Raymond Cheung

Presurgical intravenous parecoxib sodium and follow-up oral valdecoxib for pain management after laparoscopic cholecystectomy surgery reduces opioid requirements and opioid-related adverse effects

Background:  Opioids are associated with numerous adverse effects. It is unclear if reduced postoperative opioid consumption lowers the incidence and severity of opioid‐related adverse effects. This analysis – from a multicenter, randomized, double‐blind trial – tested if the reduction of opioid consumption among patients who received intravenous preoperative parecoxib 40 mg, followed by oral valdecoxib 40 mg qd postoperatively, in Days 1–4 after outpatient laparoscopic cholecystectomy surgery, reduced opioid‐related symptoms.

Safety and efficacy of pregabalin in patients with central post-stroke pain.

&NA; Pregabalin has demonstrated efficacy in several forms of neuropathic pain, but its long‐term efficacy in central post‐stroke pain (CPSP) is unproven. We evaluated the efficacy and safety of pregabalin versus placebo in patients with CPSP. A 13‐week, randomized, double‐blind, multicenter, placebo‐controlled, parallel group study of 150 to 600 mg/day pregabalin was conducted in patients aged ⩾18 years with CPSP. The primary efficacy endpoint was the mean pain score on the Daily Pain Rating Scale over the last 7 days on study drug up to week 12 or early termination visit. Secondary endpoints included other pain parameters and patient‐reported sleep and health‐related quality‐of‐life measures. A total of 219 patients were treated (pregabalin n = 110; placebo n = 109). A mean pain score at baseline of 6.5 in the pregabalin group and 6.3 in the placebo group reduced at endpoint to 4.9 in the pregabalin group and 5.0 in the placebo group (LS mean difference = –0.2; 95% CI = –0.7, 0.4; P = 0.578). Treatment with pregabalin resulted in significant improvements, compared with placebo, on secondary endpoints including MOS‐sleep, HADS‐A anxiety, and clinician global impression of change (CGIC) P < 0.05. Adverse events were more frequent with pregabalin than with placebo and caused discontinuation in 9 (8.2%) of pregabalin patients versus 4 (3.7%) of placebo patients. Although pain reductions at endpoint did not differ significantly between pregabalin and placebo, improvements in sleep, anxiety, and CGIC suggest some utility of pregabalin in the management of CPSP. Pain reductions at endpoint did not differ significantly between pregabalin and placebo, but improvements in comorbid conditions suggest some utility of pregabalin in central post‐stroke pain management.

Cardiovascular safety of the cyclooxygenase-2 selective inhibitors parecoxib and valdecoxib in the postoperative setting: an analysis of integrated data.

BACKGROUND: Studies of parecoxib, the inactive prodrug of the cyclooxygenase-2 selective inhibitor valdecoxib, and valdecoxib for postoperative pain relief in patients undergoing coronary artery bypass graft surgery revealed an increased risk of cardiovascular (CV) adverse events compared with placebo. We conducted this study to address whether parecoxib and valdecoxib increased CV risk in noncardiac surgery patients. METHODS: A pooled post hoc analysis was conducted using 2 large datasets: 17 controlled trials of parecoxib for noncardiac studies and 32 studies, including the 17 noncardiac parecoxib studies plus 15 studies of valdecoxib. The 32-study dataset provided 95% power to detect a twofold increase in the incidence of CV adverse events assuming a placebo group incidence of 1% (estimated from previous study data), and 69% power to detect a twofold increase from a 0.5% incidence. RESULTS: The incidence of total CV events for the 17 parecoxib studies was 0.44% (13 of 2966) in patients who received parecoxib and 0.37% (7 of 1915) in those receiving placebo (P > 0.20). In the analysis of 32 studies, the incidence of total CV events was 0.40% (21 of 5285) in the parecoxib/valdecoxib group compared with 0.50% (16 of 3226) in the placebo group (P > 0.20). No significant differences in the incidence of total or any individual CV event category were observed between the parecoxib or parecoxib/valdecoxib and placebo groups in the two analyses. When patients were stratified by number of baseline CV risk factors, no significant difference in CV events was detected in parecoxib/valdecoxib patients compared with placebo. CONCLUSIONS: In the largest analysis of the CV risk of cyclooxygenase selective inhibitors or nonsteroidal antiinflammatory drugs for perioperative pain management, parecoxib and valdecoxib were not found to increase the risk of CV adverse events after noncardiac surgery.

Central amplification and fibromyalgia: disorder of pain processing.

