Behavioral Battery for Testing Candidate Analgesics in Mice. I. Validation with Positive and Negative Controls.

This study evaluated a battery of pain-stimulated, pain-depressed, and pain-independent behaviors for preclinical pharmacological assessment of candidate analgesics in mice. Intraperitoneal injection of dilute lactic acid (IP acid) served as an acute visceral noxious stimulus to produce four pain-related behaviors in male and female ICR mice: stimulation of 1) stretching, 2) facial grimace, 3) depression of rearing, and 4) depression of nesting. Additionally, nesting and locomotion in the absence of the noxious stimulus were used to assess pain-independent drug effects. These six behaviors were used to compare effects of two mechanistically distinct but clinically effective positive controls (ketoprofen and oxycodone) and two negative controls that are not clinically approved as analgesics but produce either general motor depression (diazepam) or motor stimulation (amphetamine). We predicted that analgesics would alleviate all IP acid effects at doses that did not alter pain-independent behaviors, whereas negative controls would not. Consistent with this prediction, ketoprofen (0.1-32 mg/kg) produced the expected analgesic profile, whereas oxycodone (0.32-3.2 mg/kg) alleviated all IP acid effects except depression of rearing at doses lower than those that altered pain-independent behaviors. For the negative controls, diazepam (1-10 mg/kg) failed to block IP acid-induced depression of either rearing or nesting and only decreased IP acid-stimulated behaviors at doses that also decreased pain-independent behaviors. Amphetamine (0.32-3.2 mg/kg) alleviated all IP acid effects but only at doses that also stimulated locomotion. These results support utility of this model as a framework to evaluate candidate-analgesic effects in a battery of complementary pain-stimulated, pain-depressed, and pain-independent behavioral endpoints. SIGNIFICANCE STATEMENT: Preclinical assays of pain and analgesia often yield false-positive effects with candidate analgesics. This study used two positive-control analgesics (ketoprofen, oxycodone) and two active negative controls (diazepam, amphetamine) to validate a strategy for distinguishing analgesics from nonanalgesics by profiling drug effects in a battery of complementary pain-stimulated, pain-depressed, and pain-independent behaviors in male and female mice.

The Median Effective Dose of One Intravenous Bolus of Oxycodone for Postoperative Analgesia After Myomectomy and Hysterectomy With Local Ropivacaine Wound Infiltration: An Up-Down Dose-Finding Study.

BACKGROUND: Oxycodone has been shown to be an effective analgesic for early postoperative analgesia, especially for abdominal operations associated with severe visceral pain. However, the dose needed varies depending on the operation and application of multimodal analgesia, such as local ropivacaine wound infiltration. Therefore, we conducted this study to estimate the median effective dose (ED50) of oxycodone that provides analgesia for hysterectomy and myomectomy with local ropivacaine wound infiltration. METHODS: In this dose-finding study, the ED50 of oxycodone for postoperative analgesia was estimated separately for laparoscopic hysterectomy, transabdominal hysterectomy, laparoscopic myomectomy, and transabdominal myomectomy. We used the sequential allocation designed by Dixon. Trials were conducted simultaneously in the 4 surgical type groups. A predefined dose of oxycodone was injected 30 minutes before the end of the operation with an initial dose of 0.1 mg/kg. A series of trials were performed following the rule of a relative 10% increase in dose after inadequate analgesia and a relative 10% decrease in dose after adequate analgesia. The study was conducted until the collection of 7 crossover points was achieved. Local ropivacaine wound infiltration was administered during abdominal stitching. The mean blood pressure (MBP) and heart rate (HR) were analyzed to assess the hemodynamic changes associated with oxycodone administration. RESULTS: A total of 113 patients were included in the estimation of ED50: 28 each in the laparoscopic hysterectomy group and transabdominal myomectomy group, 27 in the transabdominal hysterectomy group, and 30 in the laparoscopic myomectomy group. The estimated oxycodone ED50 (95% confidence interval [CI]) after laparoscopic hysterectomy, transabdominal hysterectomy, laparoscopic myomectomy, and transabdominal myomectomy was 0.060 mg/kg (0.053-0.068), 0.079 mg/kg (0.072-0.086), 0.060 mg/kg (0.051-0.071), and 0.092 mg/kg (0.086-0.098), respectively, for postoperative analgesia with local ropivacaine wound infiltration. The ED50 of oxycodone was different between laparoscopic surgeries and transabdominal surgeries (P < .001). The MBP and HR before and after oxycodone injection were different, regardless of surgical type. CONCLUSIONS: The oxycodone ED50 for postoperative analgesia was lower for laparoscopic hysterectomy (0.060 mg/kg) and laparoscopic myomectomy (0.060 mg/kg) than for transabdominal hysterectomy (0.079 mg/kg) and transabdominal myomectomy (0.092 mg/kg) when combined with local ropivacaine wound infiltration. A single intravenous injection of oxycodone is associated with an acceptable decrease in MBP and HR within a short time.

