Sustained-release Oral Morphine Research Articles

Opioid Coprescription Through Risk Mitigation Guidance and Opioid Agonist Treatment Receipt

At the onset of the COVID-19 pandemic, the government of British Columbia, Canada, released clinical guidance to support physicians and nurse practitioners in prescribing pharmaceutical alternatives to the toxic drug supply. These alternatives included opioids and other medications under the risk mitigation guidance (RMG), a limited form of prescribed safer supply, designed to reduce the risk of SARS-CoV-2 infection and harms associated with illicit drug use. Many clinicians chose to coprescribe opioid medications under RMG alongside opioid agonist treatment (OAT). To examine whether prescription of hydromorphone tablets or sustained-release oral morphine (opioid RMG) and OAT coprescription compared with OAT alone is associated with subsequent OAT receipt. This population-based, retrospective cohort study was conducted from March 27, 2020, to August 31, 2021, included individuals from 10 linked health administrative databases from British Columbia, Canada. Individuals who were receiving OAT at opioid RMG initiation and individuals who were receiving OAT and eligible but unexposed to opioid RMG were propensity score matched at opioid RMG initiation on sociodemographic and clinical variables. Data were analyzed between January 2023 and February 2024. Opioid RMG receipt (≥4 days, 1-3 days, or 0 days of opioid RMG dispensed) in a given week. The main outcome was OAT receipt, defined as at least 1 dispensed dose of OAT in the subsequent week. A marginal structural modeling approach was used to control for potential time-varying confounding. A total of 4636 individuals (2955 [64%] male; median age, 38 [31-47] years after matching) were receiving OAT at the time of first opioid RMG dispensation (2281 receiving ongoing OAT and 2352 initiating RMG and OAT concurrently). Opioid RMG receipt of 1 to 3 days in a given week increased the probability of OAT receipt by 27% in the subsequent week (adjusted risk ratio, 1.27; 95% CI, 1.25-1.30), whereas receipt of opioid RMG for 4 days or more resulted in a 46% increase in the probability of OAT receipt in the subsequent week (adjusted risk ratio, 1.46; 95% CI, 1.43-1.49) compared with those not receiving opioid RMG. The biological gradient was robust to different exposure classifications, and the association was stronger among those initiating opioid RMG and OAT concurrently. This cohort study, which acknowledged the intermittent use of both medications, demonstrated that individuals who were coprescribed opioid RMG had higher adjusted probability of continued OAT receipt or reengagement compared with those not receiving opioid RMG.

Factors associated with 60-day adherence to "safer supply" opioids prescribed under British Columbia's interim clinical guidance for health care providers to support people who use drugs during COVID-19 and the ongoing overdose emergency.

AimsIn March 2020, British Columbia issued Risk Mitigation Guidance (RMG) to support prescribing of pharmaceutical alternatives to illicit drugs, in order to reduce risk for COVID-19, overdose, and withdrawal among people who use drugs. This study evaluated factors associated with 60-day adherence to novel opioid alternatives prescribed at an inner-city health centre in Victoria, Canada.MethodsA chart review was conducted to collect data on sociodemographic information, medical histories, and follow-up services among all clients prescribed novel opioid alternatives from March 2020-August 2020 (n = 286). Bivariable and multivariable regression were used to identify independent and adjusted factors associated with 60-day adherence.ResultsOverall, 77% of 286 clients were still receiving opioids after 60 days of follow-up. Medications included hydromorphone (n = 274), sustained-release oral morphine (n = 2), and oxycodone (n = 9). The adjusted odds of 60-day adherence to novel opioid alternatives were significantly higher for those receiving a mental health medication (aOR = 3.49, 95%CI = 1.26, 11.00), a higher maximum daily dosage of RMG prescriptions (aOR = 1.03 per mg increase, 95%CI = 1.01, 1.04), and those with continuous receipt of OAT (aOR = 6.25, 95%CI = 2.67, 15.90).ConclusionsHigher dosages and co-prescription of mental health medications and OAT may help support better adherence to this form of prescriber-based “safer supply”. Further work is needed to identify optimal prescribing practices and the longer term impacts of differing implementation scenarios.

