Pre-emptive and preventive NSAIDs for postoperative pain in adults undergoing all types of surgery.

BACKGROUND: Postoperative pain is a common consequence of surgery and can have many negative perioperative effects. It has been suggested that the administration of analgesia before a painful stimulus may improve pain control. We defined pre-emptive nonsteroidal anti-inflammatories (NSAIDs) as those given before surgery but not continued afterwards and preventive NSAIDs as those given before surgery and continued afterwards. These were compared to a control group given the NSAIDs after surgery instead of before surgery. OBJECTIVES: To assess the efficacy of preventive and pre-emptive NSAIDs for reducing postoperative pain in adults undergoing all types of surgery. SEARCH METHODS: We searched the following electronic databases: CENTRAL, MEDLINE, Embase, AMED and CINAHL (up to June 2020). In addition, we searched for unpublished studies in three clinical trial databases, conference proceedings, grey literature databases, and reference lists of retrieved articles. We did not apply any restrictions on language or date of publication. SELECTION CRITERIA: We included parallel-group randomized controlled trials (RCTs) only. We included adult participants undergoing any type of surgery. We defined pre-emptive NSAIDs as those given before surgery but not continued afterwards and preventive NSAIDs as those given before surgery and continued afterwards. These were compared to a control group given the NSAIDs after surgery instead of before surgery. We included studies that gave the medication by any route but not given on the skin. DATA COLLECTION AND ANALYSIS: We used the standard methods expected by Cochrane, as well as a novel publication bias test developed by our research group. We used GRADE to assess the certainty of the evidence for each outcome. Outcomes included acute postoperative pain (minimal clinically important difference (MCID): 1.5 on a 0-10 scale), adverse events of NSAIDs, nausea and vomiting, 24-hour morphine consumption (MCID: 10 mg reduction), time to analgesic request (MCID: one hour), pruritus, sedation, patient satisfaction, chronic pain and time to first bowel movement (MCID: 12 hours). MAIN RESULTS: We included 71 RCTs. Seven studies are awaiting classification. We included 45 studies that evaluated pre-emptive NSAIDs and 26 studies that evaluated preventive NSAIDs. We considered only four studies to be at low risk of bias for most domains. The operations and NSAIDs used varied, although most studies were conducted in abdominal, orthopaedic and dental surgery. Most studies were conducted in secondary care and in low-risk participants. Common exclusions were participants on analgesic medications prior to surgery and those with chronic pain. Pre-emptive NSAIDs compared to post-incision NSAIDs For pre-emptive NSAIDs, there is probably a decrease in early acute postoperative pain (MD -0.69, 95% CI -0.97 to -0.41; studies = 36; participants = 2032; I2 = 96%; moderate-certainty evidence). None of the included studies that reported on acute postoperative pain reported adverse events as an outcome. There may be little or no difference between the groups in short-term (RR 1.00, 95% CI 0.34 to 2.94; studies = 2; participants = 100; I2 = 0%; low-certainty evidence) or long-term nausea and vomiting (RR 0.85, 95% CI 0.52 to 1.38; studies = 5; participants = 228; I2 = 29%; low-certainty evidence). There may be a reduction in late acute postoperative pain (MD -0.22, 95% CI -0.44 to 0.00; studies = 28; participants = 1645; I2 = 97%; low-certainty evidence). There may be a reduction in 24-hour morphine consumption with pre-emptive NSAIDs (MD -5.62 mg, 95% CI -9.00 mg to -2.24 mg; studies = 16; participants = 854; I2 = 99%; low-certainty evidence) and an increase in the time to analgesic request (MD 17.04 minutes, 95% CI 3.77 minutes to 30.31 minutes; studies = 18; participants = 975; I2 = 95%; low-certainty evidence). There may be little or no difference in opioid adverse events such as pruritus (RR 0.40, 95% CI 0.09 to 1.76; studies = 4; participants = 254; I2 = 0%; low-certainty evidence) or sedation (RR 0.51, 95% CI 0.16 to 1.68; studies = 4; participants = 281; I2 = 0%; low-certainty evidence), although the number of included studies for these outcomes was small. No study reported patient satisfaction, chronic pain or time to first bowel movement for pre-emptive NSAIDs. Preventive NSAIDs compared to post-incision NSAIDs For preventive NSAIDs, there may be little or no difference in early acute postoperative pain (MD -0.14, 95% CI -0.39 to 0.12; studies = 18; participants = 1140; I2 = 75%; low-certainty evidence). One study reported adverse events from NSAIDs (reoperation for bleeding) although the events were low which did not allow any meaningful conclusions to be drawn (RR 1.95; 95% CI 0.18 to 20.68). There may be little or no difference in rates of short-term (RR 1.26, 95% CI 0.49 to 3.30; studies = 1; participants = 76; low-certainty evidence) or long-term (RR 0.85, 95% CI 0.52 to 1.38; studies = 5; participants = 456; I2 = 29%; low-certainty evidence) nausea and vomiting. There may be a reduction in late acute postoperative pain (MD -0.33, 95% CI -0.59 to -0.07; studies = 21; participants = 1441; I2 = 81%; low-certainty evidence). There is probably a reduction in 24-hour morphine consumption (MD -1.93 mg, 95% CI -3.55 mg to -0.32 mg; studies = 16; participants = 1323; I2 = 49%; moderate-certainty evidence). It is uncertain if there is any difference in time to analgesic request (MD 8.51 minutes, 95% CI -31.24 minutes to 48.27 minutes; studies = 8; participants = 410; I2 = 98%; very low-certainty evidence). As with pre-emptive NSAIDs, there may be little or no difference in other opioid adverse events such as pruritus (RR 0.56, 95% CI 0.09 to 3.35; studies = 3; participants = 211; I2 = 0%; low-certainty evidence) and sedation (RR 0.84, 95% CI 0.44 to 1.63; studies = 5; participants = 497; I2 = 0%; low-certainty evidence). There is probably little or no difference in patient satisfaction (MD -0.42; 95% CI -1.09 to 0.25; studies = 1; participants = 72; moderate-certainty evidence). No study reported on chronic pain. There is probably little or no difference in time to first bowel movement (MD 0.00; 95% CI -15.99 to 15.99; studies = 1; participants = 76; moderate-certainty evidence). AUTHORS' CONCLUSIONS: There was some evidence that pre-emptive and preventive NSAIDs reduce both pain and morphine consumption, although this was not universal for all pain and morphine consumption outcomes. Any differences found were not clinically significant, although we cannot exclude this in more painful operations. Moreover, without any evidence of reductions in opioid adverse effects, the clinical significance of these results is questionable although few studies reported these outcomes. Only one study reported clinically significant adverse events from NSAIDs administered before surgery and, therefore, we have very few data to assess the safety of either pre-emptive or preventive NSAIDs. Therefore, future research should aim to adhere to the highest methodology and be adequately powered to assess serious adverse events of NSAIDs and reductions in opioid adverse events.

