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Context: Chronic breathlessness is a clinical syndrome that results in significant distress and disability. Morphine can reduce chronic breathlessness when the contributing etiologies are optimally treated.Objectives: Does oxycodone reduce chronic breathlessness compared with placebo?Methods: A multisite, randomized, placebo-controlled, double-blind, parallel-arm, fixed-dose trial of oral controlled-release oxycodone 15 mg (5 mg, eight hourly) or placebo (ACTRN12609000806268 at www.anzctr.org.au). As-needed immediate-release morphine (2.5 mg per dose; six and less doses/day) was available for both arms as required by one ethics committee overseeing the trial. Recruitment occurred from 2010 to 2014 in 14 inpatient and outpatient respiratory, cardiology, and palliative care services across Australia. Participants were adults, with chronic breathlessness (modified Medical Research Council Scale 3 or 4), who were opioid naive. The primary end point was the proportion of people with greater than 15% reduction from baseline in the intensity of breathlessness now (0-100 mm visual analogue scale) comparing arms Days 5-7. Secondary end points were average and worst breathlessness, quality of life, function, and harms.Results: Of 157 participants randomized, 155 were included (74 oxycodone and 81 placebo), but the study did not reach target recruitment. There was difference in neither between groups for the primary outcome (P = 0.489) nor any of the prespecified secondary outcomes. Placebo participants used more as-needed morphine (mean 7.0 vs. 4.2 doses; P ≤ 0.001). Oxycodone participants reported more nausea (P < 0.001).Conclusion: There was no signal of benefit from oxycodone over placebo. Future research should focus on investigating the existence of an opioid class effect on the reduction of chronic breathlessness. [ABSTRACT FROM AUTHOR]

Context: Pulmonary arterial hypertension (PAH) affects people of all ages and is associated with poor prognosis. Chronic breathlessness affects almost all people with PAH.Objectives: This randomized, placebo-controlled, double-blind, crossover study aimed to evaluate the effects of regular, low-dose, extended-release (ER) morphine for PAH-associated chronic breathlessness.Methods: Participants with PAH-associated chronic breathlessness were randomized to 1) seven days of ER morphine 20 mg, 2) seven-day washout, and 3) seven days of identically looking placebo, or vice versa. Primary end points were breathlessness "right now"-morning and evening-measured with a Visual Analogue Scale. Secondary end points included additional breathlessness measures, quality of life, function, harms, and blinded treatment preference (ACTRN12609000209291).Results: Within a period of seven years, 50 patients were assessed in detail and 23 (46%) were randomized (despite broad eligibility criteria). Four participants withdrew while taking morphine. Nineteen participants completed the study. Breathlessness "right now" was higher on morphine compared with placebo both for morning [mean (M) ± SD 31.7 ± 25 mm vs. 26.9 ± 22 mm; effect size (80% CI) = -0.22 (-0.6 to 0.2)] and evening [(M ± SD 33.5 ± 28 mm vs. 25.6 ± 21 mm; effect size (80% CI) = -0.33 (-0.8 to 0.1)]. All secondary measures of breathlessness were higher with morphine as were nausea and constipation.Conclusion: This study does not support a Phase III study of ER morphine for people with PAH-associated chronic breathlessness. Recruiting to the target sample size was difficult, the direction of effect in every measure of breathlessness favored placebo and morphine generated more harms. [ABSTRACT FROM AUTHOR]

Background: A lack of objective outcome measures and overreliance on subjective pain reports in early proof-of-concept studies contribute to the high attrition of potentially effective new analgesics. We studied the utility of neuroimaging in providing objective evidence of neural activity related to drug modulation or a placebo effect in a double-blind, randomized, placebo-controlled, three-way crossover trial.Methods: We chronically administered pregabalin or tramadol (first-line and second-line analgesics, respectively), recommended for neuropathic pain, in 16 post-traumatic neuropathic pain patients. We measured subjective pain reports, allodynia-evoked neural activity, and brain resting state functional connectivity from patients during the three sessions and resting state data at baseline from patients after washout of their current medication. All data were collected using a 3 T MRI scanner.Results: When compared with placebo only, pregabalin significantly suppressed allodynia-evoked neural activity in several nociceptive and pain-processing areas of the brain, despite the absence of behavioural analgesia. Furthermore, placebo significantly increased functional connectivity between the rostral anterior cingulate and the brainstem, a core component of the placebo neural network.Conclusions: Functional neuroimaging provided objective evidence of pharmacodynamic efficacy in a proof-of-concept study setting where subjective pain outcome measures are often unreliable. Additionally, we provide evidence confirming the neural mechanism underpinning placebo analgesia as identified in acute experimental imaging studies in patients during the placebo arm of a clinical trial. We explore how brain penetrant active drugs potentially interact with this mechanism.Clinical Trial Registration: NCT0061015. [ABSTRACT FROM AUTHOR]

