Chi Wai Cheung

Alpha-2 agonists in acute pain management

Importance of the field: This review explores the significance of alpha-2 agonists used clinically in acute pain management. Areas covered in this review: Although alpha-2 agonists have been reported to have an analgesic effect, they are not commonly used clinically for acute pain management. Clinical studies on use of alpha-2 agonists for acute pain management are reviewed and discussed. A literature search was done using Medline with the keywords ‘alpha-2 agonist’, ‘clonidine’, ‘dexmedetomidine’, ‘fadolmidine’, ‘pharmacokinetics’, ‘pharmacodynamics’, ‘postoperative analgesia’, ‘epidural’, ‘intrathecal’, ‘peripheral nerve block’ and various combinations with these keywords. The years 1977 – 2009 have been included, with particular focus on clinical studies from between 1990 and 2009. What the reader will gain: This article helps to clarify the clinical use of alpha-2 agonists in acute pain management according to current, up-to-date evidence. Clinically, available alpha-2 agonists, including clonidine and dexmedetomidine, are discussed in detail. Take home message: Alpha-2 agonists, especially clonidine, seem to be promising with regard to acute postoperative pain management. However, more clinical evidence on dexmedetomidine is necessary to confirm its definite role in acute postoperative pain control.

Glial cell line-derived neurotrophic factor induces cell migration and matrix metalloproteinase-13 expression in glioma cells

Malignant gliomas are the most common primary brain tumors in adults and the second most common tumor in children. Gliomas are associated high morbidity and mortality because these tumors are highly invasive into surrounding brain tissue, making complete surgical resection impossible. Glial cell line-derived neurotrophic factor (GDNF) has been identified as a potent neurotrophic factor in a variety of neuronal cell populations. However, the molecular mechanisms and pathologic roles underlying GDNF-induced glioma migration remain unclear. In this study, we found that application of recombinant human GDNF enhances the migration of U87 and U251 cells but not C6 cells. In addition, we found that the expression of matrix metalloproteinase-13 (MMP-13) mRNA, protein and secretion increase in response to GDNF stimulation. The GDNF-induced increase in cell migration was antagonized by MMP-13 neutralizing antibody or silencing MMP-13. We then examined the involvement of mitogen-activated protein kinases (MAPKs) in glioma cell migration induced by GDNF. GDNF-induced MMP-13 expression and glioma migration were attenuated by MEK/extracellular signal-regulating kinase (ERK) and c-Jun N-terminal protein kinase (JNK) inhibitors, as well as ERK and JNK dominant-negative mutants. Treatment with GDNF-induced MEK/ERK and JNK/c-Jun activation and increased AP-1 DNA binding activity in a time-dependent manner. Treatment with AP-1 inhibitors (tanshinone IIA and curcumin) also reduced GDNF-induced glioma cell migration. In migration-prone sublines, cells with greater migration ability had higher GDNF expression. These results indicate that GDNF enhances migration of glioma cells through the increase of MMP-13 production and is mainly regulated by the MEK/ERK and JNK, c-Jun and AP-1 pathways.

A comparison of dexmedetomidine and midazolam for sedation in third molar surgery.

This randomised, double‐blind study compared dexmedetomidine and midazolam for intravenous sedation during third molar surgery under local anaesthesia. Sixty patients received either dexmedetomidine (up to 1 μg.kg−1) or midazolam (up to 5 mg), which was infused until the Ramsay Sedation Score was four or the maximum dose limit was reached. Intra‐operative vital signs, postoperative pain scores and analgesic consumption, amnesia, and satisfaction scores for patients and surgeons, were recorded. Sedation was achieved by median (IQR (range)) doses of 47 μg (39–52 (25–76)) or 0.88 μg.kg−1 (0.75–1.0 (0.6–1.0)) dexmedetomidine, and 3.6 mg (3.3–4.4 (1.9–5.0)) or 0.07 mg.kg−1 (0.055–0.085 (0.017–0.12)) midazolam. Heart rate and blood pressure during surgery were lower in dexmedetomidine group. There was no significant difference in satisfaction or pain scores. Midazolam was associated with greater amnesia. Dexmedetomidine produces comparable sedation to midazolam.

