betadex and Pain--Postoperative

A novel formulation of diclofenac sodium suitable for subcutaneous or intramuscular injection (Akis(®), Dicloin(®)) has been developed using the complexing agent hydroxypropyl-β-cyclodextrin (HPβCD) as a solubility enhancer. Diclofenac HPβCD is available in several European countries, where it is indicated for use in adults with acute forms of pain, including postoperative pain. Clinical trials have demonstrated the analgesic efficacy of diclofenac HPβCD in terms of relieving moderate to severe postoperative pain in patients undergoing dental surgery or minor orthopaedic surgery. Subcutaneous diclofenac HPβCD also effectively relieved moderate to severe neuropathic pain, related to cancer or not. Diclofenac HPβCD was generally well tolerated in clinical trials, with injection-site reactions among the most commonly reported adverse events. The local tolerability of diclofenac HPβCD was consistently rated as 'good' or 'excellent' across all studies. Subcutaneous administration of diclofenac is a valid alternative to intramuscular delivery, with the advantages of easier administration, the availability of additional body sites suitable for injection and the potential for self-administration. Thus, diclofenac HPβCD 25, 50 or 75 mg/mL solution for subcutaneous or intramuscular injection extends the treatment options available for use in the management of pain in adults.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adult; Anti-Inflammatory Agents, Non-Steroidal; beta-Cyclodextrins; Chemistry, Pharmaceutical; Diclofenac; Humans; Injections; Pain; Pain, Postoperative

Long-term use of nonsteroidal anti-inflammatory drugs, including selective and nonselective cyclooxygenase inhibitors, has been suggested to be associated with cardiovascular (CV) safety risks. Data are limited regarding CV risks associated with short-term nonsteroidal anti-inflammatory drug use, including injectable formulations, although it has been suggested that even a single dose may increase CV adverse event (AE) risk. The objective of this study was to examine the CV safety of an injectable diclofenac formulation solubilized with hydroxypropyl-β-cyclodextrin (HPβCD) when given for ≤5days postoperatively.. A pooled analysis of CV AEs from 2 pivotal phase III clinical trials examining the efficacy and safety of intravenous (IV) HPβCD-diclofenac vs placebo and the active comparator ketorolac was conducted.. Postoperative, with treatment initiated in the postanesthesia care unit ≤6hours postsurgery.. Overall, 608 abdominal/pelvic and orthopedic surgery patients met inclusion criteria and received ≥1 study medication dose.. Patients received either HPβCD-diclofenac, ketorolac, or placebo via IV bolus injection every 6hours, for ≤5days postsurgery.. CV AEs, reported by study investigators, were evaluated through the treatment period and follow-up (≤37days after last study medication dose), and relative CV AE risks were estimated.. IV HPβCD-diclofenac was not associated with increased treatment-emergent CV AE incidence vs placebo (11.6% vs 12.2%; relative risk, 0.96 [95% confidence interval, 0.56-1.62]). Serious CV AEs as well as treatment-related AEs were uncommon, and there were no reports of myocardial infarction or cerebrovascular accident. CV AEs were uncommon during the follow-up period, occurring in 1.3%, 0%, and 1.4% of patients in the HPβCD-diclofenac, ketorolac, and placebo groups, respectively.. Although a longer duration follow-up study in a larger patient population would expand our understanding of potential CV risks, the present analysis suggests that postoperative use of HPβCD-diclofenac does not present an added CV safety risk over placebo.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Acute Pain; Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; beta-Cyclodextrins; Cardiovascular Diseases; Diclofenac; Double-Blind Method; Excipients; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pain, Postoperative; Young Adult

