Low-dose Morphine Research Articles

Neonatal opioid toxicity: opioid withdrawal (abstinence) syndrome with emphasis on pharmacogenomics and respiratory depression.

The increasing use of opioids in pregnant women has led to an alarming rise in the number of cases of neonates with drug-induced withdrawal symptoms known as neonatal opioid withdrawal syndrome (NOWS). NOWS is a toxic heterogeneous condition with many neurologic, autonomic, and gastrointestinal symptoms including poor feeding, irritability, tachycardia, hypertension, respiratory defects, tremors, hyperthermia, and weight loss. Paradoxically, for the management of NOWS, low doses of morphine, methadone, or buprenorphine are administered. NOWS is a polygenic disorder supported by studies of genomic variation in opioid-related genes. Single-nucleotide polymorphisms (SNPs) in CYP2B6 are associated with variations in NOWS infant responses to methadone and SNPs in the OPRM1, ABCB1, and COMT genes are associated with need for treatment and length of hospital stay. Epigenetic gene changes showing higher methylation levels in infants and mothers have been associated with more pharmacologic treatment in the case of newborns, and for mothers, longer infant hospital stays. Respiratory disturbances associated with NOWS are not well characterized. Little is known about the effects of opioids on developing neonatal respiratory control and respiratory distress (RD), a potential problem for survival of the neonate. In a rat model to test the effect of maternal opioids on the developing respiratory network and neonatal breathing, maternal-derived methadone increased apneas and lessened RD in neonates at postnatal (P) days P0 and P1. From P3, breathing normalized with age suggesting reorganization of respiratory rhythm-generating circuits at a time when the preBötC becomes the dominant inspiratoryrhythm generator. In medullary slices containing the preBötC, maternal opioid treatment plus exposure to exogenous opioids showed respiratory activity was maintained in younger but not older neonates. Thus, maternal opioids blunt centrally controlled respiratory frequency responses to exogenous opioids in an age-dependent manner. In the absence of maternal opioid treatment, exogenous opioids abolished burst frequencies at all ages. Prenatal opioid exposure in children stunts growth rate and development while studies of behavior and cognitive ability reveal poor performances. In adults, high rates of attention deficit disorder, hyperactivity, substance abuse, and poor performances in intelligence and memory tests have been reported.

Effect of Intrathecal Morphine on Postdural Puncture Headache in Obstetric Anaesthesia.

Intrathecal morphine is used as an effective component of multimodal analgesia in postoperative analgesia in cesarean section patients. We aimed to analyze the relationship between intrathecal morphine administration and postdural puncture headache (PDPH), pain score and analgesia consumption in the postoperative period, and maternal fetal effects. One hundred four pregnant women aged ≥18 years (American Society of Anesthesiology physical status I or II, >36 weeks gestation) who were scheduled for elective cesarean section under spinal anaesthesia were included in this study. Spinal anesthesia consisted of bupivacaine with or without morphine (Group M: 10 mg heavy marcaine + 25 mcg fentanyl + 100 mcg morphine; Group F: 10 mg heavy marcaine + 25 mcg fentanyl). The effect of intrathecal morphine on PDPH, postoperative pain score, analgesia consumption, and maternal and fetal effects were recorded for 5 days. PDPH developed in a total of 33 patients (Group M: 18 and Group F: 15, P=0.274). When we evaluated PDPH with the VAS, there was no significant difference between the groups. The postoperative visual analogue scale (VAS) was lower in the morphine group, and no statistically significant difference was found in the VAS 1st hr and VAS 2nd hr, whereas the VAS 6th hr and VAS 24th hr were found to be statistically significant. There was no difference in terms of PDPH, the first analgesic requirement and postoperative nausea-vomiting, but meperidine consumption was lower in the morphine group. Low-dose intrathecal morphine did not affect the incidence of PDPH. It is an effective method that can be used in cesarean section patients without increasing the maternal and fetal side effects from postoperative analgesia.

