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Publications American Journal of Disaster Medicine Opioid Management
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January/February 2010; pages 11-11
January/February 2010; pages 12-14
January/February 2010; pages 17-26 Abstract Objective: This study reports the pharmacokinetics, tolerability, and safety of an intranasal fentanyl spray (INFS) in patients with cancer and breakthrough pain (BTP). Design: A randomized, open-label, two-period, crossover trial. Patients: Nineteen adult patients (mean 57.8 years) with BTP, receiving opioid treatment for chronic background pain, from clinical departments in Austria, France, and Norway entered and completed the study. Intervention: Patients were randomly assigned to receive one of six INFS dose sequences: 50/100, 100/50, 50/200, 200/50, 100/200, and 200/100 µg. INFS was administered as a single dose in one nostril. Each dose was separated by a minimum of 48 hours. Main outcome measure: Plasma fentanyl concentrations were measured by high-performance liquid chromatography and tandem mass spectrometry from blood samples obtained at 0 (predose) and frequently up to 300 minutes after INFS administration. Blood pressure, peripheral oxygen saturation, and respiratory rate were assessed eight times during each of the two treatment periods. Results: Mean fentanyl plasma concentrations increased in a dose-dependent manner, peaking for all fentanyl doses 9-15 minutes after INFS administration. Median Tmax values were 15, 12, and 15 minutes for the 50, 100, and 200 µg doses of INFS, respectively. Mean (SD) values for Cmax were 351 (±226), 595 (±400), and 1195 (±700) pg/mL, respectively, indicating dose-proportionality. Six patients (31.6 percent) experienced adverse events during the treatment period, the majority being mild in severity. Conclusion: INFS at doses of 50, 100, and 200 µg showed a short Tmax and was well tolerated in patients with cancer. These results support INFS use in patients with cancer suffering from BTP. Keywords: intranasal administration, fentanyl, pharmacokinetics DOI 10.5055/jom.2010.0001
January/February 2010; pages 29-39 Abstract Background: The rising popularity of the fentanyl transdermal patch and the striking number of deaths attributed to its prescribed use have brought attention to the large variability of fentanyl metabolism and the need for predictive models to prevent toxicity. Objective: The purpose of this study was to determine the amount of both intrasubject and intersubject variability in fentanyl metabolism and excretion, using urinary excretion data from patients with chronic pain prescribed the fentanyl transdermal patch. Methods: Liquid chromatography tandem mass spectrometry analytical technique was used to quantitate fentanyl and norfentanyl concentrations in spot urine specimens, after incubation with glucuronidase. Descriptive statistics and graphical analysis were conducted using Microsoft Excel 2007. Analysis was conducted on 206 subjects with = 2 visits listing transdermal fentanyl as current medication. Outliers and subjects with no detectable levels of drug were excluded, resulting in subject populations of 200 (all subjects analyzed) and 166 (subjects with drug concentrations above the instrument detection limit for all visits). Results: The geometric mean metabolic ratio (MR) of norfentanyl to fentanyl was 6.2 × ÷ 2.4. A wide distribution was observed in total fentanyl load (1,000-fold) and MR (200-fold). The intersubject geometric standard deviation in MR was 2.4 (95% confidence interval [CI] for MR: 1-37) and the intrasubject geometric standard deviation was 1.8 (95% CI for MR: 2-20). Conclusion: The level of intrasubject variability over time in the pharmacokinetics of the fentanyl patch is much greater than previously observed and may be due to variability in absorption, interference of metabolism by concomitant medications, and variable metabolism due to genetic polymorphisms. The variation in the MR between subjects and within subjects may explain the unpredictable adverse effects observed with use of transdermal fentanyl. Keywords: fentanyl patch, metabolism, excretion DOI: 10.5055/jom.2010.0002
January/February 2010; pages 40-46 Abstract 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 anti-inflammatory drugs (NSAIDs), allowing the reduction of their consumption, while keeping RA therapy stable. Keywords: opioids, pain control, rheumatoid arthritis, association oxicodone/acetaminophen DOI:10.5055/jom.2010.0003