OBJECTIVE : While injectable nonsteroidal anti-inflammatory drugs (NSAIDs) are a key component of postoperative multimodal analgesia, renal safety concerns may limit use in some patients. This study examined the renal safety of injectable HPβCD-diclofenac when given for ≤ 5 days following orthopedic or abdominal/pelvic surgery. METHODS : Pooled analysis of data from two randomized, placebo- and active comparator-controlled phase III trials in 608 total patients was conducted. Renal safety was assessed by examining treatment-emergent adverse events (AEs) and postoperative blood urea nitrogen (BUN) and serum creatinine shifts. RESULTS : There were three renal AEs each in the HPβCD-diclofenac (n = 318 patients) and placebo (n = 148 patients) groups, and two renal AEs in the ketorolac group (n = 142 patients). No significant difference in renal AE risk was detected for patients receiving HPβCD-diclofenac (RR: 1.40 [0.15,13.3]; P = 0.75) or ketorolac (RR: 2.08 [0.19,22.7]; P = 0.56) versus placebo. All renal AEs were mild or moderate in severity, and a single renal AE (acute renal failure in a patient receiving HPβCD-diclofenac) was treatment-related. One incidence of postoperative shift to high (> upper limit of normal) serum creatinine occurred in the HPβCD-diclofenac group (n = 2 in the ketorolac group). Mean changes in serum creatinine or BUN did not differ significantly between patients receiving HPβCD-diclofenac and placebo. CONCLUSIONS : While this analysis examined relatively brief exposure typical for parenterally administered analgesics in the postoperative setting in patients with largely normal renal function, the results suggest that HPβCD-diclofenac use for acute postoperative pain may not be associated with added renal safety risks over placebo in this patient population.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adolescent; Adult; Aged; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; beta-Cyclodextrins; Diclofenac; Double-Blind Method; Female; Humans; Kidney; Male; Middle Aged; Pain, Postoperative; Young Adult

Parenteral diclofenac is frequently used for analgesia following minor orthopedic interventions. Currently available diclofenac formulations are for intramuscular (IM) or intravenous injection. A new 1 mL volume formulation of diclofenac containing hydroxypropyl-β-cyclodextrin (HPβCD) allows both SC and IM administration. The objective of this open-label, randomized, parallel group, active-controlled study was to assess the safety and efficacy of 75 mg diclofenac HPβCD, administered SC or IM, compared with IM Voltaren® 75 mg in inpatients undergoing minor orthopedic surgeries with moderate-to-severe postoperative pain.. A total of 325 patients were randomized to treatment. Surgery-related pain was comparable between groups before treatment and rapidly declined in all patients following diclofenac injection. The primary endpoint was investigator-assessed local tolerability up to 18 hours postinjection (redness, swelling, and hardening at the injection site each scored on a 4-point scale where 0 = none, 1 = mild, 2 = moderate, and 3 = severe).. Local tolerability was found to be optimal for all the injected formulations, with mean overall scores (0 to 9) of 0.57, 0.31, and 0.26, for diclofenac HPβCD SC, diclofenac HPβCD IM, and Voltaren® IM, respectively. Consistently, the overall tolerability as judged by the patients and investigators was reported as good or excellent in more than 90% of cases in all groups.. Overall, the study results indicate that safety and efficacy were similar irrespective of the diclofenac formulation used; thus, the new SC diclofenac HPβCD has an acceptable tolerability profile and may be considered a valid alternative to IM-delivered diclofenac formulations.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; beta-Cyclodextrins; Diclofenac; Excipients; Female; Humans; Injections, Intramuscular; Injections, Subcutaneous; Male; Middle Aged; Orthopedic Procedures; Pain, Postoperative; Treatment Outcome; Young Adult

Dyloject is a novel formulation of diclofenac intended for intravenous (IV) administration. This formulation employs the solubilizing agent hydroxypropyl-β-cyclodextrin to permit bolus IV administration. The efficacy and safety of 5 dose levels of IV diclofenac were compared with IV ketorolac and placebo following third molar extraction. This was a single-dose, randomized, double-blind, placebo- and comparator-controlled, parallel-group study. A total of 353 subjects with moderate to severe pain received placebo; ketorolac 30 mg; or IV diclofenac 3.75, 9.4, 18.75, 37.5, or 75 mg (N  =  51 for all groups, except N  =  47 for ketorolac). The primary endpoint was total pain relief over 6 hours (TOTPAR6) as measured by the visual analog scale (VAS). Secondary endpoints included multiple measures of pain intensity and relief; patient global evaluation; and times to pain relief and rescue medication. Dropouts and adverse effects (AEs) were also monitored. IV diclofenac was superior to placebo as measured by TOTPAR6 (P < .0001 for all doses except 3.75 mg, for which P  =  .0341). IV diclofenac 3.75 mg was statistically superior to placebo for TOTPAR2 and TOTPAR4. IV diclofenac at both 37.5 and 75 mg was superior to placebo (P < .05) at the earliest (5 minute) assessments of pain intensity and pain relief, but ketorolac was not. The proportion of patients reporting 30% or greater pain relief at 5 minutes was significantly greater after IV diclofenac 37.5 and 75 mg than after ketorolac 30 mg or placebo. Secondary endpoints confirmed the primary findings. Treatment-related AEs were generally mild to moderate and were typical for nonsteroidal anti-inflammatory drugs (NSAIDs). The more rapid onset of action of IV diclofenac compared with the reference injectable NSAID ketorolac suggests additional clinical benefit. If confirmed in larger series, these findings may improve the safety and efficacy of postoperative NSAID analgesia.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adolescent; Adult; Aged; Analysis of Variance; Anti-Inflammatory Agents, Non-Steroidal; beta-Cyclodextrins; Diclofenac; Double-Blind Method; Drug Combinations; Female; Humans; Injections, Intravenous; Kaplan-Meier Estimate; Ketorolac; Male; Middle Aged; Molar, Third; Pain Measurement; Pain, Postoperative; Statistics, Nonparametric; Tooth Extraction; Young Adult