Dietary polyphenols drive dose-dependent behavioral and molecular alterations to repeated morphine

Opioid Use Disorder (OUD) is associated with tremendous morbidity and mortality. Despite this burden, current pharmacotherapies for OUD are ineffective or intolerable for many patients. As such, interventions aimed at promoting resilience against OUD are of immense clinical interest. Treatment with a Bioactive Dietary Polyphenol Preparation (BDPP) promotes resilience and adaptive neuroplasticity in multiple models of neuropsychiatric disease. Here, we assessed effects of BDPP treatment on behavioral and molecular responses to repeated morphine treatment in male mice. BDPP pre-treatment alters responses for both locomotor sensitization and conditioned place preference. Most notably, polyphenol treatment consistently reduced formation of preference at low dose (5 mg/kg) morphine but enhanced it at high dose (15 mg/kg). In parallel, we performed transcriptomic profiling of the nucleus accumbens, which again showed a dose × polyphenol interaction. We also profiled microbiome composition and function, as polyphenols are metabolized by the microbiome and can act as prebiotics. The profile revealed polyphenol treatment markedly altered microbiome composition and function. Finally, we investigated involvement of the SIRT1 deacetylase, and the role of polyphenol metabolites in behavioral responses. These results demonstrate polyphenols have robust dose-dependent effects on behavioral and physiological responses to morphine and lay the foundation for future translational work.

Nicotine limits avoidance conditioning with opioids without interfering with the ability to discriminate an opioid-interoceptive state

Approximately 90 % of individuals undergoing treatment for opioid use disorder (OUD) report comorbid use of nicotine. As such, further investigation into underlying mechanisms contributing to the extreme comorbidity between nicotine and opioid use are warranted. Nicotine administration significantly escalates self-administration of opioids and this increase in motivational efficacy persists despite contingent punishment of opioid consumption. Additionally, both systemic and intra-insular administration of nicotine produces a rightward shift in the dose-response function in both morphine-induced conditioned place preference and taste avoidance paradigms, particularly at higher doses (5–20 mg/kg). Two possible interpretations arise from these outcomes. One is that nicotine may specifically affect learning about the malaise-inducing effects of morphine thus facilitating acceptance of higher doses of morphine. Another interpretation is that it more generally reduces sensitivity to the interoceptive effects of morphine such that higher doses are needed to produce comparable effects in nicotine-treated, relative to control, rats. To further address these possibilities, we asked whether nicotine administration interfered with the ability to discriminate the morphine interoceptive state, irrespective of its hedonic evaluation, at a dose that is impacted by nicotine in avoidance conditioning paradigms. First, we demonstrated that systemic nicotine pretreatment significantly attenuates taste avoidance induced by a low dose of morphine (3 mg/kg). Next, we used an occasion setting paradigm with this same dose of morphine to test whether systemic nicotine pretreatment interferes with the ability to discriminate between saline- and morphine-induced interoceptive states. Within this task, nicotine had no effect on the ability to effectively discriminate between the interoceptive effects of morphine and saline. Collectively, these data suggest that nicotine may be specifically altering the overall hedonic assessment of morphine perhaps by interfering with learning about its deleterious consequences.

Modified-release morphine or placebo for chronic breathlessness: the MABEL trial protocol.

Chronic breathlessness, a persistent and disabling symptom despite optimal treatment of underlying causes, is a frightening symptom with serious and widespread impact on patients and their carers. Clinical guidelines support the use of morphine for the relief of chronic breathlessness in common long-term conditions, but questions remain around clinical effectiveness, safety and longer term (>7 days) administration. This trial will evaluate the effectiveness of low-dose oral modified-release morphine in chronic breathlessness. This is a multicentre, parallel group, double-blind, randomised, placebo-controlled trial. Participants (n=158) will be opioid-naïve with chronic breathlessness due to heart or lung disease, cancer or post-coronavirus disease 2019. Participants will be randomised 1:1 to 5 mg oral modified-release morphine/placebo twice daily and docusate/placebo 100 mg twice daily for 56 days. Non-responders at Day 7 will dose escalate to 10 mg morphine/placebo twice daily at Day 15. The primary end-point (Day 28) measure will be worst breathlessness severity (previous 24 h). Secondary outcome measures include worst cough, distress, pain, functional status, physical activity, quality of life, and early identification and management of morphine-related side-effects. At Day 56, participants may opt to take open-label, oral modified-release morphine as part of usual care and complete quarterly breathlessness and toxicity questionnaires. The study is powered to be able to reject the null hypothesis and an embedded normalisation process theory-informed qualitative substudy will explore the adoption of morphine as a first-line pharmacological treatment for chronic breathlessness in clinical practice if effective.