Peptide Mimetic of BDNF Loop 4 Blocks Behavioral Signs of Morphine Withdrawal Syndrome and Prevents the Increase in ΔFosB Level in the Striatum of Rats.

Activity of compound GSB-106, a low-molecular mimetic of loop 4 of the brain neurotrophic factor (BDNF), was studied in experimental morphine withdrawal syndrome simulated in outbred rats. Single and subchronic (5 intraperitoneal injections) administration of GSB-106 in a dose of 0.1 mg/kg significantly reduced the total index of morphine withdrawal syndrome by 55.2 and 45.6%, respectively. GSB-106 reduced the severity of some behavioral signs (piloerection, gnashing of teeth, wet-dog shaking, and runaway attempts), but had no effect on mechanical allodynia formed in the rats with dependence. Subchronic treatment with GSB-106 prevented the increase in the content of ΔFosB (product of early response gene) in the striatum induced by morphine withdrawal. The results confirmed the concept on the involvement of neurotrophins, specifically BDNF and its analogs, in the mechanisms associated with the formation of opiate dependence.

Oxycodone for cancer-related pain.

BACKGROUND: Many people with cancer experience moderate to severe pain that requires treatment with strong opioids, such as oxycodone and morphine. Strong opioids are, however, not effective for pain in all people, neither are they well-tolerated by all people. The aim of this review was to assess whether oxycodone is associated with better pain relief and tolerability than other analgesic options for adults with cancer pain. This is an updated version of the original Cochrane review published in 2015, Issue 2 on oxycodone for cancer-related pain. OBJECTIVES: To assess the effectiveness and tolerability of oxycodone by any route of administration for pain in adults with cancer. SEARCH METHODS: For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE and MEDLINE In-Process (Ovid), Embase (Ovid), Science Citation Index, Conference Proceedings Citation Index - Science (ISI Web of Science), BIOSIS (ISI), and PsycINFO (Ovid) to November 2016. We also searched four trial registries, checked the bibliographic references of relevant studies, and contacted the authors of the included studies. We applied no language, date, or publication status restrictions. SELECTION CRITERIA: We included randomised controlled trials (parallel group or cross-over) comparing oxycodone (any formulation or route of administration) with placebo or an active drug (including oxycodone) for cancer background pain in adults by examining pain intensity/relief, adverse events, quality of life, and participant preference. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the included studies using standard Cochrane methodology. We meta-analysed pain intensity data using the generic inverse variance method, and adverse events using the Mantel-Haenszel method, or summarised these data narratively along with the quality of life and participant preference data. We assessed the overall quality of the evidence using GRADE. MAIN RESULTS: For this update, we identified six new studies (1258 participants) for inclusion. In total, we included 23 studies which enrolled/randomised 2648 participants, with 2144 of these analysed for efficacy and 2363 for safety. The studies examined a number of different drug comparisons.Pooled analysis of three of the four studies comparing controlled-release (CR) oxycodone to immediate-release (IR) oxycodone showed that the ability of CR and IR oxycodone to provide pain relief were similar (standardised mean difference (SMD) 0.1, 95% confidence interval (CI) -0.06 to 0.26; low quality evidence). Pooled analyses of adverse events showed no significant differences between CR and IR oxycodone for asthenia (risk ratio (RR) 0.58, 95% CI 0.2 to 1.68), confusion (RR 0.78, 95% CI 0.2 to 3.02), constipation (RR 0.71, 95% CI 0.45 to 1.13), dizziness/lightheadedness (RR 0.74, 95% CI 0.4 to 1.37), drowsiness/somnolence (RR 1.03, 95% CI 0.69 to 1.54), dry mouth (RR 1.14, 95% CI 0.48 to 2.75), insomnia (RR 1.04, 95% CI 0.31 to 3.53), nausea (RR 0.85, 95% CI 0.56 to 1.28), nervousness (RR 0.57, 95% CI 0.2 to 1.64), pruritus (RR 1.46, 95% CI 0.65 to 3.25), vomiting (RR 0.66, 95% CI 0.38 to 1.15), and discontinuation due to adverse events (RR 0.6, 95% CI 0.29 to 1.22). The quality of the evidence was very low for all these adverse events. Three of the four studies found similar results for treatment acceptability.Pooled analysis of seven of the nine studies comparing CR oxycodone to CR morphine indicated that pain relief was significantly better after treatment with CR morphine than CR oxycodone (SMD 0.14, 95% CI 0.01 to 