Oral Controlled-release Morphine Research Articles

Pharmacokinetic and neuroimmune pharmacogenetic impacts on slow-release morphine cancer pain control and adverse effects

The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. Morphine-3-glucuronide concentrations (standardised to 11 h post-dose) were higher in patients without pain control (median (interquartile range) 1.2 (0.7–2.3) versus 1.0 (0.5–1.9) μM, P = 0.006), whereas morphine concentrations were higher in patients with cognitive dysfunction (40 (20–81) versus 29 (14–60) nM, P = 0.02). TLR2 rs3804100 variant carriers had reduced odds (adjusted odds ratio (95% confidence interval) 0.42 (0.22–0.82), P = 0.01) of opioid adverse events. IL2 rs2069762 G/G (0.20 (0.06-0.52)), BDNF rs6265 A/A (0.15 (0.02–0.63)) and IL6R rs8192284 carrier (0.55 (0.34–0.90)) genotypes had decreased, and IL6 rs10499563 C/C increased (3.3 (1.2–9.3)), odds of sickness response (P ≤ 0.02). The study has limitations in heterogeneity in doses, sampling times and diagnoses but still suggests that pharmacokinetics and immune genetics co-contribute to morphine pain control and adverse effects in cancer patients.

Comparison of the Quality of Life of Cancer Patients with Pain Treated with Oral Controlled-Release Morphine and Oxycodone and Transdermal Buprenorphine and Fentanyl.

To compare the effects of oral morphine and oxycodone and transdermal fentanyl and buprenorphine on quality of life (QoL) of cancer patients with severe pain. Cancer patients with severe pain (NRS 6-10) treated at home and in outpatient clinics who failed to respond to non-opioids and/or "weak" opioids were randomized to morphine, oxycodone, fentanyl, or buprenorphine treatment for 28 days. Immediate-release oral morphine was rescued analgesic and 10-ml lactulose twice daily was prophylaxis of constipation; no antiemetics were used for prophylaxis. Above all, 62 patients participated and 53 patients completed the study. Good analgesia was obtained with all 4 opioids. Morphine was associated with the less negative impact of pain on the ability to walk and normal work, and tendency on activity (BPI-SF) and lower consumption of rescue morphine. All 4 opioids elicited similar adverse effects. According to ESAS, the intensity of nausea and drowsiness increased at the beginning but decreased as treatment continued. Appetite, well-being, anxiety, depression, and fatigue improved. No changes were seen in constipation, vomiting and dyspnea. Constipation was rarely observed with all opioids (BFI). Any opioids improved overall QoL and emotional functioning with tendency improving physical functioning (EORTC QLQ-C15-PAL). Activity improved (Karnofsky). Morphine induced greater improvement in physical functioning and trend in improvement mood (HADS). All opioids significantly improved patients' QoL. Morphine induced less negative impact of pain on daily activities and greater improvement in physical functioning with trends of better mood and less intense fatigue.

The effect of acute exposure to morphine on breathing variability and cardiopulmonary coupling in men with obstructive sleep apnea: A randomized controlled trial.

Opioid-related deaths from respiratory depression are increasing but there is only limited information on the effect of morphine on breathing during sleep. This study aimed to detect and quantify opioid-induced cardiorespiratory pattern changes during sleep in obstructive sleep apnea (OSA) patients using novel automated methods and correlate these with conventional polysomnography (PSG) measures. Under a randomized double-blind placebo-controlled crossover design, 60 male OSA patients attended two one-night visits to the sleep laboratory, at least a week apart. Either a 40-mg controlled-release oral morphine dose or placebo was administered. Breathing during sleep was measured by standard in-laboratory PSG. We analysed the inter-breath interval (IBI) from the PSG flow channel to quantify breathing irregularity. Cardiopulmonary coupling (CPC) was analysed using the PSG electrocardiogram (ECG) channel. Following the consumption of morphine, the 60 OSA patients had fewer breaths (p=.0006), a longer inter-breath interval (p<.0001) and more irregular breathing with increased IBI coefficient of variation (CV) (p=.0015) compared to the placebo night. A higher CPC sleep quality index was found with morphine use. The change of key IBI and CPC parameters was significantly correlated with the change of key PSG sleep-disordered breathing parameters. In conclusion, 40mg controlled-release morphine resulted in a longer breathing cycle and increased breathing irregularity but generally more stable sleep in OSA patients. The significant links between the IBI and CPC techniques and a range of PSG sleep-disordered breathing parameters may suggest a practical value as surrogate overnight cardiorespiratory measurements, because both respiratory flow and ECG can be detected by small portable devices.