Background: Severe, persistent inguinal postherniorrhaphy pain (PIPP) is a debilitating condition that develops in 2-5% of patients. PIPP may be neuropathic in nature, yet the lesion in the peripheral nervous system has not been located. Most PIPP-patients demonstrate a tender point (TP) in the medial aspect of the inguinal region that triggers pain upon minimal pressure. As TPs may play a role in the pathophysiology of PIPP, the aim of this trial was to investigate the analgesic effects of local anaesthetic TP-blockade.Methods: A randomized, double-blind, placebo-controlled, crossover trial was performed in 14 PIPP-patients and six healthy volunteers. All participated in two sessions, seven days apart, receiving 10 ml of 0.25% bupivacaine or normal saline via an ultrasound-guided fascial plane block at the TP. The TP-area was used for pain assessments (at rest, on movement, with 100 kPa pressure-algometry) and quantitative sensory testing (pressure pain thresholds, thermal detection/pain thresholds, supra-threshold heat perception), before and after the TP-blockade.Results: The median (95% CI) reduction in pain was 63% (44.1 to 73.6%) after bupivacaine compared with 36% (11.6 to 49.7%; P=0.003) after placebo. Significant increases in cool detection (P=0.01) and pressure pain thresholds (P=0.009) with decreases in supra-threshold heat pain perception (P=0.003) were seen after bupivacaine only. In four out of six volunteers, increased thermal and evoked-pain thresholds after bupivacaine compared with placebo, was demonstrated.Conclusions: This trial demonstrates that peripheral afferent input from the TP-area is important for maintenance of spontaneous and evoked pain in PIPP.Clinical Trial Registration: NCT02065219. [ABSTRACT FROM AUTHOR]

Context Does octreotide reduce vomiting in cancer-associated bowel obstruction? Objectives To evaluate the net effect of adding octreotide or placebo to standardized therapies on the number of days free of vomiting for populations presenting with vomiting and inoperable bowel obstruction secondary to cancer or its treatment. Methods Twelve services enrolled people with advanced cancer presenting with vomiting secondary to bowel obstruction where surgery or anti-cancer therapies were not indicated immediately. In a double-blind study, participants were randomized to placebo or octreotide (600 μg/24 hours by infusion). Both arms received standardized supportive therapy (infusion of ranitidine [200 mg/24 hours], dexamethasone [8 mg/24 hours], and parenteral hydration [10–20 mL/kg/24 hours]). The primary outcome was patient-reported days free of vomiting at 72 hours. Results In a study that recruited to the numbers identified in its power calculation, 87 participants provided data at 72 hours (45, octreotide arm). Seventeen people (octreotide) and 14 (placebo) were free of vomiting for 72 hours ( P = 0.67). Mean days free of vomiting were 1.87 (SD 1.10; octreotide) and 1.69 (SD 1.15; placebo; P = 0.47). An adjusted multivariate regression of the incidence of vomiting over the study showed a reduced number of episodes of vomiting in the octreotide group (incidence rate ratio = 0.40; 95% CI: 0.19–0.86; P = 0.019); however, people in the octreotide arm were 2.02 times more likely to be administered hyoscine butylbromide ( P = 0.004), potentially reflecting increased colicky pain. Conclusion Although there was no reduction in the number of days free of vomiting, the multivariate analysis suggests that further study of somatostatin analogues in this setting is warranted. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether granulocyte colony-stimulating factor (G-CSG) affects endometrial thickness, implantation rates, and clinical pregnancy rates in routine, unselected IVF cycles. Design: Registered, individually randomized, two-group, parallel double-blinded placebo-controlled clinical trial. Setting: Academically affiliated private clinical and research center. Patient(s): 141 consecutive, unselected, consenting women with no history of renal disease, sickle cell disease, or malignancy who were undergoing IVF. Intervention(s): Sealed, numbered, opaque envelopes assigned 73 patients to receive G-CSF (Filgrastim, Amgen, 300 μg/1.0 mL) and 68 to receive placebo (saline). Main Outcome Measure(s): Endometrial thickness, clinical pregnancy, and embryo implantation rates. Result(s): The mean age for the whole study group was 39.59 ± 5.56 years (G-CSF: 39.79 ± 5.13 years; placebo: 39.38 ± 6.03 years). Endometrial thickness statistically significantly increased over the 5-day observation period for the whole group by approximately 1.36 mm. The increase in the G-CSF group was not statistically significantly different from the control group. Statistical models looking at treatment effects on clinical pregnancy and implantation rates demonstrated no effect of G-CSF treatment. There were no adverse events for either treatment group. Conclusion(s): In normal IVF patients, G-CSF does not affect endometrial thickness, implantation rates, or clinical pregnancy rates. Because these results were obtained in an older patient population, they may not necessarily apply to younger women. Clinical Trial Registration Number: NCT01202656. [ABSTRACT FROM AUTHOR]