The preemptive analgesic efficacy and adverse effects of preoperatively administered piroxicam-beta-cyclodextrin for post-endoscopic sinus surgery pain was determined in a prospective, double-blind, randomized, clinical study. Seventy-five American Society of Anesthesiologists status I-II patients, aged 18-65 years, were divided into three groups with similar demographic characteristics: group 1 received 20 mg piroxicam-beta-cyclodextrin, group 2 received 40 mg piroxicam-beta-cyclodextrin and group 3 received placebo orally before induction of general anesthesia. A blinded observer recorded the incidence and severity of pain at admission to the post-anesthesia care unit (PACU), at 15, 30, and 45 min in the PACU, and 1, 2, 4, 6, and 24 h postoperatively. All patients received patient-controlled morphine analgesia during the postoperative period and consumption was recorded for 24 h. During the PACU period, mean visual analogue scale values were significantly lower in groups 1 and 2 compared to group 3 (P < 0.05). During the postoperative period, morphine consumption was 3.03 +/- 2.54, 2.7 +/- 2.8, and 5.56 +/- 3.12 mg for each group, respectively (P < 0.05). As a side effect, bleeding was observed in groups 1 and 3, nausea and vomiting in all groups, and edema only in group 3. However, no significant differences were detected in any of the parameters analyzed, which also included epigastric pain, constipation/diarrhea and headache. Similar hematological test results were obtained for all groups. Preemptive administration of piroxicam-beta-cyclodextrin effectively reduced analgesic consumption, and 40 mg of the drug was more effective than 20 mg piroxicam-beta-cyclodextrin without side effects during the postoperative period.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; beta-Cyclodextrins; Dose-Response Relationship, Drug; Double-Blind Method; Endoscopy; Female; Humans; Male; Middle Aged; Pain Measurement; Pain, Postoperative; Piroxicam; Preoperative Care; Prospective Studies; Sinusitis; Young Adult

Two hundred ninety-eight patients with post-operative pain after the surgical removal of an impacted third molar were randomly assigned, on a double-blind basis, to receive a single oral dose of piroxicam 20 mg, or piroxicam-beta-cyclodextrin equivalent to 20 mg piroxicam, or paracetamol 500 mg, or placebo. Using a semi-quantitative self-rating scale, patients rated their pain and its relief at 30-min intervals for the first 2 h, and then hourly for 4 h after treatment administration. All active medications were reported to be significantly superior to placebo. The three active drugs were comparable for the degree of analgesia up to the third hour, after which the effect of paracetamol decreased significantly as compared to piroxicam-beta-cyclodextrin and piroxicam. Piroxicam-beta-cyclodextrin and paracetamol were more rapid than piroxicam in inducing analgesia. The tolerability for the active drugs was comparable to that for placebo.

