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- Long-term efficacy and tolerability of intranasal fentanyl in the treatment of breakthrough cancer pain. [JOURNAL ARTICLE]
- Support Care Cancer 2014 Oct 29.
The aim of the present study was to assess the long-term tolerability and efficacy of intranasal fentanyl (INFS) in opioid-tolerant patients with breakthrough cancer pain (BTP).A 6 months, observational, prospective, cohort study design was employed to follow advanced cancer patients with BTP receiving INFS under routine clinical practice. Eligible adult cancer patients suffering from BTP had been prescribed INFS at effective doses. Data were collected at T0 and at month intervals for six months. The principal outcomes were the evaluation of possible serious adverse effects with prolonged use of INFS, the efficacy of BTP treatment with INFS, the quality of sleep, the rate of INFS discontinuation, and reasons for that.Seventy-five patients were surveyed. Thirty-four patients (45.3 %) had a follow-up at 3 months, and twelve patients (16 %) were followed up at 6 months. The mean opioid doses, expressed as oral morphine equivalents, ranged 111-180 mg/day, while the mean INFS doses were 87-119 μg. Adverse effects were reported in a minority of patients and were considered to be associated with opioid therapy used for background pain. The quality of sleep significantly improved during the first 3-4 months. Finally, efficacy based on a general impression regarding the efficacy of INFS was good-excellent in most patients and statistically improved in time up to the third month.The long-term use of INFS in advanced cancer patients is effective and safe. No serious adverse effects were found up to six months of assessment. The level of quality of sleep and patients' satisfaction was relatively good, considering the advanced stage of disease.
- Naloxone-precipitated withdrawal causes an increase in impulsivity in morphine-dependent rats. [JOURNAL ARTICLE]
- Behav Pharmacol 2014 Oct 27.
Opiate dependence is associated with increased impulsivity in both humans and animals. Although the state of withdrawal appears to contribute to this effect, a causal relationship has not been shown. Here, we test whether precipitating withdrawal in morphine-dependent rats through naloxone can cause increased impulsivity. Rats were trained on a delay discounting task and then randomly assigned to either a dependent group that received a nightly 30 mg/kg subcutaneous dose of morphine or a naive group that received nightly saline. Once dependence was established, 2-day test delay discounting curves were determined 1 h after three doses of naloxone (0, 0.25, 0.5 mg/kg). In dependent rats both doses of naloxone caused increased preference for the small reward at short delays. Naloxone had no effect on delay discounting in naive rats. We conclude that precipitating withdrawal in dependent rats can cause increased impulsivity.
- Blockade and reversal of spinal morphine tolerance by P2X3 receptor antagonist. [JOURNAL ARTICLE]
- Behav Pharmacol 2014 Oct 27.
In recent years, studies have substantiated the view that P2X3 receptors play a part in the generation and transmission of purinergic signals in inflammatory and chronic neuropathic pain. Data have also been presented to suggest that the process of P2X3 receptor antagonism inhibits inflammatory hyperalgesia, involving the spinal opioid system. The aim of this study was to investigate the effect of the selective P2X3 receptor antagonist A-317491 on the development of antinociceptive tolerance to chronic morphine administration in mice. Daily systemic injection of A-317491 attenuated the morphine-induced antinociceptive tolerance to von Frey and thermal stimuli. Repeated morphine injections alone led to a significant rightward shift in the morphine dose-response curve compared with that with A-317491. A single dose of A-317491 also showed a reversal effect in morphine-tolerant mice. In a withdrawal test, co-administration of A-317491 and morphine also reduced the naloxone-induced withdrawal symptoms compared with the morphine-alone group. Thus, we propose that the P2X3 receptor is involved in the process of morphine antinociceptive tolerance and may be a new therapeutic target in the prevention of tolerance to morphine-induced antinociception.
- Pharmacological and toxicological profile of opioid-treated, chronic low back pain patients entering a mindfulness intervention randomized controlled trial. [JOURNAL ARTICLE]
- J Opioid Manag 2014 September/October; 10(5):323-335.
