Oxycodone Solution Research Articles

Sex differences in oral oxycodone self-administration and stress-primed reinstatement in rats.

The opioid epidemic has become a severe public health problem, with approximately 130 opioid-induced deaths occurring each day in the United States. Prescription opioids are responsible for approximately 40% of these deaths. Oxycodone is one of the most commonly abused prescription opioids, but despite its prevalent misuse, the number of preclinical studies investigating oxycodone-seeking behaviors is relatively limited. Furthermore, preclinical oxycodone studies that include female subjects are even more scarce, and it is critical that future work includes both sexes. Additionally, the oral route of administration is one of the most common routes for recreational users, especially in the early stages of drug experimentation. However, currently, only two studies have been published investigating operant oral oxycodone self-administration in rodents. Therefore, the primary goal of the present study was to establish an oral oxycodone operant self-administration model in adult male and female rats, as well as to examine a potential mechanism of stress-primed reinstatement. We found that females consumed significantly more oral oxycodone than males in operant self-administration sessions. We also found that active oxycodone self-administration was reduced by mu opioid receptor antagonism and by substitution of water for oxycodone solution. Lastly, we induced stress-primed reinstatement and found that this behavior was significantly attenuated by antagonism of the neurokinin-1 receptor, consistent with our prior work examining stress-induced reinstatement of alcohol- and cocaine-seeking.

Impact of physical manipulation on in vitro and in vivo release profiles of oxycodone DETERx®: an extended-release, abuse-deterrent formulation.

In vitro: To assess the effect of common crushing techniques on particle size reduction (PSR) and in vitro drug-release kinetics of oxycodone DETERx® (herein DETERx) and of a commercially available oxycodone extended-release (ER) tablet. In vivo: To evaluate the impact of the most effective manipulation method identified in the in vitro study and the effect of chewing on the pharmacokinetics (PK) of DETERx relative to oxycodone solution. In vitro: Mechanical manipulation of dosage forms using common household utensils. In vivo: Open-label, randomized, active-controlled, crossover PK study. In vivo: Forty-four healthy male and female volunteers. In vitro: DETERx capsule contents and marketed comparator tablets were subjected to manipulation (crushing) using 10 different household utensils. Particle size and dissolution analysis were conducted. In vivo: Subjects were randomly assigned to receive DETERx 40-mg capsules intact, crushed, or chewed or oxycodone solution. Serial blood samples were drawn for PK assessment. In vitro: The utensils used to manipulate DETERx capsule contents were either ineffective in reducing the particle size or produced only a small change in the median particle size and dissolution rate relative to the marketed comparator. In vivo: DETERx intact capsules provided significantly lower Cmax and longer Tmax values than oxycodone solution. Manipulation of DETERx by crushing (using the most effective method established in vitro) or chewing resulted in bioequivalent plasma concentration-time profiles to the intact dosage form. These mechanical manipulation and PK studies demonstrated that DETERx beads retained their ER properties after mechanical tampering and chewing by study subjects.

Pharmacokinetics of Intranasal Crushed OxyContin and Intravenous Oxycodone in Nondependent Prescription Opioid Abusers

Prescription opioid misuse and unintentional overdose deaths involving these analgesics are increasing public health concerns among all ages in the United States.1-4 According to the US Centers for Disease Control and Prevention, prescription opioid-related overdose deaths have become the leading cause of injury deaths, outpacing motor-vehicle crashes in 6 US states and Washington, DC, in 2006.5 The increases in illicit prescription opioid use and related deaths are associated with a marked increase in number of opioid prescriptions written.6,7 OxyContin (Purdue Pharma) is an extended-release oxycodone formulation approved by the US Food and Drug Administration (FDA) for treatment of moderate to severe pain. It is a Schedule II controlled substance in the United States with a significant history of aggressive commercial marketing as well as abuse and diversion.8,9 Pharmacokinetic studies of orally administered OxyContin report a mean terminal half-life (t1/2) of approximately 4.5 to 6.5 hours, mean time to maximum concentration (Tmax) of 2.5 to 5 hours, and oral bioavailability equivalent to immediate-release oxycodone (mean 60%, standard deviation [SD] 20%).10-12 Oxycodone is metabolized by N-demethylation via cytochrome P450 3A4 to noroxycodone, its primary metabolite. It is unlikely that noroxycodone contributes to the pharmacodynamic response in humans, because it has 4-fold lower affinity for the receptor than oxycodone and low μ-opioid receptor activation in GTPγS binding studies.13 However, oxycodone also is metabolized by O-demethylation via cytochrome P450 2D6 to oxymorphone,13 a μ-opioid agonist with analgesic potency approximately 10 times that of parenteral morphine.14 Immediate-release oxycodone products are prescribed approximately 5 times more frequently than extended-release oxycodone products; however, emergency department visits report the nonmedical use of extended-release oxycodone products approximately 4 times more often than immediate-release oxycodone products.15 OxyContin tablets can be easily crushed and snorted or injected to bypass the sustained-release feature, which likely contributes to its abuse liability. In 2008, 15% of publically funded substance abuse treatment admissions with prescription opioid abuse (eg, abuse defined as substance causing problems leading to the admission) reported snorting prescription opioids.16 However, there are no intranasal (IN) pharmacokinetic data demonstrating that OxyContin tablets have immediate-release characteristics when crushed, and the IN bioavailability of OxyContin is unknown despite its common misuse by this route. Thus, this study evaluated the pharmacokinetics of oxycodone and its key metabolites when administered as IN crushed OxyContin tablets compared with intravenous (IV) immediate-release oxycodone solution.