Sublingual fentanyl for refractory episodic acute dyspnea in patients with advanced chronic obstructive pulmonary disease (COPD): A real-world study

BACKGROUND Dyspnea is an extremely prevalent and debilitating symptom in chronic obstructive pulmonary disease (COPD), affecting up to 74% of patients despite optimal medical therapy. Sublingual fentanyl citrate (SLF) has a fast onset of action and a short half-life, both interesting characteristics to treat acute breakthrough dyspnea without inducing metabolite accumulation. The Montreal Chest Institute (MCI) COPD specialty clinic has been using low-dose SLF for patients with advanced COPD experiencing significant episodic dyspnea despite high intensity inhaled therapy. We present here a retrospective chart review, the largest to date, to report on a “real life” experience. METHODS All included patients had a formal diagnosis of COPD and were seen in the MCI COPD specialty clinic between January 1, 2015 and January 1, 2021. All patients prescribed SLF, irrespective of the duration of use, were enrolled in this chart review. Extent of symptom relief, categorized into either major, intermediate or no improvements, and adverse effects were inferred from in-person or telephone follow-up appointment clinical notes. An exacerbation was defined as a self-reported acute increase in symptoms leading to oral corticosteroid use or hospitalization. Rates of exacerbation and hospitalization in the 12 months before SLF initiation and during SLF use were compared. RESULTS In total, 17 COPD patients were given SLF during the study period. The mean FEV1 was 0.51 L (21% predicted). All participants reported MRC5/5 dyspnea and were prescribed regular low-dose oral morphine for daily breathlessness prior to SLF initiation. Most patients used SLF for more than 6 months, and 76.5% of the study group found intermediate or major improvement in breathlessness episodes. There was no significant change in the rates of exacerbation and admission for acute respiratory failure while on SLF. CONCLUSION In this review, we report real-life, long-term data on severe COPD patients using self-controlled as-needed SLF, showing patient acceptability, an improvement in dyspnea, and limited side effects. Hence, this represents an important step toward the first effective alternative rescue medication for the relief of breakthrough dyspnea since short-acting inhalers. Further study using a randomized trial design is required to confirm the efficacy of this therapy.

Cannabis-based medicines and medical cannabis for adults with cancer pain.

Cannabis-based medicines and medical cannabis for adults with cancer pain.

Long-term opioid treatment and endocrine measures in chronic non-cancer pain patients.

The prevalence of chronic non-cancer pain (CNCP) has increased dramatically the past decades, which combined with indiscriminate use of prescribed opioids has become a public health problem. Endocrine dysfunction may be a complication of long-term opioid treatment (L-TOT), but the evidence is limited. This study aimed at investigating the associations between L-TOT and endocrine measures in CNCP patients. Cortisol (spot and after stimulation), thyrotropin (TSH), thyroxin (T4), insulin-like growth factor 1 (IGF-1), prolactin (PRL), 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone (DHEAS), sex hormone-binding globulin (SHBG), total testosterone (TT) and free testosterone (fT) were measured. Group comparisons were done between CNCP patients in L-TOT and controls as well as between patients on high- or low-dose morphine equivalents. Eighty-two CNCP patients (38 in L-TOT and 44 controls not receiving opioids) were included. Low TT (p = 0.004) and fT concentrations (p < 0.001), high SHBG (p = 0.042), low DEAS (p = 0.017) and low IGF-1 (p = 0.003) in men were found when comparing those in L-TOT to controls and high PRL (p = 0.018), low IGF-1 standard deviation score (SDS) (p = 0.006) along with a lesser, but normal cortisol response to stimulation (p = 0.016; p = 0.012) were found when comparing L-TOT to controls. Finally, a correlation between low IGF-1 levels and high opioid dose was observed (p < 0.001). Our study not only supports previous findings but even more interestingly disclosed new associations. We recommend future studies to investigate endocrine effects of opioids in larger, longitudinal studies. In the meanwhile, we recommend monitoring endocrine function in CNCP patients when prescribing L-TOT. This clinical study found associations between L-TOT, androgens, growth hormone and prolactin in patients with CNCP compared to controls. The results support previous studies as well as add new knowledge to the field, including an association between high opioid dose and low growth hormone levels. Compared to existing research this study has strict inclusion/exclusion criteria, a fixed time period for blood sample collection, and adjustments for potential confounders, which has not been done before.

Does the combination of intrathecal fentanyl and morphine improve clinical outcomes in patients undergoing lumbar fusions?