Carbonyl-protein content increases in brain and blood of female rats after chronic oxycodone treatment.

BACKGROUND: Opioids are the most effective drugs commonly prescribed to treat pain. Due to their addictive nature, opioid pain relievers are now second to marijuana, ahead of cocaine with respect to dependence. Ours and other studies suggest potential toxic effects of chronic opioid administration leading to neuronal degeneration. It has been suggested that protein carbonylation may represent a sensitive biomarker of cellular degeneration. To evaluate whether prolonged oxycodone administration is associated with accumulation of protein aggregates that may contribute to neuronal degeneration we measured protein carbonylation levels in brain and also in blood plasma of rats after 30-days of 15 mg/kg daily oxycodone administration. RESULTS: We observed a significant increase in the level of carbonylated proteins in rat brain cortex after 30-days of oxycodone treatment compare to that in water treated animals. Also, oxycodone treated rats demonstrated accumulation of insoluble carbonyl-protein aggregates in blood plasma. CONCLUSIONS: Our data suggests that tests detecting insoluble carbonyl-protein aggregates in blood may serve as an inexpensive and minimally invasive method to monitor neuronal degeneration in patients with a history of chronic opioid use. Such methods could be used to detect toxic side effects of other medications and monitor progression of aging and neurodegenerative diseases.

Re: Intra-operative Oxycodone Reduced Postoperative Catheter-Related Bladder Discomfort Undergoing Transurethral Resection Prostate. A Prospective, Double Blind Randomized Study.

none.

Oxycodone concentrations in the central nervous system and cerebrospinal fluid after epidural administration to the pregnant ewe.

The main sites of the analgesic action of oxycodone are the brain and spinal cord. The present study describes the concentrations of oxycodone and its metabolites in the brain and spinal cord after epidural administration to the ewe. Twenty pregnant ewes undergoing laparotomy were randomized into two groups to receive epidural oxycodone: infusion group (n = 10, 0.1 mg·kg-1 bolus followed by continuous infusion of 0.05 mg·kg-1 ·h-1 for five days) or repeated boluses group (n = 10, 0.2 + 2x0.1 mg·kg-1 bolus followed by a 0.2 mg·kg-1 bolus every 12 hours for five days). After five days of oxycodone administration, arterial blood samples were collected, the sheep were killed, and a CSF sample and tissue samples from the cortex, thalamus, cerebellum and spinal cord were obtained for the quantification of oxycodone and its main metabolites. The median plasma and CSF concentrations of oxycodone were 9.0 and 14.2 ng·mL-1 after infusion and 0.4 and 1.1 ng·mL-1 after repeated boluses. In the infusion group, the cortex, thalamus and cerebellum oxycodone concentrations were 4-8 times higher and in the spinal cord 1310 times higher than in plasma. In the repeated boluses group, brain tissue concentrations were similar in the three areas, and in the spinal cord were 720 times higher than in plasma. Oxymorphone was the main metabolite detected, which accumulated in the brain and spinal cord tissue. In conclusion, first, accumulation of oxycodone and oxymorphone in the CNS was observed, and second, high spinal cord concentrations suggest that epidural oxycodone may provide segmental analgesia.