Refractory chronic low back pain (CLBP) often leads to treatment with long-term opioids. Our goal was to describe the pharmaco-toxicological profile of opioid-treated CLBP patients and identify potential areas for care optimization.Cross-sectional analysis.Outpatient primary care.CLBP patients prescribed ≥ 30 mg/d of morphine-equivalent dose (MED) for ≥3 months.Self-reported clinical, medication (verified) and substance use, and urine drug testing (UDT) data were collected.Participants (N = 35) were 51.8 ± 9.7 years old, 80 percent female with CLBP for 14.2 ± 10.1 years, treated with opioids for 7.9 ± 5.7 years, with severe disability (Oswestry Disability Index score: 66.7 ± 11.4), and average pain score of 5.6 ± 1.5 (0-10 rating scale). Participants reported using tobacco (N = 14), alcohol (N = 9) and illicit drugs or unprescribed medications (N = 10). On average, participants took 13.4 ± 6.8 daily medications, including 4.7 ± 1.8 pain-modulating and 4.7 ± 2.0 sedating medications. Among prescribed opioids, 57.1 percent were long-acting and 91.4 percent were short-acting, with a total of 144.5 ± 127.8 mg/d of MED. Sixteen participants were prescribed benzodiazepines and/or zolpidem/ zaleplon. Fifteen participants had UDT positive for illicit drugs or unprescribed medications; in addition, eight tested positive for alcohol and 19 for cotinine. Compared to those with negative UDTs, those with positive UDTs (N = 15) received lower daily "total" and "extended release" opioid doses, and were more likely to test positive for cotinine (p < 0.05).Study findings corroborate existing evidence for high medication burden and high likelihood of substance misuse among opioid-treated CLBP patients. Further research is needed to help understand causality and ways to optimize care and clinical outcomes.
- Addition of transversus abdominis plane block to patient controlled analgesia for laparoscopic high anterior resection improves analgesia, reduces opioid requirement and expedites recovery of bowel function. [JOURNAL ARTICLE]
- Ann R Coll Surg Engl 2014 Nov; 96(8):579-585.
Opioid sparing in postoperative pain management appears key in colorectal enhanced recovery. Transversus abdominis plane (TAP) blocks offer such an effect. This study aimed to quantify this effect on pain, opioid use and recovery of bowel function after laparoscopic high anterior resection.This was a retrospective analysis of prospective data on 68 patients. Patients received an epidural (n=24), intravenous morphine patient controlled analgesia (PCA, n=22) or TAP blocks plus PCA (n=22) determined by anaesthetist preference. Outcome measures were numerical pain scores (0-3), cumulative intravenous morphine dose and time to recovery of bowel function (passage of flatus or stool).There were no differences in patient characteristics, complications or extraction site. The TAP block group had lower pain scores (0.7 vs 1.36, p<0.001) and morphine requirements (8mg vs 15mg, p=0.01) than the group receiving PCA alone at 12 hours and 24 hours. Earlier passage of flatus (2.0 vs 2.7 vs 3.4 days, p=0.002), stool (3.1 vs 4.1 vs 5.5 days, p=0.04) and earlier discharge (4 vs 5 vs 6 days, p=0.02) were also seen.Use of TAP blocks was found to reduce pain and morphine use compared with PCA, expedite recovery of bowel function compared with PCA and epidural, and expedite hospital discharge compared with epidural.
- Postoperative analgesic effects of epidural administration of neostigmine alone or in combination with morphine in dogs undergoing orthopedic surgery of the pelvic limbs. [JOURNAL ARTICLE]
- Am J Vet Res 2014 Nov; 75(11):956-963.