Microbiological and Physicochemical Stability of Oxycodone Hydrochloride Solutions for Patient-Controlled Delivery Systems

The use of patient-controlled analgesia (PCA) allows patients to be managed at home and may increase the quality of life of patients with regard to drug administration. To ensure that intact drug is delivered to the patient in this setting, it is important to study its microbiological and physicochemical stability. Although these factors have been widely studied for many parenteral opioids, very few authors have investigated oxycodone stability associated with long-duration infusion in cancer patients. The aim of this study was to assess the microbiological and physicochemical stability of oxycodone hydrochloride solution in PCA devices and thereby to determine the feasibility of extending the expiration dates after mixing. Sixteen CADD reservoirs and 32 Rythmic reservoirs were filled aseptically with pure (10 mg/mL) and diluted (1 mg/mL) oxycodone solution. Three different vehicles (0.9% sodium chloride, water for injection, and 5% dextrose) were used for dilution. Among the PCA systems stored over 28 days at room temperature, 16 Rythmic reservoirs were protected from light. Microbiological stability was assessed by performing sterility tests. The physicochemical study was performed by determining aspect, pH, osmolality evolution, and weight. Drug concentrations were determined using the stability-indicating high performance liquid chromatography combined to ultraviolet detection technique. There was no significant change in pH, weight, and osmolality values of any solutions. No precipitation or change in color was observed in any of the sample solutions. There was no significant loss of oxycodone, and no trace of degradation products was detected. This study indicates that pure and diluted oxycodone solutions in the PCA systems are stable for 28 days at room temperature when prepared aseptically.

Oral versus Intravenous Opioid Dosing for the Initial Treatment of Acute Musculoskeletal Pain in the Emergency Department

The objective was to compare the time to medication administration, the side effects, and the analgesic effect at sequential time points after medication administration of an oral treatment strategy using oxycodone solution with an intravenous (IV) treatment strategy using morphine sulfate for the initial treatment of musculoskeletal pain in emergency department (ED) patients. This was a prospective randomized clinical trial of patients >6 years old who were going to receive IV morphine sulfate for the treatment of musculoskeletal pain but did not yet have an IV. Consenting patients were randomized to have the treating physician order either 0.1 mg/kg morphine sulfate IV or 0.125 mg/kg oxycodone orally in a 5 mg/5 mL suspension as their initial treatment for pain. The time from the placement of the order to the administration of the medication was recorded. Pain was measured using a 100-mm visual analog scale (VAS) and recorded at 0, 10, 20, 30 and 40 minutes after drug administration. A total of 405 eligible patients were identified during the study period; 328 (81.0%) patients consented to be in the study. A total of 158 patients were randomized to the IV morphine sulfate treatment group, and 162 were randomized to the oral oxycodone treatment group. Of the patients who were randomized to IV therapy, 34 were withdrawn from the study prior to drug administration; leaving 125 patients in the IV group for analysis. Of the patients who randomized to oral therapy, 22 were withdrawn from the study prior to drug administration, leaving 140 patients for analysis. No serious adverse events were detected. There was a 12-minute difference between the median time of the order and the administration of oral oxycodone (8.5 minutes) and IV morphine (20.5 minutes). The mean percent change in VAS score was larger for patients in the IV therapy group than those in the oral therapy group at 10 and 20 minutes. At 30 and 40 minutes, the authors could no longer detect a difference. The satisfaction scale score was higher after treatment for the morphine group (median = 4; interquartile range [IQR] = 4 to 5) than for the oxycodone group (median = 4; IQR = 2 to 5; p = 0.008). The oral loading strategy was associated with delayed onset of analgesia and decreased patient satisfaction, but a shorter time to administration. The oral loading strategy using an oxycodone solution provided similar pain relief to the IV strategy using morphine 30 minutes after administration of the drug. Oral 0.125 mg/kg oxycodone represents a feasible alternative to 0.1 mg/kg IV morphine in the treatment of severe acute musculoskeletal pain when difficult or delayed IV placement greater than 30 minutes presents a barrier to treatment.

