A phase 2, double-blind,randomized, placebo-controlled,dose-escalation study to evaluate the efficacy,safety, and tolerability of naloxegol in patients with opioid-induced constipation

Naloxegol (previously known as NKTR-118) is a peripherally acting μ-opioid receptor antagonist engineered using polymer conjugate technology in development as an oral, once-daily agent for the treatment of opioid-induced constipation (OIC). Eligible patients with OIC (n = 207), defined as <3 spontaneous bowel movements (SBMs) per week with accompanying symptoms, on a stable opioid regimen of 30–1000 mg/day morphine equivalents for ?2 weeks were randomized to receive 4 weeks of double-blind placebo or naloxegol (5, 25, or 50 mg) once daily in sequential cohorts after a 1-week placebo run-in. The primary end point, median change from baseline in SBMs per week after week 1 of drug administration, was statistically significant for the 25- and 50-mg naloxegol cohorts vs placebo (2.9 vs 1.0 [P = 0.0020] and 3.3 vs 0.5 [P = 0.0001], respectively). The increase in SBMs vs placebo was maintained over 4 weeks for naloxegol 25 mg (3.0 vs 0.8 [P = 0.0022]) and 50 mg (3.5 vs 1.0 [P < 0.0001]). Naloxegol was generally well tolerated across all dosages. The most frequent adverse events (AEs) were abdominal pain, diarrhea, and nausea. Most AEs at 5 and 25 mg/day were mild and transient. Similar AEs occurred with increased frequency and severity in the 50-mg cohort. There was no evidence of a statistically significant increase from baseline in pain, opioid use for the 25- and 50-mg cohorts, or centrally mediated opioid withdrawal signs and/or symptoms with naloxegol. These data demonstrate that once-daily oral naloxegol improves the frequency of SBMs compared with placebo and is generally well tolerated in this population of patients with OIC.     

Peripheral opioid receptor blockade increases postoperative morphine demands—A randomized,double-blind,placebo-controlled trial

Experimental studies suggest that a large proportion of opioid analgesia can be mediated by peripheral opioid receptors. This trial examined the contribution of such receptors to clinical analgesia induced by intravenous morphine. We hypothesized that the selective blockade of peripheral opioid receptors by methylnaltrexone (MNX) would increase the patients’ demand for morphine to achieve satisfactory postoperative pain relief. In a double-blind, placebo-controlled, sequential 2-center trial, 50 patients undergoing knee replacement surgery were randomized (1:1) to receive either subcutaneous MNX (0.9 mg/kg) (hospital I: n = 14; hospital II: n = 11) or saline (hospital I: n = 13; hospital II: n = 12) at the end of surgery. The primary endpoint was the cumulative amount of intravenous morphine administered during the first 8 hours. Secondary endpoints were pain scores at rest and during movement (by numerical rating scale and McGill Questionnaire), vital signs, adverse side effects, and withdrawal symptoms. After MNX, demands for morphine were strongly (by about 40%) increased (hospital I: 35.31 ± 12.99 mg vs 25.51 ± 7.92 mg, P = 0.03; hospital II: 35.42 ± 11.73 mg vs 24.80 ± 7.84 mg, P = 0.02; pooled data: P < .001; means ± SD). Secondary endpoints were similar in all groups (P > .05). Thus, a significant proportion of analgesia produced by systemically administered morphine is mediated by peripheral opioid receptors. Drugs that selectively activate such receptors should have the potential to produce powerful clinical pain relief.     