0.27; low quality evidence). However, sensitivity analysis did not corroborate this result (SMD 0.12, 95% CI -0.02 to 0.26).Pooled analyses of adverse events showed no significant differences between CR oxycodone and CR morphine for confusion (RR 1.01 95% CI 0.78 to 1.31), constipation (RR 0.98, 95% CI 0.82 to 1.16), dizziness/lightheadedness (RR 0.76, 95% CI 0.33 to 1.76), drowsiness/somnolence (RR 0.9, 95% CI 0.75 to 1.08), dry mouth (RR 1.01, 95% CI 0.8 to 1.26), dysuria (RR 0.71, 95% CI 0.4 to 1.26), nausea (RR 1.02, 95% CI 0.82 to 1.26), pruritus (RR 0.81, 95% CI 0.51 to 1.29), vomiting (RR 0.94, 95% CI 0.68 to 1.29), and discontinuation due to adverse events (RR 1.06, 95% CI 0.43 to 2.6). However, the RR for hallucinations was significantly lower after treatment with CR oxycodone compared to CR morphine (RR 0.52, 95% CI 0.28 to 0.97). The quality of the evidence was very low for all these adverse events. There were no marked differences in treatment acceptability or quality of life ratings.The remaining studies either compared oxycodone in various formulations or compared oxycodone to different alternative opioids. None found any clear superiority or inferiority of oxycodone for cancer pain, neither as an analgesic agent nor in terms of adverse event rates and treatment acceptability.The quality of this evidence base was limited by the high or unclear risk of bias of the studies and by imprecision due to low or very low event rates or participant numbers for many outcomes. AUTHORS' CONCLUSIONS: The conclusions have not changed since the previous version of this review. The data suggest that oxycodone offers similar levels of pain relief and overall adverse events to other strong opioids including morphine. Although we identified a clinically insignificant benefit on pain relief in favour of CR morphine over CR oxycodone, this did not persist following sensitivity analysis and so we do not consider this important. However, in this updated analysis, we found that hallucinations occurred less often with CR oxycodone than with CR morphine, but the quality of this evidence was very low so this finding should be treated with utmost caution. Our conclusions are consistent with other reviews and suggest that while the reliability of the evidence base is low, given the absence of important differences within this analysis it seems unlikely that larger head to head studies of oxycodone versus morphine are justified, although well-designed trials comparing oxycodone to other strong analgesics may well be useful. For clinical purposes, oxycodone or morphine can be used as first-line oral opioids for relief of cancer pain in adults.

Intrathecal Catheterization and Drug Delivery in Guinea Pigs: A Small-animal Model for Morphine-evoked Granuloma Formation.

BACKGROUND: Intrathecal infusion of opioids in dogs, sheep, and humans produces local space-occupying masses. To develop a small-animal model, the authors examined effects of intrathecal catheterization and morphine infusion in guinea pigs. METHODS: Under isoflurane, polyethylene or polyurethane catheters were advanced from the cisterna magna to the lumbar enlargement. Drugs were delivered as a bolus through the externalized catheter or continuously by subcutaneous minipumps. Hind paw withdrawal to a thermal stimulus was assessed. Spinal histopathology was systematically assessed in a blinded fashion. To assist in determining catheter placement, ex vivo images were obtained using magnetic resonance imaging in several animals. Canine spinal tissue from previous intrathecal morphine studies was analyzed in parallel. RESULTS: (1) Polyethylene (n = 30) and polyurethane (n = 25) catheters were implanted in the lumbar intrathecal space. (2) Bolus intrathecal morphine produced a dose-dependent (20 to 40 µg/10 µl) increase in thermal escape latencies. (3) Absent infusion, a catheter-associated distortion of the spinal cord and a fibrotic investment were noted along the catheter tract (polyethylene > polyurethane). (4) Intrathecal morphine infusion (25 mg/ml/0.5 µl/h for 14 days) resulted in intrathecal masses (fibroblasts, interspersed collagen, lymphocytes, and macrophages) arising from meninges proximal to the catheter tip in both polyethylene- and polyurethane-catheterized animals. This closely resembles mass histopathology from intrathecal morphine canine studies. CONCLUSIONS: Continuous intrathecal infusion of morphine leads to pericatheter masses that morphologically resemble those observed in dogs and humans. This small-animal model may be useful for studying spinal drug toxicology in general and the biology of intrathecal granuloma formation in particular.