January/February 2010; pages 47-54 Abstract Background: Although the addition of a background infusion for intravenous patient-controlled analgesia (IV-PCA) has been identified as a risk factor for the development of respiratory depression, this has not clearly been examined in a systematic fashion. The authors undertook a systematic review and meta-analysis of available randomized controlled trials (RCTs) to examine whether the addition of a background or continuous infusion to an IV-PCA regimen would be associated with an increased risk of respiratory depression. Methods: Studies were identified by searching the National Library of Medicine’s PubMed database (1966 to November 30, 2008). Inclusion criteria were a clearly defined analgesic technique of demand-only IV-PCA versus IV-PCA utilizing both a demand dose and background infusion, opioid medication used, and randomized trials. Data were abstracted and analyzed with the RevMan 4.2.7 (The Cochrane Collaboration, 2004). Results: The search yielded 687 abstracts from which the original articles were obtained and data abstracted with a total of 14 articles analyzed. There were 402 subjects in the continuous IV-PCA with demand group versus the 394 subjects in the demand-only IV-PCA group. Addition of a background infusion to the demand dose for IV-PCA with opioids was associated with a significant increased risk for respiratory depression (odds ratio [OR] = 4.68, 95% confidence interval [CI]: 1.20-18.21). Subgroup analysis revealed that this increased risk was seen in adult but not in pediatric patients. Conclusions: Our meta-analysis indicates that the addition of a continuous or background infusion to the demand dose for IV-PCA is associated with a higher incidence of respiratory events than demand IV-PCA alone in adult but not in pediatric patients; however, our overall results should be interpreted with caution due to the relatively small sample size and the wide range of definitions for respiratory depression in studies examined. Keywords: background infusion, continuous infusion, patient-controlled analgesia, postoperative pain, meta-analysis DOI:10.5055/jom.2010.0004
January/February 2010; pages 55-62 Abstract Objective: To evaluate the feasibility of infants’ weaning of opioids and sedatives at home. Design: Retrospective observational study. Setting: Level 3 pediatric intensive care unit. Patients: Neonates treated for congenital diaphragmatic hernia (CDH) with extra corporeal membrane oxygenation (ECMO). Intervention: Eligible infants were discharged early and further weaned of analgesics and/or sedatives at home. Results: Of the 30 neonates treated for CDH with ECMO from 2003 to 2005, 15 survived. Five of these were weaned at home, on the guidance of telephone contact once a week. The mean infusion rates of morphine and midazolam for these children were significantly higher than those for other infants. Weaning at home took 11, 42, 107, 173, and 180 days, respectively, in the resultant mean savings on hospitalization costs per patient amounted to €150,000. Conclusions: The results indicate that home weaning reduced the length of hospital stay by a median of 107 days for the five infants in this study, and thereby considerably reduced healthcare costs. Parents need to be informed clearly about possible withdrawal symptoms and should consent in this strategy. The strategy of final weaning with the aid of weekly telephone consultations with a consultant pediatric intensivist was feasible for these parents. Keywords: opioids, benzodiazepines, withdrawal symptoms, drug weaning, children DOI:10.5055/jom.2010.0005
January/February 2010; pages 63-66 Abstract Background: One of the major challenges faced by the treatment planning teams is how to manage postoperative pain. Previous studies agreed upon the effects of preoperative administration of nonsteroidal anti-inflammatory drugs on postoperative pain, but all have focused on patients with surgical noninflammatory diseases (ie, inguinal hernia or breast biopsy). The aim of this study was to evaluate the effects of rectal indomethacin on reducing postoperative pain in patients with acute appendicitis. Methods: It is a simple randomized, clinical trial including 200 patients with acute appendicitis who were divided into two groups (A1 and A2). The case group (A1) received 100 mg rectal indomethacin during 2 hours before the operation. Pain intensity was assessed in all patients using a visual analog scale (VAS). Similarly, total dosage of meperidine analgesic medication and postoperative time to use of rescue analgesia were evaluated. Results: Patients who received preoperative rectal indomethacin (A1) showed a significant reduction in the VAS score. Also, a reduction in total dose of meperidine and longer time to use of rescue analgesic medication were observed in A1 group. Conclusion: Preoperative administration of rectal indomethacin in acute appendicitis reduces postoperative pain. Keywords: postoperative pain, indomethacin, appendectomy DOI:10.5055/jom.2010.0006
