilatory responses to hypoxia and hypercarbia challenges. Infants with NOWS are also at an increased risk of sudden infant death syndrome (SIDS), which is associated with impairments in respiratory control and increased gliosis in key brainstem respiratory control regions including the nucleus tractus solitarius (nTS). Objective Use a rat model of neonatal opioid withdrawal syndrome to assess whether pre- and postnatal morphine exposure attenuates the ventilatory responses to hypoxia and hypercarbia challenges in the offspring and whether they are associated with increased nTS microglia expression. Design/Methods Pregnant female rats (dams) received twice-daily subcutaneous injections of morphine (5mg/kg) during the third (last) week of pregnancy to simulate 3rd trimester in utero opioid exposure. After birth, the pups received once-daily subcutaneous injections of morphine (1mg/kg), through postnatal day 10 to simulate postnatal morphine therapy. Whole-body plethysmography was used precisely 24 hours later to assess ventilatory defense responses to acute hypoxia (HVR) and hypercapnia (HCVR) challenge (5 minutes at 10% O2 and 5% CO2, respectively). Brainstems were removed to assess nTS microglia expression using immunohistochemistry and a glial (Iba-1) marker. Results Compared to saline-treated pups, morphine exposure attenuated the HCVR, but not the HVR (Fig. 1A). Morphine-exposed offspring also expressed increased number of microglia in the nTS (Fig. 1B). Conclusion The disturbances in neonatal hypercarbia challenge are associated with increased brainstem microglia expression, which could contribute to the etiology underlying the increased risk of SIDS in infants with NOWS.

Morphine Reduces Tumor Growth in Glioma Mouse Xenograft through Modulation of IDH1 Activity and Metabolic Reprogramming

Background Isocitrate dehydrogenase 1 (IDH1) is a key extra-mitochondrial enzyme, responsible for converting isocitrate to α-ketoglutarate. In low grade gliomas, IDH1 is often mutated (Arg132His), altering the enzymatic product to the oncometabolite 2-hydroxyglutarate (2HG) and inducing drastic metabolic reprogramming1. 2HG also inhibits DNA demethylases thus causing DNA hypermethylation. Contrary to expectation, IDH1 mutation slows tumor growth and increases susceptibility to antineoplastic agents, improving patient outcome2. We previously found that morphine, a commonly used opiate for pain management in cancer patients, is a mixed partial inhibitor of wild type IDH1. We sought to determine if morphine's effect on IDH1 activity replicates the beneficial changes caused by IDH1 mutation. Methods U87 cells (IDH1 wild type) were treated with clinically relevant concentrations of morphine (0.1-10µM) or equipotent hydromorphone for 7 days. Hydromorphone has no effect on IDH1 activity and served as a negative opiate control. DNA methylation was quantified by ELISA assay. Targeted metabolomics was performed using LC/MS. Mitochondrial function was determined using a Seahorse assay. The in vivo effect of morphine was tested using a mouse xenograft model (intraperitoneal U87 injection), with daily subcutaneous injections of morphine (5mg/kg or 10mg/kg) or hydromorphone (2mg/kg). Tumors at 30 days were measured by weight and histopathology. Cooperative capacity of morphine and the antineoplastic drug temozolomide (TMZ) was determined by measuring in vitro cell viability. Results We observed a dose-dependent increase in both DNA methylation (91%, p<0.05) and 2HG oncometabolite levels (75%, p<0.01) relative to vehicle in morphine samples. Levels of 22 metabolites were uniquely affected by morphine (fig. 1). Pathway enrichment analysis highlighted changes to glutamate metabolism, glycolysis, and the pentose phosphate pathway, all previously implicated in the beneficial IDH1 mutant glioma phenotype. Consistent with metabolic reprogramming, morphine reduced basal and ATP-coupled respiration (15%, p<0.01). Tumors from morphine treated mice were significantly smaller than vehicle (3.7-fold, p<0.01). Histological staining of these tumors revealed increased apoptosis (172%, p<0.01) and reduced proliferation (26%, p<0.01) (fig. 2). Morphine potentiated the effect of TMZ, co-treatment exhibited more cell death after 36 hours (18%, p<0.05) than either drug alone. Conclusion Our research has shown that morphine treatment, through its interaction with IDH1, is able to increase 2HG and DNA methylation. The opiate altered pathways significant in glioma metabolism and energy production. Moreover, it significantly reduced glioma tumor growth and enhanced the chemotherapeutic effect of TMZ, much like the known impact of the IDH1 mutation. We conclude that the interaction between morphine and IDH1 mimics the beneficial IDH1 mutation phenotype. Our research highlights the need for personalized medicine pathways, illustrating that that even the choice of opiate for pain management can potentially alter the course of oncologic disease. Sources 1. Dang, L. et al. Nature (2009) 2. Paldor, I. et al. J. Clin. Neurosci. (2016)