Remifentanil Preconditioning Reduces Hepatic Ischemia― Reperfusion Injury in Rats via Inducible Nitric Oxide Synthase Expression

BACKGROUND Opioid preconditioning against ischemia reperfusion injury has been well studied in myocardial and neuronal tissues. The objective of this study was to determine whether remifentanil could attenuate hepatic injury and to investigate the mechanisms. METHODS A rat model of hepatic ischemia reperfusion injury and a hepatocyte hypoxia reoxygenation (HR) injury model were used, respectively, in two series of experiments. Remifentanil was administered before ischemia or hypoxia and the experiments were repeated with previous administration of naloxone, L-arginine and N-ω-nitro-L-arginine methyl ester, a nonselective opioid receptor antagonist, a nitric oxide donor, and nitric oxide synthase (NOS) inhibitor, respectively. Serum aminotransferase, cytokines, and hepatic lipid peroxidation were measured. Histopathology examination and apoptotic cell detection were assessed. For the in vitro study, cell viability, intracellular nitric oxide, apoptosis, and NOS expression were evaluated. RESULTS Remifentanil and L-arginine pretreatment reduced concentrations of serum aminotransferases and cytokines, decreased the concentrations of hepatic malondialdehyde and myeloperoxidase activity, and increased superoxide dismutase, nitric oxide, and inducible NOS expression in vivo. Decreased histologic damage and apoptosis were also seen in these two groups. These changes were prevented by previous administration of N-ω-nitro-L-arginine methyl ester but not naloxone. There was an increase in inducible NOS protein expression but not endogenous NOS in remifentanil and L-arginine pretreated groups compared with control, naloxone, and N-ω-nitro-L-arginine methyl ester groups. CONCLUSION Pretreatment with remifentanil can attenuate liver injury both in vivo and in vitro. Inducible NOS but not opioid receptors partly mediate this effect by exhausting reactive oxygen species and attenuating the inflammatory response.

Opioids in chronic non-cancer pain

Introduction: The use of chronic opioid therapy for chronic non-cancer pain is growing and is now accepted as an effective treatment modality. Areas covered: Although there are guidelines and reviews for chronic opioid therapy for chronic non-cancer pain patients, physicians may still have concerns and be reluctant to prescribe strong opioids for chronic non-cancer pain. Common issues and concerns when prescribing opioid for chronic pain management are reviewed and discussed. The literature search was done using Medline with key words ‘chronic non-cancer pain’, ‘chronic opioid therapy’, ‘effectiveness’, ‘opioid tolerance’, ‘opioid-induced hyperalgesia’, ‘adverse effect’, ‘opioid dependency’, ‘addiction’, ‘monitoring’, ‘opioid contract’ and various combinations with these key words. Studies from 1990 – 2010 have been included. This article helps readers to update, clarify and understand the common concerns when using opioid for chronic non-cancer pain. Clinical effectiveness and adverse effects with chronic opioid therapy, opioid tolerance and opioid-induced hyperalgesia, opioid dependency and addiction, monitoring during chronic opioid use, and opioid contact are discussed in detailed. Expert opinion: Not much strongly positive data supports the long-term use of opioids for pain relief, and the evidence for an improvement in functional activity is inconclusive. With careful selection of patients, meticulous prescription and monitoring protocol, chronic non-cancer pain patients who are likely to benefit from potent opioids should not be prevented from obtaining this treatment.

