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

BACKGROUND: 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. METHODS: In a randomized controlled trial, participants with advanced COPD were assigned to 10 mg 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. RESULTS: 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%. CONCLUSION: 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. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02429050).

Oxycodone versus morphine for cancer pain titration: A systematic review and pharmacoeconomic evaluation.

OBJECTIVE: To evaluate the efficacy, safety and cost-effectiveness of Oxycodone Hydrochloride Controlled-release Tablets (CR oxycodone) and Morphine Sulfate Sustained-release Tablets (SR morphine) for moderate to severe cancer pain titration. METHODS: Randomized controlled trials meeting the inclusion criteria were searched through Medline, Cochrane Library, Pubmed, EMbase, CNKI,VIP and WanFang database from the data of their establishment to June 2019. The efficacy and safety data were extracted from the included literature. The pain control rate was calculated to eatimate efficacy. Meta-analysis was conducted by Revman5.1.4. A decision tree model was built to simulate cancer pain titration process. The initial dose of CR oxycodone and SR morphine group were 20mg and 30mg respectively. Oral immediate-release morphine was administered to treat break-out pain. The incremental cost-effectiveness ratio was performed with TreeAge Pro 2019. RESULTS: 19 studies (1680 patients)were included in this study. Meta-analysis showed that the pain control rate of CR oxycodone and SR morphine were 86% and 82.98% respectively. The costs of CR oxycodone and SR morphine were $23.27 and $13.31. The incremental cost-effectiveness ratio per unit was approximate $329.76. At the willingness-to-pay threshold of $8836, CR oxycodone was cost-effective, while the corresponding probability of being cost-effective at the willingness-to-pay threshold of $300 was 31.6%. One-way sensitivity analysis confirmed robustness of results. CONCLUSIONS: CR oxycodone could be a cost-effective option compared with SR morphine for moderate to severe cancer pain titration in China, according to the threshold defined by the WHO.

Slow release oral morphine versus methadone for opioid use disorder in the fentanyl era (pRESTO): Protocol for a non-inferiority randomized clinical trial.

BACKGROUND: North America is facing an unprecedented public health crisis of opioid-related morbidity and mortality, increasingly as a result of the introduction of illicitly manufactured fentanyl into the street drug market. Although the treatment of opioid use disorder (OUD) is a key element in the response to the opioid overdose epidemic, currently available pharmacotherapies (e.g., methadone, buprenorphine) may not be acceptable to or effective in all patients. Available evidence suggests that slow-release oral morphine (SROM) has similar efficacy rates as methadone with respect to promoting abstinence, and with improvements in a number of patient-reported outcomes among persons using heroin. However, little is known about the relative effectiveness and acceptability of SROM compared to methadone in the context of fentanyl use. This study aims to address this research gap. METHODS: pRESTO is a 24-week, open-label, two arm, non-inferiority, randomized controlled trial comparing SROM versus methadone for the treatment of OUD. Participants will be 298 clinically stable, non-pregnant adults with OUD, recruited from outpatient clinics in Vancouver, Canada, where the majority of the illicit opioids are contaminated with fentanyl. The primary outcome is suppression of illicit opioid use, measured by bi-weekly urine drug screens. Secondary outcomes include: treatment retention, medication safety, overdose events, treatment satisfaction, psychological functioning, changes in drug-related problems, changes in quality of life, opioid cravings, other substance use, and cost-effectiveness. DISCUSSION: pRESTO will be among the first studies to evaluate treatment options for individuals primarily using synthetic street opioids, providing important evidence to guide treatment strategies for this population.

Patient-Controlled Intravenous Morphine Analgesia Combined with Transcranial Direct Current Stimulation for Post-Thoracotomy Pain: A Cost-Effectiveness Study and A Feasibility For Its Future Implementation.

This prospective randomized study aims to evaluate the feasibility and cost-effectiveness of combining transcranial direct current stimulation (tDCS) with patient controlled intravenous morphine analgesia (PCA-IV) as part of multimodal analgesia after thoracotomy. Patients assigned to the active treatment group (a-tDCS, n = 27) received tDCS over the left primary motor cortex for five days, whereas patients assigned to the control group (sham-tDCS, n = 28) received sham tDCS stimulations. All patients received postoperative PCA-IV morphine. For cost-effectiveness analysis we used data about total amount of PCA-IV morphine and maximum visual analog pain scale with cough (VASP-Cmax). Direct costs of hospitalization were assumed as equal for both groups. Cost-effectiveness analysis was performed with the incremental cost-effectiveness ratio (ICER), expressed as the incremental cost (RSD or US$) per incremental gain in mm of VASP-Cmax reduction. Calculated ICER was 510.87 RSD per VASP-Cmax 1 mm reduction. Conversion on USA market (USA data 1.325 US$ for 1 mg of morphine) revealed ICER of 189.08 US$ or 18960.39 RSD/1 VASP-Cmax 1 mm reduction. Cost-effectiveness expressed through ICER showed significant reduction of PCA-IV morphine costs in the tDCS group. Further investigation of tDCS benefits with regards to reduction of postoperative pain treatment costs should also include the long-term benefits of reduced morphine use.