Oral Sedation Postdischarge Adverse Events in Pediatric Dental Patients.

The study investigated patient discharge parameters and postdischarge adverse events after discharge among children who received oral conscious sedation for dental treatment. This prospective study involved 51 patients needing dental treatment under oral conscious sedation. Each patient received one of various regimens involving combinations of a narcotic (ie, morphine or meperidine), a sedative-hypnotic (ie, chloral hydrate), a benzodiazepine (ie, midazolam or diazepam), and/or an antihistamine (ie, hydroxyzine HCl). Nitrous oxide and local anesthesia were used in conjunction with all regimens. After written informed consent was obtained, each guardian was contacted by phone with specific questions in regard to adverse events following the dental appointment. Out of 51 sedation visits, 46 were utilized for analysis including 23 boys and 23 girls ranging from 2 years 2 months to 10 years old (mean 5.8 years). 60.1% of patients slept in the car on the way home, while 21.4% of that group was difficult to awaken upon reaching home. At home, 76.1% of patients slept; furthermore, 85.7% of patients who napped following the dental visit slept longer than usual. After the appointment, 19.6% exhibited nausea, 10.1% vomited, and 7.0% experienced a fever. A return to normal behavior was reported as follows: 17.4% in <2 hours, 39.1% in 2-6 hours, 28.3% in 6-10 hours, and 15.2% in >10 hours. Postdischarge excessive somnolence, nausea, and emesis were frequent complications. The time to normality ranged until the following morning demonstrating the importance of careful postdischarge adult supervision.

Impact of morphine, fentanyl, oxycodone or codeine on patient consciousness, appetite and thirst when used to treat cancer pain.

BACKGROUND: There is increasing focus on providing high quality care for people at the end of life, irrespective of disease or cause, and in all settings. In the last ten years the use of care pathways to aid those treating patients at the end of life has become common worldwide. The use of the Liverpool Care Pathway in the UK has been criticised. In England the LCP was the subject of an independent review, commissioned by a Health Minister. The Neuberger Review acknowledged that the LCP was based on the sound ethical principles that provide the basis of good quality care for patients and families when implemented properly. It also found that the LCP often was not implemented properly, and had instead become a barrier to good care; it made over 40 recommendations, including education and training, research and development, access to specialist palliative care services, and the need to ensure care and compassion for all dying patients. In July 2013, the Department of Health released a statement that stated the use of the LCP should be "phased out over the next 6-12 months and replaced with an individual approach to end of life care for each patient".The impact of opioids was a particular concern because of their potential influence on consciousness, appetite and thirst in people near the end of life. There was concern that impaired patient consciousness may lead to an earlier death, and that effects of opioids on appetite and thirst may result in unnecessary suffering. This rapid review, commissioned by the National Institute for Health Research, used standard Cochrane methodology to examine adverse effects of morphine, fentanyl, oxycodone, and codeine in cancer pain studies as a close approximation to possible effects in the dying patient. OBJECTIVES: To determine the impact of opioid treatment on patient consciousness, appetite and thirst in randomised controlled trials of morphine, fentanyl, oxycodone or codeine for treating cancer pain. SEARCH METHODS: We assessed adverse event data reported in studies included in current Cochrane reviews of opioids for cancer pain: specifically morphine, fentanyl, oxycodone, and codeine. SELECTION CRITERIA: We included randomised studies using multiple doses of four opioid drugs (morphine, fentanyl, oxycodone, and codeine) in cancer pain. These were taken from four existing or ongoing Cochrane reviews. Participants were adults aged 18 and over. We included only full journal publication articles. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted adverse event data, and examined issues of study quality. The primary outcomes sought were numbers of participants experiencing adverse events of reduced consciousness, appetite, and thirst. Secondary outcomes were possible surrogate measures of the primary outcomes: delirium, dizziness, hallucinations, mood change and somnolence relating to patient consciousness, and nausea, vomiting, constipation, diarrhoea, dyspepsia, dysphagia, anorexia, asthenia, dehydration, or dry mouth relating to appetite or thirst.Comparative measures of harm were known to be unlikely, and we therefore calculated the proportion of participants experiencing each of the adverse events of interest with each opioid, and for all four opioid drugs combined. MAIN RESULTS: We included 77 studies with 5619 randomised participants. There was potential bias in most studies, with small size being the most common; individual treatment groups had fewer than 50 participants in 60 studies. Participants were relatively young, with mean age in the studies typically between 50 and 70 years. Multiple major problems with adverse event reporting were found, including failing to report adverse events in all participants who received medication, all adverse events experienced, how adverse events were collected, and not defining adverse event terminology or whether a reporting system was used.Direct measures of patient consciousness, patient appetite, or thirst were not apparent. For opioids used to treat cancer pain adverse event incidence rates were 25% for constipation, 23% for somnolence, 21% for nausea, 17% for dry mouth, and 13% for vomiting, anorexia, and dizziness. Asthenia, diarrhoea, insomnia, mood change, hallucinations and dehydration occurred at incidence rates of 5% and below. AUTHORS' CONCLUSIONS: We found no direct evidence that opioids affected patient consciousness, appetite or thirst when used to treat cancer pain. However, somnolence, dry mouth, and anorexia were common adverse events in people with cancer pain treated with morphine, fentanyl, oxycodone, or codeine.We are aware that there is an important literature concerning the problems that exist with adverse event measurement, reporting, and attribution. Together with the known complications concerning concomitant medication, data collection and reporting, and nomenclature, this means that these adverse events cannot always be attributed unequivocally to the use of opioids, and so they provide only a broad picture of adverse events with opioids in cancer pain. The research agenda includes developing definitions for adverse events that have a spectrum of severity or importance, and the development of appropriate measurement tools for recording such events to aid clinical practice and clinical research.