P-122 Gastrointestinal side effects of morphine in cancer pain: A comparison between the smoking and non-smoking patients

The use of morphine analgesics is associated with a number of side effects, especially morphine-induced gastrointestinal dysfunction. Gastrointestinal side effects of morphine have a negative impact on patient quality of life. The complex relationship between nicotine and opioids is a controversial one and still not well understood. Some animal studies suggest that nicotine binds some opioid receptors. The aim of this study was to prospectively compare the incidence of gastrointestinal side effects of morphine between smokers and non-smokers in cancer pain patients. The study was conducted in our institution between 2019 and 2021. We included all patients receiving oral morphine, at least 60 mg daily, for cancer pain, for a week or longer before inclusion. All patients received oral sustained-release morphine sulfate and morphine sulfate immediate release. We used a prospective survey with a questionnaire administered weekly for 4 weeks. The participants were free of psychiatric disturbance, substance abuse (other than nicotine), had no renal or hepatic disease failure, and had no gastrointestinal disease. Patients were divided into two groups: smokers (n=40) and non-smokers (n=40). Gastrointestinal side effects of morphine were recorded and compared between the two groups. Of the 96 patients, 80 completed the entire study by answering the questionnaire on 4 consecutive occasions. There were 40 smokers and 40 non-smokers. The group of smokers was all men and the group of non-smokers had 17 men and 23 women. The mean age was 50 years (range: 26-65). The gastrointestinal side effects in the smokers group were: constipation in 20%, nausea in 18%, dry mouth in 18%, reflux in 5%, dyspepsia in 4%, anorexia in 1%, and abdominal pain in 1%. The gastrointestinal side effects in the non-smokers group were: constipation in 65% nausea in 60%, vomiting in 20%, dry mouth in 20%, reflux in 7%, dyspepsia in 7%, anorexia in 6%, abdominal pain in 6%. The gastrointestinal side effects were often moderate in the two groups; we rotated morphine in just two patients in the group of non-smoker patients as a result of vomiting. Overall, gastrointestinal side effects of morphine in non-smokers were statistically higher than in smokers (77% vs. 27%, p=0.001). 60% of non-smokers had nausea versus 18% in smokers (p=0.001). 20% of non-smokers had vomiting versus 0% in smokers (p=0.003). 65% of non-smokers had constipation versus 20% in smokers (p=0.005). Although other gastrointestinal side effects were higher in non-smoking patients compared to smoker patients, they did not reach statistical significance. There was a significant difference in terms of gastrointestinal side effects between smoker and non-smoker patients. Higher levels of morphine-induced gastrointestinal adverse effects were observed in non-smoking patients. Specifically, non-smokers reported more nausea, vomiting, and constipation than smokers.

Cost-effectiveness of sustained-release morphine for refractory breathlessness in COPD: A randomized clinical trial.

Chronic breathlessness is a frequent symptom in advanced Chronic Obstructive Pulmonary Disease (COPD) and has major impact on quality of life, daily activities and healthcare utilization. Morphine is used as palliative treatment of chronic breathlessness. The aim is to analyze cost-effectiveness of regular, low-dose morphine in patients with advanced COPD from a healthcare and societal perspective. In a randomized controlled trial, participants with advanced COPD were assigned to 10mg regular, oral sustained-release morphine or placebo twice daily for four weeks. Quality of life (COPD Assessment Test; CAT), quality-adjusted life years (QALY's; EQ-5D-5L), healthcare costs, productivity, and patient and family costs were collected. Incremental cost-effectivity ratio's (ICERs) using healthcare costs and CAT scores, and incremental cost-utility ratio's (ICURs) using societal costs and QALY's were calculated. Data of 106 of 124 participants were analyzed, of which 50 were in the morphine group (mean [SD] age 65.4 [8.0] years; 58 [55%] male). Both ICER and ICUR indicated dominance for morphine treatment. Sensitivity analyses substantiated these results. From a healthcare perspective, the probability that morphine is cost-effective at a willingness to pay €8000 for an minimal clinically important difference of 2 points increase in CAT score is 63%. From a societal perspective, the probability that morphine is cost-effective at a willingness to pay €20,000 per QALY is 78%. Morphine for four weeks is cost-effective regarding the healthcare and the societal perspective. To estimate the long-term costs and effects of morphine treatment, a study of longer follow-up should be performed. ClinicalTrials.gov (NCT02429050).