January/February 2010; pages 67-69 Abstract Chemotherapy-induced and radiation-induced mucositis is a debilitating and often painful condition resulting in an inability to swallow, and thus inability to maintain adequate quality of life and overall functioning. To date, attempts on palliation of mucositis-related pain have primarily used topical anesthetic solutions and intravenous opioids; these approaches have achieved only limited success, particularly in oncology patients. The authors present a novel case of mucositis-related pain that is effectively treated with sublingual methadone. Sublingual methadone is an alternative to standard treatment options for mucositis-related pain and has unique pharmacokinetic and pharmacodynamic properties that make methadone a suitable agent for this pathology. These properties are addressed and discussed, as is the need for additional study to better understand the potential benefits, burdens, and risks that may be associated with this formulation of methadone when treating chemotherapy-induced and/or radiation therapy-induced mucositis in patients with cancer. Keywords: mucositis, methodone, sublingual, esophageal, cancer DOI:10.5055/jom.2010.0007 Journal of Opioid Management March/April 2010, Volume 6, Number 2
March/April 2010; pages 83-84
March/April 2010; pages 87-94 Abstract Background: The 3-glucuronide metabolites of morphine and hydromorphone have been implicated as a causative factor for patients exhibiting myoclonus. Objective: The primary goal of this study was to determine plasma levels of morphine-3-glucuronide (M3G) or hydromorphone-3-glucuronide (H3G) in patients demonstrating myoclonus and identify any trends or associations between the two. Setting: Patients were recruited from San Diego Hospice and the Institute for Palliative Medicine’s inpatient unit. Design: A prospective convenience sample comprised of 17 subjects, 12 with myoclonus and 5 without yoclonus. Analysis included demographic, metabolicand clinical variables. Plasma was assayed via high performance liquid chromatography for morphine, M3G, and morphine-6-glucuronide or hydromorphone and hydromorphone-3-glucuronide. Results: No trends or associations were identified between plasma levels of M3G or H3G and myoclonus. Ratio levels of 3-glucuronide metabolite to their corresponding parent opioid were dramatically lower than anticipated. Conclusion: In this small pilot study, it appears that the serum levels of metabolites M3G and H3G do not correlate with myoclonus. Keywords: morphine-3-glucuronide, hydromorphone-3-glucuronide, opioid neurotoxicity, myoclonus morphine, hydromorphone DOI:10.5055/jom.2010.0008
March/April 2010; pages 97-108 Abstract Background: Most breakthrough pain (BTP) studies assess patients with advanced cancer or those receiving inpatient care. Studies in noncancer populations are limited to surveys of pain clinics and patients with other advanced diseases. To better understand BTP, data are needed from less selected populations. Aim: The aim of this study was to evaluate BTP in opioid-treated ambulatory patients with chronic cancer or noncancer pain treated in community practices. Methods: Primary care physicians or community-based oncologists recruited a convenience sample for a cross-sectional study of BTP at 17 sites in the United States. Physicians could not be pain specialists. Patients were eligible if they had any type of pain for = 3 months and were receiving an opioid drug on a regular basis that controlled the pain. The patients responded to a structured interview comprising items that assessed the baseline pain and items that assessed BTP, if present. Results: In total, 355 patients were screened, 191 were eligible and 177 (93 percent) provided data for analysis. Seventy-eight patients had cancer pain and 99 had noncancer pain. Patients with cancer were older (mean ± SD age 61.3 ± 11.2 years vs 51.4 ± 13.6 years, p < 0.001), and patients without cancer had more neuropathic pain (21 vs 12 percent, p < 0.05) and a longer pain duration (median 3.5 vs 1 years, p < 0.001). BTP occurred in 33 percent with cancer and 48 percent with noncancer pain (p = 0.042). BTP did not vary by diagnosis, but neuropathic pain was more common in those with BTP (27 vs 10 percent, p < 0.001). In patients with and without cancer, the median daily number of episodes was 1, the median time to maximum pain was 1-2 minutes, and the median duration was 45-60 minutes. There were fewer BTP precipitants in the patients with cancer (46 vs 80 percent of pains, p < 0.05), and they had less predictable pain (p < 0.05). Conclusions: The prevalence of BTP among community-dwelling patients is lower than that found in prior studies of more selected populations. BTP is more prevalent among patients with noncancer pain than patients with cancer pain, and although there are many similarities, some differences may be relevant to treatment strategies. Keywords: breakthrough pain, chronic pain, survey DOI:10.5055/jom.2010.0009