Intrathecal morphine (ITM) has been widely effective in improving postoperative outcomes in patients undergoing a multitude of surgeries, including lumbar spine fusion. A major limitation of ITM administration is the increase in the incidence of respiratory depression in a dose-dependent manner. One way to bypass this is to use a more potent opioid with a shorter half-life, such as fentanyl. This is a retrospective analysis of patients who underwent one- or two-level transforaminal lumbar interbody fusions. The patients received one of two interventions: 0.2mg intrathecal duramorph/morphine (ITM group; n=70), 0.2mg duramorph + 50 mcg fentanyl (ITM + fentanyl group; n=68) and the control group (n=102). Primary outcomes included postoperative pain (Visual Analog Scale) and opioid intake (MED - morphine equivalent dosage, mg) for postoperative days (POD) 1- 4. Secondary outcomes included opioid-related side effects. One-way analyses of variance and follow-up post-hoc Tukey's honest significant difference statistical tests were used to measure treatment effects. Significantly lower POD1 pain scores for both the ITM and ITM + fentanyl groups vs. control were detected, with no difference between the ITM vs. ITM + fentanyl groups. Similar results were found for POD1 MED intake. A multivariate regression analysis controlling for confounding variables did not attenuate the differences seen in POD1 pain scores while revealing that only the ITM + fentanyl predicted a decrease in POD1 MED intake. No differences were seen for postoperative opioid-related side effects. Our study provides support for supplementing a low dose of both intrathecal morphine and fentanyl to improve postoperative outcomes.

445 Evaluation of Low Dose Intrathecal Morphine Delivery in the Treatment of Chronic Pain

INTRODUCTION: The use of low-dose intrathecal morphine via a morphine drug delivery system is an alternative to oral analgesics in the treatment of chronic pain. METHODS: This was a retrospective chart-review. Patients were enrolled from June 2016 to April 2019. An out-patient intrathecal morphine trial was performed by injecting a single dose of 0.1-0.2 mg of preservative-free morphine in the lumbar intrathecal space. Following at least 60% reduction in pain, patients were weaned off oral analgesics completely over several weeks, and a permanent intrathecal catheter and morphine pump was implanted. Follow-up data was included at 3 and 6 months and 1 and 3 years. RESULTS: 20 patients were enrolled (median age 59, 60% female). 10 patients were diagnosed with CPS and 10 were diagnosed with PLS. Pain was significantly controlled and reduced at each time point post-implantation compared to baseline. (p &lt; 0.05). Intrathecal dosing did increase over the 3-year period on average, but the increase in dose was moderate. (p &lt; 0.01) (median increase: 0.09 mg/day over 3 years).All patients were on oral medication for their pain prior to implantation as summarized: Remarkably, no patients previously taking oral opiates/analgesics restarted oral opiate/analgesic therapy following implantation up to and including the 3 years follow-up. There were no infections or complications present in the study. CONCLUSIONS: Low dose intrathecal drug delivery was shown to significantly reduce pain following treatment at each follow-up time point. This study further characterizes the efficacy of the use of low-dose intrathecal drug delivery in the treatment of chronic pain. A future multi-center study is desired.

Analgesic efficacy of inter-semispinal fascial plane block in Patients undergoing Cervical Spine Surgery through Posterior Approach: a randomized controlled trial

BackgroundPosterior cervical spine surgery is commonly performed in elderly patients with significant comorbidities and is considered one of the most painful surgical procedures. Accordingly, perioperative pain management during posterior cervical spine surgery represents a unique challenge for anesthesiologists. Inter-semispinal plane block (ISPB) represents a promising analgesic technique for spine surgery through the blockade of the dorsal rami of the cervical spinal nerves. The present study aimed to investigate the analgesic effect of bilateral ISPB as an opioid-sparing nerve block technique for posterior cervical spine surgeries. MethodsThis prospective randomized controlled trial enrolled 52 patients planned for cervical spine surgery via the posterior approach. Patients were randomly assigned to one of two groups in a one-to-one ratio, with 26 patients allocated to the block group (ISPB) who received general anesthesia preceded by bilateral ISP using 20 mL 0.25% bupivacaine on each side and the remaining 26 patients allocated to the control group who received general anesthesia only. The primary outcome was total perioperative opioid consumption through two co-primary outcomes, i.e. total amount of fentanyl administered intraoperatively and total morphine consumption during the first 24 hours postoperatively. The secondary outcomes included intraoperative hemodynamic parameters, assessment of numerical rating scores (NRS) during the first 24 hours postoperatively, time to first rescue analgesia and opioid-related side effects. ResultsA significantly lower amount of intraoperative fentanyl was administered in the ISPB group (median, 175 μg; range, 110–220 μg] compared to the control group [median, 290 μg; range 110–350 μg). Patients in the ISPB group consumed significantly lower doses of morphine (median, 7 mg; range, 5–12 mg]) within the first 24 h postoperatively compared to the control group (median, 12 mg; range, 8–21 mg). In addition, NRS values were significantly lower in the ISPB group during the first 12 h postoperatively than in the control group. No significant differences in mean arterial pressure (MAP) or heart rate (HR) were observed between intraoperative time points in the ISPB group. However, a significant increase in MAP was observed during surgery in the control group (p < 0.001). The incidence of opioid side effects such as nausea, vomiting, and sedation was significantly greater in the control group compared to the ISPB group. ConclusionsInter-semispinal plane block (ISPB) represents an effective analgesic technique and reduces opioid consumption in both intra- and postoperative settings. Moreover, the ISPB could significantly decrease opioid-associated side effects.