Effect of Sustained-Release Morphine for Refractory Breathlessness in Chronic Obstructive Pulmonary Disease on Health Status

Morphine is used as palliative treatment of chronic breathlessness in patients with advanced chronic obstructive pulmonary disease (COPD). Evidence on respiratory adverse effects and health status is scarce and conflicting. To assess the effects of regular, low-dose, oral sustained-release morphine on disease-specific health status (COPD Assessment Test; CAT), respiratory outcomes, and breathlessness in patients with COPD. Participants were randomly assigned to 10 mg of regular, oral sustained-release morphine or placebo twice daily for 4 weeks, with the possibility to increase to 3 times daily after 1 or 2 weeks. The Morphine for Treatment of Dyspnea in Patients With COPD (MORDYC) study was a randomized, double-blind, and placebo-controlled study of a 4-week intervention. Patients were enrolled between November 1, 2016, and January 24, 2019. Participants were recruited in a pulmonary rehabilitation center and 2 general hospitals after completion of a pulmonary rehabilitation program. Outpatients with COPD and moderate to very severe chronic breathlessness (modified Medical Research Council [mMRC] breathlessness grades 2-4) despite optimal pharmacological and nonpharmacological treatment were included. A total of 1380 patients were screened, 916 were ineligible, and 340 declined to participate. Primary outcomes were CAT score (higher scores represent worse health status) and arterial partial pressure of carbon dioxide (Paco2). Secondary outcome was breathlessness in the previous 24 hours (numeric rating scale). Data were analyzed by intention to treat. Subgroup analyses in participants with mMRC grades 3 to 4 were performed. A total of 111 of 124 included participants were analyzed (mean [SD] age, 65.4 [8.0] years; 60 men [54%]). Difference in CAT score was 2.18 points lower in the morphine group (95% CI, -4.14 to -0.22 points; P = .03). Difference in Paco2 was 1.19 mm Hg higher in the morphine group (95% CI, -2.70 to 5.07 mm Hg; P = .55). Breathlessness remained unchanged. Worst breathlessness improved in participants with mMRC grades 3 to 4 (1.33 points lower in the morphine group; 95% CI, -2.50 to -0.16 points; P = .03). Five participants of 54 in the morphine group (9%) and 1 participant of 57 in the placebo group (2%) withdrew because of adverse effects. No morphine-related hospital admissions or deaths occurred. In this randomized clinical trial, regular, low-dose, oral sustained-release morphine for 4 weeks improved disease-specific health status in patients with COPD without affecting Paco2 or causing serious adverse effects. The worst breathlessness improved in participants with mMRC grades 3 to 4. A larger randomized clinical trial with longer follow-up in patients with mMRC grades 3 to 4 is warranted. ClinicalTrials.gov Identifier: NCT02429050.

LO68: Kelowna emergency department buprenorphine/naloxone for opioid use disorder: a program evaluation study