Fibromyalgia (FM), a complex chronic pain disorder affecting a heterogeneous patient population, is an area of active basic and clinical research. Although diagnostic criteria for FM have been available for 2 decades, there remains no definitive diagnostic and no consensus regarding its etiology. Accumulating evidence suggests the underlying cause of FM pain results from abnormal pain processing particularly in the central nervous system rather than from dysfunction in peripheral tissues where pain is perceived. In this review, we examine recent studies investigating abnormalities in central pain processing as a component of FM in both preclinical models of generalized muscle hypersensitivity and clinical research in patients with FM. We focus our discussion on two areas where strong evidence exists for abnormalities in sensory signaling: the reduction of descending control, including suppression of descending inhibitory pathways and/or enhancement of descending facilitatory pathways, and changes in key neurotransmitters associated with central sensitization. Finally, we discuss currently available pharmacological treatments indicated for the management of pain in FM patients, based on their proposed mechanism of action and efficacy.

Evaluation of the safety and efficacy of pregabalin in older patients with neuropathic pain: results from a pooled analysis of 11 clinical studies

BackgroundOlder patients are typically underrepresented in clinical trials of medications for chronic pain. A post hoc analysis of multiple clinical studies of pregabalin in patients with painful diabetic peripheral neuropathy (DPN) or postherpetic neuralgia (PHN) was conducted to evaluate the efficacy and safety of pregabalin in older patients.MethodsData from 11 double-blind, randomized, placebo-controlled clinical studies of pregabalin in patients with DPN or PHN were pooled. Efficacy outcomes included change in Daily Pain Rating Scale score, ≥30% and ≥50% responders, and endpoint pain score ≤3. Safety was based on adverse events (AEs). Primary efficacy was analyzed by analysis of covariance with terms for treatment, age category, protocol, baseline pain, and treatment-by-age category interaction.Results2516 patients (white, n = 2344 [93.2%]; men, n = 1347 [53.5%]; PHN, n = 1003 [39.9%]; pregabalin, n = 1595) were included in the analysis. Patients were grouped by age: 18 to 64 years (n = 1236), 65 to 74 years (n = 766), and ≥75 years (n = 514). Baseline mean pain and sleep interference scores were comparable across treatment and age groups. Significant improvements in endpoint mean pain were observed for all pregabalin dosages versus placebo in all age groups (p ≤ 0.0009), except for the lowest dosage (150 mg/day) in the youngest age group. Clinically meaningful pain relief, defined as ≥30% and ≥50% pain response, was observed in all age groups. The most common AEs were dizziness, somnolence, peripheral edema, asthenia, dry mouth, weight gain, and infections. The relative risks for these AEs increased with pregabalin dose, but did not appear related to older age or type of neuropathic pain.ConclusionsPregabalin (150-600 mg/day) significantly reduced pain in older patients (age ≥65 years) with neuropathic pain and improvements in pain were comparable to those observed in younger patients. Titration of pregabalin to the lowest effective dose should allow for effective pain relief while minimizing AEs in older patients with neuropathic pain. Given the common use of polypharmacy in older patients, the absence of known drug-drug interactions makes pregabalin an important treatment option for older patients with pain of neuropathic origin.

Analgesic efficacy of celecoxib in postoperative oral surgery pain: A single-dose, two-center, randomized, double-blind, active- and placebo-controlled study

BACKGROUND Celecoxib 200 mg has been reported to reduce pain following dental extraction but to offer poorer pain relief than active comparators. OBJECTIVE The aim of this study was to compare the efficacy and tolerability of celecoxib 400 mg, the recommended loading dose for treatment of acute pain, with that of ibuprofen 400 mg and placebo following oral surgery. METHODS This was a single-dose, 2-center, randomized, double-blind, active- and placebo-controlled study in which patients with moderate to severe pain following third molar extraction were randomized to receive a single dose of celecoxib 400 mg, ibuprofen 400 mg, or placebo. Pain assessments were completed using a 4-point pain intensity scale where 0=no pain and 3=severe pain and a 5-point pain relief scale where 0=no pain relief and 4= complete pain relief at baseline and 18 time points over 24 hours. Primary efficacy outcome measures were time to onset of analgesia (the median time to perceptible pain relief in those patients who achieved meaningful pain relief), time-specific pain intensity difference (PID), time-specific pain relief (PR), time-specific sum of PID and PR, and time to use of rescue medication. Times to perceptible and meaningful pain relief (secondary efficacy outcome measures) were recorded using 2 stopwatches. Tolerability was assessed through recording of adverse events, clinical laboratory tests, and physical examinations (including collection of vital signs). RESULTS One hundred seventy-one patients were randomized to celecoxib 400 mg (30 women and 27 men; mean [SD] age, 21.4 [4.2] years); ibuprofen 400 mg (30 women and 27 men; mean [SD] age, 22.0 [4.7] years); or placebo (34 women and 23 men; mean [SD] age, 21.6 [5.0] years). Mean times to onset of analgesia with celecoxib 400 mg and ibuprofen 400 mg were rapid and comparable (median 28 minutes and 26 minutes, respectively) and were significantly shorter than with placebo (>24 hours) (both, P<0.05 vs placebo). Compared with placebo, mean time-specific PID scores were significantly greater with celecoxib from 0.5 to 24 hours and with ibuprofen from 0.5 to 16 hours (all, P<0.05 vs placebo). Time-specific PR scores with celecoxib and ibuprofen were significantly greater from 0.75 and 0.5 hour, respectively, compared with placebo (all, P<0.05 vs placebo). PID was significantly greater with celecoxib compared with ibuprofen beginning at 11 hours (all, P<0.05). PR scores were significantly higher with celecoxib versus ibuprofen beginning at 9 hours (all, P<0.05). Median (95% CI) time to use of rescue medication with celecoxib (>24 hours) was significantly longer than with ibuprofen (10 hours, 58 minutes [8 hours, 30 minutes- 14 hours, 34 minutes]) or placebo (1 hour, 51 minutes [1 hour, 40 minutes-2 hours, 22 minutes]) (both, P<0.05). The 3 most common adverse events experienced in the celecoxib group were headache (9 [15.8%] patients), nausea (9 [15.8%] patients), and dizziness (6 [10.5%] patients). CONCLUSIONS In this postsurgical dental pain study, the onset and magnitude of pain relief with celecoxib 400 mg and ibuprofen 400 mg were found to be comparable. In addition, patients who received celecoxib 400 mg as a single dose had a significantly longer time to use of rescue medication and had higher pain relief scores later in the study than those who received ibuprofen 400 mg. Celecoxib was well tolerated compared with placebo.