Evaluation of dexmedetomidine withdrawal in critically ill adults

BackgroundDexmedetomidine (DEX) withdrawal syndrome has been reported in the pediatric population, but literature describing DEX withdrawal in critically ill adults is limited. The purpose of this study was to determine the incidence of DEX withdrawal in adult patients and to identify factors associated with DEX withdrawal syndrome.MethodsA retrospective chart review was performed in the adult intensive care units of two tertiary medical centers. Eligible patients were at least 18 years of age and received DEX for 24 h or more. Patients were excluded if they presented with a primary neurologic diagnosis, had a history of substance abuse, or received any other α2-agonists 24 h before discontinuation of DEX. The primary outcome was the percentage of patients who developed withdrawal as defined by the presence of two or more symptoms (tachycardia, hypertension, vomiting, agitation) within the 24 h following DEX discontinuation.ResultsOf the 165 patients included, 50 patients experienced withdrawal (30.3%), lasting a median of two days. The incidence of withdrawal was higher in surgical (40%) compared to medical (28%) or cardiac (32%) patients (p = 0.004). Median duration of infusion was 52.5 h (interquartile range [IQR], 37.8 to 102.8) in the withdrawal group and 52 h (IQR, 41 to 87) in the non-withdrawal group (p = 0.887). Median DEX dose was 0.56 μg/kg/h (IQR, 0.39 to 0.83) in the withdrawal group and 0.48 μg/kg/h (0.36 to 0.65) in the non-withdrawal group (p = 0.12). Weaning did not reduce the incidence of withdrawal as compared to abrupt discontinuation (p = 0.68). The withdrawal group was more likely to have concomitantly discontinued opioids (54% vs 12.2%) and benzodiazepines (36% vs 0%) at the time of DEX discontinuation compared to the non-withdrawal group (p = 0.004).ConclusionDevelopment of DEX-associated withdrawal occurred in approximately 30% of adult patients, comparable to rates reported in pediatric literature. There appeared to be no correlation between dose, exposure, and weaning in the occurrence of withdrawal, but concomitant discontinuation of opioids or benzodiazepines as well as ICU admission type could highlight cases requiring closer monitoring.     

Association Between Pain Intensity and Discontinuing Opioid Therapy or Transitioning to Intermittent Opioid Therapy After Initial Long-Term Opioid Therapy: A Retrospective Cohort Study

The purpose of this study was to evaluate changes in pain intensity among Veterans transitioning from long-term opioid therapy (LTOT) to either intermittent therapy or discontinuation compared to continued LTOT. Pain intensity was assessed using the Numeric Rating Scale in 90-day increments starting in the 90-day period prior to potential opioid transitions and the two ensuing 90-day periods after transition. Primary analyses used a 1:1 greedy propensity matched sample. A total of 29,293 Veterans switching to intermittent opioids and 5,972 discontinuing opioids were matched to Veterans continuing LTOT. Covariates were well balanced after matching except minor differences in baseline mean pain scores. Pain scores were lower in the follow up periods for those switching to intermittent opioids and discontinuing opioids compared to those continuing LTOT (0–90 days: Intermittent: 3.79, 95%CI: 3.76, 3.82; LTOT: 4.09, 95%CI: 4.06, 4.12, P < .0001; Discontinuation: 3.06, 95%CI: 2.99, 3.13; LTOT: 3.86, 95%CI: 3.79, 3.94, P = <.0001; 91–180 days: Intermittent: 3.76, 95%CI: 3.73, 3.79; LTOT: 3.99, 95%CI: 3.96, 4.02, P < .0001; Discontinuation: 3.01, 95%CI: 2.94, 3.09; LTOT: 3.80, 95%CI: 3.73, 3.87, P = <.0001). Sensitivity analyses found similar results. Discontinuing opioid therapy or switching to intermittent opioid therapy was not associated with increased pain intensity.PerspectiveThis article evaluates the association of switching to intermittent opioid therapy or discontinuing opioids with pain intensity after using opioids long-term. Pain intensity decreased after switching to intermittent therapy or discontinuing opioids, but remained relatively stable for those continuing long-term opioid therapy. Switching to intermittent opioids or discontinuing opioids was not associated with increased pain intensity.     