Introduction: Emergency department (ED) buprenorphine/naloxone inductions for opioid use disorder are an effective and safe way to initiate addictions care in the ED. Kelowna General Hospital's ED buprenorphine/naloxone (KEDSS) program was implemented in September 2018 in order to respond to a community need for accessible and evidence-based addictions care. The objective of our program evaluation study was to examine the implementation of the first five months of the KEDSS program through evaluating patient characteristics and service outcomes. Methods: The KEDSS treatment pathway consists of a standardized protocol (pre-printed order set) to facilitate buprenorphine/naloxone induction and stabilization in the acute care setting (ED and inpatient wards) at Kelowna General Hospital, a community academic hospital. All patients referred to the outpatient addictions clinic via the order set during September 2018-January 2019 (the first 5 months) were included in the study population. A retrospective descriptive chart review was completed. Outcome measures included population characteristics (sociodemographic information, clinical characteristics) and service outcomes (number of patients initiated, patient follow-up). Descriptive statistics and bivariate analyses using t-tests or Pearson's χ2 statistic, as appropriate, were conducted to compare the ED-initiated group with the inpatient-initiated group. Results: During the first five months of the KEDSS program, a total of 35 patients (26% female, mean age 36.6 years, 54% homeless) were started on the treatment pathway, 16 (46%) in the ED. Compared to the inpatient-initiated group, the ED-initiated group were less likely to have psychiatric comorbidities (ED 1.0 vs. inpatient 1.5, p = 0.002), require methadone or sustained-release oral morphine (ED 13% vs. inpatient 37%, p = 0.048), and have attended follow-up (ED 56% vs. inpatient 84%, p = 0.004). Conclusion: This study provides a preliminary look at a new opioid agonist therapy (OAT) treatment pathway (KEDSS) at Kelowna General Hospital, and provides insight into the population that is accessing the program. We found that the majority of patients who are started on buprenorphine/naloxone in the ED are seen in follow-up at the addictions clinic. Future work will examine ongoing follow-up and OAT adherence rates in the study population to quantify the program's impact on improving access to addictions treatment within this community hospital setting.

Breathlessness and opioid prescribing in COPD in general practice: a cross-sectional, observational study.

Chronic breathlessness is a disabling syndrome, prevalent in people with advanced chronic obstructive pulmonary disease (COPD). Regular, low-dose, oral sustained-release morphine is approved in Australia to reduce symptomatic chronic breathlessness. We aimed to determine the current prescribing patterns of opioids for chronic breathlessness in COPD in Australian general practice and to define any associated patient and practitioner characteristics.Five years (2011 to 2016) of the Bettering the Evaluation and Care of Health database, an Australian national, continual, cross-sectional study of clinical care in general practice were used. The database included 100 consecutive clinical encounters from almost 1000 general practitioners annually (n=488 100 encounters). Descriptive analyses with subsequent regression models were generated.Breathlessness as a patient-defined reason for encounter was identified in 621 of 4522 encounters where COPD was managed. Opioids were prescribed in 309 of 4522 encounters where COPD was managed (6.8%; (95% CI) 6.1–7.6), of which only 17 were prescribed for breathlessness, and the rest for other conditions almost entirely related to pain. Patient age (45–64 years versus age 80+ years, OR 1.68; 1.19–2.36), Commonwealth Concession Card holders (OR 1.70; 1.23–2.34) and socioeconomic disadvantage (OR 1.30; 1.01–1.68) were associated with increased likelihood of opioid prescription at COPD encounters. The rate of opioid prescriptions rose over the 5 years of study.In primary care encounters for COPD, opioids were prescribed in 6.8% of cases, but almost never for breathlessness. These data create a baseline against which to compare changes in prescribing as the treatment of chronic breathlessness evolves.

No excess harms from sustained-release morphine: a randomised placebo-controlled trial in chronic breathlessness

ObjectivesWe aimed to identify and evaluate: (1) treatment-emergent adverse events (TEAE (worse or new since baseline)) and the subgroup of severe TEAEs in a placebo-controlled 7-day randomised trial of regular,...

A preliminary study of the effect of naldemedine tosylate on opioid-induced nausea and vomiting.