The diverse therapeutic actions of pregabalin: is a single mechanism responsible for several pharmacological activities?

Pregabalin is a specific ligand of the alpha2-delta (α2-δ) auxiliary subunit of voltage-gated calcium channels. A growing body of evidence from studies of anxiety and pain indicate that the observed responses with pregabalin may result from activity at the α2-δ auxiliary protein expressed presynaptically, in several different circuits of the central nervous system (CNS). The disorders that appear to be effectively treated with pregabalin are thematically linked by neuronal dysregulation or hyperexcitation within the CNS. This review proposes how binding to the α2-δ protein target in different regions of the CNS may contribute to the observed clinical activity of pregabalin, as well as to the adverse event profile of the compound. Whether this compound regulates synaptic function via α2-δ in additional conditions is yet to be discovered. The potential of pregabalin to regulate neuronal hyperactivity involving other CNS circuits will require further exploration.

Relationship Between Pain Relief and Improvements in Patient Function/Quality of Life in Patients With Painful Diabetic Peripheral Neuropathy or Postherpetic Neuralgia Treated With Pregabalin

BACKGROUND In patients with chronic pain due to diabetic peripheral neuropathy (DPN) or postherpetic neuralgia (PHN), pregabalin treatment results in pain relief and improved patient function/quality of life (QoL). Few studies, however, have examined the exact relationship between pain relief and improvements in patient function/QoL. It is unclear, for example, whether pregabalin has a direct independent effect on patient function/QoL or whether improvements in function/QoL are an indirect consequent of pain relief. OBJECTIVES To determine whether improvements in function/QoL in response to pregabalin treatment are related to the extent of pain relief in patients with neuropathic pain due to DPN or PHN and to determine whether pregabalin has a direct independent effect on patient function/QoL that is distinct from its effects on pain. METHODS Data from 11 randomized, double-blind, placebo-controlled trials of pregabalin for the treatment of DPN or PHN were pooled for this analysis. Changes in patient function/QoL scores were plotted according to the extent of pain relief to assess whether greater levels of pain relief were associated with greater improvement in function/QoL. A novel mediation analysis was used to asses to what extent the effects of pregabalin on function/QoL scores are a direct treatment effect as opposed to an indirect effect mediated through improvements in pain or sleep. RESULTS Moderate-to-substantial pain relief (a ≥30% decrease in pain) in response to pregabalin treatment was associated with significant (P < 0.05) improvements in 36-Item Short Form Health Survey (SF-36) scores (used to assess patient function/QoL). In many patients, greatest improvement in SF-36 scores was reported by patients achieving ≥50% decrease in pain. Analysis of Patient Global Impression of Change scores revealed a similar trend, where >80% of patients who achieved substantial pain relief also reported their status as much or very much improved. A substantial direct pregabalin treatment effect was evident for many SF-36 domains that could not be explained by pain relief or improvement in sleep. CONCLUSIONS In patients with chronic pain due to DPN or PHN, improvements in patient function/QoL in response to pregabalin treatment are correlated with the extent of pain relief. However, such improvements in function/QoL are not mediated entirely through pain relief but are the result of a combination of pregabalins effects on pain and sleep disturbance and a direct effect on patient function itself.