Effects of oral morphine on experimentally evoked itch and pain: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Pain and itch share similar neuronal networks; hence, it is difficult to explain why opioids can relieve pain but provoke itching. The present human volunteer study aimed to investigate the similarities and differences in responses to experimentally provoked pain and itching to explore the underlying fundamental mechanisms. METHODS: Twenty-four healthy volunteers were enrolled in this single-center, randomized, double-blind, placebo-controlled, parallel-group trial. Three volar forearms and two mandibular areas were marked, and participants randomly received morphine (20 mg) or identical placebo tablets. Heat, cold, and pressure pain thresholds, and vasomotor responses were assessed at baseline and after oral morphine administration. Itch provocations were induced by intradermal application of 1 % histamine or a topical cowhage (non-histaminergic itch) to a marked area of the skin. The participants were subsequently asked to rate their itching and pain intensities. The assessments were repeated for all marked areas. RESULTS: Morphine caused analgesia, as assessed by the significant modulation of cold and pressure pain thresholds (p<0.05). There were no significant differences in histaminergic or non-histaminergic itch or pain intensity between the morphine and placebo groups. Superficial blood perfusion (vasomotor response) following histamine provocation was significantly increased by morphine (p<0.05) in both areas. No correlation was found between the provoked itch intensity and analgesic efficacy in any area or group. CONCLUSIONS: Oral administration of morphine caused analgesia without modulating itch intensities but increased neurogenic inflammation in response to histamine, suggesting that different opioid mechanisms in histaminergic and non-histaminergic neurons evoke neurogenic inflammation.

Minocycline alleviates the symptoms of morphine withdrawal via the CaMKII-Ras-ERK signaling pathway.

OBJECTIVE: To investigate the effect of minocycline on morphine withdrawal symptoms. METHODS: We established a rat model of morphine dependence, then injected the animals with naloxone to induce withdrawal symptoms. Minocycline was injected into the midbrain periaqueductal gray and its effect on withdrawal symptoms and Ca2+-dependent protein kinase (CaMKII), Ras, and phospho-extracellular signal-regulated kinase (p-ERK) expression was observed. RESULTS: Minocycline inhibited withdrawal symptoms such as "wet dog" shakes, teeth chatter, and ptosis, perhaps by inhibiting the activation of microglia and the expression of CaMKII, Ras, and p-ERK. Minocycline had no effect on the behavior of control rats or on CaMKII, Ras, or p-ERK expression. CONCLUSION: Minocycline alleviates morphine withdrawal symptoms by inhibiting the activation of microglia and downregulating the expression of CaMKII, Ras, and p-ERK.

Morphine withdrawal produces circadian rhythm alterations of clock genes in mesolimbic brain areas and peripheral blood mononuclear cells in rats.

Previous studies have shown that clock genes are expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus, other brain regions, and peripheral tissues. Various peripheral oscillators can run independently of the SCN. However, no published studies have reported changes in the expression of clock genes in the rat central nervous system and peripheral blood mononuclear cells (PBMCs) after withdrawal from chronic morphine treatment. Rats were administered with morphine twice daily at progressively increasing doses for 7 days; spontaneous withdrawal signs were recorded 14 h after the last morphine administration. Then, brain and blood samples were collected at each of eight time points (every 3 h: ZT 9; ZT 12; ZT 15; ZT 18; ZT 21; ZT 0; ZT 3; ZT 6) to examine expression of rPER1 and rPER2 and rCLOCK. Rats presented obvious morphine withdrawal signs, such as teeth chattering, shaking, exploring, ptosis, and weight loss. In morphine-treated rats, rPER1 and rPER2 expression in the SCN, basolateral amygdala, and nucleus accumbens shell showed robust circadian rhythms that were essentially identical to those in control rats. However, robust circadian rhythm in rPER1 expression in the ventral tegmental area was completely phase-reversed in morphine-treated rats. A blunting of circadian oscillations of rPER1 expression occurred in the central amygdala, hippocampus, nucleus accumbens core, and PBMCs and rPER2 expression occurred in the central amygdala, prefrontal cortex, nucleus accumbens core, and PBMCs in morphine-treated rats compared with controls. rCLOCK expression in morphine-treated rats showed no rhythmic change, identical to control rats. These findings indicate that withdrawal from chronic morphine treatment resulted in desynchronization from the SCN rhythm, with blunting of rPER1 and rPER2 expression in reward-related neurocircuits and PBMCs.

Continuous infusion of butorphanol combined with intravenous morphine patient-controlled analgesia after total abdominal hysterectomy: a randomized, double-blind controlled trial.