Opioid-induced nausea and vomiting (OINV) is induced by opioid receptor stimulation of chemoreceptor trigger zones and vestibular apparatus by opioids. Naldemedine tosylate (NALD) is a peripherally acting non-selective opioid receptor antagonist, used for opioid-induced constipation (OIC). However, the effect of NALD on OINV had not yet been investigated. In this retrospective study, we investigated the secondary effects of NALD on OINV. Patients who received sustained-release oral morphine or oxycodone preparation were enrolled in the study. Patients who used NALD (0.2mg) within 2days of opioid initiation were included in the analysis. The use of rescue antiemetics within 7days from opioid initiation was defined as OINV expression. Patients who received antiemetics before opioid initiation or those who received chemotherapy around 4days from opioid initiation were excluded from the analysis. The incidence of OINV was compared between patients who used and did not use NALD. In total, 982 patients were included in the study. Among them, 89 patients who received NALD and 614 patients who did not receive NALD were analyzed. The incidence of OINV in patients who used NALD was significantly lower than that of patients who did not use NALD (36.0% vs. 47.2%, p = 0.046). For patients with constipation, using NALD at an early stage of opioid initiation might have secondary benefits, such as relief from OINV, besides improvement of OIC. To confirm the effectiveness of NALD for OINV, the symptom grade and intensity during concomitant use of NALD should be observed in a future study.

1793P - Painkiller-related dizziness in malignant tumors: A systematic review

Background: To our knowledge, there is no systematic review on painkiller-related dizziness, which often occurs. Methods: Papers from core clinical journals on PubMed-database resulted in 340 articles on dizziness in malignant tumors until 31st Dec 2017. Eight studies with level of evidence (LoE) 1 focused on dizziness as a side effect of painkillers. Results: In a meta-analysis on codeine, dizziness was reported in 18.06 % of patients (LoE 1a) [1]. In randomized controlled trials (LoE 1b), oxycodone-associated dizziness was only seen in controlled release (8.3 %) and not in immediate release oxycodone [2]. In a systematic review (LoE 1a) [3], controlled release oxycodone was associated with 11.9 % of dizziness reports. A meta-analysis on immediate release morphine and transmucosal fentanyl (7 % dizziness) favoured transmucosal fentanyl for breakthrough cancer pain, but did not differentiate between the painkillers for dizziness [4]. Effective analgesia with rare (1.8 to 7.5 %) events of dizziness was reported for intranasal fentanyl spray (LoE 1b) [5]. For long-acting analgesia, a systematic review favoured transdermal fentanyl over sustained release oral morphine (LoE 1a) [6]. A randomized controlled trial in bone metastases favoured the combination of two nonsteroidal anti-inflammatory drugs (NSAIDs) plus morphine (10.3 % dizziness reports) over one NSAID plus morphine (> 25 %), presumably due to lower morphine need in two NSAIDs (LoE 1b) [7]. Finally, both hydromorphone and morphine had at least 15 % of dizziness reports in a systematic review (LoE 1a) [8]. Conclusions: There is level of evidence 1a to 1b that immediate release oxycodone, transmucosal or intranasal fentanyl are associated with the lowest incidence of dizziness. For long-acting analgesia, transdermal fentanyl is a promising option.

Compliance for Transdermal Fentanyl Patch versus Sustained Release Oral Morphine in Cancer Pain

Compliance for Transdermal Fentanyl Patch versus Sustained Release Oral Morphine in Cancer Pain

Ondansetron Does Not Reduce Withdrawal in Patients With Physical Dependence on Chronic Opioid Therapy.

Individuals taking opioids for an extended period of time may become physically dependent, and will therefore experience opioid withdrawal should they stop taking the medication. Previous work in animal and human models has shown that the serotonin (5-HT3) receptor may be implicated in opioid withdrawal. In this study, we investigated if ondansetron, a 5-HT3-receptor antagonist, could reduce the symptoms of opioid withdrawal after chronic opioid exposure in humans. In this double-blinded, randomized, crossover study, 33 chronic back pain patients (N = 33) were titrated onto sustained-release oral morphine for 30 days. After titration, participants attended 2 study sessions, 1 week apart, in which opioid withdrawal was induced with intravenous naloxone, with or without 8 mg intravenous ondansetron pretreatment. Opioid withdrawal symptoms were assessed by a blinded research assistant (objective opioid withdrawal score [OOWS]) and by the research participant (subjective opioid withdrawal score [SOWS]). Clinically significant signs of withdrawal were observed during both the ondansetron (ΔOOWS = 3.58 ± 2.22, P < 0.0001; ΔSOWS = 12.48 ± 11.18, P < 0.0001) and placebo sessions (ΔOOWS = 3.55 ± 2.39, P < 0.0001; ΔSOWS = 12.21 ± 10.72, P < 0.0001), but no significant differences were seen between the treatment sessions in either the OOWS or SOWS scores. We hypothesized that ondansetron would reduce opioid withdrawal symptoms in human subjects, but found no difference in withdrawal severity between ondansetron and placebo sessions. These findings suggest that more investigation may be necessary to determine if 5-HT3-receptor antagonists are suitable treatment options for opioid withdrawal.