Acute oral ulcerations

A 50-year-old woman was referred to the Center for Oral Disease at Brigham and Women's Hospital, Boston, for evaluation and treatment of painful oral ulcerations. Four days before, she had become aware of discomfort while eating, with salad dressing especially causing her mouth to burn. The following day, she broke out in ulcerations (Figures 1 and 2) and developed what she reported as the worst pain that she had ever experienced. She sought treatment in her local emergency department over the weekend, received a prescription for an acetaminophen and oxycodone solution and a so-called “magic mouthwash” (bismuth salicylate, lidocaine and diphenhydramine hydrochloride, in equal parts) for pain, and was referred to the clinic the following Monday morning.

Oral Oxycodone Solution versus Intravenous Morphine Sulfate for the Treatment of Pain from Musculoskeletal Injuries in the Emergency Department

Oral Oxycodone Solution versus Intravenous Morphine Sulfate for the Treatment of Pain from Musculoskeletal Injuries in the Emergency Department

Differential Effects of Food on the Bioavailability of Controlled-Release Oxycodone Tablets and Immediate-Release Oxycodone Solution

AbstractThe effects of a high-fat meal on the bioavailability of oxycodone hydrochloride, administered as a recently developed 40mg controlled-release (CR) tablet or a 20mg immediate-release (IR) solution, were evaluated in a randomized crossover study in 22 normal male and female subjects. Serial blood samples were collected for 36h after dosing and analyzed for oxycodone by a validated method using gas chromatography/mass spectrometry. There was no significant food effect with CR oxycodone as judged by 90% confidence interval (CI) analysis of AUC0−∞and Cmax values under fed and fasted conditions. For the IR solution, both oxycodone bioavailability and peak plasma oxycodone concentration were significantly altered by consumption of the high-fat meal, with the mean value for AUC0−∞ increasing to 120% (CI=109– 132%) and the mean value for Cmax decreasing to 82% (CI=47–91%) of values observed in the fasted condition. Adverse events reported for both formulations were mostly mild to moderate in severity and typical of those observed with opioids.

Steady-state bioavailability of controlled-release oxycodone in normal subjects

The steady-state bioavailability of a controlled-release (CR) oxycodone tablet was compared with that of an immediate-release (IR) oxycodone solution in a randomized, analytically masked, multiple-dose, crossover study in 24 normal subjects. Each subject received either one 10-mg CR oxycodone tablet every 12 hours for 4 days or 5 mL of a 1-mg/1 mL IR oxycodone solution every 6 hours for 4 days. Steady state was achieved after approximately 1 day of dosing. The mean (±SD) maximum plasma oxycodone concentrations for CR oxycodone and IR oxycodone were 15.1 ± 4.7 ng/mL and 15.6 ± 4.4 ng/mL, respectively. The time to maximum concentration (T max) was approximately twice as long for CR oxycodone (3.2 ± 2.2 hours) as for IR oxycodone (1.4 ± 0.7 hours) ( P = 0.005). The area under the plasma concentation—time curve from 0 to 12 hours at steady state was 103.6 ± 40.0 ng • h/mL for CR oxycodone and 99.0 ± 35.8 ng • h/mL for IR oxycodone. Except for T max, there were no significant differences in pharmacokinetic parameters between treatments. Approximately twice as many adverse experiences, several of longer duration than noted with CR oxycodone, were reported with IR oxycodone. The bioavailability of the CR tablet was equal to that of the IR solution; however, the rate of oxycodone absorption from the CR tablet was slower than that from the IR solution, as shown by the T max value. The use of CR oxycodone will allow selection of the most clinically appropriate nonopioid analgesic, as well as independent titration and dosing, thereby enhancing therapeutic flexibility.

Dose-ranging study of oxycodone for chronic pain in advanced cancer.

We assessed the analgesic efficacy and safety of single-entity oxycodone solution at doses greater than 10 mg orally every 4 hours in 24 patients with chronic cancer pain not controlled by weaker analgesics. Twenty of 24 patients completed the study. Pain relief was obtained with doses up to 60 mg every 4 hours. When oxycodone was taken for long periods, further dose increments could be made safely. The side effects of oxycodone are mild, and common to all opioids, with sedation and constipation most frequent. Nausea was more common in females in all age groups and in patients of either sex less than 50 years of age. Episodes of serious toxicity were rare, and responded to dose reduction. Patients older than 65 years required lower doses, suggesting pharmacokinetic similarities between oxycodone and morphine. Patients changed from oral oxycodone to morphine remained pain-free when relative milligram potency ratios of 1:1 to oral morphine and 3:1 to intravenous morphine were used. Oxycodone has been shown for the first time to be as versatile and flexible as oral morphine in the management of chronic pain in patients with advanced cancer.