BACKGROUND AND OBJECTIVE: Postoperative pain therapy is still a problem for clinicians. Continuous basal infusion of drugs combined with standard patient-controlled analgesia (PCA) is considered to be an effective means of postoperative acute pain management. This study was designed to investigate the analgesic efficacy, morphine-sparing effects and side effects of butorphanol delivered as a continuous infusion adjunct to intravenous morphine PCA after abdominal hysterectomy. METHODS: One hundred and eighty-six ASA physical status I-II patients, undergoing total abdominal hysterectomy, were allocated to this randomized double-blind controlled study and assigned to one of two groups. In the butorphanol (n = 96) group, patients received an intravenous loading dose of 10 microg kg(-1) butorphanol followed by infusion of 2 microg kg(-1) h(-1) butorphanol combined with intravenous PCA set at a bolus of 0.02 mg kg(-1) morphine after surgery. The control group (n = 90) received a physiological saline infusion combined with the same morphine PCA. Pain intensity on movement and at rest, sedation, satisfaction with analgesia, morphine consumption and side effects were recorded. RESULTS: A total of 164 patients completed the study. The butorphanol group had analgesia superior to the physiological saline control (P < 0.001). The butorphanol infusion group produced higher sedation ratings (P < 0.001) and better satisfaction (P < 0.05) and a lower incidence of side effects (P < 0.001) with the exception of sweating and dry mouth (P < 0.05) than the physiological saline group. The butorphanol group consumed less morphine over 48 h, 24.6 mg (95% confidence interval, 18.7-46.6), than the physiological saline group, 58.5 mg (95% confidence interval, 41.5-79.2; P = 0.006). There were no differences between urinary catheterization of more than 24 h, first time out of bed and time to discharge to home. CONCLUSION: Basal infusion of butorphanol combined with intravenous morphine PCA in patients undergoing abdominal hysterectomy shows effective analgesia with sedation and fewer side effects.

[Comparison of the peripheral and central effects of opiates after iliac crest transplants. Reconstruction of severely atrophied maxilla]. / Vergleich der peripheren und zentralen Opiatwirkung bei Beckenkammtransplantaten. Rekonstruktion eines hoch atrophen Oberkiefers.

PURPOSE: Severe pain is one of the main problems after harvesting iliac crest transplants. In this randomized double-blind study differences in the peripheral and central effects of opiates for pain treatment in the iliac crest region after augmentation of the severely resorbed maxilla were examined. MATERIALS AND METHODS: In 20 consecutive patients with severe atrophy of the edentulous maxilla, augmentation was performed with the use of iliac crest transplants. In 10 patients a gelatine sponge soaked with a 10 mg morphine hydrochloride solution was placed in the iliac region after harvesting the transplant ipsilaterally for local opiate therapy. In the control group the same opiate was injected into the contralateral glutaeus maximus muscle for systemic therapy. Both groups were followed up for pain intensity every 2 h during the first 48 h and 3 times a day from postoperative days 3-10. Thereafter the patients were followed up 1, 3, 6 and 12 months postoperatively. At each time of control the VAS score, as well as the quality of pain with and without movement and the consumption of NSAIDs were registered. RESULTS: Lower pain values were registered in the control group within the early postoperative period, whereas the mean VAS score was less from postoperative days 3-10 in the study group (2.3 compared to 1.3 VAS). The consumption of NSAIDs corresponded to the pain scores in both groups during the control periods. There were no statistically significant differences for long term results at 1, 3, 6 and 12 months postoperatively. CONCLUSIONS: The effect of centrally given opiates is more effective in the early postoperative period. In the early rehabilitation period the effect of intraoperatively local peripherally placed opiates is superior to intraoperatively centrally administered opiates.

Intra-incisional liposomal bupivacaine and its impact on postcesarean analgesia: a retrospective study.

PURPOSE: The efficacy of long-acting intraincisional bupivacaine in reducing postoperative opioid use among women who have undergone a cesarean is currently unknown. MATERIALS AND METHODS: This was a retrospective case-control study with a 1:1 allocation. We identified 40 patients in each group, for a total of 80. The treatment group was administered 266 mg of liposomal bupivacaine after completion of the cesarean and was compared to historical controls. Data regarding anesthesia administered, opioid consumption, nonsteroidal anti-inflammatory use, acetaminophen use, type of cesarean, reason for cesarean, and length of postoperative stay were recorded. RESULTS: The treatment group used 41.51 mg of morphine equivalents, while the control group consumed 69.90 mg (p < .001); multivariate analysis demonstrated a mean difference of 26.52 mg (95%CI 12.76-40.28). Univariate analysis demonstrated mean difference in intravenous (IV) ketorolac (40.77 mg, p < .001) and IV acetaminophen (1333.33 mg, p < .001) was different and greater in the treatment group; this was controlled for in the multivariate model. There was no difference in oral and IV ibuprofen or oral acetaminophen use between groups. There were no differences between the type of anesthesia, length of stay, reason for cesarean, and classical sections between groups. CONCLUSIONS: Incisional administration of liposomal bupivacaine may be an effective adjunct in reducing opioid use postoperatively and may be a useful adjunct within an enhanced recovery program.

Naloxegol for opioid-induced sphincter of Oddi spasm/dysfunction.

The paper describes a case report of a patient with a significant history of opioid-induced dysfunction of the sphincter of Oddi, who required morphine sulfate to manage oral mucositis pain, and who was successfully treated with concomitant oral naloxegol (Moventig: Kyowa Kirin, Galashiels, UK).

