Douglas A. Hamilton

Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: A randomized, double-blind, placebo-controlled, crossover study

&NA; Few placebo‐controlled trials have investigated the treatment of breakthrough pain (BTP) in patients with chronic pain. We evaluated the efficacy and safety of intranasal ketamine for BTP in a randomized, double‐blind, placebo‐controlled, crossover trial. Twenty patients with chronic pain and at least two spontaneous BTP episodes daily self‐administered up to five doses of intranasal ketamine or placebo at the onset of a spontaneous BTP episode (pain intensity ≥5 on a 0–10 scale). Two BTP episodes at least 48 h apart were treated with either ketamine or placebo. Patients reported significantly lower BTP intensity following intranasal ketamine than after placebo (P<0.0001), with pain relief within 10 min of dosing and lasting for up to 60 min. No patient in the ketamine group required his/her usual rescue medication to treat the BTP episode, while seven out of 20 (35%) patients in placebo group did (P=0.0135). Intranasal ketamine was well tolerated with no serious adverse events. After ketamine administration, four patients reported a transient change in taste, one patient reported rhinorrhea, one patient reported nasal passage irritation, and two patients experienced transient elevation in blood pressure. A side effect questionnaire administered 60 min and 24 h after drug or placebo administration elicited no reports of auditory or visual hallucinations. These data suggest that intranasal administration of ketamine provides rapid, safe and effective relief for BTP.

Dyloject, a novel injectable diclofenac formulation, offers greater safety and efficacy than voltarol for postoperative dental pain.

Background and Objectives: Voltarol for injection (a diclofenac sodium formulation employing polyethylene glycol and benzyl alcohol [PG-BA] as excipients) is marketed in Europe but not in North America. A suspension, PG-BA diclofenac sodium, requires preparation for each patient and slow IV infusion to minimize venous irritation. Dyloject, a novel diclofenac formulation, employs hydroxypropyl &bgr;-cyclodextrin (HP&bgr;CD) to solubilize diclofenac in a small volume. We compared the efficacy and safety of an IV HP&bgr;CD diclofenac sodium bolus, a 30-minute PG-BA diclofenac sodium infusion, and placebo in post–molar extraction pain. Methods: A total of 155 adult patients were randomized to receive HP&bgr;CD diclofenac sodium 75 mg, PG-BA diclofenac sodium 75 mg, or placebo. Primary endpoints were superiority of HP&bgr;CD diclofenac sodium to placebo and noninferiority of HP&bgr;CD diclofenac sodium to PG-BA diclofenac sodium with respect to total pain relief over 4 hours (TOTPAR4) on a 0 to 100-mm visual analog scale (VAS). Secondary endpoints included categorical TOTPAR4, VAS and categorical TOTPAR up to 8 hours, other measures of pain intensity and relief, patient global evaluation, and time to rescue medication. Results: HP&bgr;CD diclofenac sodium had efficacy superior to both placebo and PG-BA diclofenac sodium. At 15 minutes, more patients given HP&bgr;CD diclofenac sodium than PG-BA diclofenac sodium reported 30% reduction in pain intensity (52% vs. 21%, P = .0022). Both diclofenac products had a 6-hour duration of effect and were well tolerated. Patient global evaluations of HP&bgr;CD diclofenac sodium were high, superior to placebo, and similar to PG-BA diclofenac sodium. The adverse event (AE) incidence was similar for HP&bgr;CD diclofenac sodium and PG-BA diclofenac sodium, except that in the current trial and in integrated safety results from the present and prior studies, phlebitis was more common with PG-BA diclofenac sodium. No cardiac or renal AEs or gastrointestinal bleeding were reported or observed. Conclusions: IV bolus HP&bgr;CD diclofenac sodium produced analgesia more quickly than, and with equal duration as, the 30-minute PG-BA diclofenac sodium infusion. Pooled data on thrombophlebitis from the present investigation and our prior studies of the novel formulation indicate this adverse effect is less frequent and less severe with HP&bgr;CD diclofenac sodium than with PG-BA diclofenac sodium.

Analgesic Efficacy and Safety of Morphine‐Chitosan Nasal Solution in Patients with Moderate to Severe Pain Following Orthopedic Surgery

INTRODUCTION Parenteral opioids are the standard of care for treating moderate to severe postsurgical pain. This randomized, double-blind, dose-ranging study compared the safety and efficacy of intranasal (IN) morphine with intravenous (IV) morphine and placebo. METHODS In total, 187 postbunionectomy patients with moderate to severe pain were randomized to receive IN morphine 3.75 mg, 7.5 mg, 15 mg, or 30 mg, IV morphine 7.5 mg, or placebo in the single-dose phase and IN morphine 7.5 mg or 15 mg thereafter. The primary outcome was a dose-response assessment for total pain relief based upon visual analog scales. Secondary endpoints included pain intensity, pain relief, patient global evaluation, and time to rescue medication. Safety assessments included adverse events and nasal examination. RESULTS A statistically significant linear dose response was observed over the IN morphine dose range for 4-hour total pain relief. Patients reported statistically significant pain relief and pain intensity differences following IV morphine and IN morphine at doses of 7.5 mg and greater within 30 minutes postdose, compared with placebo. Median times to rescue medication were 124 and 140 minutes for IN morphine 7.5 mg and 15 mg dosage groups, respectively, and 130 minutes for IV morphine. Local adverse events associated with IN morphine were transient and mostly mild (bad taste, nasal congestion, throat irritation, and sneezing). Systemic adverse events, regardless of route of administration, were dose-related and consistent with expected opioid effects. CONCLUSIONS By multiple measures of pain intensity and pain relief, IN morphine provides sustained analgesia in postsurgical patients and thus may offer a safe and less invasive alternative to IV morphine.