Which Strategy to Manage Severe Vaso-occlusive Crisis in Patients with Sickle Cell Disease in Countries with Limited Healthcare Capacities?

We evaluated the treatment of morphine by intravenous patient controlled analgesia versus intermittent subcutaneous routes on patients with sickle cell disease developing severe vaso-occlusivecrisis.&#x0D; Objectives: The primary objective was to compare intravenous patient controlled analgesia (PCA) versus intermittent subcutaneous injection of morphine (SC) on sickle cell patients developing severe vaso-occlusive crisis during the first 24 hours of admission. The secondary objective was to assess the side effects of morphine in both regimens.&#x0D; Methods: A randomized controlled trial of 77 patients in the PCA and 81 in the SC group was conducted at the Sickle Cell Center of Brazzaville in the Republic of Congo. Participants aged from&#x0D; 15 to 45 years old with severe vaso-occlusive crisis were included in the study.&#x0D; Results: Both regimens provided pain relief. However, a significant pain reduction was observed 30 minutes after the administration of morphine in the PCA group (P= 0.001). The mean scores in the PCA and SC regimens were respectively: 1.16±1.40 and 4.30±2.32. The total median dose of morphine administered in the PCA regimen was markedly lower: 24,6±4,16 mg versus 36.6±3.1 mg in the SC group (P=0.01). Morphine administered by PCA provided pain relief during 24 hours while intermittent severe pain was experienced in the SC group (P=0.014). Sedation score S2, S3 was significantly observed in the SC group (P&lt; 0.05).

Sub-chronic exposure to morphine alters general anesthetic potency by differentially regulating the expression of neurotransmitter receptor subunits in mice

BackgroundSub-chronic exposure to morphine can increase the potency of propofol but decrease the potency of ketamine by unknown mechanisms. The present study was designed to investigate the effects of sub-chronic exposure to morphine on the expression of neurotransmitter receptor subunits, which might contribute to the potency changes of ketamine and propofol in vivo. MethodsSub-chronic exposure to morphine was established by administering subcutaneous injections of morphine for 5 consecutive days. The median effective dose (ED50) of ketamine and/or propofol was measured on day 1, day 3, day 7 and day 15, after the last morphine dosage. Mice in the sham group received an equal volume of normal saline. The expressions of N-methyl D-aspartate (NMDA) receptor and γ-aminobutyric acid A (GABAA) receptor subunits in the forebrain were measured. Knockdown or overexpression of a subunit was used to determine the causality between the change in anesthetic potency and the expression of an identified receptor subunit. ResultsAfter sub-chronic exposure of mice to morphine, the expression of NMDA receptor 1 (NR1) was most elevated in the forebrain on day 1 (P < 0.0001 vs. sham). In contrast, the expression of GABAA receptor β3 (GABAARβ3) gradually decreased to its lowest level on day 7 (P = 0.005 vs. sham) in the forebrain. Regression analysis revealed that the expression of NR1 in the forebrain was relevant to the increased ED50 of ketamine (P = 0.0002), while the expression of GABAARβ3 in the forebrain was relevant to the decreased ED50 of propofol (P = 0.0051) after morphine exposure. Knockdown expression of NR1 in the forebrain reversed the elevated ED50 of ketamine after morphine treatment. Overexpression of GABAARβ3 in the forebrain increased the ED50 of propofol to the sham-level after morphine treatment. ConclusionsSub-chronic exposure to morphine can differentially modulate the expressions of NR1 and GABAARβ3 in mice, which may contribute to the changes in ED50 of ketamine and propofol in vivo.