Ondansetron does not prevent physical dependence in patients taking opioid medications chronically for pain control

ObjectivesIn this study, we investigated the co-administration of ondansetron with morphine, and whether it could prevent the development of physical dependence in patients taking opioids for the treatment of chronic pain. MethodsA total of 48 chronic back pain patients (N = 48) participated in this double-blinded, placebo-controlled, randomized study. Patients were titrated onto sustained-release oral morphine and randomized to take 8 mg ondansetron or placebo three times daily concurrently with morphine during the 30-day titration. Following titration, patients underwent Naloxone induced opioid withdrawal. Opioid withdrawal signs and symptoms were then assessed by a blinded research assistant (objective opioid withdrawal score: OOWS) and by the research participant (subjective opioid withdrawal score: SOWS). ResultsWe observed clinically significant signs of naloxone-precipitated opioid withdrawal in all participants (ΔOOWS = 4.3 ± 2.4, p < 0.0001; ΔSOWS = 14.1 ± 11.7, p < 0.0001), however no significant differences in withdrawal scores were detected between treatment groups. ConclusionWe hypothesized that ondansetron would prevent the development of physical dependence in human subjects when co-administered with opioids, but found no difference in naloxone-precipitated opioid withdrawal scores between ondansetron and placebo treatment groups. These results suggest that further studies are needed to determine if 5HT3 receptor antagonists are useful in preventing opioid physical dependence.

Preoperative Oral Morphine and Sub-Anesthetic Ketamine Co-Administration Reduce Acute Post-Mastectomy Pain

Objectives: To assess the analgesic efficacy and tolerability of co-administration of pre-emptive single oral dose of sustained release morphine and sub- anesthetic ketamine infusion for modified radical mastectomy (MRM) with axillary evacuation. Methods: Sixty four adult female patients scheduled for MRM were divided to two groups, morphine group (n=32) received preoperative oral sustained release morphine tablet, 30 mg and placebo group (n=32) received placebo tablet. Both groups received preoperative ketamine bolus, 0.5 mg/kg followed by continuous infusion 0.1 mg/kg/h for 24 h postoperatively. VAS pain score, time to first analgesic request, 24 h analgesic consumption were reported. Results: The mean VAS pain score during movement was significantly decreased in morphine group in comparison to placebo group from 2 h till 72 h postoperatively, 2 h (2.87 ± 1.0 vs. 4.53 ± 1.67) mean difference (-1.67) (95% CI)-(2.38-0.95), 72 h (1.20 ± 0.76 vs. 1.83 ± 0.91) mean difference (-0.63) (95% CI)-(1.07-0.20) while the mean VAS pain score during rest was significantly decreased in morphine group in comparison to placebo group from 2 h till 24 h postoperatively, 2 h (2.03 ± 0.85 vs. 3.47 ± 0.93) mean difference (-1.33) (95% CI)-(1.78-0.90), 24 h (1.40 ± 0.72 vs. 1.77 ± 0.68) mean difference (-0.37) (95% CI)-(0.73-0.01). The median (IQ) time to first analgesic request was significantly delayed in morphine group in comparison to placebo group, 11.8 (9.7:14.2) h vs. 2.3 (2.1:2.5) h, (P<0.001). The number (percentage) of patients required paracetamol in the first postoperative 24 h was significantly lower in morphine group in comparison to placebo group, 10 (33%) vs. 30 (100 %) (P<0.001). Conclusion: Analgesic technique based on pre-emptive sustained release oral morphine and perioperative infusion of sub-anesthetic dose of ketamine provides satisfactory analgesia for patients undergoing MRM.