March/April 2010; pages 109-116 Abstract Background: Prior studies of breakthrough pain (BTP) largely focus on patients with advanced cancer or those receiving inpatient care. Very few studies have evaluated BTP in populations with chronic noncancer pain. Data that illuminate the impact of BTP may not generalize to other, less selected patient populations. Aim: The aim of this study was to evaluate the impact of BTP in opioid-treated ambulatory patients with chronic cancer pain or noncancer pain treated in community practices. Methods: Eligible patients–those with any diagnosis who reported chronic pain for at least 3 months, who were receiving long-term opioid therapy, and who met criteria for controlled baseline pain–were recruited for a cross-sectional observational study by primary care physicians or community-based oncologists at 17 sites in the United States. The patients responded to a structured interview for breakthrough pain and also completed the Brief Pain Inventory-Modified Short Form (BPI-SF) and the Brief Battery for Health Improvement 2 (BBHI 2). Results: Of 355 patients screened, 191 were eligible and 177 (93 percent) provided data for analysis. Twenty-six of the 78 with cancer pain (33 percent) and 48 of the 99 with noncancer pain (48 percent) had BTP. Compared with those without BTP, both patients with cancer (p = 0.004) and patients without cancer (p = 0.019) with BTP had increased pain interference in function, as measured by the BPI-SF, and patients without cancer were more impaired than patients with cancer. On the BBHI 2, BTP was associated with increased somatic complaints (p = 0.036 cancer and p = 0.024 noncancer) and pain complaints (p = 0.037 cancer and p = 0.037 noncancer); among patients without cancer, BTP was also associated with increased difficulties with functioning (p = 0.023), depression (p = 0.039), and decreased quality of life (p = 0.003). Conclusions: These data extend published observations about the association between BTP and adverse effects on mood and function to populations undergoing routine treatment in the community setting and provide evidence that these associations are greater in those with noncancer pain. They suggest the need for additional studies to clarify causality and determine whether undertreatment of BTP is a factor contributing to adverse pain-related outcomes. Keywords: breakthrough pain, chronic pain, functional impairment, psychological distress DOI:10.5055/jom.2010.0010
March/April 2010; pages 117-124 Abstract Background: Iatrogenic opioid abstinence syndrome (IOAS) can occur in critically ill infants/children following abrupt discontinuation of opioids. There are no standard guidelines for the prevention of IOAS. Transdermal fentanyl (TF) has been infrequently used at our institution for the prevention of IOAS. Methods: This was a retrospective, descriptive study of children less than 18 years of age receiving TF for the prevention of IOAS. Baseline demographics, IV sedative/analgesic regimen, TF regimen, and IOAS symptoms were collected. The primary objective was to describe the TF regimen. The secondary objectives were to classify the number/type of withdrawal symptoms and to identify the number of intermittent opioids administered for withdrawal symptoms. Results: Fifteen patients were identified with a median age of 7 years (0.3-17); the median cumulative IV fentanyl dose prior to initiation of TF was 1,356 µg kg-1 (164.1-9595.8). The median initial dose of TF was 1.9 µg kg-1 h-1 (0.4-6.1) or 25 µg h-1 (12.5-500); TF was continued for a median duration of 16 days (5-27). To provide the desired dose, the TF patch was partially covered with Tegaderm™ in eight patients. Eighty-six intermittent opioid doses were administered during TF therapy with 51 (59 percent) administered within 5 days of TF initiation. Seven patients (46.7 percent) had IOAS. No significant differences in IOAS symptoms were observed between patients whose patch was partially covered versus not covered, 3 versus 4, respectively (p > 0.05). There was no correlation between the number of opioid doses administered and IOAS symptoms from days 1 to 5, correlation coefficient 0.347 (p _ 0.206). Conclusions: In this cohort, most patients required additional opioids for IOAS symptoms during the first 5 days of TF. TF therapy cannot be routinely recommended for the prevention of IOAS until further prospective studies can confirm these results. This pilot study highlights future directions to standardize documentation and to educate clinicians on IOAS symptoms. Keywords: children, transdermal fentanyl, opioid withdrawal DOI:10.5055/jom.2010.0011