Topics: Acetaminophen; Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; beta-Cyclodextrins; Cyclodextrins; Double-Blind Method; Drug Combinations; Female; Food Additives; Humans; Male; Middle Aged; Molar, Third; Pain, Postoperative; Piroxicam; Surgery, Oral; Surveys and Questionnaires; Tooth Extraction

Acute postoperative pain is a common experience in oral surgery practice. Non-steroidal anti-inflammatory drugs (NSAIDs) are quite effective against mild to moderate pain and they are generally better suited in ambulatory outpatients than narcotic analgesics. The analgesic activity of piroxicam, a well known NSAID has been documented in many pain states. Piroxicam can be administered once daily because of its long half-life, but its absorption in the gastrointestinal tract is slow as it is its onset of action. Piroxicam-beta-cyclodextrin (PBCD) is a new formulation of piroxicam which is the product of supermolecular encapsulation of piroxicam with the cyclic oligosaccharide beta-cyclodextrin. PBCD is absorbed much faster than standard piroxicam, and its action as an analgesic is consequently more rapid. The purpose of this study was to assess the efficacy and the rapidity of action of piroxicam-beta-cyclodextrin in comparison with standard piroxicam, paracetamol and placebo following surgical extraction of impacted third molars.. The study population was composed of 32 patients of both sexes and in good health. To be included into the study, patients must have had third molar removal resulting in acute post-surgical pain of at least moderate intensity. The patients were then randomly assigned to one of four treatment groups. PBCD 20 mg tablets; piroxicam 20 mg capsules; paracetamol 500 mg tablets, or placebo. The study was conducted according to a double-blind, double-dummy design. Pain intensity and pain relief were recorded at 0.5, 1, 1.5, 2, 3, 4 hours after a single dose of the study drugs, by means of a Keele-type rating scale. Rescue analgesics were not allowed before one and a half hour after taking the study drugs. A global evaluation of study drugs was expressed by patients at the end of the observation period.. Treatment groups were homogeneous for demographic characteristics of the patients and for pain intensity at the time of medication with study drugs. All patients who received placebo requested supplemental analgesics, while none of the patients treated with the active drugs needed rescue analgesics. PBCD and paracetamol were comparable for their analgesic effect, while the time lag before a significant reduction of pain intensity with piroxicam was longer. Piroxicam and PBCD were superior to paracetamol because they showed a substantial analgesic effect through the 4-hour study duration, while paracetamol did not induce a complete relief from pain.. One of the most commonly utilized model for the evaluation of analgesics is the third molar extraction pain. Our study clearly differentiated between active drugs and placebo. Furthermore, while PBCD and paracetamol showed a rapid effect, piroxicam was slow in inducing pain relief. The analgesic and anti-inflammatory activity of PBCD and piroxicam brought about the resolution of pain and inflammation consequent to the dental extraction. Paracetamol, a pure analgesic, was not equally active and pain persisted, even if at a low grade, throughout the observation period; probably this was due to local inflammation and edema. The results of our study appear to confirm the pharmacokinetic data on PBCD, which showed that therapeutic blood levels are reached faster with PBCD than with the standard piroxicam formulation. This results should be confirmed in studies with an adequate number of patients.

Topics: Acetaminophen; Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; beta-Cyclodextrins; Cyclodextrins; Double-Blind Method; Drug Combinations; Drug Tolerance; Female; Humans; Male; Middle Aged; Molar, Third; Pain Measurement; Pain, Postoperative; Piroxicam; Placebos; Tooth Extraction

The aim of the study was to develop a polyester visceral implant modified with a cyclodextrin polymer for the local and prolonged delivery of ropivacaine to reduce post operatory pain. Therefore, we applied a coating of an inguinal mesh with a crosslinked polymer of hydroxypropyl-β-cyclodextrin (HPβCD) whose specific host-guest complex forming properties were expected to improve the adsorption capacity of the implant toward anesthetic, and then to release it within a sustained period. The modification reaction of the textile with cyclodextrin was explored through the study of the influence of the pad/dry/cure process parameters and the resulting implant (PET-CD) was characterized by solid state NMR and SEM. Besides, the inclusion complex between ropivacaine and CD was studied by NMR and capillary electrophoresis in PBS medium. Finally, ropivacaine sorption test showed that a maximum of 30 mg/g of ropivacaine could be adsorbed on the functionalized samples. In dynamic batch tests in PBS at pH 7.4, the release could be observed up to 6h. The cytocompatibility of the PET-CD loaded with ropivacaine was also studied and reached 65% cell vitality after 6 days.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adsorption; Amides; Anesthetics, Local; Animals; beta-Cyclodextrins; Cells, Cultured; Delayed-Action Preparations; Drug Delivery Systems; Drug Implants; Excipients; Magnetic Resonance Spectroscopy; Mice; NIH 3T3 Cells; Pain, Postoperative; Polyesters; Ropivacaine; Time Factors