Evaluation of the effects of a metabotropic glutamate receptor 5-antagonist on electrically induced pain and central sensitization in healthy human volunteers.

BACKGROUND: This study aimed to investigate the effect of a single dose of the mGluR5-antagonist AZD9272 on electrically induced pain, central sensitization and axon reflex flare. METHODS: This was a randomized, double-blind, placebo-controlled crossover study. Twenty-five healthy male volunteers received a single oral dose of AZD9272 or placebo on two occasions separated by 10-20 days. Electrical stimulation with a constant current for 100 min delivered through intracutaneous electrodes inserted on the forearm was used to induce a stable level of pain (6 of 10 on a 0-10 numerical rating scale; NRS). Pain intensity was assessed every 10 min during stimulation. The area of punctate hyperalgesia, area of dynamic mechanical allodynia, and area and intensity of flare reaction were measured every 20 min during stimulation. The stimulation procedure, current intensity and measurements were identical at both treatment visits. The AUC0-100 min (area under curve, 100 min stimulation) was calculated for each variable. The AUC0-100 min for pain NRS and hyperalgesia area were defined as primary variables. Linear mixed effects models were used for the statistical analysis. RESULTS: Twenty-one subjects completed the study per protocol. No significant differences were found between AZD9272 and placebo regarding any of the AUC0-100 min variables for pain NRS, hyperalgesia area, allodynia area, flare area or flare intensity. The plasma levels of AZD9272 were maximal during the pain measurements and corresponded to >50% brain mGluR5 receptor occupancy. CONCLUSION: Single doses of the centrally acting mGluR5-antagonist AZD9272 did not reduce C-fibre evoked pain, central sensitization or flare reaction.

Switching from other antipsychotics to once-daily extended release quetiapine fumarate in patients with schizophrenia.

OBJECTIVE: To evaluate the clinical benefit, efficacy and tolerability of switching patients experiencing suboptimal efficacy or tolerability with their current antipsychotic to once-daily extended release quetiapine fumarate (quetiapine XR). RESEARCH DESIGN AND METHODS: 12-week, multicenter, open-label study in adult, in- or outpatients with schizophrenia. Quetiapine XR (mg/day) was initiated during a 4-day cross-titration phase (day 1: 300; day 2: 600; days 4-84: 400-800 [flexible-dosing]). The primary endpoint was the percentage of patients achieving clinical benefit (improvement on the Clinical Global Impression-Clinical Benefit [CGI-CB] scale). Secondary endpoints included CGI-Improvement (CGI-I) and Positive and Negative Syndrome Scale (PANSS) total scores. Tolerability was assessed by adverse events (AEs), Simpson-Angus Scale (SAS) and Barnes Akathisia Rating Scale (BARS) scores. Changes in rating scale scores were analyzed using analysis of covariance and are presented as least squares mean (LSM) changes using the baseline level as a covariate. RESULTS: Of 477 patients switched to quetiapine XR, 77.6% completed treatment. Following switching, 295 of 470 patients adequate for evaluation (62.8%) achieved a clinical benefit (95% confidence interval [CI] 58.4, 67.1; p < 0.0001). Significant improvements in LSM (95% CI) CGI-I of 2.88 (2.67, 3.08) and the LSM change in PANSS total scores of -12.3 (-14.95, -9.58) were observed (both p < 0.001). Common AEs included somnolence (17.8%), sedation (15.1%), dizziness and dry mouth (14.0% each). The incidence of extrapyramidal symptoms (EPS) was 8.0%. Mean improvements from baseline in SAS and BARS scores were -2.1 and -0.4, respectively (both p < 0.001). CONCLUSIONS: Switching to quetiapine XR was associated with clinical benefit and good efficacy and tolerability.

A comparison of the SF-36 and Nottingham Health Profile in patients with chronic neuropathic pain.