A novel injectable formulation of diclofenac compared with intravenous ketorolac or placebo for acute moderate-to-severe pain after abdominal or pelvic surgery: a multicenter, double-blind, randomized, multiple-dose study.

BACKGROUND:Injectable formulations of diclofenac have long been available in Europe and other countries. These formulations use a default dose of 75 mg of diclofenac delivered IV over 30 to 120 minutes or as an IM injection. A novel formulation of injectable diclofenac sodium, Dyloject®, is solubilized with hydroxypropyl &bgr;-cyclodextrin (HP&bgr;CD) so that it can be given IV or IM in a small volume bolus. In this multicenter, multiple-dose, multiple-day, randomized, double-blind, parallel-group phase 3 study, we investigated whether lower doses of HP&bgr;CD diclofenac delivered as a small volume bolus would be effective for the management of acute pain after abdominal or pelvic surgery. METHODS:Adults with moderate and severe pain, defined as ≥50 mm on a 0 to 100 mm visual analog scale, within 6 hours after surgery were randomly assigned (1:1:1:1 ratio) to receive HP&bgr;CD diclofenac, 18.75 mg or 37.5 mg; ketorolac tromethamine 30 mg; or placebo. Patients in all treatment arms received a bolus IV injection every 6 hours until discharged. They were observed for at least 48 h, and for up to 5 days. Rescue IV morphine was available any time, up to a total of 7.5 mg over a 3-hour period. The primary efficacy measure was the sum of pain intensity differences from 0 to 48 hours after study drug initiation. RESULTS:Three hundred thirty-one patients received ≥1 dose of study drug. Over the first 48 hours, both IV HP&bgr;CD diclofenac doses, as well as ketorolac, produced significant reductions in pain intensity over placebo (all P < 0.05), as well as significant reductions in the need for rescue morphine administration. Both doses of HP&bgr;CD diclofenac, as well as ketorolac, significantly reduced rescue morphine dosages, as compared to placebo (P < 0.0001), and time to rescue morphine administration was significantly increased by treatment with 18.75 mg diclofenac and ketorolac. The overall incidence of treatment-related adverse events was 20.2%. No treatment-related serious adverse events were reported in either diclofenac dose group, whereas only 1 was reported in the ketorolac group. CONCLUSIONS:For patients with acute moderate and severe pain after abdominal or pelvic surgery, repeated 18.75 mg and 37.5 mg doses of HP&bgr;CD diclofenac provided significant analgesic efficacy, as compared to placebo. Significant analgesic efficacy was also provided by the active comparator ketorolac. Both HP&bgr;CD diclofenac and ketorolac significantly reduced the need for opioids.

A Double-Blind Placebo-Controlled Comparison of a Novel Formulation of Intravenous Diclofenac and Ketorolac for Postoperative Third Molar Extraction Pain

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.

The Analgesic Efficacy and Safety of a Novel Intranasal Morphine Formulation (morphine plus Chitosan), Immediate Release Oral Morphine, Intravenous Morphine, and Placebo in a Postsurgical Dental Pain Model

BACKGROUND:Opioids are standard treatment for postoperative pain. In this study, we compared the safety and efficacy of intranasal (IN) morphine to IV and oral morphine and placebo. METHODS:Two-hundred-twenty-five patients with moderate-to-severe pain after third molar extraction were randomized to receive a single dose of IN morphine 7.5 mg or 15 mg, IV morphine 7.5 mg, oral morphine 60 mg or placebo. Pain intensity was assessed using visual analog and categorical scales, and pain relief using a categorical scale. Outcomes included total pain relief, pain intensity difference, summed pain intensity difference, time to analgesic onset, time to requesting rescue medication, and patients’ global evaluation of their treatment. Safety assessments included adverse event recording and nasal examinations. RESULTS:Across the various efficacy outcomes, both IN morphine doses were statistically similar to the positive comparators (IV and oral morphine), and all four morphine treatments were statistically superior to placebo. Overall, IN morphine 15 mg presented an efficacy profile similar to IV morphine 7.5 mg; both treatments demonstrated rapid onset of efficacy, generally persistent throughout the 6-h assessment period. The lower dose of IN morphine, 7.5 mg, was statistically similar to the other active treatments at 2 h and 6 h and similar to placebo at 4 h. Study medications were generally well tolerated, with no withdrawals due to adverse events or other safety concerns, and no serious adverse events reported. The most frequently reported adverse events were typical systemic opioid effects. CONCLUSIONS:IN morphine offers a noninvasive alternative to IV morphine for postoperative analgesia.