Phloroglucinol derivative MCPP induces cell apoptosis in human colon cancer

This study is the first to investigate the anticancer effects of the new phloroglucinol derivative (3,6‐bis(3‐chlorophenylacetyl)phloroglucinol; MCPP) in human colon cancer cells. MCPP induced cell death and antiproliferation in three human colon cancer, HCT‐116, SW480, and Caco‐2 cells, but not in primary human dermal fibroblast cells. MCPP‐induced concentration‐dependent apoptotic cell death in colon cancer cells was measured by fluorescence‐activated cell sorter (FACS) analysis. Treatment of HCT‐116 human colon cancer cells with MCPP was found to induce a number of signature endoplasmic reticulum (ER) stress markers; and up‐regulation of CCAAT/enhancer‐binding protein homologous protein (CHOP) and glucose‐regulated protein (GRP)‐78, phosphorylation of eukaryotic initiation factor‐2α (eIF‐2α), suggesting the induction of ER stress. MCPP also increased GSK3α/β(Tyr270/216) phosphorylation and reduced GSK3α/β(Ser21/9) phosphorylation time‐dependently. Transfection of cells with GRP78 or CHOP siRNA, or treatment of GSK3 inhibitor SB216163 reduced MCPP‐mediated cell apoptosis. Treatment of MCPP also increased caspase‐7, caspase‐9, and caspase‐3 activity. The inhibition of caspase activity by z‐DEVE‐FMK or z‐VAD‐FMK significantly reduced MCPP‐induced apoptosis. Furthermore, treatment of GSK3 inhibitor SB216763 also dramatically reversed MCPP‐induced GRP and CHOP up‐regulation, and pro‐caspase‐3 and pro‐caspase‐9 degradation. Taken together, the present study provides evidences to support that GRP78 and CHOP expression, and GSK3α/β activation in mediating the MCPP‐induced human colon cancer cell apoptosis. J. Cell. Biochem. 112: 643–652, 2011.

Analgesic and sedative effects of intranasal dexmedetomidine in third molar surgery under local anaesthesia

BACKGROUND Dexmedetomidine (DEX) is an alpha 2-adrenoreceptor agonist, which induces sedation and analgesia. This study aimed to determine whether intranasal DEX offered perioperative sedation and better postoperative analgesia. METHODS Patients having unilateral third molar surgery under local anaesthesia were recruited and allocated to receive either intranasal DEX 1 µg kg(-1) (Group D) or same volume of saline (Group P) 45 min before surgery. Patient-controlled sedation with propofol was offered as a rescue sedative. Perioperative sedation, postoperative pain relief and analgesic consumption, vital signs, adverse events, postoperative recovery, and satisfaction in sedation and analgesia were assessed. RESULTS Thirty patients from each group were studied. Areas under curve (AUC) of postoperative numerical rating scale (NRS) pain scores 1-12 h at rest and during mouth opening were significantly lower in Group D (P=0.003 and 0.009, respectively). AUC BIS values and OAA/S sedation scores were significantly lower before surgery and at the recovery area (all P<0.01) with significantly less intra-operative propofol used in group D (P<0.01). In group D, heart rate was significantly lower at recovery period (P=0.005) while systolic blood pressure in different periods of the study (all P<0.01), but the decreases did not require treatment. More patients from placebo group experienced dizziness (P=0.026) but no serious adverse event was found. No difference was found in postoperative psychomotor recovery and satisfaction in pain relief and sedation. CONCLUSIONS Patients receiving intranasal DEX for unilateral third molar surgery with local anaesthesia were more sedated perioperatively with better postoperative pain relief. No delay in psychomotor recovery was seen.

An audit of postoperative intravenous patient‐controlled analgesia with morphine: Evolution over the last decade

The development and refinement of an acute pain service based on the increased availability of clinical evidence would be expected to improve the quality of postoperative pain control. This report reviews the application of postoperative patient‐controlled analgesia (PCA) using intravenous morphine in a single institution between 2002 and 2005. More than 5000 patients were evaluated and the results were compared with a similar study performed 10 years ago. Prescription of PCA had increased by more than threefold. Morphine consumption from post‐operative day 1 to day 3 (19.1 vs. 26.1, 8.6 vs. 18.1 and 4.5 vs. 19.0μg/kg/h, respectively), demand‐to‐delivery ratio (1.35–1.76 vs. 2.4–2.8) and the incidence of respiratory depression (0.06% vs. 2%) were significantly reduced (p<0.001), but there was no improvement in pain relief. A substantial proportion of patients still experienced postoperative nausea (47%) and vomiting (18.5%) despite a reduction in morphine consumption. Most patients ranked PCA as good and only 0.3% were dissatisfied. We conclude that, in our institution over the last decade, PCA has become more popular for postoperative pain management but with no attendant improvement in pain relief or reduction in side effects. Using PCA alone may result in poorer quality postoperative analgesia. Our findings add to the growing body of evidence that postoperative pain management has not substantially improved despite increased adoption of acute pain services.