March/April 2010; pages 125-132 Abstract Objective: Postoperative pain should be aggressively treated to decrease the development of chronic postsurgical pain. There has been an increase in the use of Human Patient Simulator (HPS) for teaching advanced courses in pharmacology to medical students, residents, and nurses. The aim of this educational investigation was to pilot the HPS for the training of medical students and surgical recovery room staff nurses in the pharmacology of opioids for the management of postoperative pain. Methods: The computerized HPS mannequin is fully monitored with appropriate displays and includes a voice speaker mounted in the head. Medical students and Postanesthesia care unit nurses, led by faculty in the Department of Anesthesiology in small groups of 4-6, participated in a 2- to 3-hour HPS course on the use of opioids for the management of acute postoperative pain. Trainees were asked to treat the acute and severe postoperative pain of a simulated patient. Opioid effects and side effects (such as respiratory depression) were presented on the mannequin in real time to the participants. Side effects of naloxone to reverse opioid depression were presented as a crisis in real time to the participants. Participants completed a 10-item course evaluation using a 5-point Likert scale (1 = strongly disagree; 5 = strongly agree). Results: Twenty-two nurses and nine medical students completed the HPS opioid pharmacology scenario. Almost all participants rated the HPS course very highly and rated every item as either agree or strongly agree. Most participants agreed that the simulator session improved their understanding of opioid pharmacology including opioid side effects and management of opioid complications. Course participants felt most strongly (median, interquartile range) that the simulator session improved their understanding of naloxone pharmacology (5, 0), simulators serve as a useful teaching tool (5, 0), and that they would be pleased to participate in any additional HPS teaching sessions (5, 0). Conclusions: The HPS provides a novel educational format to teach essential information regarding opioid pharmacology for the management of acute postoperative pain. The HPS provides a realistic format to teach the pharmacology of acute opioid side effects and the management of acute and life-threatening side effects of naloxone therapy. Keywords: patient simulation, resident education, opioid pharmacology, opioid pharmacodynamics, Human Patient Simulator, naloxone DOI:10.5055/jom.2010.0012
March/April 2010; pages 133-139 Abstract Purpose: Data suggest an increase in prescription opioid abuse in recent years. Young veterans represent a group with major risk factors for prescription opioid abuse. The objectives of this study are: (A) to determine the prevalence of chronic opioid use in young veterans over time; (B) to describe the prescribing patterns and monitoring of chronic opioid therapy in young veterans; and (C) to assess opioid management within Veterans Affairs Palo Alto Health Care System (VAPAHCS) with an emphasis on effectiveness and safety. Methods: This is a Veterans Affairs Research and Development (R&D) Committee and IRB-approved retrospective, single-center study of young veterans aged 18-30 years on chronic opioid therapy during the study years January 1, 2003, to October 1, 2008. A subset of the study population who were receiving long-acting opioids for a minimum of 6 months was included in the effectiveness and safety analyses. Data were obtained from the Veterans Integrated Service Network (VISN 21) data warehouse, outpatient prescription records, and from electronic chart review. Results: The prevalence of chronic opioid use in young veterans has increased from 3 percent in 2003 to 4.5 percent in 2007. Patients on average were exposed to two different opioids and had three different opioid prescribers. Nearly 80 percent of the opioid prescriptions during the study were prescribed by primary care providers and less than 1 percent was from pain specialists. Only 31 percent of patients on chronic opioids had undergone urine drug testing and only 5 percent had signed opioid treatment agreements. No difference in median pain score was observed following initiation of long-acting opioid therapy, and 22 percent of patients (4 of 18) met the prespecified definition of being a responder to long-acting opioid therapy. Five patients (28 percent) on long-acting opioids experienced adverse drug reactions. Conclusion: The prevalence of chronic opioid use in young veterans has been on the rise in recent years. Young veterans receiving care at VAPAHCS have often had multiple opioid prescribers and have trialed multiple opioid analgesics. Many improvements in appropriate monitoring and management of these patients can be made, which may include providing more training to current staff, the development of an opioid refill clinic, and greater utilization of the pain management specialists. Further larger study is warranted to identify successful strategies for improving prescribing and monitoring of opioids as well as potential predictors of response to chronic long-acting opioid therapy. Keywords: opioids, veterans, pain, chronic, prevalence, monitoring, safety, efficacy DOI:10.5055/jom.2010.0013