Likelihood of depressive symptoms in US older adults by prescribed opioid potency: National Health and Nutrition Examination Survey 2005-2013.

OBJECTIVES: To investigate the relationships between depressive symptoms and opioid potency among adults aged 50 years and older reporting use of one or more prescription opioids in the past 30 days. MATERIALS/DESIGN: Adjusted multiple linear regression models were conducted with 2005-2013 files from a secondary cross-sectional dataset, the National Health and Nutrition Examination Survey (NHANES). Respondents were community-dwelling, noninstitutionalized adults 50 years or older (n = 1036). Predictor variables included a positive screen for minor depression symptoms (Patient Health Questionnaire [PHQ-9] score greater than or equal to 5 and less than or equal to 9), moderate depression symptoms (PHQ-9 greater than or equal to 10 and less than or equal to 14), and severe depression symptoms (PHQ-9 greater than or equal to 15). Criterion variables included weaker-than-morphine analgesics (eg, codeine and tramadol) and morphine-equivalent opioids (eg, morphine and hydrocodone), which served as the reference category, as well as stronger-than-morphine opioid analgesics (eg, fentanyl and oxycodone). RESULTS: Prevalence rates for symptoms of minor depression, moderate depression, and severe depression were n = 236 (22.8%), n = 135 (13.0%), and n = 122 (11.8%), respectively. Severe depression was significantly associated with high-potency opioid use (odds ratio [OR]: 2.27; confidence interval [CI], 1.16-4.46). In post hoc tests, severe depression remained significantly associated with high-potency opioid use only among respondents without arthritis (OR: 5.80; CI, 1.59-21.13). CONCLUSIONS: Compared with older adults without depressive symptoms, older adults with severe depressive symptoms are more likely to be taking high-potency opioid medications. Future prescription opioid medication research should prioritize investigations among older adults with pain-related diagnoses, other than arthritis, reporting preexisting or new symptoms of severe depression.

Intra-operative Oxycodone Reduced Postoperative Catheter-Related Bladder Discomfort Undergoing Transurethral Resection Prostate. A Prospective, Double Blind Randomized Study.

PURPOSE: To observe the efficacy of intravenously injected oxycodone intraoperative on postoperative urinary catheter-related bladder discomfort (CRBD). MATERIALS AND METHODS: Patients with ASA I-III received trans-urethral resection prostate under general anesthesia were observed. Patients were randomized allocated to the group control (n = 45) received placebo and the group oxycodone (n =46 ) received 0.03mg/kg of oxycodone before the end of operative 10min. The incidence and severity (mild, moderate, severe) of CRBD were assessed at 0, 1/2 h, 2 h and 6 h postoperatively. VAS scores were used to assess pain intensity during the same period. Postoperative PCA analgesic sufentanil dose and the incidences of nausea, vomiting, dizziness, over sedation were recorded in these patients. RESULTS: Compared with the control group, the incidence of CRBD was significantly lower in the oxycodone group at 0 [22 (49 %) vs. 10 (22%); P = .007], 1/2h [18 (40%) vs. 9 (20%); P= .033], 2h [11 (24%) vs. 4 (9%); P = .001]. The severity of CRBD at 0 [mild, 9 (38%) ; moderate 9 (20%), severe 4 (9%)] was lower in the group Q than the controlled group [mild, 4 (38%) P ? .023; moderate 5 (11%), P ?.034, severe 1 (2%), P ? .012]. 1/2 h [mild, 11 (24%) Vs 5(11%), P ? .020]. Compared with the group C, VAS scores were lower in group Q at 0, 1/2h (P ? .001) and significantly decreased sufentanil dosage within 6h ( P= .001). There were no significant differences in the incidence of postoperative adverse effects between two groups. CONCLUSION: Oxycodone can effectively prevent patients with CRBD after TURP without incurring serious adverse effects.

Analgesic Efficacy of an Acetaminophen/Ibuprofen Fixed-dose Combination in Moderate to Severe Postoperative Dental Pain: A Randomized, Double-blind, Parallel-group, Placebo-controlled Trial.