Do sex differences exist in opioid analgesia? A systematic review and meta-analysis of human experimental and clinical studies

Although a contribution of sex in opioid efficacy has garnered much attention, the confirmation and direction of any such difference remain elusive. We performed a systematic review of the available literature on sex differences in μ and mixed μ/κ opioid effect on acute and experimental pain. Fifty unique studies (including three unpublished studies) were included in the analyses. Across the 25 clinical studies on μ-opioids there was no significant sex-analgesia association. Restricting the analysis to patient-controlled analgesia (PCA) studies (irrespective of the opioid) yielded greater analgesia in women (n = 15, effect size 0.22, 95% c.i. 0.02-0.42, P = 0.028). Further restricting the analysis to PCA morphine studies yielded an even greater effect in women (n = 11, effect size = 0.36, 95% c.i. 0.17-0.56, P = 0.003). Meta-regression indicated that the longer the duration of PCA, the difference in effect between the sexes further increased. Across experimental pain studies on μ-opioids women had greater antinociception from opioids (n = 11, effect size = 0.35; 95% c.i. 0.01-0.69, P = 0.047), which was predominantly due to 6 morphine studies. Female patients had greater μ/κ opioid analgesia (n = 7, effect size 0.84; 95% c.i. 0.25-1.43, P = 0.005), but no sex-analgesia association was present in experimental studies (n = 7). Sex differences exist in morphine-induced analgesia in both experimental pain studies and clinical PCA studies, with greater morphine efficacy in women. The data on non-morphine μ and mixed μ/κ-opioids are less convincing and require further study.     

A prospective study of adverse reactions to the weaning of opioids and benzodiazepines among critically ill children.

The aim of this study was to identify the optimal rates at which opioids and benzodiazepines should be weaned in order to prevent withdrawal reactions in the pediatric intensive care unit (PICU). This study follows an earlier investigation that developed a graphical analysis method for examining behavioral signs of withdrawal in relation to changes in opioid and benzodiazepine administration. This method was utilized in this present study for a prospective sample of all patients admitted to a tertiary/quaternary level PICU within a 4-week interval (n=27). The findings of this study indicate that the required rate of weaning (in order to prevent withdrawal reactions) is related to the number of days the child has been on a continuous infusion of opioids and/or benzodiazepines. Adverse withdrawal reactions were prevented when the daily rate of weaning did not exceed: 20% for children receiving continuous infusions for 1-3 days; 13-20% for 4-7 days; 8-13% for 8-14 days; 8% for 15-21 days; and 2-4% for more than 21 days of infusions. The authors recommend that the rate of weaning of opioids and benzodiazepines in critically ill children be tailored to the length of time the child received continuous infusions of these agents.     

The effects of depression and smoking on pain severity and opioid use in patients with chronic pain

Depression and smoking are common comorbid conditions among adults with chronic pain. The aim of this study was to determine the independent effects of depression on clinical pain and opioid use among patients with chronic pain according to smoking status. A retrospective design was used to assess baseline levels of depression, clinical pain, opioid dose (calculated as morphine equivalents), and smoking status in a consecutive series of patients admitted to a 3-week outpatient pain treatment program from September 2003 through February 2007. Depression was assessed using the Centers for Epidemiologic Studies-Depression scale, and clinical pain was assessed using the pain severity subscale of the Multidimensional Pain Inventory. The study cohort (n = 1241) included 313 current smokers, 294 former smokers, and 634 never smokers. Baseline depression (P = .001) and clinical pain (P = .001) were greater among current smokers compared to former and never smokers, and the daily morphine equivalent dose was greater among smokers compared to never smokers (P = .005). In multivariate linear regression analyses, baseline pain severity was independently associated with greater levels of depression, but not with smoking status. However, status as a current smoker was independently associated with greater opioid use (by 27 mg/d), independent of depression scores. The relationship between depression, smoking status, opioid use, and chronic pain is complex, and both depression and smoking status may be potentially important considerations in the treatment of patients with chronic pain who utilize opioids.     

Morphine consumption is not modified in patients with severe pain and classified by the DN4 score as neuropathic