March/April 2010; pages 141-147 Abstract Background: Intravenous patient-controlled analgesia (IV PCA) with tramadol is an accepted method to deliver postoperative analgesia outside North America; however, the analgesic efficacy of this analgesic agent when compared with IV PCA with opioids is uncertain. As such, the authors undertook a systematic review to compare the analgesic efficacy of IV PCA tramadol with that of IV PCA with opioids. Methods: The authors used the National Library of Medicine’s Medline database to search for terms related to tramadol and patient-controlled analgesia. Inclusion criteria were randomized controlled trials (RCTs) comparing IV PCA tramadol with IV PCA opioid and RCTs published in the English language. Relevant data were abstracted from accepted studies. Meta-analysis was performed using RevMan 4.2.10 (The Cochrane Collaboration, 2004). A random effects model was used. Results: A total of 190 abstracts were obtained from the above search, and a total of 12 RCTs met the above inclusion criteria. There was no difference in weighted visual analog scale pain scores between IV PCA tramadol versus IV PCA opioid at 48 hours postoperatively or risk of sedation or fatigue. IV PCA tramadol was associated with a higher odds of postoperative nausea and vomiting [odds ratio (OR) = 1.52, 95% confidence interval (CI) = 1.07-2.14) but a lower odds of pruritus (OR = 0.43, 95% CI = 0.19-0.98). Discussion: IV PCA tramadol appears to produce similar pain scores when compared with that from IV PCA opioids; however, the side effect profile is different between the two groups. Because of the relatively small sample size, no determination of the relative “safety” (eg, respiratory depression) of one regimen over the other can be made, and larger RCTs would be needed for such a determination. Keywords: tramadol, patient-controlled analgesia, postoperative pain, meta-analysis DOI:10.5055/jom.2010.0014 Journal of Opioid Management May/June 2010, Volume 6, Number 3
May/June 2010; pages 159-160
May/June 2010; pages 161-161
May/June 2010; pages 166-167
May/June 2010; pages 169-179 Abstract Objective: To examine discontinuations due to nausea and/or vomiting or constipation with tapentadol immediate release (IR) or oxycodone IR treatment. Design: Post hoc analyses of a 90-day, phase 3, randomized, double-blind, flexibledose study. Setting: United States, Canada, United Kingdom. Patients: Adults with moderate to severe low back or osteoarthritis (OA) pain for = 3 months. Interventions: Tapentadol IR 50 or 100 mg or oxycodone HCl IR 10 or 15 mg every 4-6 hours as needed. Main outcome measures: Adverse events and discontinuations were recorded. Results: Post hoc analyses included data from 679 patients receiving tapentadol IR and 170 receiving oxycodone IR (4:1 randomization). Tapentadol IR 50 or 100 mg and oxycodone HCl IR 10 or 15 mg provided similar levels of pain relief. Overall, 21.2 percent of patients receiving tapentadol IR discontinued treatment for adverse events versus 31.2 percent of patients receiving oxycodone IR. The percentage of patients who discontinued for nausea and/or vomiting was significantly lower with tapentadol IR (5.9 percent) than oxycodone IR (14.7 percent; p = 0.0003); patients treated with oxycodone IR discontinued because of nausea and/or vomiting significantly earlier than with tapentadol IR (p < 0.0001). The percentage of patients who discontinued because of constipation was significantly lower with tapentadol IR (1.5 percent) than with oxycodone IR (5.9 percent; p = 0.0023); patients treated with oxycodone IR discontinued because of constipation significantly earlier versus tapentadol IR (p = 0.0003). Conclusions: A lower percentage of patients discontinued because of nausea and/or vomiting or constipation with tapentadol IR versus oxycodone IR while receiving comparable pain relief, suggesting tapentadol may improve the management of low back and OA pain. Keywords: tapentadol, low back pain, osteoarthritis pain, study discontinuations, gastrointestinal tolerability, oxycodone DOI:10.5055/jom.2010.0015
May/June 2010; pages 181-191 Abstract Objective: To evaluate the long-term safety, tolerability, and effectiveness of oxymorphone extended release (ER) in patients with cancer-related pain. Design: Post hoc analysis of two = 1-year open-label extension studies. Setting: Multiple US cancer treatment facilities. Patients: Patients with cancer pain who had participated in two short-term crossover comparator trials of oxymorphone ER: one open-label and one doubleblind randomized. Interventions: Patients who had been taking oxymorphone ER continued the dose established in the previous study. Patients who had been taking a comparator opioid were switched to an equianalgesic dose of oxymorphone ER. All patients underwent individualized oxymorphone ER dose titration to optimize effectiveness and tolerability. Assessments: Current, average, worst, and least pain scores were normalized to a 100-point scale. Patients rated treatment on a five-point global assessment of study medication (Poor = 1 to Excellent = 5). All adverse events (AEs) were recorded. Results: Of the 80 patients who entered the extension trials, 26 completed 52 weeks, 7 discontinued owing to loss of effectiveness, and 20 discontinued owing to AEs, most of which were unrelated to study drug. No significant increase in mean (standard deviation [SD]) average pain intensity was observed from baseline (30.5 [19.6], 100-point scale) to final visit (35.9 [21.1], p = 0.37). The most common AEs were concomitant disease progression (28.8 percent, n = 23), nausea (22.5 percent, n = 18), dyspnea (16.3 percent, n = 13), fatigue (16.3 percent, n = 13), and edema of the lower limb (15 percent, n = 12). Conclusions: In these patients with pain related to cancer, oxymorphone ER was generally well tolerated and provided stable long-term pain control. Keywords: cancer, cancer pain, chronic pain, extension trial, opioid, oxymorphone DOI:10.5055/jom.2010.0016