PURPOSE: Acute pain is a significant burden to the individual and to society. There is a clear need for a pain medication that provides improved analgesia over common analgesics, without compromising tolerability. The goal of this study was to determine the efficacy of a new fixed-dose combination of acetaminophen 975 mg and ibuprofen 292.5 mg (FDC 975/292.5) relative to acetaminophen or ibuprofen monotherapy, or placebo. METHODS: This prospective, multicenter, randomized, double-blind, placebo-controlled, Phase III trial included 408 adult volunteers aged 18 to 60 years experiencing moderate to severe pain after surgical removal of at least 2 impacted third molars. Subjects were randomized in a 3:3:3:2 ratio to the following interventions: FDC 975/292.5, acetaminophen 975 mg, ibuprofen 292.5 mg, and placebo. Self-reported pain intensity scores were recorded over a 48-hour double-blind treatment period using a 100-mm visual analog scale. In addition, time to perceptible and meaningful pain relief was assessed by using the two-stopwatch method; use of rescue medication (oxycodone) was recorded; and patients rated their pain relief on a 5-point categorical scale. All adverse events during the 30-day study period were assessed. FINDINGS: The majority of participants were female (67.4%) and white (90.0%), with a mean age of 24.8 years. Demographic and baseline characteristics were balanced across treatment groups, with a mean baseline pain score of 56.4 mm. The primary end point was the time-adjusted sum of pain intensity differences over 48 hours, which was found to be significantly greater for FDC 975/292.5 than for both monotherapies and placebo (all, P < 0.001). The robustness of the procedures used in the calculation of the primary end point was confirmed in a series of sensitivity analyses. Statistical superiority of the combination was evident in all secondary end points (time to meaningful pain relief, maximum pain score, response rate, participants using supplementary analgesia, time to rescue, oxycodone consumption, and categorical pain relief score) with the exception of time to perceptible pain relief versus monotherapies and the time to peak response versus ibuprofen. The percentage of patients reporting adverse events was 37.3% in the FDC 975/292.5 group, with no significant differences between treatment groups. Nausea was the most common adverse event across all groups. IMPLICATIONS: Overall, the fixed-dose combination of acetaminophen and ibuprofen provided greater and more rapid analgesia than comparable doses of either agent alone or placebo in adults after removal of impacted third molars. ClinicalTrials.gov identifier: NCT01420653.

Fixed time interval compared with on-demand oral analgesia protocols for post-caesarean pain: a randomised controlled trial.

OBJECTIVES: To compare the efficacy, safety and satisfaction from two modes of oral analgesia administration for the treatment of post-caesarean pain in the first 48 h following surgery: on-demand versus fixed time interval administration. DESIGN: Open label parallel-group, randomised-controlled trial from February to December 2013. SETTING: University-affiliated hospital in Israel. POPULATION: Two-hundred women who underwent caesarean delivery with regional anaesthesia. METHODS: Patients were randomly assigned to receive predetermined combinations of tramadol, paracetamol and diclofenac either following patient demand or at predetermined 6-h intervals for the first 48 h. If the patient requested additional analgesia, Percocet (oxycodone and paracetamol) was given as a rescue treatment. MAIN OUTCOME MEASURES: Pain intensity and satisfaction were self-evaluated with visual analogue scale of 0 (no pain/least satisfaction) to 10 (worst pain/highest satisfaction). Breastfeeding, need for supplemental formula, and maternal and neonatal adverse effects were also evaluated. RESULTS: The 'fixed time interval' group, compared with the 'on-demand' group, had lower mean pain score (2.8 ± 0.84 versus 4.1 ± 0.48, respectively; P < 0.0001), higher satisfaction rate (9.1 ± 1.2 versus 8.3 ± 1.5, respectively; P < 0.0001), more breastfeeds (23.7 ± 6.5 versus 19.2 ± 6.2, respectively; P < 0.0001) and less use of supplemental formulas (8.2 ± 5.2 versus 11.9 ± 6.5, respectively; P < 0.0001). The number of times that drugs were given was slightly higher in the 'fixed time interval' group without an increase in maternal adverse effects, which were mild. No adverse effects were reported for the neonates. CONCLUSION: Administration of oral analgesia in fixed time intervals is superior to drug administration following patient demand without increasing maternal or neonatal adverse outcomes. TWEETABLE ABSTRACT: Oral analgesia in fixed time intervals is superior to analgesia following demand.