The Effect of Epidural Infusion of Dexmedetomidine on Postoperative Analgesia After Thoracotomy: A Randomized Clinical Trial.

The unique analgesic properties of dexmedetomidine have led anesthesiologists to use it as an alternative to relieve pain after major surgeries. We aimed to evaluate the effect of continuous injection of thoracic epidural dexmedetomidine on analgesia after thoracotomy. In this randomized, double-blind clinical trial, 46 patients (18 to 70 years old) who were candidates for thoracotomy surgery were randomly assigned to receive ropivacaine alone or combined with dexmedetomidine after epidural anesthesia as postoperative epidural anesthesia. The postoperative sedation rate, pain score, and opioid use were assessed within 48 hours after surgery and compared between the 2 groups. Comparing the mean postoperative sedation scores indicated no difference between the 2 study groups. The pain score assessment showed a lower pain score 6 to 36 hours after surgery in the group receiving concurrent ropivacaine and dexmedetomidine than in the group receiving ropivacaine alone. In the 2 groups receiving ropivacaine with and without dexmedetomidine, the rate of morphine administration after surgery was 43.4% and 65.2%, respectively, indicating no difference. However, the first group received significantly lower doses of morphine after the end of surgery (3.26 ± 0.90 mg vs. 7.04 ± 1.48 mg; P = 0.035). A combination of ropivacaine and dexmedetomidine as epidural analgesia can lead to lower postoperative pain scores and reduced doses of opioids required.

Neuronal activity of the medial prefrontal cortex, nucleus accumbens, and basolateral amygdala in conditioned taste aversion and conditioned place preference induced by different doses of morphine administrations in rats.

To re-examine the paradoxical effect hypothesis of abused drugs, the present study concerned whether different doses of morphine disparately affect neuronal activity and associations among the subareas of the medial prefrontal cortex (mPFC: cingulate cortex 1-Cg1, prelimbic cortex-PrL, infralimbic cortex-IL), the subregions of the nucleus accumbens (NAc; both core and shell), and the basolateral amygdala (BLA) following conditioned taste aversion (CTA) and conditioned place preference (CPP). All rats were given a 0.1% saccharin solution for 15-min, and they were intraperitoneally injected with saline or 20, 30, or 40mg/kg morphine to form the aversive CTA learning. Later, half of the rats were tested for CPP (including the CTA and then CPP tests) for 30-min. Finally, the immunohistochemical staining with c-Fos was conducted after the behavioral test. After the CTA test, c-Fos (%) in the Cg1 and PrL (but not the IL) was more in 20-40mg/kg of the morphine groups; c-Fos (%) in the NAc core, NAc shell, and BLA was more in the 30-40mg/kg morphine group. After the CPP test, the Cg1, PrL, IL, and BLA showed more c-Fos (%) in 20mg/kg morphine; the NAc core showed fewer in c-Fos (%) in the 30-40mg/kg morphine groups. The mPFC subregions (e.g., Cg1, PrL, and IL), NAc subareas (e.g., NAc core and NAc shell), and BLA were involved in the different doses of morphine injections. The correlation analysis showed that a positive correlation was observed between PrL and IL with NAc core with low doses of morphine and with NAc shell with increasing doses of morphine after the CTA test. After the CPP, an association between PrL and NAc core and NAc shell at low doses and between IL and BLA and NAc shell with increasing doses of morphine. Therefore, different neural substrates and the neural connectivity are observed following different doses of morphine and after the CTA and CPP tests. The present data extend the paradoxical effect hypothesis of abused drugs.