Morphine, gabapentin, or their combination for neuropathic pain.

BACKGROUND: The available drugs to treat neuropathic pain have incomplete efficacy and dose-limiting adverse effects. We compared the efficacy of a combination of gabapentin and morphine with that of each as a single agent in patients with painful diabetic neuropathy or postherpetic neuralgia. METHODS: In this randomized, double-blind, active placebo-controlled, four-period crossover trial, patients received daily active placebo (lorazepam), sustained-release morphine, gabapentin, and a combination of gabapentin and morphine--each given orally for five weeks. The primary outcome measure was mean daily pain intensity in patients receiving a maximal tolerated dose; secondary outcomes included pain (rated according to the Short-Form McGill Pain Questionnaire), adverse effects, maximal tolerated doses, mood, and quality of life. RESULTS: Of 57 patients who underwent randomization (35 with diabetic neuropathy and 22 with postherpetic neuralgia), 41 completed the trial. Mean daily pain (on a scale from 0 to 10, with higher numbers indicating more severe pain) at a maximal tolerated dose of the study drug was as follows: 5.72 at baseline, 4.49 with placebo, 4.15 with gabapentin, 3.70 with morphine, and 3.06 with the gabapentin-morphine combination (P<0.05 for the combination vs. placebo, gabapentin, and morphine). Total scores on the Short-Form McGill Pain Questionnaire (on a scale from 0 to 45, with higher numbers indicating more severe pain) at a maximal tolerated dose were 14.4 with placebo, 10.7 with gabapentin, 10.7 with morphine, and 7.5 with the gabapentin-morphine combination (P<0.05 for the combination vs. placebo, gabapentin, and morphine). The maximal tolerated doses of morphine and gabapentin were lower (P<0.05) with the combination than for each drug as single agent. At the maximal tolerated dose, the gabapentin-morphine combination resulted in a higher frequency of constipation than gabapentin alone (P<0.05) and a higher frequency of dry mouth than morphine alone (P<0.05). CONCLUSIONS: Gabapentin and morphine combined achieved better analgesia at lower doses of each drug than either as a single agent, with constipation, sedation, and dry mouth as the most frequent adverse effects.

The analgesic efficacy and safety of a novel intranasal morphine formulation (morphine plus chitosan), immediate release oral morphine, intravenous morphine, and placebo in a postsurgical dental pain model.

BACKGROUND: Opioids are standard treatment for postoperative pain. In this study, we compared the safety and efficacy of intranasal (i.n.) morphine to i.v. and oral morphine and placebo. METHODS: Two-hundred-twenty-five patients with moderate-to-severe pain after third molar extraction were randomized to receive a single dose of i.n. morphine 7.5 mg or 15 mg, i.v. morphine 7.5 mg, oral morphine 60 mg or placebo. Pain intensity was assessed using visual analog and categorical scales, and pain relief using a categorical scale. Outcomes included total pain relief, pain intensity difference, summed pain intensity difference, time to analgesic onset, time to requesting rescue medication, and patients' global evaluation of their treatment. Safety assessments included adverse event recording and nasal examinations. RESULTS: Across the various efficacy outcomes, both i.n. morphine doses were statistically similar to the positive comparators (i.v. and oral morphine), and all four morphine treatments were statistically superior to placebo. Overall, i.n. morphine 15 mg presented an efficacy profile similar to i.v. morphine 7.5 mg; both treatments demonstrated rapid onset of efficacy, generally persistent throughout the 6-h assessment period. The lower dose of i.n. morphine, 7.5 mg, was statistically similar to the other active treatments at 2 h and 6 h and similar to placebo at 4 h. Study medications were generally well tolerated, with no withdrawals due to adverse events or other safety concerns, and no serious adverse events reported. The most frequently reported adverse events were typical systemic opioid effects. CONCLUSIONS: I.n. morphine offers a noninvasive alternative to i.v. morphine for postoperative analgesia.

Mirtazapine, a noradrenergic and specific serotonergic antidepressant, attenuates morphine dependence and withdrawal in Sprague-Dawley rats.

The effects of mirtazapine, a noradrenergic and specific serotonergic antidepressant, on morphine withdrawal and morphine conditioned place preference (CPP) were investigated in rats. Our results showed that some morphine withdrawal signs, including teeth chattering, grooming, chewing, and escape attendance, were attenuated by single pretreatments with 3, 10, or 30 mg/kg mirtazapine. Wet-dog shakes, rearing, and grooming were inhibited by daily pretreatment with 1, 3, or 10 mg/kg mirtazapine. The expression of morphine-induced CPP was significantly blocked by mirtazapine (10 or 30 mg/kg, i.p.), while chronic treatment with mirtazapine (1 or 10 mg/kg, i.p. once, daily, for six consecutive days) significantly attenuated the acquisition of morphine CPP. Our results demonstrated that mirtazapine attenuates morphine withdrawal and morphine-induced CPP in rats and suggest that mirtazapine may have therapeutic potential in the treatment of opiate dependence.

Topical ketamine and morphine for post-tonsillectomy pain.