The research on long-term clinical effects and patients' satisfaction of gabapentin combined with oxycontin in treatment of severe cancer pain.

Gabapentin has been used as an adjuvant for treatment of cancer pain. Previous studies showed that opioids combined with gabapentin for management of cancer pain reduced the dosage of opioids.The objective of this study was to explore the clinical effect and patients' satisfaction of oxycontin combined with gabapentin in treatment of severe cancer pain. After titration of morphine, 60 severe cancer patients with visual analog score (VAS) more than 7 were randomly divided into trial group (n = 30) and control group (n = 30). The control group was administered oxycontin and placebo, and the trial group was given oxycontin and gabapentin. VAS score was recorded pre- and post-treatment; while daily dose of oxycontin, daily cost of pain relief and life quality score were observed 1 week, 1 month, 2 months, 3 months, and 6 months post-treatment. We found that daily dose of oxycontin 1 month post was comparable between the 2 groups (P > 0.05). Three months post, compared with control group (58.0 ±â€Š15.2 mg), average daily dose of oxycontin was significant lower in trial group (33.4 ±â€Š11 mg) (P < 0.001). Average daily cost of pain relief in trail group (34.5 ±â€Š10.2 RMB) was less than the control group (52.4 ±â€Š13.7 RMB) (P < 0.001). Life quality score increased in all of the patients in both group post-treatment (P < 0.05); while life quality score in trail group was greater than in control group 3 months (46.8 ±â€Š4.5 vs 43.5 ±â€Š4.6, P = 0.007) and 6 months (46.5 ±â€Š4.8 vs 41.4 ±â€Š4.3, P < 0.001) post-treatment. The incidence of drowsiness and dizziness was comparable between the 2 groups (P > 0.05), while the incidence of nausea and vomiting (P = 0.038), and constipation (P < 0.001) was higher in the control group.We concluded that oxycontin combined with gabapentin used in severe cancer pain management can control pain effectively, decreased the dose of oxycontin and the cost of cancer pain relief, and reduced the incidence of nausea and vomiting, and constipation, increased the life quality.

Pharmacokinetic and pharmacodynamic evaluation of oxycodone and naltrexone for the treatment of chronic lower back pain.

INTRODUCTION: Chronic low back pain (CLBP) is a common and difficult illness to manage. Some individuals with CLBP have pain processing disorders and are also at risk for opioid abuse, misuse; addiction and diversion. Guidelines have been published to guide management; neuromodulation, exercise, mindfulness-based stress reduction and cognitive behavior therapies among other non-pharmacological reduce the pain of CLBP with minimal toxicity. Pharmacological management includes acetaminophen, NSAIDs and antidepressants, mainly duloxetine. Abuse-deterrent opioids have been developed which have been shown to reduce pain and opioid abuse risk. ALO-02 is a tamper-resistant sustained release opioid consisting of extended release oxycodone and sequestered naltrexone. Pivotal studies of ALO-02 have centered on patients with CLBP. AREAS COVERED: This manuscript will review CLBP, the pivotal analgesic and clinical abuse potential studies of ALO-02. The opinion will cover whether opioids should be used for CLBP, when they should be used and opioid choices. EXPERT OPINION: ALO-02 is one of several opioids which can be considered in the management of CLBP. The outcome to a trial of opioids should be function rather than analgesia. Most analgesic trials for CLBP have had analgesia as the primary outcome and function has not been vigorously studied as an outcome. Opioids should be considered as a trial only when other non-opioid analgesics have failed to improve analgesia and function. Universal precautions should be routinely part of phase III analgesic trial particularly for chronic non-malignant pain.

Topical application of a novel oxycodone gel formulation (tocopheryl phosphate mixture) in a rat model of peripheral inflammatory pain produces localized pain relief without significant systemic exposure.