Analgesic efficacy and safety of a novel injectable formulation of diclofenac compared with intravenous ketorolac and placebo after orthopedic surgery: a multicenter, randomized, double-blinded, multiple-dose trial.

Objectives:A novel injectable formulation of diclofenac, Dyloject, utilizes hydroxypropyl-&bgr;-cyclodextrin (HP&bgr;CD) as a solubilizing agent, allowing dosing as a small-volume intravenous bolus for postoperative pain. In this test of the efficacy and safety of HP&bgr;CD diclofenac, we hypothesized that HP&bgr;CD diclofenac would relieve moderate and severe pain after orthopedic surgery. Patients and Methods:Adults 18 to 85 years old with moderate and severe pain within 6 hours after surgery were randomized to HP&bgr;CD diclofenac, ketorolac tromethamine, or placebo, and stratified by risk cohort. The HP&bgr;CD diclofenac non–high-risk cohort dose was 37.5 mg, the high-risk cohort received 18.75 mg, and patients ≥95 kg received 50 mg. The ketorolac dose was 30 mg in the non–high-risk and high-weight cohorts and 15 mg in the high-risk cohort. Rescue intravenous morphine was given for pain as needed. Efficacy was measured by the sum of pain intensity differences (SPID). Results:Mean SPID scores of 277 patients were significantly better with HP&bgr;CD diclofenac and ketorolac than with placebo (P<0.0001), across all risk cohorts (P<0.05). HP&bgr;CD diclofenac was associated with better SPID scores, faster onset of analgesia, and significantly lower opioid requirement (P<0.008) than ketorolac. In patients more than or equal to 65 years, HP&bgr;CD diclofenac was associated with significantly better analgesic efficacy (P=0.05), and lower opioid requirement versus ketorolac. The incidence of treatment-related adverse events was similar across groups. Discussion:HP&bgr;CD diclofenac is safe and efficacious for acute moderate and severe pain after orthopedic surgery and significantly spares morphine use.

Single‐Dose and Multiple‐Dose Pharmacokinetics and Dose Proportionality of Intravenous and Intramuscular HPβCD‐Diclofenac (Dyloject) Compared with Other Diclofenac Formulations

To evaluate single‐ and repeated‐dose pharmacokinetics (PK) and dose proportionality of hydroxypropyl‐β‐cyclodextrin (HPβCD)‐diclofenac compared with Voltarol after intravenous (IV) and intramuscular (IM) administration.

Effects of Injectable HPβCD-Diclofenac on the Human Delayed Rectifier Potassium Channel Current In Vitro and on Proarrhythmic QTc In Vivo

BACKGROUND Novel formulations and administration routes of established drugs may result in higher maximum concentrations or total exposures and potentially cause previously unrecognized adverse events. OBJECTIVE This study evaluated the proarrhythmic potential of hydroxypropyl-β-cyclodextrin (HPβCD)-diclofenac, a novel injectable diclofenac formulation solubilized with hydroxypropyl-β-cyclodextrin (HPβCD), on ventricular electrical conduction in preclinical and clinical models. METHODS We assessed the effects of diclofenac, HPβCD, and HPβCD-diclofenac on the human delayed rectifier potassium channel (IKr) using human embryonic kidney (HEK) 293 cells transfected with a human ether-à-go-go-related gene (hERG) using whole-cell patch-clamp. In a single-dose, active- and placebo-controlled, 4-period crossover, thorough QT in vivo study, 70 healthy volunteers (mean age, 23.3 years; range, 18-49 years; 55.75% male) received HPβCD-diclofenac at 37.5- and 75-mg doses, inactive vehicle (placebo), and an active control (moxifloxacin). RESULTS In vitro, diclofenac produced no statistically significant effect on IKr. Significant, non-dose-dependent effects were observed in the presence of HPβCD or HPβCD-diclofenac of similar magnitude across the 300-fold dose range of concentrations tested, suggesting an artifact due to the detergent effect of HPβCD in this in vitro model. In vivo, neither HPβCD-diclofenac dose resulted in QTc prolongation ≥2 ms (≥5 ms is the threshold of clinical concern). No correlation was evident between changes in QTc and plasma concentrations of diclofenac or HPβCD. Confirming study sensitivity, moxifloxacin produced a mean QTc prolongation >10 ms. CONCLUSIONS The findings from the present study suggest that HPβCD-diclofenac does not have a dose-dependent effect in the in vitro hERG assay system and does not produce proarrhythmic QTc prolongation in vivo. ClinicalTrials.gov identifier: NCT01812538.

A Pooled Analysis Evaluating Renal Safety in Placebo- and Active Comparator-Controlled Phase III Trials of Multiple-Dose Injectable HPβCD-Diclofenac in Subjects with Acute Postoperative Pain.

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.