Restraint Stress Potentiated Morphine Sensitization: Involvement of Dopamine Receptors within the Nucleus Accumbens.

Sensitization to psychostimulant drugs, as well as morphine, subjected to cross-sensitization with stress. The development of morphine sensitization is associated with enhancements in dopamine overflow in the Nucleus accumbens (NAc). This study aimed to examine the role of accumbal D1/D2-like dopamine receptors in restraint stress (RS) induced sensitization to morphine antinociceptive effects. Adult male Wistar rats weighing 220-250 g underwent stereotaxic surgery. Two stainless steel guide cannulae were bilaterally implanted, 1 mm above the NAc injection site. Different solutions of SCH-23390, as a D1-like receptor antagonist or sulpiride, as a D2-like receptor antagonist, were microinjected into the NAc five min before exposure to RS. Restraint stress lasted for 3 h, 10 min after RS termination; animals received a subcutaneous injection of morphine (1 mg/kg) for 3 consecutive days. The procedure was followed by a 5-day drug and/or stress-free period. After that, on the 9th day, the nociceptive response was evaluated by the tail-flick test. The results revealed that intra-NAc administration of D1/D2-like dopamine receptor antagonists, SCH-23390 or sulpiride, respectively, blocked morphine sensitization-induced by RS and morphine co-administration in rats for three consecutive days. This work provides new insight into the determinant role of accumbal dopamine receptors in morphine sensitization produced by RS-morphine co-administration.

The Role of Hydrogen Sulfide in the Development of Tolerance and Dependence to Morphine in Mice

Objective: Hydrogen sulfide is an endogenous gaseous mediator that has been indicated to have a role in pain mechanisms. In this study, we aimed to detect brain and spinal cord hydrogen sulfide levels during different phases of tolerance and dependence to morphine and to determine the effects of inhibition of endogenous hydrogen sulfide production on the development of tolerance and dependence. Methods: Morphine tolerance and dependence was developed by subcutaneous injection of morphine (10 mg/kg) twice daily for 12 days. Physical dependence was determined by counting the jumps for 20 min, which is a withdrawal symptom occurring after a single dose of naloxone (5 mg/kg) administered intraperitoneally (i.p.). Propargylglycine (30 mg/kg, i.p.), a cystathionine-γ-lyase inhibitor, and hydroxylamine (12.5 mg/kg, i.p.), a cystathionine-β-synthase inhibitor, were used as hydrogen sulfide synthase inhibitors. The tail-flick and hot-plate tests were used to determine the loss of antinociceptive effects of morphine and development of tolerance. Results: It was found that chronic and acute uses of both propargylglycine and hydroxylamine prevented the development of tolerance to morphine, whereas they had no effect on morphine dependence. Chronic and acute administrations of hydrogen sulfide synthase inhibitors did not exert any difference in hydrogen sulfide levels in brain and spinal cords of both morphine-tolerant and -dependent animals. Conclusion: It has been concluded that hydrogen sulfide synthase inhibitors may have utility in preventing morphine tolerance.