Abstract: Context: Opioid therapy often shows insufficient efficacy and substantial adverse events in patients with advanced cancer. Objectives: To assess the efficacy of caffeine infusion as an adjuvant analgesic to opioid therapy in patients with advanced cancer. Methods: A double-blind, randomized, placebo-controlled trial was conducted in the palliative care wards of two teaching hospitals in South Korea. A total of 20 of 41 participants were assigned to the caffeine group and 21 to the placebo group. The participants received caffeine (200mg) or normal saline intravenously once a day for two days. The primary outcome was pain, which was measured using a 10-point rating scale. Other outcomes included drowsiness, confusion, nausea, sleep disturbance, fatigue, and sadness. Results: Three participants (two in the caffeine group and one in the placebo group) dropped out after the first intervention because of insomnia; thus, 38 participants completed the trial. Pain score was significantly lower in the caffeine group than in the placebo group after the second trial (P =0.038). The mean reduction in pain intensity in the caffeine group was 0.833 (95% confidence interval [CI] 0.601–1.066), whereas that in the placebo group was 0.350 (95% CI 0.168–0.532). Considering an improvement higher than 30% from baseline as the threshold value, drowsiness improved significantly in the caffeine group after the first trial (P =0.041). Adverse event rate did not differ between the two groups. Conclusion: Caffeine infusion significantly reduced pain and drowsiness, but the reduction did not reach clinical significance in patients with advanced cancer undergoing opioid therapy. Further investigations are warranted. [Copyright &y& Elsevier]

Objective To assess the efficacy and safety of tumor necrosis factor (TNF)-α inhibition with infliximab (IFX) in treating recurrent and disabling chronic sciatica pain associated with post-operative peridural lumbar fibrosis. Methods A double-blind, randomized, placebo controlled study randomized 35 patients presenting sciatica pain associated with post-operative peridural lumbar fibrosis to 2 groups: IFX ( n = 18), a single intravenous injection of 3 mg/kg IFX; and placebo n = 17), a single saline serum injection. The primary outcome was a 50% reduction in sciatica pain on visual analog scale (VAS) at day 10. Secondary outcomes were radicular and lumbar VAS pain at day 0 and radicular and lumbar VAS pain, Québec disability score, drug sparing effect and tolerance at days 10, 30, 90, and 180. Results At day 10, the placebo and IFX groups did not differ in the primary outcome (50% reduction in sciatica pain observed in 3 [17.6%] vs 5 [27.8%] patients, p = 0.69). The number of patients reaching the Patient Acceptable Symptom State for radicular pain was significantly higher in the placebo than IFX group after injection (12 [70.6%] vs 5 [27.8%], p = 0.01). The 2 groups were comparable for all other secondary outcomes. Conclusion Treatment with a single 3-mg/kg IFX injection for post-operative peridural lumbar fibrosis-associated sciatica pain does not significantly reduce radicular symptoms at day 10 after injection. [ABSTRACT FROM AUTHOR]