Clinical and Economic Analysis of Morphine Versus Fentanyl in Managing Ventilated Neonates With Respiratory Distress Syndrome in the Intensive Care Setting.

PURPOSE: Morphine and fentanyl opioids are common analgesic agents for consideration in the neonatal intensive care unit (NICU) for neonates with respiratory distress syndrome (RDS) and undergoing mechanical ventilation (MV). The aim of this study was to evaluate the clinical and economic impact of morphine versus fentanyl in neonates with RDS undergoing MV. METHODS: Retrospective cost-effectiveness analysis of critically ill neonates with RDS receiving standard doses of morphine versus fentanyl at Women's Wellness and Research Center, Qatar. Clinical data of neonates were extracted from medical records of patients from 2014 to 2016. A decision analytic model based on the hospital's perspective was constructed to follow possible consequences of the initial dosing of analgesia, before potential titration. Primary end points were successful pain relief rate based on the Premature Infant Pain Profile scale and overall direct medical cost of therapy. Study population of 126 neonates was used to achieve results with 80% power and 0.05 significance. Sensitivity analysis was conducted to enhance robustness of conclusions against input uncertainties and to increase generalizability of results. FINDINGS: Morphine achieved a success of 68% versus 43% with fentanyl (risk ratio = 1.72; 95% CI, 1.16-2.56; P = 0.0075). Morphine was associated with a minimal incremental cost-effectiveness ratio of USD 135 per additional case of successful pain relief over fentanyl. Higher morphine cost was reported in 2% of cases. Sensitivity analysis found model insensitivity to input uncertainties except NICU stay and cost of MV. IMPLICATIONS: This is the first cost-effectiveness evaluation of morphine versus fentanyl in the NICU. Morphine significantly improved the relieve of pain over fentanyl. It had 98% probability of dominance over fentanyl. Results in this study support the use of morphine over fentanyl as first-line monotherapy with MV in NICU settings.

Intra-operative low-dose ketamine does not reduce the cost of post-operative pain management after surgery: a randomized controlled trial in a low-income country.

BACKGROUND: In developing countries, post-operative pain remains underestimated and undertreated due to economic constraints, lack of awareness and limited resources. In contrast, ketamine is an effective, readily available, easy to use and inexpensive drug frequently used in poor settings. OBJECTIVES: The aim of this study was to explore the overall reduction in the medication treatment cost of acute post-operative pain by adding intra-operative low-dose ketamine to traditional intravenous morphine for surgery in a low-income country. METHODS: A double blind randomized controlled trial with placebo-controlled parallel group was performed in Mulago National Hospital (Uganda). Consenting adults scheduled for elective surgery were randomized into two study arms: Group K received ketamine 0.15mg/kg bolus at induction and a continuous infusion of 0.12 mg/kg/hour till start of skin closure; Group C (control) received normal saline. Both groups received Morphine 0.1 mg/kg IV at debulking. The total medication cost was registered. NRS pain scores and other measurements such vital signs and incidence of major and minor side effects were also recorded. RESULTS: A total of 46 patients were included. Patients' baseline characteristics were comparable in both groups. No statistically significant difference was found between the groups concerning the overall medication cost of post-operative pain management. Pain scores, patients' satisfaction in the first 24 hours after surgery and hospital length of stay were similar in both groups. CONCLUSION: Our results do not support the utilization of intra-operative low dose ketamine as a cost-saving post-operative pain treatment strategy for all types of surgery in low-resource settings.

Availability and affordability of priority life-saving medicines for under-five children in health facilities of Tigray region, northern Ethiopia.