Effects of dopamine D1- and D2-like receptors in the CA1 region of the hippocampus on expression and extinction of morphine-induced conditioned place preference in rats

Considering the extent of drug use and its relapse rate worldwide, in the present study, we explored the role of intra-CA1 administration of D1-like and D2-like receptor antagonists on the expression and extinction of morphine-induced CPP. To induce morphine CPP, adult male Wistar rats received a daily subcutaneous injection of morphine (5 mg/kg) during a 3-day conditioning phase. Different doses of SCH23390 (0.25, 1 or 4 μg/0.5 μl saline), as a selective D1-like receptor antagonist, and sulpiride (0.25, 1, or 4 μg/0.5 μl DMSO), as a selective D2-like receptor antagonist, were bilaterally microinjected into the CA1 region in the expression and extinction phases 1 h before CPP evaluation. Conditioning scores and locomotor activities were recorded during the tests. Results indicated that the injection of the antagonists into the CA1 region dose-dependently attenuated the expression of the morphine-induced CPP and sulpiride revealed prominent behavioral results compared to SCH23390 in the expression phases. Furthermore, microinjections of SCH23390 and sulpiride shortened the extinction phase of the morphine-induced CPP without changing the locomotor activity. The results indicated the involvement of D1- and D2-like receptors within the CA1 region in the expression and extinction of rewarding properties of morphine.

Differential effects of opioid versus alcohol dependence on pain avoidance behavior and regional endocannabinoid system deficiency

In contrast to their analgesic effects, chronic use of opioids or alcohol often creates the paradoxical emergence of heightened pain sensitivity, termed hyperalgesia, during withdrawal. A hallmark symptom of hyperalgesia is the development of motivational strategies to avoid painful stimuli, and we have shown that adult male Wistar rats display pain avoidance behavior using the mechanical conflict avoidance system when in withdrawal from morphine (n=10–11/group) and alcohol (n=8–9/group). The present study seeks to identify how morphine and alcohol differentially affect pain avoidance behavior and endocannabinoid signaling within pain‐ and avoidance‐ associated brain regions, including the periaqueductal grey (PAG) and basolateral amygdala (BLA).Morphine dependence was induced via daily subcutaneous morphine injections (escalating dose of 10–20mg/kg) over 3 weeks. Alcohol dependence was induced via exposure to chronic intermittent ethanol vapor (CIEV) for 14 hours per day for 8 weeks. Pain avoidance behavior was quantified using the MCS as the latency for rats to exit a brightly lit start chamber onto nociceptive probes of varying heights (0–5mm) to enter a dark goal box. Western blotting was conducted for quantification of endocannabinoid system‐related proteins cannabinoid receptor 1 (CB1R) and eCB synthetic and catabolic enzymes diacylglycerol lipase alpha (DAGLa), monoacylglycerol lipase (MAGL).We found that morphine and alcohol dependence produced distinct patterns of pain avoidance behavior, where morphine dependence produced a hyperalgesic behavior and ethanol dependence produced an allodynic phenotype. This behavior negatively correlated with PAG levels of CB1R and DAGLa in morphine dependent animals and with the ratio of BLA DAGLa:MAGL in alcohol dependent animals, reflective of a decreased eCB tone in these animals. This suggests that exogenous cannabinoid treatment may be an effective therapy for substance‐induced hyperalgesia. Because substance‐induced hyperalgesia and negative affective components of pain are integral to addiction reinforcement, targeting these behaviors therapeutically could treat substance abuse.Support or Funding InformationNIAAA: T32AA007577, R00AA020839, R01AA025996, R21AA025736, NIH‐NICHD‐2018‐05

The role of Smyrnium cordifolium Boiss extract and curzerene on withdrawal syndrome in mice