Neuropathic pain has been poorly investigated in the emergency department, although it is known to be less sensitive to opioids than other forms of pain. We tested the hypothesis that morphine requirements are increased in patients having severe pain classified as neuropathic using the DN4 score. We included adult patients with acute severe pain (visual analog scale ≥ 70), assessed using the DN4 score, and treated with intravenous morphine titration (bolus of 2 or 3 mg [body weight > 60 kg] with 5-minute intervals between each bolus). Pain relief was defined as a visual analog scale 30 or less. Patients were divided into 2 groups: control group (DN4 score < 4) and neuropathic pain group (DN4 score ≥ 4). The main outcome was the total dose of morphine administered. Data are mean ± SD or median (interquartile range). Among the 239 patients included (mean age, 43 + 14 years), 35 patients (15%) had a DN4 score 4 or more. The main characteristics of the 2 groups were comparable. There were no significant differences between the 2 groups in morphine dose (0.16 + 0.09 vs 0.17 + 0.11 mg/kg, P = .32), number of boluses administered (3.5 [3-5] vs 3 [3-6], P = .97), proportion of patients with pain relief (75 vs 83%, P = .39), or morphine-related adverse effects (11% vs 3%, P = .14). In conclusion, morphine consumption was not significantly modified in patients having severe pain classified as neuropathic using the DN4 score as compared with a control group, suggesting that specific detection of neuropathic pain may not be useful in the emergency department.     

Intrathecal combination of ziconotide and morphine for refractory cancer pain: a rapidly acting and effective choice

Ziconotide is a nonopioid intrathecal analgesic drug used to manage moderate to severe chronic pain. The aim of this work is to assess the safety and efficacy of intrathecal (IT) combination of ziconotide and morphine in malignant pain refractory to high doses of oral opioids. Patients with malignant pain refractory to high oral opioids doses with a mean visual analogue scale of pain intensity (VASPI) score of ?70 mm were enrolled. An IT combination therapy was administered: Ziconotide was started at a dose of 2.4 μg/day, followed by increases of 1.2 μg/day at intervals of at least 7 days, and an initial IT daily dose of morphine was calculated based on its oral daily dose. Percentage change in VASPI scores from baseline was calculated at 2 days, at 7 days, and weekly until the first 28 days. The mean percentage change of VASPI score from baseline was used for efficacy assessment. Safety was monitored based on adverse events and routine laboratory values. Twenty patients were enrolled, with a mean daily VASPI score at rest of 90 ± 7. All had a disseminated cancer with bone metastases involving the spine. The percentage changes in VASPI mean scores from baseline to 2 days, 7 days, and 28 days were 39 ± 13% (95% confidence interval [CI] = 13.61-64.49, P < .001), 51 ± 12% (95% CI = 27.56-74.56, P < .001), and 62 ± 13% (95% CI = 36.03-87.89%, P < .001), respectively. Four patients experienced mild adverse events related to the study drugs. In conclusion, an IT combination of low doses of ziconotide and morphine allows safe and rapid control of oral opioid-refractory malignant pain.     

Is intraoperative dexmedetomidine a new option for postoperative pain treatment? A meta-analysis of randomized controlled trials

In the present meta-analysis, we assessed the efficacy and safety of intravenous administration of dexmedetomidine (DEX) compared with placebo or opioids for acute postoperative pain treatment in adults undergoing surgery. The meta-analysis was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement and the recommendations of the Cochrane Collaboration. Randomized controlled trials investigating perioperative administration of DEX were included. For dichotomous outcomes relative risks (RR; 95% confidence intervals [CI]) and for continuous outcomes mean differences (MD; 95% CI) were calculated. Twenty-eight randomized controlled trials including 1420 patients were finally included. Patients treated with DEX reported lower postoperative pain intensity (MD_{1 h postoperatively}: −1.59 U (numeric rating scale: 0 to 10) 95% CI: −2.37 to −0.82; P = .000001) and showed a lower postoperative opioid consumption (MD_{24 h postoperatively}: −17.24 mg; 95% CI: −24.38 to −10.10; P = .00001) compared with placebo. Additionally, the DEX group showed a lower RR for opioid-related adverse events (e.g. RR_{Nausea (postanesthesia care unit)}: 0.66; 95% CI: 0.43 to 1.02; P = .06). The most common adverse event in patients treated with DEX was intraoperative bradycardia with a RR of 2.66 (RR: 2.66; 95% CI: 1.54 to 4.58; P = .0004) compared with placebo. There is evidence that DEX administration leads to lower postoperative pain, reduced opioid consumption, and a lower risk for opioid-related adverse events. The comparison of DEX vs opioids for postoperative pain treatment is less clear due to limited data. The most common adverse event was intraoperative bradycardia after DEX administration. Therefore cautions in patients at risk are warranted, and large trials focusing on long-term outcomes after intraoperative DEX use are needed.     