The aim of this study was to evaluate and compare the psychometric properties of two generic health-related quality of life (HRQoL) instruments, the Short Form Health Survey (SF-36) and the Nottingham Health Profile (NHP) in a group of patients with chronic peripheral neuropathic pain (PNP). The sample consisted of 126 adults (56 men and 70 women) with PNP following a lesion of a peripheral nerve, spinal nerve or nerve root or patients with post-herpetic neuralgia. The battery of tests included visual analogue scales (VASs) for pain assessment and global rating of health and verbal rating scales of pain and other symptoms, as well as patient descriptors. The SF-36 had higher internal consistency reliability coefficients (alpha=0.79, range 0.70-0.90) than the NHP (alpha=0.68, range 0.49-0.79). Correlations between comparable dimensions of the two instruments were significant (range from -0.79 for the physical and mental dimensions to -0.29 for the social dimension) indicating a moderate degree of convergent validity. The study population had significantly worse scores on all dimensions of the two instruments when compared with the general population. Subjects with high VAS scores for pain on movement and those with low global health ratings had poorer scores on the both instruments. Overall, the SF-36 performed somewhat better on psychometric testing than did the NHP. However, the NHP contains dimensions such as sleep and more pain items which might be of particular importance in the PNP population. Since the instruments are short, both could be retained for continued testing in outcome studies of this population.

Prolonged epidural infusions of ropivacaine (2 mg/mL) after colonic surgery: the impact of adding fentanyl.

UNLABELLED: We evaluated the safety and efficacy of a 72-h epidural infusion of ropivacaine and measured the impact of adding fentanyl 2 microg/mL to the required infusion rate, on the quality of postoperative pain relief and the incidence of side effects, after colonic surgery. One hundred fifty-five patients scheduled for elective colonic surgery were randomized in this trial. Epidural infusions of ropivacaine 2 mg/mL with fentanyl 2 microg/mL (R + F) and without fentanyl (R) were commenced during surgery and continued for 72 h postoperatively. This was a prospective, randomized, double-blinded, multi-center trial. The median infusion rate required was less in the R + F group (9.3 vs 11.5 mL/h, P < 0.001). Median pain scores at rest and on coughing were lower in the R + F group (P < 0.0001). The incidence of hypotension was more in the R + F group (P = 0.01). Time to readiness for discharge was delayed in the R + F group (median 6.6 vs 5.5 days, P = 0.012). The addition of fentanyl to ropivacaine resulted in decreased infusion rates and enhanced pain control; however, adverse effects were increased and readiness to discharge was delayed. IMPLICATIONS: Epidural infusions of ropivacaine with and without fentanyl were administered to patients to control pain after colonic surgery. Patients who received ropivacaine with fentanyl had better pain control, increased side effects, and delayed readiness to discharge. This study questions the value of adding opioids to epidural infusions of local anesthetics.

A comparison of epidural ropivacaine infusion alone and in combination with 1, 2, and 4 microg/mL fentanyl for seventy-two hours of postoperative analgesia after major abdominal surgery.

UNLABELLED: Our aim in this prospective, randomized, double-blinded study was to compare the analgesic effectiveness and side effects of epidural infusions with ropivacaine 2 mg/mL alone (Group R; n = 60) and in combination with fentanyl 1 microg/mL (R1F; n = 59), 2 microg/mL (R2F; n = 62), and 4 microg/mL (R4F; n = 63) for up to 72 h after major abdominal surgery. Effective epidural neural blockade was established before surgery; postoperatively, the infusion rate was titrated to a maximum of 14 mL/h for analgesia. No additional analgesics other than acetaminophen were permitted during the infusion. The median of individual visual analog scale score with coughing were <20 mm for all groups (0 = no pain, 100 = worst pain) and was significantly lower (P < 0.01) for Group R4F at rest and with coughing (compared with Group R). Infusions were discontinued due to inability to control pain in significantly fewer patients in Group R4F (16%) than the other groups (34% to 39%; P < 0.01). For all groups, >90% of patients had no detectable motor block after 24 h. Hypotension, nausea, and pruritus were more common with the larger dose of fentanyl. We conclude that, after major abdominal surgery, an epidural infusion of ropivacaine 2 mg/mL with fentanyl 4 microg/mL provided significantly more effective pain relief over a 3-day period than ropivacaine alone or ropivacaine with lower concentrations of fentanyl. IMPLICATIONS: Postoperative epidural analgesic infusions are widely used, but there is little information regarding optimal strengths of opioid with local anesthetic. In this blinded, prospective study, we compared four different epidural infusion solutions for efficacy and side effects over a clinically useful postoperative period and conclude that an epidural infusion of ropivacaine 2 mg/mL with fentanyl 4 microg/mL was most effective.