Morphine is the most effective medication to relieve pain, antinociception and withdrawal syndrome, but clinical application of these compounds is greatly affected by the occurrence of addiction. The aim of this research was the influence of SE and curzerene (Cur) on withdrawal syndrome signs in mice contrasted with clonidine. Extraction of the S. cordifolium extract (SE) was done by the Soxhlet method. Addiction was produced using the subcutaneous injections of morphine for 7 days. To estimate the influences of SE and Cur, the 64 male mice were separated into eight of 8. Sets 1, 2 and 3 were treated SE (100,200,300 mg/kg). Sets 4, 5 and 6 were treated Cur (0.03, 0.06, 0.12mg/kg). The findings showed that curzerene was the most important effective component S. cordifolium extract. Curzerene and SE reduced the mean of weight loss, diarrhea, and wet dog shakes in morphine-dependent mice in comparison with clonidine. All doses of Curzerene and SE extract reduced the locomotor activity and body weight loss when compared to the control group in morphine-dependent mice but not to clonidine compared. The SE (100mg/kg) and Cur (0.03mg/kg) are reduced signs of withdrawal syndrome equally to clonidine. SE (200 mg/kg) and Cur (0.06 mg/kg), are reduced of the body weight loss significantly in relation to clonidine (P&lt;0.05). SE (200 mg/kg) and Cur (0.06 mg/kg), are reduced of diarrhea significantly in relation to clonidine (P&lt;0.01). This was while SE (300mg/kg) and cur (0.12mg/kg) had deadly effect. Curzerene and SE are able to decrease the signs of withdrawal syndrome, which might have a human therapeutic capacity. Curzerene may be one of the terpenoids responsible for the effect of the S. cordifolium extract. Nevertheless, more investigations are needed to determine the exact mechanism of the effect of SE and curzerene.

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.

PCN203 - HEALTHCARE RESOURCE USE IN PATIENTS WITH END-STAGE ADVANCED CUTANEOUS T-CELL LYMPHOMA (CTCL): RESULTS OF SEVEN SEMI-STRUCTURED INTERVIEWS ACROSS LEADING UK CENTRES

To estimate the healthcare resource use burden for patients with advanced stage cutaneous T-cell lymphoma (CTCL) who have exhausted all systemic treatment options, have progressed and whose symptoms are being managed until end of life in the UK. Semi-structured interviews were conducted with clinical experts from six of the seven supra-regional centres for CTCL in England and a leading Welsh centre between March 2018 and June 2018. Each respondent was responsible for end stage patient management within their catchment area. Interviews were guided by a questionnaire capturing resource use associated with pain, anxiety/depression, itch relief, pharmacological support, and skin care and wound management. The greatest burden was associated with dressings and wound care, which necessitated frequent and lengthy nurse visits (up to two hours) and constant therapies to control infection, pain and intractable pruritus. The questionnaire found that 100% of these patients needed expensive specialised dressings of which up to 20-25% required full-body coverage of dressings, with the remaining 75%-80% requiring localised coverage. Due to the frailty of skin, specialised (non-adhesive borders) dressings are needed, costing up to £63.64 per dressing. Multiple interventions were reported to be given in an attempt to alleviate the symptoms of pruritus, including anti-histamines and anti-epileptics/anti-depressants. In addition, patients are treated with oral opioids for background pain with episodes of breakthrough pain requiring subcutaneous injections of morphine on average reported monthly. The weekly cost of resource use for these patients was up to £2,095 per patient. A striking feature of end-stage management of CTCL compared to the management of other cancers at this stage is the frequency of visits and touch-points with multiple healthcare providers, all the way until death. This is likely due to the “double nature” of CTCL which requires both oncologic relief and extensive skin care, which requires daily attention and management.

Morphine for Refractory Dyspnea in Interstitial Lung Disease: A Phase I Study (JORTC-PAL 05).

Background: Dyspnea is common in interstitial lung disease (ILD) patients and often refractory to conventional treatment. Little is known regarding the safety of systemic morphine in ILD patients. Objective: The objective of this study is to evaluate the safety of a single subcutaneous morphine injection and to determine the recommended dose of morphine for alleviating dyspnea in ILD patients. Design: We conducted a dose-escalation Phase I study for investigating the recommended dose of a single subcutaneous morphine injection to alleviate dyspnea in ILD patients. Setting/Subjects: Eligible subjects were ILD inpatients with dyspnea at rest who were refractory to conventional dyspnea treatment. The morphine doses used were 1 mg and 2 mg in cohort 1 and cohort 2, respectively. The primary endpoint was dose-limiting toxicity, which was defined as (1) respiratory depression, that is, 30% reduction of respiratory rate and 10 Torr increase of PaCO2 compared with baseline; (2) hypotension, that is, 20% reduction of systemic blood pressure compared with baseline and presentation of hypotension-related symptoms; or (3) grade 3, 4, or 5 treatment-emergent adverse events graded by Common Terminology Criteria for Adverse Events (version 4). Results: A total of six patients were enrolled, with three patients each in cohorts 1 and 2. No dose-limiting toxicities were observed; three patients experienced worsened somnolence, but no patients experienced sedation. Conclusion: We conclude that 2 mg of morphine has a tolerable safety profile in ILD patients with dyspnea, and can be tested in further clinical trials.