May/June 2010; pages 193-202 Abstract Background: This multicenter, parallel-group, 35-day study in adults with osteoarthritis (OA) pain evaluated the analgesic efficacy and safety of buprenorphine transdermal system (BTDS) designed for 7-day wear. Methods: Patients with OA pain inadequately controlled with nonsteroidal anti-inflammatory drugs or patients who had taken opioids for OA pain within the past year entered a 7-day run-in period during which they took ibuprofen only. Patients with pain = 7 on a 0-10 scale had their ibuprofen discontinued and were randomized into a 28-day double-blinded period to receive either BTDS at 1 of 3 dose levels (5, 10, or 20 µg/h) or placebo. Doses were titrated to effectiveness over a period of 21 days and maintained for 7 days. No rescue medication was allowed during the study. The primary efficacy measure was the proportion of patients who achieved treatment success, defined as a patient satisfaction score of good, very good, or excellent (on day 28 or at early discontinuation) for those who did not discontinue due to ineffective treatment. Results: More BTDS-treated patients experienced treatment success than placebo TDS-treated patients (44 percent and 32 percent; odds ratio = 1.66, p = 0.036). Fewer patients taking BTDS titrated to the highest dose compared with placebo (p < 0.05). There were two serious adverse events (both in the placebo group) and no deaths. The most common (= 5 percent) adverse events reported in BTDS treated patients were nausea, headache, dizziness, somnolence, application site pruritus, and vomiting. Conclusion: Compared with placebo, BTDS treatment was effective in treating patients with moderate to severe pain due to OA of the knee or hip. BTDS was well tolerated. Keywords: buprenorphine, transdermal, pain, analgesia, osteoarthritis, randomized controlled trials DOI:10.5055/jom.2010.0017
May/June 2010; pages 203-210 Abstract Acute postoperative pain remains inadequately managed. Although patient controlled analgesia (PCA) represents a significant advance in postoperative pain management, drawbacks may include invasiveness and the potential for programming errors. The analysis presented here is based on pooled patient-level safety data from four multicenter, randomized, active-controlled trials that evaluated the safety and tolerability of the needle-free, preprogrammed fentanyl HCl iontophoretic transdermal system (ITS) versus morphine intravenous PCA for postoperative pain management; the results for patients who received fentanyl ITS are presented here. Adverse events (AEs), serious AEs, and clinically relevant respiratory depression were assessed across patient subpopulations categorized by age. A total of 1,288 patients, including 356 elderly (> 65 years of age) patients, received fentanyl ITS following surgery. The most commonly reported AEs included nausea, fever, vomiting, headache, anemia, pruritus, and hypotension. The incidence of AEs was generally lower for elderly patients than for patients 65 years or younger. Application-site reactions were reported for 18.6 percent of patients using fentanyl ITS and were generally mild to moderate in severity. No cases of clinically relevant respiratory depression were eported for patients who received fentanyl ITS. The results demonstrate that fentanyl ITS is safe and well tolerated for postoperative pain management for patients overall and for subpopulations divided according to age. Keywords: tolerability, pain management, postoperative, fentanyl ITS, patient-controlled analgesia DOI:10.5055/jom.2010.0018