Comparing the Effects of Low-Dose Ketamine, Fentanyl, and Morphine on Hemorrhagic Tolerance and Analgesia in Humans

Hemorrhage is a leading cause of preventable battlefield and civilian trauma deaths. Ketamine, fentanyl, and morphine are recommended analgesics for use in the prehospital (i.e., field) setting to reduce pain. However, it is unknown whether any of these analgesics reduce hemorrhagic tolerance in humans. We tested the hypothesis that fentanyl (75 µg) and morphine (5 mg), but not ketamine (20 mg), would reduce tolerance to simulated hemorrhage in conscious humans. Each of the three analgesics was evaluated independently among different cohorts of healthy adults in a randomized, crossover (within drug/placebo comparison), placebo-controlled fashion using doses derived from the Tactical Combat Casualty Care Guidelines for Medical Personnel. One minute after an intravenous infusion of the analgesic or placebo (saline), we employed a pre-syncopal limited progressive lower-body negative pressure (LBNP) protocol to determine hemorrhagic tolerance. Hemorrhagic tolerance was quantified as a cumulative stress index (CSI), which is the sum of products of the LBNP and the duration (e.g., [40 mmHg x 3 min] + [50 mmHg x 3 min] …). Compared with ketamine (p = 0.002 post hoc result) and fentanyl (p = 0.02 post hoc result), morphine reduced the CSI (ketamine (n = 30): 99 [73–139], fentanyl (n = 28): 95 [68–130], morphine (n = 30): 62 [35–85]; values expressed as a % of the respective placebo trial’s CSI; median [IQR]; Kruskal-Wallis test p = 0.002). Morphine-induced reductions in tolerance to central hypovolemia were not well explained by a prediction model including biological sex, body mass, and age (R2=0.05, p = 0.74). These experimental data demonstrate that morphine reduces tolerance to simulated hemorrhage while fentanyl and ketamine do not affect tolerance. Thus, these laboratory-based data, captured via simulated hemorrhage, suggest that morphine should not be used for a hemorrhaging individual in the prehospital setting.

Low Current Intensity Plus an Ineffective Dose of Morphine Affect Conditioning Place Preference Through Different Pathways in the Lateral Habenula.

The involvement of lateral habenula and the ineffective dose of morphine on reward-related learning and memory is less well-known. This study looked into the effects of electrical stimulation, GABAB receptor blockade, and a combination of both with morphine on conditioned place preference. In this experiment, male rats were anesthetized with ketamine/xylazine (six rats in each group). A 5-day biased conditioned place preference paradigm was used for the behavioral test. The effects of electrical stimulation and phaclofen plus a low dose of morphine on the acquisition and expression phases were examined during conditioning sessions and before the test phase, respectively. The conditioning scores were reduced by antagonist injection during the acquisition phase. Interestingly, different intensities exhibited opposite effects on the acquisition phase. Conditioned place preference scores during the acquisition phase were significantly induced by 25 μA electrical stimulation, while conditioning scores were suppressed by electrical stimulation at 150 μA. Phaclofen (2 μg/rat) combined with high intensity induced aversion during the acquisition phase, while inhibiting expression. In contrast, high intensity with phaclofen (1 μg/rat) inhibited only the acquisition session. However, low intensity during the acquisition phase had an additive effect that was prevented by pretreatment with phaclofen (2 μg/rat), but this response was modified by the antagonist's low dose. A behavioral technique called conditioned place preference is frequently used to evaluate learning that is related to rewards. Therefore, lateral habenula electrical stimulation and phaclofen plus morphine could affect place preference through the involvement of the reward system.

The Effect of Preemptive Local Infiltration on Postoperative Pain After Vaginal Hysterectomy: A Retrospective Study

To investigate the effect of preemptive infiltration on postoperative pain and the use of analgesics after vaginal hysterectomy (VH). A retrospective study. An urogynecology unit in a tertiary medical center. A total of 120 patients who had undergone VH. The study group contained 60 patients who participated in a former randomized control study, in which preemptive local infiltration of bupivacaine (n=30) or sodium chloride 0.9% (n=30) was performed. The control group included 60 consecutive patients who underwent a VH, for whom no local infiltration was performed. Postoperative pain at rest was assessed using the 10 cm visual analog scale at 3, 8, and 24 hours after surgery. The levels of pain, as well as the use of analgesics, postoperatively, were compared between the groups. The mean surgery length in the infiltration group was shorter (86.4±29 vs 118.6±30, p <.001) and the rate of posterior colporrhaphy was lower (73.1% vs 91.3%, p=.010) than the control group. There were no differences in levels of pain at all points of time. However, the infiltration group required a lower morphine dose in the recovery unit (3.7 ± 2.3 mg vs 5.3 ± 2.4 mg, p <.001) and less use of analgesia (all kinds) 24 hours after surgery (54.2% vs 79.6%, p <.001) compared with the control group. On multivariant analysis, preemptive infiltration was found to be independently inversely associated with the dose of morphine used in recovery, as well as analgesics used 24 hours after surgery. Preemptive local infiltration of either bupivacaine or sodium chloride 0.9% reduced the use of morphine in the recovery unit, as well as the use of analgesics 24 hours after VH, compared with no infiltration at all.