Involvement of D1- and D2-like dopamine receptors in the dentate gyrus in the acquisition, expression, and extinction of the morphine-induced conditioned place preference in rats

In the current study, we investigated the role of intra-dentate gyrus (DG) administration of D1 and/or D2 receptor antagonists on the expression, acquisition, and extinction of morphine-CPP. Cannulae were implanted bilaterally into the DG region in male Wistar rats and CPP was induced by the subcutaneous injection of morphine (5 mg/kg) during a 3-day conditioning phase. Three experimental designs were separately employed in the CPP paradigm during the acquisition, expression and extinction phases, and different doses (0.25, 1, or 4 μg/0.5 μl saline) of SCH23390, as a selective D1-like receptor antagonist, and sulpiride (0.25, 1, or 4 μg/0.5 μl DMSO), as a selective D2-like receptor antagonist, were bilaterally microinjected into the DG region. Conditioning scores and locomotor activities were recorded during the test. Results showed that the injection of the antagonists into the DG region dose-dependently attenuated the acquisition and expression of the morphine-induced CPP and sulpiride revealed prominent behavioral results compared to SCH23390 in both mentioned phases. Moreover, the blockade of D1- and D2-like receptors shortened the extinction phase of the morphine-induced CPP but had no effect on the locomotor activity. We found that the dopamine receptors within the DG region are involved in the acquisition and expression of morphine-CPP and have a critical role in the association between a morphine-paired context and the rewarding proprieties of morphine.

Rapid titration of opiate doses via patient-controlled intravenous analgesia for patients with severe cancer pain

This study was to investigate the feasibility and safety of patient-controlled intravenous analgesia for opiate titration in patients with severe cancer. Eligible patients with cancer pain were randomly divided into two groups, which were titrated with a subcutaneous injection of morphine and patient-controlled intravenous analgesia, respectively. The time required for patients to begin titration to reach visual analog scale score ⩽ 3, the adverse reactions during titration, the time spent by nurses in titrating each patient, and the time to complete the titration with a delayed-release dosage form analgesic effect and adverse reaction. The mean titration time of patient-controlled intravenous analgesia group (1.09 ± 0.82 vs 2.97 ± 1.98) and morphine dosage (18.78 ± 12.32 vs 13.23 ± 8.07) were significantly lower than those in the subcutaneous group ( P &lt; 0.05). The incidences of nausea, vomiting, pruritus, urinary retention, and sedation in the subcutaneous injection group were significantly lower than those in the subcutaneous injection group ( P &lt; 0.05). The assessment times of the two groups (10.19 ± 3.72 vs 10.25 ± 4.88) were similar ( P &gt; 0.05). However, the time required for subcutaneous injection in patients under patient-controlled intravenous analgesia was significantly lower than that in the subcutaneous injection group (36.36 ± 12.15 vs 132.36 ± 32.79), which was statistically significant ( P &lt; 0.05). After the titration, the controlled release opioid was used to treat cancer pain. The visual analog scale score of the patient-controlled intravenous analgesia group was significantly lower than that of the subcutaneous group (2.44 ± 1.37 vs 2.73 ± 0.91) at 7 days after treatment in the subcutaneous group (1.05 ± 0.30 vs 2.45 ± 1.29; P &lt; 0.05). Patient-controlled intravenous analgesia technique can effectively and quickly complete the titration of cancer pain treatment with less occupational care resources and is better than the subcutaneous injection titration.