May/June 2010; pages 211-222 Abstract Introduction: Untreated emotional distress negatively impacts the management of cancer pain. Objectives: The authors evaluated 64 patients with cancer pain who completed baseline and follow-up measures to identify if (1) measures of psychosocial well being, pain intensity, and pain management were associated with survival time; (2) higher opioid doses were associated with less psychosocial distress; and (3) intrasubject correlations across time altered the relationship between pain, depression, social support, spirituality, and increased desire for hastened death (DHD). Methods: The main outcome measures included the Brief Pain Inventory (BPI), Daily Morphine Equivalent Dose (DMED), Beck Depression Inventory-II (BDI-II), DHD scale, Bottomley Social Support Scale, FACIT Spiritual Well-Being Scale (FACIT-Sp), Karnofsky Performance Rating Scale (KPRS), and State-Trait Anxiety Inventory (STAI). Results: There were significant differences between baseline and follow-up DHD (0.84 vs 1.38, p = 0.021) and BPI scores (6.36 vs 4.86, p < 0.001). Lower existential well being was associated with reduced survival (HR = 0.78, p = 0.019); improvement in pain was associated with longer survival (HR = 1.33, p = 0.034). Higher religious wellbeing was associated with higher probability of survival to 1 year (HR = 0.41, p = 0.014), as was higher KPRS (HR = 0.97, p = 0.001) but not DMED > 300 mg. Higher existential distress and lower Bottomley scores were associated with higher hazard ratios for death at 1 year (HR = 2.78, p = 0.02) and (HR = 14.94, p = 0.002). There were significant differences in average BDI-II for persons with BPI > 7 versus those with moderate or mild pain (12.12 vs 6.82, p < 0.0001) and in DHD (1.71 vs 0.64, p = 0.002). Depression decreased in persons with DMED > 300 mg between baseline and follow-up (-1.67 vs 2.72, p = 0.024). Mean DHD was lower for persons whose pain improved versus others (0.96 vs 2.0, p = 0.026). A generalized linear model was conducted with DHD as the dependent variable and the other above variables as predictors. Higher existential wellbeing and KPRS were associated with lower DHD (ß = -0.135, p = 0.049) and (ß = -0.79, p = 0.006), respectively. Conclusions: The major findings of this study are that in persons with cancer pain, lower social support and existential wellbeing, but not higher DMED, were associated with shorter survival time. Treatment of cancer pain was associated with lessening of emotional distress. Lower levels of existential wellbeing and physical performance status appear to be associated with greater DHD. Keywords: cancer pain, opioid medications, psychosocial wellbeing DOI:10.5055/jom.2010.0019
May/June 2010; pages 223-226 Abstract Tapentadol hydrochloride (17(—)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol) is a newly released analgesic that works at two levels: by acting as a µ-opioid agonist and as a modulator of descending inhibitory pathways through its effects on neurotransmitters involved in these pathways. The theoretical advantage is the provision of synergistic analgesic activities, which may lessen the need for opioid escalation. The advantage is its potential as a possible new agent in neuropathic pain. Preclinical models confirm analgesic properties in acute pain and neuropathic pain models, but with less potency than morphine. Tapentadol has minimal CYP 450 interactions limiting potential for drug interactions. Human clinical trial data in nonmalignant pain suggest less potency than a step-3 opioid, and the drug remains to be tested in patients with cancer pain and neuropathic pain. Keywords: tapentadol, affinity, neuropathic DOI:10.5055/jom.2010.0020
May/June 2010; pages 227-231 Abstract Background: Heroin use carries a large burden of morbidity and mortality. Heroin overdose and in particular events that need intensive care unit (ICU) admission have not been widely examined. The aim of this study was to describe the causes of ICU admission and the outcome of patients with a heroin overdose. Methods: A retrospective chart review of all patients with a heroin overdose admitted to the ICU between 1987 and 2006 was conducted. Results: Forty-two records were available for review. The average age of the patients was 28 years. In the field, 19 persons were found in coma Glasgow Coma Scale (GCS < 8) and respiratory depression and were treated with naloxone. The reasons for ICU admission included hypoxemia in 37 (88 percent), 28 of whom had acute lung injury (ALI) and nine aspiration pneumonia, shock in three (7.2 percent) and persistent mental compromise in two patients (4.8 percent). Intubation and mechanical ventilation (MV) were instituted in 37 patients. In 19 of the 37 patients, weaning and extubation became possible within the first 24 hours. Sixteen patients suffered complications and received MV for 5 ± 2 days, with a mean length of ICU stay of 8 ± 1 days, while two patients succumbed because of anoxemic encephalopathy and brain death. The complications observed were acute respiratory distress syndrome in eight patients, severe sepsis in four, catheter-related bacteremia in one, iatrogenic pneumothorax in one, and rhabdomyolysis in two, while four among them died due to severe sepsis. Conclusions: In our study, ALI and aspiration pneumonia were the most frequently observed respiratory complications after acute heroin overdose requiring intubation and ICU admission. Mortality rate was 14.2 percent and was attributed to septic complications and irreversible brain damage. Keywords: heroin overdose, acute drug intoxication, ICU management DOI:10.5055/jom.2010.0021 |
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