BACKGROUND: In developing countries, child health outcomes are influenced by the non-availability of priority life-saving medicines at public sector health facilities and non-affordability of medicines at private medicine outlets. This study aimed to assess availability, price components and affordability of priority life-saving medicines for under-five children in Tigray region, Northern Ethiopia. METHODS: A cross-sectional study was conducted in Tigray region from December 2015 to July 2016 using a standard method developed by the World Health Organization and Health Action International (WHO/HAI). Data on the availability and price of 27 priority life-saving medicines were collected from 31 public and 10 private sectors. Availability and prices were expressed in percent and median price ratios (MPRs), respectively. Affordability was reported in terms of the daily wage of the lowest-paid unskilled government worker. RESULTS: The overall availability of priority life-saving drugs in this study was low (34.1%). The average availabilities of all surveyed medicines in public and private sectors were 41.9 and 31.5%, respectively. The overall availability of medicines for malaria was found to be poor with average values of 29.3% for artemisinin combination therapy tablet, 19.5% for artesunate injection and 0% for rectal artesunate. Whereas, the availability of oral rehydration salt (ORS) and zinc sulphate dispersible tablets for the treatment of diarrhea was moderately high (90% for ORS and 82% for zinc sulphate). Medicines for pneumonia showed an overall percent availability in the range of 0% (ampicillin 250 mg and 1 g powder for injection and oxygen medicinal gas) to 100% (amoxicillin 500 mg capsule). The MPRs of 12 lowest price generic medicines were 1.5 and 2.7 times higher than the international reference prices (IRPs) for the private and public sectors, respectively. About 30% of priority life-saving medicines in the public sector and 50% of them in the private sector demanded above a single daily wages to purchase the standard treatment of the prevalent diseases of children. CONCLUSIONS: The lower availability, high price and low affordability of lowest price generic priority life-saving medicines in public and private sectors reflect a failure to implement the health policy on priority life-saving medicines in the region.

Opioid Medications in Expensive Formulations Are Sold at a Lower Price than Immediate-Release Morphine in Countries throughout the World: Third Phase of Opioid Price Watch Cross-Sectional Study.

BACKGROUND: International Association for Hospice and Palliative Care implemented Opioid Price Watch (OPW) to monitor availability, dispensing prices and affordability of opioids. We found that opioids with complex delivery mechanisms [fentanyl transdermal (TD) patches, sustained-release (SR) morphine, and SR oxycodone] had lower dispensing prices than immediate-release (IR) morphine formulations. OBJECTIVE: Identify the extent that SR and TD formulations are dispensed at lower prices than generic IR morphine and the possible reasons to explain this observation. DESIGN: Using OPW data for 30-day treatment Defined Daily Dosages, we identified where SR and TD formulations are dispensed at lower prices than IR morphine. Then we analyzed national lists of essential medicines (EML) in middle- and low-income countries to answer two questions: (1) Do they have opioids included? If yes, (2) Which ones? We then sought information on selection, budget allocation, and procurement for EML. OPW participants confirmed/verified the EML information. RESULTS: Eighteen countries reported higher dispensing prices for IR morphine (oral and/or injectable) than TD or SR formulation. Injectable morphine was highest in seven and lowest in two (range: $74-$742). SR morphine was the least expensive, while TD fentanyl was second. Median dispensing price for IR oral morphine was higher than SR morphine. The EML for 10 countries include opioids in TD and/or SR formulations. CONCLUSIONS: Opioids in expensive formulations are being favored over IR morphine both at the dispensing level and in their inclusion in national EML. Governments must take decisions based on efficacy, safety, and cost-effectiveness of medications.

Cost comparison of intrathecal morphine to intravenous patient-controlled analgesia for the first 24 h post cesarean delivery: a retrospective cohort study.

PURPOSE: Intrathecal morphine provides superior pain control for patients undergoing cesarean delivery when compared to intravenous opioid patient-controlled analgesia. However, no study has assessed the overall cost associated with each modality as a primary outcome. The aim of this study is to determine the overall cost of each modality for the first 24 h post cesarean delivery. METHODS: Charts of patients undergoing cesarean delivery at our institution from January 1, 2014 to December 31, 2014 were reviewed. Patients receiving intrathecal morphine were compared to patients undergoing general anesthesia and receiving intravenous opioid patient-controlled analgesia for post-procedure analgesia. The primary outcome measured was total cost of each modality for the first 24 h after delivery. Secondary outcomes included post-procedure pain scores, time to removal of the Foley catheter, need for rescue medications, and adverse events. RESULTS: There was a significant difference in total cost of intrathecal morphine when compared to intravenous opioid patient-controlled analgesia ($51.14 vs. $80.16, p < 0.001). Average pain scores between 0-1 h (0 vs. 5, p < 0.001) and 1-6 h (2.5 vs. 3.25, p < 0.001) were less in the intrathecal morphine group. The intrathecal morphine group received more ketorolac (p < 0.001) and required more rescue opioids (p = 0.042). There were no significant differences in documented adverse events. CONCLUSIONS: The use of intrathecal morphine for post-cesarean pain control leads to a significant cost savings for the first 24 h when compared to intravenous opioid patient-controlled analgesia. Patients also experienced less pain and were not at increased risk for adverse events.