Withdrawal following sufentanil/propofol and sufentanil/midazolam

Purpose Patients in the ICU after long-term administration of an opioid/hypnotic often develop delirium. To assess the nature of this phenomenon, patients in a surgical ICU following ventilatory support and sedation with an opioid/hypnotic/sedative were studied.Methodology Following sufentanil/midazolam (group 1; n =14) or sufentanil/propofol (group 2; n =15) sedation, patients were evaluated for changes in mean arterial blood pressure and heart rate, the activity of the central nervous system (sensory evoked potentials, spectral edge frequency of EEG), and the endogenous opioids plasma concentrations (-endorphin, met-enkephalin). Data obtained were correlated with the individual intensities of withdrawal symptoms 6-, 12-, and 24 h following sedation.Results Following a mean duration of ventilation of 7.7 days (±3.6 SD) in groups 1 and 3.5 (±1.7 SD) in group 2, withdrawal intensities peaked within the 6th hour after cessation. Plasma -endorphin and met-enkephalin levels were low during sedation, and only the sufentanil/midazolam group demonstrated a postinhibitory overshoot. Withdrawal symptom intensities demonstrated an inverse correlation with -endorphin and met-enkephalin levels, a direct linear correlation with amplitude height of the evoked potential, and blood pressure and heart rate changes. Withdrawal intensities did not correlate with EEG power spectral edge frequency.Conclusion The endorphinergic system is suppressed when a potent exogenous opioid like sufentanil is given over a long period of time. Following sedation, abstinence symptoms seem to be related to postinhibitory increased endorphin synthesis. This is mostly seen in the combination of sufentanil/midazolam. In addition, an increase in the amplitude of the sensory-evoked potential suggests a postinhibitory excitatory state within the nociceptive system.Preliminary results were presented at the ASA Meeting in Dallas, Texas, October 1999     

Association between transient acute kidney injury and morbidity and mortality after lung transplantation: A retrospective cohort study

Purpose

Acute kidney injury (AKI) is a common occurrence after lung transplantation (LTx). Whether transient AKI or early recovery is associated with improved outcome is uncertain. Our aim was to describe the incidence, factors, and outcomes associated with transient AKI after LTx.

Materials and Methods

We performed a retrospective cohort study of all adult recipients of LTx at the University of Alberta between 1990 and 2011. Our primary outcome transient AKI was defined as return of serum creatinine below Kidney Disease–Improving Global Outcome AKI stage I within 7 days after LTx. Secondary outcomes included occurrence of postoperative complications, mortality, and long-term kidney function.

Results

Of 445 LTx patients enrolled, AKI occurred in 306 (68.8%) within the first week after LTx. Of these, transient AKI (or early recovery) occurred in 157 (51.3%). Transient AKI was associated with fewer complications including tracheostomy (17.2% vs 38.3%; P < .001), reintubation (16.4% vs 41.9%; P < .001), decreased duration of mechanical ventilation (median [interquartile range], 69 [41-142] vs 189 [63-403] hours; P < .001), and lower rates of chronic kidney disease at 3 months (28.5% vs 51.1%, P < .001) and 1 year (49.6% vs 66.7%, P = .01) compared with persistent AKI. Factors independently associated with persistent AKI were higher body mass index (per unit; odds ratio [OR], 0.91; 95% confidence interval, 0.85-0.98; P = .01), cyclosporine use (OR, 0.29; 0.12-0.67; P = .01), longer duration of mechanical ventilation (per hour [log transformed]; OR, 0.42; 0.21-0.81; P = .01), and AKI stages II to III (OR, 0.16; 0.08-0.29; P < .001). Persistent AKI was associated with higher adjusted hazard of death (hazard ratio, 1.77 [1.08-2.93]; P = .02) when compared with transient AKI (1.44 [0.93-2.19], P = .09) and no AKI (reference category), respectively.

Conclusions

Transient AKI after LTx is associated with fewer complications and improved survival. Among survivors, persistent AKI portends an increased risk for long-term chronic kidney disease.     