This study was designed to assess the analgesic efficacy and systemic exposure of oxycodone administered topically in a novel tocopheryl phosphate mixture (TPM) gel formulation, to the inflamed hindpaws in a rat model of inflammatory pain. Unilateral hindpaw inflammation was induced in male Sprague-Dawley rats by intraplantar (i.pl.) injection of Freund's complete adjuvant (FCA). Mechanical hyperalgesia and hindpaw inflammation were assessed by measuring paw pressure thresholds and hindpaw volume, respectively, just prior to i.pl. FCA and again 5-6 days later. The analgesic effects of oxycodone administered topically (1 mg in TPM gel) or by i.pl. injection (50 µg), were assessed. Systemic oxycodone exposure was assessed over an 8-h postdosing interval following topical application. Skin permeation of oxycodone from the gel formulation was assessed in vitro using Franz diffusion cells. Oxycodone administered topically or by i.pl. injection produced significant (p < 0.05) analgesia in the inflamed hindpaws. Systemic oxycodone exposure was insignificant after topical dosing. The in vitro cumulative skin permeation of oxycodone was linearly related to the amount applied. Topical TPM/oxycodone gel formulations have the potential to alleviate moderate to severe inflammatory pain conditions with minimal systemic exposure, thereby avoiding central nervous system (CNS)-mediated adverse effects associated with oral administration of opioid analgesics.

Effect of preemptive intravenous oxycodone on low-dose bupivacaine spinal anesthesia with intrathecal sufentanil.

OBJECTIVES: To evaluate the efficacy of preemptive intravenous oxycodone on low-dose bupivacaine spinal anesthesia with intrathecal sufentanil in patients undergoing transurethral resection of the prostate (TURP). METHODS: In this randomized, double-blinded, placebo-controlled trial, 60 patients undergoing TURP were allocated into 2 groups: oxycodone group (group O, n=30) and a normal saline group (group N, n=30). Oxycodone 0.1 mg/kg, or normal saline 0.1 ml/kg was administered intravenously 10 minutes before surgical procedures in group O, or in group N. All patients received sufentanil 5 µg + bupivacaine 0.5% (0.8 ml) + normal saline 0.7 ml - in total, bupivacaine 0.25% (1.6 ml) intrathecally. Spinal block characteristics, hemodynamic values, the perioperative analgesic requirements, visual analogue scale (VAS) scores, Ramsay sedation scale, and side effects were assessed. The study was carried out at the First Hospital of Jilin University, Jilin, China between March and September 2014. RESULTS: The time to 2-segment regression of sensory block, full recovery of sensory block, and first analgesic request was longer in group O. Fewer patients required postoperative analgesics, and the VAS pain scores at 4, 8, 16, and 24 hour after operation were significantly lower in group O. CONCLUSION: Preemptive intravenous oxycodone was an efficient and safe method to decrease postoperative pain and reduce tramadol analgesia in patients under low-dose dilute bupivacaine spinal anesthesia combined with intrathecal sufentanil.

Aberrant drug-related behavior observed during a 12-week open-label extension period of a study involving patients taking chronic opioid therapy for persistent pain and fentanyl buccal tablet or traditional short-acting opioid for breakthrough pain.

OBJECTIVE: Evaluate aberrant drug-related behaviors in patients administering fentanyl buccal tablet or traditional short-acting opioids for breakthrough pain. DESIGN: Twelve-week open-label extension. SETTING: Forty-two US sites. SUBJECTS: Opioid-tolerant patients with chronic pain who completed the previous randomized, double-blind, crossover portion of a study comparing fentanyl buccal tablet and immediate-release oxycodone for treatment of breakthrough pain. METHODS: Patients were rerandomized to continue treatment with fentanyl buccal tablet or begin any traditional short-acting opioid. Assessments included Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) at baseline and Addiction Behaviors Checklist and Current Opioid Misuse Measure at baseline and final visit. Case report forms were reviewed retrospectively to identify aberrant drug-related behaviors. RESULTS: One hundred thirty patients entered the open-label extension (fentanyl buccal tablet, N = 65; traditional short-acting opioid, N = 65). SOAPP-R scores were <18 (low risk of aberrant drug-related behavior) in 74% of patients; no significant differences in SOAPP-R scores were observed between treatment groups. At the final visit, ≤14% of patients in each treatment group had scores indicating potential aberrant drug-related behavior (Addiction Behaviors Checklist ≥3, Current Opioid Misuse Measure ≥9); no significant differences in scores were observed between treatment groups. Baseline SOAPP-R score ≥18 was not predictive of Addiction Behaviors Checklist ≥3 but was predictive of Current Opioid Misuse Measure ≥9. Aberrant behaviors were identified in 12 (18%) fentanyl buccal tablet patients and 13 (20%) traditional short-acting opioid patients. CONCLUSIONS: Incidence of aberrant drug-related behaviors was similar between patients taking fentanyl buccal tablet and traditional short-acting opioids over 12 weeks.