Objective-To evaluate the postoperative analgesic effects of epidural administration of morphine and neostigmine, either alone or in combination, in dogs. Animals-30 dogs undergoing orthopedic surgery on a pelvic limb. Procedures-Anesthetic protocols were standardized. At the end of surgery, 10 dogs each received 1 of 3 epidural treatments: morphine (0.1 mg/kg), neostigmine (5 μg/kg), or morphine plus neostigmine (0.1 mg/kg and 5 μg/kg, respectively). Postoperative pain scores and the need for rescue analgesia were evaluated for 24 hours. Results-Pain scores were higher in the neostigmine group, compared with scores for the morphine-neostigmine group, at 2 and 24 hours after surgery and higher in the morphine group than in the morphine-neostigmine group at 2 and 4 hours. During 24 hours, rescue analgesia was provided for 4, 7, and 2 of 10 dogs each in the morphine, neostigmine, and morphine-neostigmine groups, respectively. The number of dogs given rescue analgesia was significantly different among groups at 2, 3, 4, and 6 hours after surgery. Dogs in the morphine and morphine-neostigmine groups had a lower probability of receiving rescue analgesia within 24 hours than did dogs in the neostigmine group. Conclusions and Clinical Relevance-When administered epidurally, morphine alone or in combination with neostigmine provided effective postoperative analgesia in most dogs after orthopedic surgery, whereas neostigmine alone did not. Findings for this study suggested a potential role for neostigmine as an adjuvant for epidural analgesia in dogs undergoing orthopedic surgeries on the pelvic limbs.
- Oral administration of morphine versus ibuprofen to manage postfracture pain in children: a randomized trial. [JOURNAL ARTICLE]
- CMAJ 2014 Oct 27.
Recent warnings from Health Canada regarding codeine for children have led to increased use of nonsteroidal anti-inflammatory drugs and morphine for common injuries such as fractures. Our objective was to determine whether morphine administered orally has superior efficacy to ibuprofen in fracture-related pain.We used a parallel group, randomized, blinded superiority design. Children who presented to the emergency department with an uncomplicated extremity fracture were randomly assigned to receive either morphine (0.5 mg/kg orally) or ibuprofen (10 mg/kg) for 24 hours after discharge. Our primary outcome was the change in pain score using the Faces Pain Scale - Revised (FPS-R). Participants were asked to record pain scores immediately before and 30 minutes after receiving each dose.We analyzed data from 66 participants in the morphine group and 68 participants in the ibuprofen group. For both morphine and ibuprofen, we found a reduction in pain scores (mean pre-post difference ± standard deviation for dose 1: morphine 1.5 ± 1.2, ibuprofen 1.3 ± 1.0, between-group difference [δ] 0.2 [95% confidence interval (CI) -0.2 to 0.6]; dose 2: morphine 1.3 ± 1.3, ibuprofen 1.3 ± 0.9, δ 0 [95% CI -0.4 to 0.4]; dose 3: morphine 1.3 ± 1.4, ibuprofen 1.4 ± 1.1, δ -0.1 [95% CI -0.7 to 0.4]; and dose 4: morphine 1.5 ± 1.4, ibuprofen 1.1 ± 1.2, δ 0.4 [95% CI -0.2 to 1.1]). We found no significant differences in the change in pain scores between morphine and ibuprofen between groups at any of the 4 time points (p = 0.6). Participants in the morphine group had significantly more adverse effects than those in the ibuprofen group (56.1% v. 30.9%, p < 0.01).We found no significant difference in analgesic efficacy between orally administered morphine and ibuprofen. However, morphine was associated with a significantly greater number of adverse effects. Our results suggest that ibuprofen remains safe and effective for outpatient pain management in children with uncomplicated fractures. Trial registration: ClinicalTrials.gov, no. NCT01690780.
- Quality of surgical care in hospitals providing internship training in Kenya. [JOURNAL ARTICLE]
- Trop Med Int Health 2014 Oct 28.
To evaluate services in hospitals providing internship training to graduate doctors in Kenya.A survey of 22 internship training hospitals. Availability of key resources spanning infrastructure, personnel, equipment, and drugs was assessed by observation. Outcomes and process of care for pre-specified priority conditions (head injury, chest injury, fractures, burns and acute abdomen) were evaluated by auditing case records.Each hospital had at least one consultant surgeon. Scheduled surgical outpatient clinics, major ward rounds and elective (half-day) theatre lists were provided once per week in 91%, 55% and 9% respectively. In all other hospitals these were conducted twice weekly. Basic drugs were not always available (eg. gentamicin, morphine and pethidine in 50%, injectable anti-staphyloccal penicillins 5% hospitals). Fewer than half of hospitals had all resources needed to provide oxygen. 145 of 956 cases evaluated underwent operations under general or spinal anaesthesia. We found operation notes for 99% and anaesthetic records for 72%. Pre-operatively measured vital signs were recorded in 80% of cases and evidence of consent to operation was found in 78%. Blood loss was documented in only one case and sponge and instrument counts in 7%.Evaluation of surgical services would be improved by development and dissemination of clear standards of care. This survey suggests that internship hospitals may be poorly equipped and documented care suggests inadequacies in quality and training. This article is protected by copyright. All rights reserved.