Efficacy of Pregabalin in Acute Postoperative Pain Under Different Surgical Categories: A Meta-Analysis

AbstractThe efficacy of pregabalin in acute postsurgical pain has been demonstrated in numerous studies; however, the analgesic efficacy and adverse effects of using pregabalin in various surgical procedures remain uncertain. We aim to assess the postsurgical analgesic efficacy and adverse events after pregabalin administration under different surgical categories using a systematic review and meta-analysis of randomized controlled trials.A search of the literature was performed between August 2014 to April 2015, using PubMed, Ovid via EMBASE, Google Scholar, and ClinicalTrials.gov with no limitation on publication year or language. Studies considered for inclusion were randomized controlled trials, reporting on relevant outcomes (2-, 24-hour pain scores, or 24 hour morphine-equivalent consumption) with treatment with perioperative pregabalin.Seventy-four studies were included. Pregabalin reduced pain scores at 2 hours in all categories: cardiothoracic (Hedges g and 95%CI, −0.442 [−0.752 to −0.132], P = 0.005), ENT (Hedge g and 95%CI, −0.684 [−1.051 to −0.316], P < 0.0001), gynecologic (Hedge g, 95%CI, −0.792 [−1.235 to −0.350], P < 0.0001), laparoscopic cholecystectomy (Hedge g, 95%CI, –0.600 [–0.989 to –0.210], P = 0.003), orthopedic (Hedge g, 95%CI, −0.507 [−0.812 to −0.202], P = 0.001), spine (Hedge g, 95%CI, −0.972 [−1.537 to −0.407], P = 0.001), and miscellaneous procedures (Hedge g, 95%CI, −1.976 [−2.654 to −1.297], P < 0.0001). Pregabalin reduced 24-hour morphine consumption in gynecologic (Hedge g, 95%CI, −1.085 [−1.582 to −0.441], P = 0.001), laparoscopic cholecystectomy (Hedge g, 95%CI, –0.886 [–1.652 to –0.120], P = 0.023), orthopedic (Hedge g, 95%CI, −0.720 [−1.118 to −0.323], P < 0.0001), spine (Hedge g, 95%CI, −1.016 [−1.732 to −0.300], P = 0.005), and miscellaneous procedures (Hedge g, 95%CI, −1.329 [−2.286 to −0.372], P = 0.006). Pregabalin resulted in significant sedation in all surgical categories except ENT, laparoscopic cholecystectomy, and gynecologic procedures. Postoperative nausea and vomiting was only significant after pregabalin in miscellaneous procedures.Analgesic effects and incidence of adverse effects of using pregabalin are not equal in different surgical categories.

The novel phloroglucinol derivative BFP induces apoptosis of glioma cancer through reactive oxygen species and endoplasmic reticulum stress pathways

Prenyl-phloroglucinol derivatives from hop plants have been shown to have anticancer activities. This study is the first to investigate the anticancer effects of the new phloroglucinol derivative (2,4-bis(4-fluorophenylacetyl)phloroglucinol; BFP). BFP induced cell death and anti-proliferation in three glioma, U251, U87 and C6 cells, but not in primary human astrocytes. BFP-induced concentration-dependently cell death in glioma cells was determined by MTT and SRB assay. Moreover, BFP-induced apoptotic cell death in glioma cells was measured by Hochest 33258 staining and fluorescence-activated cell sorter (FACS) of propidine iodine (PI) analysis. Treatment of U251 human glioma cells with BFP was also found to induce reactive oxygen species (ROS) generation, which was detected by a fluorescence dye used FACS analysis. Treatment of BFP also increased a number of signature endoplasmic reticulum (ER) stress markers glucose-regulated protein (GRP)-78, GRP-94, IRE1, phosphorylation of eukaryotic initiation factor-2α (eIF-2α) and up-regulation of CAAT/enhancer-binding protein homologous protein (CHOP). Moreover, treatment of BFP also increased the down-stream caspase activation, such as pro-caspase-7 and pro-caspase-12 degradation, suggesting the induction of ER stress. Furthermore, BFP also induced caspase-9 and caspase-3 activation as well as up-regulation of cleaved PARP expression. Treatment of antioxidants, or pre-transfection of cells with GRP78 or CHOP siRNA reduced BFP-mediated apoptotic-related protein expression. Taken together, the present study provides evidences to support that ROS generation, GRP78 and CHOP activation are mediating the BFP-induced human glioma cell apoptosis.