Local infiltration analgesia with levobupivacaine compared with intrathecal morphine in total hip arthroplasty patients.

BACKGROUND: Recently, local infiltration analgesia (LIA) has been promoted for pain control after total hip arthroplasty (THA). We hypothesized that LIA would offer equal analgesic efficacy but less adverse effects, e.g., nausea and vomiting, when compared with an established regimen [intrathecal morphine (it-M)] after THA. METHODS: This randomized controlled trial comprised 60 patients undergoing THA under spinal anaesthesia. For LIA, the surgeon administered levobupivacaine, ketorolac and epinephrine at the surgical site intraoperatively. LIA patients received a LIA top-up through a wound catheter on the morning of the 1st post-operative day (POD). In group it-M, 0.1 mg morphine was given together with the spinal anaesthetic. Study parameters included pain scores, vital parameters and side effects, e.g., post-operative nausea and vomiting (PONV). Besides, levobupivacaine plasma concentrations were determined in 10 LIA patients. RESULTS: The median (25th/75th percentiles) rescue oxycodone demand differed significantly with LIA 15 (10/25) mg vs. 8.5 (1.5/15) mg with it-M (P < 0.006) during the day of surgery, but not anymore on 1st or 2nd POD. The LIA top-up had no effect. However, both analgesic regimens resulted in comparable pain scores and patient satisfaction. PONV incidence and medication did not vary significantly. LIA offered certain advantages regarding early post-operative mobilization. Maximum levobupivacaine plasma concentrations (229-580 ng/ml) remained under the toxic level. CONCLUSIONS: While LIA might enable earlier mobilization after THA, it was not associated with less nausea as compared with it-M. Less rescue oxycodone was given early after it-M, but urinary retention was more common in that group.

The role of specialist palliative care in managing patients with multimorbidity.

This case report describes a patient with multiple morbidity resulting from complicated type 2 diabetes, psoriatic arthritis and abdominal surgery. It highlights the importance of specialist palliative care services in meeting his complex holistic care needs. We acknowledge the growing number of patients living with multiple morbidity and the challenges this group can present. There is then a debate around when to involve specialist palliative care services in the management of multiple morbidity given that there is often an uncertain disease trajectory.

Cannabinoid-opioid interaction in chronic pain.

Cannabinoids and opioids share several pharmacologic properties and may act synergistically. The potential pharmacokinetics and the safety of the combination in humans are unknown. We therefore undertook a study to answer these questions. Twenty-one individuals with chronic pain, on a regimen of twice-daily doses of sustained-release morphine or oxycodone were enrolled in the study and admitted for a 5-day inpatient stay. Participants were asked to inhale vaporized cannabis in the evening of day 1, three times a day on days 2-4, and in the morning of day 5. Blood sampling was performed at 12-h intervals on days 1 and 5. The extent of chronic pain was also assessed daily. Pharmacokinetic investigations revealed no significant change in the area under the plasma concentration-time curves for either morphine or oxycodone after exposure to cannabis. Pain was significantly decreased (average 27%, 95% confidence interval (CI) 9, 46) after the addition of vaporized cannabis. We therefore concluded that vaporized cannabis augments the analgesic effects of opioids without significantly altering plasma opioid levels. The combination may allow for opioid treatment at lower doses with fewer side effects.