Regular, low-dose methadone for reducing breathlessness in people experiencing or at risk of neurotoxic effects from morphine: A single-center case series.

Breathlessness is a common symptom suffered by people living with advanced malignant and non-malignant diseases, one which significantly limits their quality of life. If it emerges at minimal exertion, despite the maximal, guidelines-directed, disease-specific therapies, it should be considered persistent and obliges clinicians to prescribe symptomatic, non-pharmacological, and pharmacological treatment to alleviate it. Opioids are recommended for the symptomatic treatment of persistent breathlessness, with morphine most extensively studied for this indication. It is extensively metabolized in the liver into water-soluble 3- and 6-glucuronides, excreted by the kidneys. In the case of advanced renal failure, the glucuronides accumulate, mainly responsible for toxicity 3-glucuronides. Some people, predominantly those with advanced renal failure, develop neurotoxic effects after chronic morphine, even when prescribed at a very low dose. A single-center case series of consecutive patients experiencing neurotoxic effects after long-term, low-dose morphine or at risk of such effects were transferred to methadone to avoid the accumulation of neurotoxic metabolites. Over the course of 4.5 years, 26 patients have been treated with methadone in the median dose of 3.0 mg/24 h p.o., for persisting breathlessness. Sixteen of them had been treated previously with an opioid (usually morphine) at the median dose of 7.0 mg/24 h (morphine oral daily dose equivalent). They were transferred to methadone, with the median dose of 3.0 mg/24 h orally (methadone oral daily dose equivalent), and the median morphine-to-methadone dose ratio was 2.5:1. All patients experienced a meaningful improvement in breathlessness intensity after methadone, by a median of 5 points (range 1-8) on the 0-10 numerical rating scale (NRS) in the whole group, and by 2 points (range 0-8) in those pretreated with other opioids, mainly morphine. Low-dose methadone can be considered an efficient alternative to morphine for reducing breathlessness in people experiencing neurotoxic effects or at risk of developing them following treatment with morphine.

Effect of different low doses of intrathecal morphine (0.1 and 0.2 mg) on pain and vital functions in patients undergoing total hip arthroplasty: a randomised controlled study

BackgroundOrthopaedic surgeries are among the most painful procedures. By adding low-dose morphine to intrathecal bupivacaine for spinal anaesthesia, the analgesic effect can be improved. The objeсtive of the study was tо compare the efficacy and safety of lоw-dоse (0.1 mg аnd 0.2 mg) intrаtheсаl mоrphine (ITM).MethodsА prоspeсtive rаndоmised study was соnduсted at the Hоspitаl оf Trаumаtоlоgy аnd Оrthоpaediсs, Riga, Latvia (February 2020 tо May 2021) and enrolled 90 patients undergoing primary hip arthroplasty. All subjects were randomised intо three study grоups, using the online tool оn www.randomiser.org. Treatment groups were allocated to intrathecal morphine (0.1 mg and 0.2 mg) in addition to bupivacaine (15 to 18 mg). The primary outcome was postoperative pain intensity among the three study groups within 24 hours by NRS. The secondary outcomes: pain at rest 4 h, 7 h, 12 h, 24 h postoperatively, respiratory rate, SpО2, morphine соnsumptiоn, оxygen supply, opioid-related аdverse reасtiоns within 24 hours postoperatively. Dаtа were аnаlysed using R version 4.2.0, applying the Mann-Whitney test, Pearson’s chi-squared test, Fisher’s exact test, Friedman test, Wilcoxon test.ResultsThe primary outcome in the control, ITM 0.1 mg, ITM 0.2 mg groups, respectively: 2.56, 0.87, 0.28 (p < 0.001). The secondary outcomes in the control, ITM 0.1 mg, ITM 0.2 mg group, respectively: pain scores 4h – 1.21, 0.48, 0.17 (p = 0.068); 7 h – 2.62, 1.00, 0.17 (p < 0.001); 12 h – 3.08, 0.65, 0.37 (p < 0.001); 24 h – 2.50, 1.20, 0.41 (p < 0.001); rescue medication requests (incidence, %): 77%, 16.7%, 13.3% (p < 0.001); mean respiratory rate (breath/min) – 15.2; 15.2 (p > 0.05); mean SpO2 (%): 96.7%; 95.7%; 96.07%. Significant adverse effects: pruritus in ITM 0.2 mg group (23% of subjects, p < 0.001).ConclusionsAdult patients undergoing THA under spinal anaesthesia with bupivacaine and 0.2 mg morphine had superior analgesia to patients who received spinal analgesia with bupivacaine or bupivacaine and 0.1 mg morphine.Trial registrationStudy ID ISRCTN37212222; 20/04/2022 (registered retrospectively)