- Local anaesthetic infiltration at the end of carotid endarterectomy improves post-operative analgesia. [JOURNAL ARTICLE]
- Acta Anaesthesiol Scand 2014 Oct 28.
Wound infiltration at the end of carotid endarterectomy under general anaesthesia is a simple technique that can be delegated to the surgeon. It was hypothesised that this technique could improve early post-operative analgesia by reducing the need for post-operative opioids.Forty patients underwent carotid endarterectomy under general anaesthesia with desflurane and remifentanil supplemented with morphine for post-operative analgesia. In a prospective double-blinded randomised study, patients were allocated pre-operatively to receive either subcutaneous infiltration of both wound edges with 20 ml of 0.75% ropivacaine or infiltration with isotonic saline. The primary outcome was morphine consumption while in the post-anaesthesia care unit (PACU). Pain scores at rest and movement, sedation, and patient satisfaction were the other main outcomes used to assess post-operative analgesia.The median dose of morphine administered in the PACU was 2 mg [0-3] in the ropivacaine vs. 4 mg [3-6] in the placebo group (P = 0.0004, Mann-Whitney's test). Pain at rest and at movement was lower in the ropivacaine group throughout observation in the PACU. No difference was found for both pain and opioid consumption after discharge from the PACU or for patient satisfaction. Sedative events in the early post-operative period were less frequent in the ropivacaine group.Local anaesthetic wound infiltration performed before closure reduces the need for additional opioids, lowers the immediate post-operative pain and improves alertness. These results argue for the use of local infiltration anaesthesia for carotid endarterectomy.
- Analgesic Properties of a Peripherally-Acting GAL2 Receptor-Preferring Galanin Analog in Inflammatory, Neuropathic and Acute Pain Models. [JOURNAL ARTICLE]
- J Pharmacol Exp Ther 2014 Oct 27.
There are ongoing efforts to develop pain therapeutics with novel mechanisms of action that avoid common side effects associated with other analgesics. The anticonvulsant neuropeptide galanin is a potent regulator of neuronal excitability and has a well-established role in pain modulation, making it a potential target for novel therapies. Our previous efforts focused on improving blood-brain-barrier penetration and enhancing the metabolic stability of galanin analogs to protect against seizures. More recently, we designed peripherally-acting galanin analogs that reduce pain-related behaviors by acting in the periphery and exhibit preferential binding towards GAL2 over GAL1 galanin receptors. Here we report preclinical studies of a monodisperse oligoethylene glycol (dPEG)-containing galanin analog, NAX 409-9 (previously reported as Gal-R2-dPEG24 in Zhang et al., 2013), in rodent analgesic and safety models. Results obtained with NAX 409-9 in these tests were compared to the representative analgesics gabapentin, ibuprofen, acetylsalicylic acid, acetaminophen, and morphine. In mice that received intraplantar carrageenan, NAX 409-9 increased paw withdrawal latency with an ED50 of 6.6 mg/kg, i.p. NAX 409-9 also increased the paw withdrawal threshold to mechanical stimulation following partial sciatic nerve ligation in rats (2 mg/kg). Conversely, NAX 409-9 had no effect in the tail flick or hot plate assays (up to 24 mg/kg). Importantly, NAX 409-9 did not negatively affect gastrointestinal motility (4-20 mg/kg), respiratory rate (40-80 mg/kg), or bleed time (20 mg/kg). These studies illustrate that this non-brain-penetrating galanin analog reduces pain behaviors in several models and does not produce some of the dose-limiting toxicities associated with other analgesics.