A randomized controlled trial on the benefits and respiratory adverse effects of morphine for refractory dyspnea in patients with COPD: Protocol of the MORDYC study

Dyspnea is one of the most reported symptoms of patients with advanced Chronic Obstructive Pulmonary Disease (COPD) and is often undertreated. Morphine has proven to be an effective treatment for dyspnea and is recommended in clinical practice guidelines, but questions concerning benefits and respiratory adverse effects remain. This study primarily evaluates the impact of oral sustained release morphine (morphine SR) on health-related quality of life and respiratory adverse effects in patients with COPD. Secondary objectives include the impact on exercise capacity, the relationship between description and severity of dyspnea and the presence of a clinically relevant response to morphine, and cost-effectiveness.A single-center, randomized, double blind, placebo controlled intervention study will be performed in 124 patients with COPD who recently completed a comprehensive pulmonary rehabilitation program. Participants will receive 20–30mg/24h morphine SR or placebo for four weeks. After the intervention, participants will be followed for twelve weeks. Outcomes include: the COPD Assessment Test, six minute walking test, Multidimensional Dyspnea Scale and a cost diary. Furthermore, lung function and arterial blood gasses will be measured. These measures will be assessed during a baseline and outcome assessment, two home visits, two phone calls, and three follow-up assessments. The intervention and control group will be compared using uni- and multivariate regression analysis and logistic regression analysis. Finally, an economic evaluation will be performed from a societal and healthcare perspective. The current manuscript describes the rationale and methods of this study and provides an outline of the possible strengths, weaknesses and clinical consequences.

Effects of low-dose morphine on perceived sleep quality in patients with refractory breathlessness: A hypothesis generating study.

The management of chronic refractory breathlessness is one of the indications for regular low-dose (≤30 mg/24 h) oral sustained release morphine. Morphine may disrupt sleep in some conditions and improve sleep quality in others. This study aimed to determine any signal of regular, low-dose morphine on perceived sleep disruption due to breathlessness and perceived sleep quality. This is a secondary analysis of data from 38 participants with refractory breathlessness (30 male; 33 with COPD) aged 76 ± 0.9 years who completed a double-blind, randomized, placebo-controlled, cross-over study in which they received 20 mg oral sustained release morphine daily and placebo for 4 days each. Participant ratings of sleep disruption due to breathlessness and perceived sleep quality were obtained daily throughout the 8-day trial. Perceived sleep disruption due to breathlessness over the 4-day period ranged between 13% and 32% of participants for placebo and 13% and 26% for morphine, decreasing by each day of the study during the morphine arm. Most participants reported 'very good' or 'quite good' sleep throughout the trial and were less likely to perceive poor sleep quality during the morphine arm (odds ratio = 0.55, 95% confidence interval: 0.34-0.88, P = 0.01). Participants who reported decreased breathlessness during the 4 days on morphine were also likely to report improved sleep quality with morphine (P = 0.039). Four days of low-dose morphine improved perceived sleep quality in elderly participants with refractory breathlessness. Regular low-dose morphine targeted to reduce refractory breathlessness may yield associated benefits by reducing sleep disruption and improving sleep quality.

Understanding Heroin Overdose: A Study of the Acute Respiratory Depressant Effects of Injected Pharmaceutical Heroin.