BACKGROUND AND OBJECTIVES: Tonsillectomy is frequently associated with postoperative pain of considerable duration, which is usually accompanied by the substantial consumption of both opioid and non-opioid analgesics. Despite the use of different surgical and anaesthetic techniques in the search for safe and effective post-tonsillectomy pain relief, this problem remains a clinical dilemma. The aim of the current study was to evaluate the potential effects of topically administered ketamine and morphine by an oral rinse into the tonsillar fossae. METHODS: In all, 60 children, 15 for each group, aged between 3 and 12 yr scheduled for tonsillectomy were randomly assigned to one of four groups. Study drugs were administered to both tonsillar fossae for 5 min. Group K received 0.4 mL (20 mg) ketamine in 10 mL artificial saliva, Group KM received 0.4 mL (20 mg) ketamine + 5 mL (20 mg) 4 per thousand morphine aqueous solution in 5 mL artificial saliva, Group M received 5 mL (20 mg) 4 per thousand morphine aqueous solution in 5 mL artificial saliva, Group C received only 10 mL artificial saliva. Postoperative pain, nausea, vomiting, sedation and bleeding were evaluated. RESULTS: Pain scores were higher in the control group at arrival in the recovery ward (P < 0.05). Morphine and ketamine groups had longer effective analgesia time than the morphine + ketamine and control groups. The 24-h analgesic consumption was significantly higher in the control group. CONCLUSION: Topical ketamine and morphine seems to be a safe and easy analgesic approach for decreasing adenotonsillectomy pain.

Attenuation of Morphine-Induced Tolerance and Dependence by Pretreatment with Cerebrolysin in Male rats.

BACKGROUND: Dependence and tolerance to morphine are major problems which limit its chronic clinical application. PURPOSE: This study was aimed to investigate the attenuation effect of Cerebrolysin, a mixture of potent growth factors (BDNF, GDNF, NGF, CNTF etc,), on the development of Morphine-induced dependence and tolerance. METHODS: Male Wistar rats were selected randomly and divided into different groups (n=8) including: a control group, groups received additive doses of morphine (5-25 mg/kg, ip, at an interval of 12 h until tolerance completion), and groups pretreated with Cerebrolysin (40, 80 and 160 mg/kg, ip, before morphine administration). Development of tolerance was assessed by tail-flick test and the attenuation effect of Cerebrolysin on morphine-induced dependence was evaluated after injection of naloxone (4 mg/kg, ip, 12 h after the morning dose of morphine). Seven distinct withdrawal signs including: jumping, rearing, genital grooming, abdominal writhing, wet dog shake and teeth grinding were recorded for 45 min and total withdrawal score (TWS) was calculated. RESULTS: Results showed that administration of Cerebrolysin could prolonged development (10 and 14 days in administration of 80 mg/kg and 160 mg/kg Cerebrolysin) and completion (4, 10 and 14 days in administration of 40, 80 and 160 mg/kg Cerebrolysin, respectively) of tolerance. Results also indicated that administration of Cerebrolysin (40, 80 and 160 mg/kg) could significantly decreased the TWS value (62±2, 77±4 and 85±6%, respectively). CONCLUSION: In conclusion, it was found that pretreatment with Cerebrolysin could attenuated morphine-induced tolerance and dependence.

Comparison of Two Morphine-Benzodiazepine-Hydroxyzine Combinations for the Oral Sedation of Pediatric Dental Patients: A Retrospective Study.

PURPOSE: To investigate the effectiveness of oral morphine sulfate regimens in sedating pediatric dental patients and assess whether pre-sedation disposition and willingness to take the sedative were related to the outcome of the sedation. METHODS: The sedation records of 271 pediatric dental patients sedated with oral morphine were reviewed. Children were either sedated with regimen one (morphine plus midazolam plus hydroxyzine) or regimen two (morphine plus diazepam plus hydroxyzine). Data gathered included the patient's pre-sedation disposition, willingness to take the sedative, effectiveness of sedation, and occurrence of any adverse event. Data analysis was conducted using descriptive statistics, Pearson's chi-square, and logistic regression. RESULTS: Regimens one and two had an overall success rate of 80 percent (143 out of 178) and 81 percent (75 out of 93), respectively. A positive correlation was observed between the patient's willingness to take his/her sedative medication and the effectiveness of the sedation using both the Pearson's chi-square (P=.004) and logistic regression (P=.028). Adverse events occurred in six percent (17 out of 271) of the cases. CONCLUSIONS: Overall rate of effective sedation using various oral morphine sulfate regimens was above 80 percent. Minimal adverse events occurred. The patient's willingness to take the sedative was positively associated with the outcome of the sedation regimen.

Naloxegol to Treat Constipation in a Patient Taking Opioids for Cancer Pain: A Case Report.

Opioid-induced constipation (OIC) is a common gastrointestinal adverse effect of opioids, which can severely affect compliance and adherence to pain medication regimens and quality of life. Naloxegol has demonstrated efficacy against OIC in several studies involving patients with nonmalignant chronic pain. Here we report efficacy and tolerability of naloxegol in a 68-year-old patient with metastatic lung cancer and severe pain, treated with opioids, who presented with OIC resistant to traditional measures. Addition of naloxegol produced rapid improvement in his OIC symptoms and no apparent adverse effects while taking extended-release morphine 130 mg orally every 12 hours.