Intrathecal Morphine Infusion Therapy in Management of Chronic Pain: Present and Future Implementation in Korea.

PURPOSE: Intrathecal morphine pump (ITMP) infusion therapy is efficient in managing malignant and nonmalignant chronic pain refractory to standard treatment. However, the high cost of an ITMP is the greatest barrier for starting a patient on ITMP infusion therapy. Using the revised Korean reimbursement guidelines, we investigated the cost effectiveness of ITMP infusion therapy and conducted a patient survey. MATERIALS AND METHODS: A retrospective chart review of 12 patients who underwent ITMP implantation was performed. Morphine dose escalation rates were calculated, and numeric rating scale (NRS) scores were compared before and after ITMP implantation. We surveyed patients who were already using an ITMP as well as those who were candidates for an ITMP. All survey data were collected through in-person interviews over 3 months. Data on the cost of medical treatment were collected and projected over time. RESULTS: The NRS score decreased during the follow-up period. The median morphine dose increased by 36.9% over the first year, and the median time required to reach a financial break-even point was 24.2 months. Patients were more satisfied with the efficacy of ITMP infusion therapy than with conventional therapy. The expected cost of ITMP implantation was KRW 4000000-5000000 in more than half of ITMP candidates scheduled to undergo implantation. CONCLUSION: The high cost of initiating ITMP infusion therapy is challenging; however, the present results may encourage more patients to consider ITMP therapy.

Comparison of intravenous morphine and paracetamol.

One of the main complaints from patients who present to emergency departments with illness or injury is pain, yet often this is not well managed in emergency settings. Nurse prescribers are in an ideal position to make a rapid assessment and then prescribe and treat patients' pain, and must quickly decide which is the safest and most effective drug for each individual. This article compares intravenous morphine with intravenous paracetamol for managing pain in patients with isolated limb trauma who then require manipulation under sedation. A case study examines the decision-making process.

Positive subjective measures in abuse liability studies and real-world nonmedical use: Potential impact of abuse-deterrent opioids on rates of nonmedical use and associated healthcare costs.

OBJECTIVE: To quantify the potential impact of reductions in positive subjective measures from human abuse liability studies on real-world rates of nonmedical use of prescription drugs and associated healthcare resource utilization and costs. DESIGN: Positive subjective endpoints "overall drug liking," in-the-moment "drug liking," and "drug high" Emaxs (peak effects) were recorded from published studies. Nonmedical use data were obtained from the 2010 National Survey on Drug Use and Health (NSDUH) and Drug Abuse Warning Network surveys. Multivariate regressions evaluated the association between the positive subjective endpoints and nonmedical use rates, controlling for prescription volume, whether the drug is an opioid, and controlled substance schedule. A published budget-impact model was used to assess healthcare resource utilization and cost impacts of abuse-deterrent opioid formulations. RESULTS: A five-point reduction in overall drug liking/drug liking/drug high Emax was associated with a 0.25/0.10/0.05 (standard errors: 0.11/0.12/0.07) percentage point decrease in the NSDUH lifetime nonmedical use rates. Those decreases yielded a 11.3/4.2/2.1 percent reduction compared to the samples' lifetime nonmedical use rates of 2.21/2.38/2.36 percent. On the basis of a number of assumptions, these reductions were associated with private payer cost reductions for a morphine and oxycodone abuse-deterrent formulation in the ranges of $147.9-324.1 million and $230.7-958.7 million, respectively. CONCLUSIONS: Reductions in overall drug liking were significantly associated with reduced real-world nonmedical use, healthcare utilization, and costs. Associations using drug high and drug liking were directionally consistent with this finding though not statistically significant. A reduction in positive subjective measures associated with an abuse-deterrent formulation has potential to reduce abuse and associated healthcare utilization and costs.

Pharmacoeconomics evaluation of morphine, MS contin and oxycodone in the treatment of cancer pain.