Pharmacological activation of mediodorsal thalamic GABA-A receptors modulates morphine/cetirizine-induced changes in the prefrontal cortical GFAP expression in a rat model of neuropathic pain

The present study investigated the involvement of mediodorsal thalamic (MD) GABA-A receptors in cetirizine/morphine-induced anti-allodynia using a rat model of neuropathic pain. To assess the importance of the prefrontal cortex (PFC) for chronic pain processing, its expression level changes of glial fibrillary acidic protein (GFAP) were measured following drug treatments. Each animal was subjected to chronic constriction of the sciatic nerve surgery simultaneously with the MD cannulation under stereotaxic surgery. The results showed that the administration of morphine (3–5 mg/kg) or cetirizine (1–3 mg/kg) produced significant analgesia in neuropathic rats. Systemic administration of cetirizine (2.5 and 3 mg/kg) potentiated the analgesic response to a low and intolerance dose of morphine (3 mg/kg). Intra-MD microinjection of muscimol, a selective GABA-A receptor agonist (0.005–0.01 μg/rat), increased the cetirizine/morphine-induced anti-allodynia, while muscimol by itself did not affect neuropathic pain. The neuropathic pain was associated with the increased PFC expression level of GFAP, suggesting the impact of chronic pain on PFC glial management. Interestingly, the anti-allodynia was associated with a decrease in the PFC expression level of GFAP under the drugs' co-administration. Thus, cetirizine has a significant potentiating effect on morphine response in neuropathic pain via interacting with the MD GABA-A receptors. It seems that neuropathic pain affects the prefrontal cortex GFAP signaling pathway. In clinical studies, these findings can be considered to create a combination therapy with low doses of GABA-A receptor agonist plus cetirizine and morphine to manage neuropathic pain.

P009 The effects of low-dose morphine on sleep and breathlessness in chronic obstructive pulmonary disease

Abstract Introduction Low-dose morphine is prescribed for refractory breathlessness in chronic obstructive pulmonary disease (COPD). Preliminary investigations suggest improved perceived sleep quality, although concerns exist regarding opioid-induced sedation. This study assessed the effects of morphine on subjective sleep quality and alertness, and potential links between sleep quality and breathlessness. Methods Analysis of sleep questionnaire and breathlessness data at baseline and after one week of low-dose slow-release morphine versus placebo according to a double-blind randomised controlled design was performed. Participants were randomised to placebo, 8mg or 16mg/day oral morphine for one week (before further dose escalation). Epworth Sleepiness Scale (ESS), Karolinska Sleep Score (KSS), Leeds Sleep Evaluation Questionnaire (LSEQ) and breathlessness severity scores were assessed. Dose effects on sleep measures were assessed via linear regression (including baseline sleep measures). Drug effects on the relationship between sleep quality and breathlessness were assessed via linear mixed models with random effects and three-way interaction between sleep measures, dose, and visit. Results 156 patients were randomised as follows: 8mg, n=55; 16mg, n=51; placebo n=50. Overall, there was a neutral effect of morphine on ESS, KSS, and LSEQ (all p&amp;gt;0.05). Morphine did not modify the relationship between sleep measures and breathlessness. Discussion Despite safety concerns, one week of morphine did not negatively impact subjective sleep or daytime alertness measures. There was no clear relationship between morphine’s effects on sleep and next-day breathlessness perception. Objective data assessing sleep and next-day alertness are required to further explore potential links between sleep and breathlessness in people with COPD.