Economic evaluation of OROS hydromorphone for chronic pain: a Pan-European perspective.

OBJECTIVES: OROS hydromorphone (osmotic extended-release oral delivery system [OROS] hydromorphone) is a long-acting opioid analgesic, which is approved in Europe for the management of severe pain. The authors aimed to estimate the economic value of this product relative to other widely used oral opioids, including sustained-release morphine, extended-release (ER) oxycodone, and twice-daily (bid) hydromorphone. DESIGN: An adaptable, decision-analytic cost-utility model was developed. Separate versions of the model were developed for five European countries: Germany, Denmark, Slovakia, Portugal, and Italy. RESULTS: OROS hydromorphone represents a cost-effective alternative to other strong oral opioids in the treatment of both nonmalignant and malignant pain in all five countries. In the treatment of chronic severe nonmalignant pain, OROS hydromorphone was dominant (ie, lower cost and incremental quality-adjusted life years gains) when compared with ER oxycodone in Denmark and bid hydromorphone in Germany. Likewise, OROS hydromorphone was dominant in the treatment of chronic severe malignant pain when compared with ER oxycodone in both Germany and Denmark and when compared with bid hydromorphone in all markets where hydromorphone was marketed. CONCLUSIONS: This model demonstrates the cost effectiveness of OROS hydromorphone relative to other strong oral opioids in the treatment of chronic severe malignant and nonmalignant pain.

[Oxycodone and pregabalin using transdermal fentanyl patch provided relief of symptoms for postherpetic neuropathic pain in a patient with non-small cell lung cancer].

This paper presents a man in his 70's with non-small cell lung cancer (cT3N2M0, Stage III A) after chemoradiation therapy during follow-up visits. He was referred to the department of palliative care 1 month after the occurrence of herpes zoster, because of pain. Opioids (transdermal fentanyl patch and rapid-release oxycodone) were administered for his cancer pain previously. Additionally, gabapentin was given for neuropathic pain uncontrolled by opioids. However, this was replaced by pregabalin because he experienced somnolence. Although numbing improved remarkably with pregabalin, the pain was only slightly improved. The dose of rapid-release oxycodone was increased and controlled-release oxycodone was added. This provided for marked pain relief. We conclude that administration of pregabalin as an analgesic adjuvant, and oxycodone, which is an opioid, should be considered in the treatment of cancer patients without improvement of neuropathic pain from herpes zoster through use of the transdermal fentanyl patch.

Oxycodone/acetaminophen at low dosage: an alternative pain treatment for patients with rheumatoid arthritis.

OBJECTIVES: To assess efficacy and safety of the association oxycodone/acetaminophen (oxycodone/acetaminophen) for pain treatment and disability improvement in patients with rheumatoid arthritis (RA). METHODS: Patients with RA (n = 29), suffering from moderate to severe pain for more than 3 months, were included in the study, except those under RA therapy with biological drugs. The treatment started with oxycodone/acetaminophen at the dosage of 5 mg/325 mg, and then the dosage was titrated until the attainment of good pain relief. Antiemetic and laxative therapy was used for the prophylaxis of known opioid-related adverse events. RESULTS: Patients continued their RA therapy without changing the dosages, reported reduced pain intensity and disease activity, and improvement of disability. Forty-two percent of patients had a good clinical response to oxycodone/acetaminophen treatment, according to European League against Rheumatism (EULAR) assessment criteria, and 50 percent of patients reached the American College of Rheumatology 20 percent improvement criteria (ACR20). At the end of the study, the mean (+/- SD) daily effective oxycodone/acetaminophen dose was 13.8 (+/- 6.8) mg/720.4 (+/- 291.0) mg. No serious adverse event was observed. Nausea, vomiting, and stipsis of mild-moderate intensity were the most common adverse events. CONCLUSION: Oxycodone/acetaminophen at low dosages for the treatment of chronic pain in RA patients can be a good alternative to non-steroidal antiinflammatory drugs (NSAIDs), allowing the reduction of their consumption, while keeping RA therapy stable.