Effects of parecoxib and dipyrone on platelet aggregation in patients undergoing meniscectomy: a double-blind, randomized, parallel-group study.

BACKGROUND Based on a PubMed search of the literature using the terms parecoxib, platelets, thromboxane, bleeding, and platelet aggregation, the effects of parecoxib on platelet function have not fully been established under clinical conditions. OBJECTIVE The aim of this study was to determine platelet aggregation, thromboxane B(2) (TxB(2)) formation, and plasma concentrations with the use of parecoxib in postoperative pain management. METHODS This double-blind, randomized, parallel-group trial was conducted at the University Hospital for Orthopedic Surgery, Friedrichsheim, Frankfurt, Germany. Male and female patients aged 18 to 55 years and scheduled to undergo routine partial meniscectomy (or a similar arthroscopic procedure) were eligible. All patients received dose-adjusted enoxaparin before surgery and parecoxib 40 mg BID or dipyrone 1000 mg QID. Blood samples were drawn before first injection (predose) and at 0.5, 2, and 6 hours after injection. Platelet aggregation (expressed as percentage of the maximal light transmittance [A(max)]) was induced with arachidonic acid (A(max)AA) and collagen (A(max)CO). TxB(2) formation was determined using enzyme-linked immunosorbent assay. RESULTS This study included 26 patients. In both treatment groups, 8 males and 5 females, all white, were enrolled. In the dipyrone group, the mean age was 48 years (range, 32-61 years) and the mean weight was 85 kg (range, 63-122 kg); in the parecoxib group, the mean age was 47 years (range, 31-61 years) and the mean weight was 81 kg (range, 57-100 kg). Median (interquartile range [IQR]) predose values for A(max)AA were 76% (65%-83%) in the parecoxib group and 87% (80%-89%) in the dipyrone group. At 0.5 hour after injection, A(max)AA was 52% (5%-77%) with parecoxib and 8% (0%-11%) with dipyrone (P=0.004). At 2 hours after injection, A(max)AA was 78% (72%-80%) in the parecoxib group versus 7% (5%-11%) in the dipyrone group (P<0.001). At 6 hours after study drug administration, no treatment differences were found. For A(max)CO, no statistically significant differences were found. Consistent with the stronger inhibition of aggregation, patients who received dipyrone had lower TxB(2) formation values. Six hours after parecoxib administration, mean TxB(2) formation was significantly enhanced compared with predose values (132 ng/mL [IQR, 62-228 ng/mL] vs 185 ng/mL [IQR, 135-239 ng/mL]; P=0.05). CONCLUSIONS Platelet aggregation and TxB(2) formation were significantly lower for 6 hours in dipyronetreated patients compared with parecoxib-treated patients. In contrast, TxB(2) formation was increased with parecoxib 6 hours after administration compared with pretreatment values. In this small study, parecoxib did not affect platelet aggregation in a population of patients undergoing routine partial meniscectomy (or a similar arthroscopic procedure) under clinical conditions.

Prediction of Pregabalin-Mediated Pain Response by Severity of Sleep Disturbance in Patients with Painful Diabetic Neuropathy and Post-Herpetic Neuralgia

OBJECTIVE To evaluate the predictive value of disturbed sleep on the ability of pregabalin to reduce pain associated with diabetic peripheral neuropathy (DPN) and post-herpetic neuralgia (PHN). DESIGN A post-hoc analysis of data pooled from 16 placebo-controlled trials of pregabalin in patients with DPN or PHN. METHODS Pain relief at endpoint was compared in patients with mild, moderate, or severe levels of baseline sleep disturbance. Sleep disturbance was based on a scale from 0-10 and scores <4, 4 to 7, and ≥7 were classified as mild, moderate, and severe, respectively. RESULTS Pregabalin significantly reduced mean pain scores in the DPN (N = 3,056) and PHN (N = 1,471) cohorts (mean placebo-adjusted reductions were -0.73 and -1.08 for patients with DPN/PHN, respectively; both P < 0.05). The greatest extent of pain relief occurred in patients with severe sleep interference scores at baseline. Data analyses using the pooled DPN/PHN population identified a subset of patients (N = 707) exhibiting marked levels of pain relief at endpoint (mean placebo-adjusted reduction of -2.88), all of whom had severe sleep interference scores at baseline. Baseline sleep interference scores were a moderately good predictor of global patient improvement in response to pregabalin treatment in both patient cohorts. Finally, path analysis showed a high degree of association between improvements in sleep and pain relief in patients with DPN/PHN. CONCLUSION Overall, these data suggest that the presence of comorbid sleep disturbance in patients with DPN/PHN might, in part, predict substantial pain relief in response to pregabalin treatment.