Opioid Interruptions,Pain, and Withdrawal Symptoms in Nursing Home Residents

PurposeInterruptions in opioid use have the potential to cause pain relapse and withdrawal symptoms. The objectives of this study were to observe patterns of opioid interruption during acute illness in nursing home residents and examine associations between interruptions and pain and withdrawal symptoms.MethodsPatients from 3 nursing homes in a metropolitan area who were prescribed opioids were assessed for symptoms of pain and withdrawal by researchers blinded to opioid dosage received, using the Brief Pain Inventory Scale and the Clinical Opioid Withdrawal Scale, respectively, during prespecified time periods. The prespecified time periods were 2 weeks after onset of acute illness (eg, urinary tract infection), and 2 weeks after hospital admission and nursing home readmission, if they occurred. Opioid dosing was recorded and a significant interruption was defined as a complete discontinuation or a reduction in dose of >50% for ≥1 day. The covariates age, sex, race, comorbid conditions, initial opioid dose, and initial pain level were recorded. Symptoms pre- and post-opioid interruptions were compared and contrasted with those in a group without opioid interruptions.FindingsSixty-six patients receiving opioids were followed for a mean of 10.9 months and experienced a total of 104 acute illnesses. During 64 (62%) illnesses, patients experienced any reduction in opioid dosing, with a mean (SD) dose reduction of 63.9% (29.9%). During 39 (38%) illnesses, patients experienced a significant opioid interruption. In a multivariable model, residence at 1 of the 3 nursing homes was associated with a lower risk of interruption (odds ratio = 0.073; 95% CI, 0.009 to 0.597; P < 0.015). In patients with interruptions, there were statistically insignificant changes in mean (SD) pain score (difference −0.50 [2.66]; 95% CI, −3.16 to 2.16) and withdrawal score (difference −0.91 [3.12]; 95% CI, −4.03 to 2.21) after the interruption as compared with before interruption. However, when compared with patients without interruptions, patients with interruptions experienced larger increases in pain scores during the follow-up periods (difference 0.09 points per day; 95% CI, −0.01 to 0.019; P = 0.08). In particular, patients who received the highest quartile of opioid dose before interruption experienced increases in pain scores over time that were 0.22 points per day larger (95% CI, 0.02 to 0.41; P = 0.03) than those without interruption. Withdrawal scores were not associated with opioid interruption regardless of dose before interruption.ImplicationsNursing home patients often experience interruptions in opioid dosing, which can be associated with worse pain, but not withdrawal symptoms, during acute illnesses. Clinicians should be aware of the potential risks and effects of opioid interruptions during acute illnesses in this patient group.     

High-frequency,high-intensity transcutaneous electrical nerve stimulation as treatment of pain after surgical abortion

The aim of the study was to compare the pain-relieving effect and the time spent in the recovery ward after treatment with high-frequency, high-intensity transcutaneous electrical nerve stimulation (TENS) or intravenous (IV) conventional pharmacological treatment after surgical abortion. Two-hundred women who underwent surgical abortion and postoperatively reported a visual analogue scale (VAS) pain score ? 3 were included. The patients were randomised to TENS or conventional pharmacological treatment for their postoperative pain. The TENS treatment was given with a stimulus intensity between 20 and 60 mA during 1 min and repeated once if insufficient pain relief (VAS ? 3). In the conventional pharmacological treatment group, a maximum dose of 100 μg fentanyl was given IV. There was no difference between the groups with regard to pain relief according to the VAS pain score (TENS = VAS 1.3 vs. IV opioids = VAS 1.6; p = 0.09) upon discharge from the recovery ward. However, the patients in the TENS group spent shorter time (44 min) in the recovery ward than the conventional pharmacological treatment group (62 min; p < 0.0001). The number of patients who needed additional analgesics in the recovery ward was comparable in both groups, as was the reported VAS pain score upon leaving the hospital (TENS = 2.0 vs. conventional pharmacological treatment = 1.8, NS). These results suggest that the pain-relieving effect of TENS seems to be comparable to conventional pharmacological treatment with IV opioids. Hence, TENS may be a suitable alternative to conventional pain management with IV opioids after surgical abortion.