Opioids are respiratory depressants and heroin/opioid overdose is a major contributor to the excess mortality of heroin addicts. The individual and situational variability of respiratory depression caused by intravenous heroin is poorly understood. This study used advanced respiratory monitoring to follow the time course and severity of acute opioid-induced respiratory depression. 10 patients (9/10 with chronic airflow obstruction) undergoing supervised injectable opioid treatment for heroin addiction received their usual prescribed dose of injectable opioid (diamorphine or methadone) (IOT), and their usual prescribed dose of oral opioid (methadone or sustained release oral morphine) after 30 minutes. The main outcome measures were pulse oximetry (SpO2%), end-tidal CO2% (ETCO2%) and neural respiratory drive (NRD) (quantified using parasternal intercostal muscle electromyography). Significant respiratory depression was defined as absence of inspiratory airflow >10s, SpO2% < 90% for >10s and ETCO2% per breath >6.5%. Increases in ETCO2% indicated significant respiratory depression following IOT in 8/10 patients at 30 minutes. In contrast, SpO2% indicated significant respiratory depression in only 4/10 patients, with small absolute changes in SpO2% at 30 minutes. A decline in NRD from baseline to 30 minutes post IOT was also observed, but was not statistically significant. Baseline NRD and opioid-induced drop in SpO2% were inversely related. We conclude that significant acute respiratory depression is commonly induced by opioid drugs prescribed to treat opioid addiction. Hypoventilation is reliably detected by capnography, but not by SpO2% alone. Chronic suppression of NRD in the presence of underlying lung disease may be a risk factor for acute opioid-induced respiratory depression.

Oral ketamine for phantom limb pain: An option for challenging cases

Phantom limb pain (PLP) is a referred neuropathic pain perceived to arise from an amputated part of the body. It occurs in up to 80% of limb amputees and affects the patient's quality of life and rehabilitation.[1,2] The mechanisms of PLP remain unknown but involve both peripheral and central neural factors including activation of N-methyl-D-aspartate (NMDA) receptors.[2] Although ketamine, an NMDA receptor blocker, has been successfully used in many neuropathic pain conditions, its role in treating PLP is unclear.[3,4] We describe a challenging case of PLP where treatment with oral ketamine provided adequate relief.

The effect of prolonged exposure to morphine on canine cerebral 5-HT2A receptors measured with 123I-R91150 SPECT

Down-stream neuronal alterations, including changes in the 5-HT-2A receptor system, play an important role in the etiology and treatment of depression. The present study examined the effect of prolonged opioid treatment on cerebral 5-HT2A receptors. Cerebral 5-HT2A receptor availability was estimated in seven healthy five-year-old female neutered Beagle dogs pre and post 10-day morphine treatment (oral sustained release morphine 20mg twice daily for 10 days) with 123I-R-91150, a 5-HT2A selective radioligand, and SPECT. 5-HT2A receptor binding indices (BI) for the frontal, parietal, temporal and occipital cortex and the subcortical region were calculated. Statistical analysis was performed using a linear mixed-effect model with treatment as fixed effect and dog as random effect. Morphine treatment significantly (P≤0.05) lowered 5-HT2A BIs in the right and left frontal cortex, the right and left temporal cortex, the right and left parietal cortex, and the subcortical region. The decreased cerebral 5-HT2A receptor availability following prolonged morphine exposure provides further evidence for an interaction between the opioid and serotonergic system.

Starting Step III opioids for moderate to severe pain in cancer patients: Dose titration: A systematic review

The European Association for Palliative Care recommendation for starting morphine for cancer pain is dose titration with immediate release (IR) oral morphine given every 4 h with additionally doses for breakthrough pain. As part of a EU 6th framework programme to revise the guidelines we review the evidence regarding starting treatment and dose titration of opioids in adult patients with moderate to severe cancer pain. Relevant papers were identified though a systematic search in Medline for papers published until the end of 2009. We identified 15 relevant papers. Thirteen papers were descriptive papers reporting the results from starting treatment with oral morphine (six studies), starting treatment with intravenous morphine (two studies) and starting treatment with transdermal fentanyl (four studies). All treatment strategies resulted in acceptable pain control and were well tolerated. Two randomized controlled trials were identified. One study compared starting opioid treatment with intravenous morphine versus IR oral morphine and one study compared IR oral morphine versus sustained release oral morphine.