OBJECTIVE: To analyze cost-effectiveness of morphine, MS contin and oxycodone in the treatment of cancer pain, providing guidance for rational drug use in the clinic. METHODS: Confirmed by histology, a total of 171 patients with various cancers who required analgesic treatment were selected and divided into 3 groups, 57 cases for each group, given morphine, MS contin and oxycodone, respectively. If there appeared a poor short-term effect or aggravated sudden pain during the treatment, a short-acting morphine injection was given and adverse reactions were processed by symptomatic treatment. The pain relief rate and adverse reactions of groups were observed and pharmacoeconomics evaluation was undertaken. RESULTS: The pain relief rates with morphine, MS contin and oxycodone were 89.5%(51/57), 91.2%(52/57) and 93.0%(53/57), respectively, with no difference samong groups (χ2=4.4489, P=0.6162). The occurrence rates of adverse reactions were 59.7%(34/57), 54.4%(31/57) and 43.9%(25/57), again with no significant variation (P>0.05). The ratios of cost-effectiveness (C/E) for the 3 groups were 14.6±7.21, 15.0±7.44 and 16.1±8.10. When the price of 3 kinds of analgesics was reduced by 10%, the ratios of cost-effectiveness were 12.2±6.53, (13.4±6.08 and 14.5±6.74 but there was no differences when compared with before the price adjustment (t=1.86, P=0.0651; t=1.30, P=0.1948; t=1.17, P=0.2453). CONCLUSION: Morphine, MS contin and oxycodone give similar pain relief and adverse reaction rates but of all, morphine is the preferred drug for the treatment of cancer pain from the perspective of pharmacoeconomics.

Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in Latin America and the Caribbean: a report from the Global Opioid Policy Initiative (GOPI).

The nations of the Caribbean, Central America and South America form a heterogeneous region with substantial variability in economic, social and palliative care development. Palliative care provision is at varied stages of development throughout the region. The consumption of opioids in Latin America and the Caribbean is variable with moderate levels of consumption by international standards (1-10 mg morphine equivalents/capita/year) observed in Argentine, Brazil, Chile, Colombia, Cuba, Mexico, Costa Rica, Uruguay and most of the Caribbean but relatively low levels of consumption in other countries particularly Guatemala, Honduras and Bolivia. Data for Latin American and Caribbean is reported on the availability and accessibility of opioids for the management of cancer pain in 24 of the 33 countries surveyed. The results of this survey are relevant to 560 million of the region's 595 million people (94%). Opioid availability continues to be low throughout most of Latin America and the Caribbean. While formularies in this region generally include all recommended morphine formulations, access is significantly impaired by widespread over-regulation that continues to be pervasive across the region.

A morphine manifesto.

In conjunction with World Cancer Day 2012, three leading pain and palliative care organizations developed a statement on access to analgesics to provide freedom from pain as a human right. Numerous other professional organizations subsequently signed this manifesto calling upon governments, the pharmaceutical industry, and health institutions to make available immediate-release morphine at affordable prices for all in need of pain relief. This report is reprinted with permission of the originating organizations. For more information see: http://palliumindia.org/manifesto/.

Morphine administration by Paramedics: an application of the Theory of Planned Behaviour.

Timely and appropriate pain management in the pre-hospital environment is paramount to effective patient care. Experts agree that there are many factors that hinder the delivery of adequate pain management to patients with pain. The purpose of this study was to use the Theory of Planned Behaviour (TPB) model to identify the factors influencing Ambulance Paramedics' intention to administer morphine to patients with pain. Participants of this study were Advanced Care and Intensive Care Paramedics who were deemed competent in morphine administration. Data were collected by means of a questionnaire that used the constructs of the TPB, including subjective norm, perceived behavioural control and attitude. Whilst participants reported strong intentions to administer morphine they also reported negative attitudes towards the behaviour. The constructs of the TPB explained 26% of the variance in intention to administer morphine with subjective norm being the strongest significant predictor. The findings related to specific attitudes and normative pressures provide an understanding into Paramedic's pain management behaviour.

Chronic methadone treatment shows a better cost/benefit ratio than chronic morphine in mice.

Chronic treatment of pain with opiate drugs can lead to analgesic tolerance and drug dependence. Although all opiate drugs can promote tolerance and dependence in practice, the severity of those unwanted side effects differs depending on the drug used. Although each opiate drug has its own unique set of pharmacological profiles, methadone is the only clinically used opioid drug that produces substantial receptor endocytosis at analgesic doses. Here, we examined whether moderate doses of methadone carry any benefits over chronic use of equianalgesic morphine, the prototypical opioid. Our data show that chronic administration of methadone produces significantly less analgesic tolerance than morphine. Furthermore, we found significantly reduced precipitated withdrawal symptoms after chronic methadone treatment than after chronic morphine treatment. Finally, using a novel animal model with a degrading µ-opioid receptor we showed that, although endocytosis seems to protect against tolerance development, endocytosis followed by receptor degradation produces a rapid onset of analgesic tolerance to methadone. Together, these data indicated that opioid drugs that promote receptor endocytosis and recycling, such as methadone, may be a better choice for chronic pain treatment than morphine and its derivatives that do not.