The effect of acute morphine on obstructive sleep apnoea: a randomised double-blind placebo-controlled crossover trial

ObjectiveAnaesthesiology guidelines suggest that opioids worsen obstructive sleep apnoea (OSA) despite no randomised controlled trial evidence. We therefore conducted a randomised controlled trial to evaluate the effects of a common...

Comparison of the Tolerability Profile of Controlled-Release Oral Morphine and Oxycodone for Cancer Pain Treatment. An Open-Label Randomized Controlled Trial

ContextOxycodone and morphine are recommended as first-choice opioids for moderate/severe cancer pain, but evidence about their relative tolerability has significant methodological limitations. ObjectivesThis study was mainly aimed at comparing the risk of developing adverse events (AEs) with controlled-release oral morphine vs. oxycodone; secondary aims were comparing their analgesic efficacy and testing heterogeneity in tolerability across different age and renal function subgroups. MethodsAn open-label multicenter RCT (EudraCT number: 2006-003151-21) was carried out in patients with moderate/severe cancer pain. At baseline, 7 and 14 days, patients scored on 0–10 rating scales (0–10 numerical rating scale) the intensity of pain and of a list of common opioid side effects. The primary end point was the percentage of patients reporting an AE (a worsening ≥ 2 points on any of the listed side effects); tolerability by subgroups and average follow-up pain intensity were compared through regression models. ResultsOne hundred eighty-seven patients were enrolled (47% of originally planned). Intention to treat (ITT) analysis (N = 185, morphine 94, oxycodone 91) did not show any difference in the risk of developing AEs (risk difference −0.6%, 95% CI −11.0% to 9.9%) nor in analgesia (0–10 numerical rating scale pain intensity difference −0.28, 95% CI −0.83 to 0.27). No evidence of heterogeneity of tolerability across age and renal function patient subgroups emerged. ConclusionThis trial failed to show any difference in tolerability and analgesic efficacy of morphine and oxycodone as first-line treatment for moderate/severe cancer pain but results interpretation is difficult due to lack of power, potential bias from open-label design, and concerns about assay sensitivity. These data, however, can significantly contribute to future meta-analyses comparing WHO Step-III opioids and are relevant in designing future randomized studies.

A Pharmacokinetic-Pharmacodynamic Model of Morphine Exposure and Subsequent Morphine Consumption in Postoperative Pain.

To characterize the pharmacokinetic-pharmacodynamic (PK-PD) relationship between exposure of morphine and subsequent morphine consumption and to develop simulation tools for model validation. Dose, formulation and time of morphine administration was available from a published study in 63 patients receiving intravenous, oral immediate release or oral controlled release morphine on request after hip surgery. The PK-PD relationship between predicted exposure of morphine and morphine consumption was modeled using repeated time to event (RTTE) modeling in NONMEM. To validate the RTTE model, a visual predictive check method was developed with simulated morphine consumption given the exposure of preceding morphine administration. The probability of requesting morphine was found to be significantly related to the exposure of morphine as well as night/day. Oral controlled release morphine was more effective than intravenous and oral immediate release formulations at equivalent average concentrations. Maximum effect was obtained for 8 h by oral controlled release doses ≥ 15 mg, where probability of requesting a new dose was reduced to 20% for a typical patient. This study demonstrates the first quantitative link between exposure of morphine and subsequent morphine consumption and introduces an efficient visual predictive check approach with simulation of adaptive dosing.

Opioid Concentrations in Oral Fluid and Plasma in Cancer Patients With Pain

ContextMeasuring opioid concentrations in pain treatment is warranted in situations where optimal opioid analgesia is difficult to reach. ObjectivesTo assess the usefulness of oral fluid (OFL) as an alternative to plasma in opioid concentration monitoring in cancer patients on chronic opioid therapy. MethodsWe collected OFL and plasma samples from 64 cancer patients on controlled-release (CR) oral morphine, CR oral oxycodone, or transdermal (TD) fentanyl for pain. Samples were obtained on up to five separate days. ResultsA total of 213 OFL and plasma samples were evaluable. All patients had detectable amounts of the CR or TD opioid in both plasma and OFL samples. The plasma concentrations of oxycodone and fentanyl (determination coefficient R2 = 0.628 and 0.700, respectively), but not morphine (R2 = 0.292), were moderately well correlated to the daily opioid doses. In contrast to morphine and fentanyl (mean OFL/plasma ratio 2.0 and 3.0, respectively), the OFL oxycodone concentrations were significantly higher than the respective plasma concentrations (mean OFL/plasma ratio 14.9). An active transporter could explain the much higher OFL vs. plasma concentrations of oxycodone compared with morphine and fentanyl. ConclusionOFL analysis is well suited for detecting the studied opioids. For morphine and fentanyl, an approximation of the plasma opioid concentrations is obtainable, whereas for oxycodone, the OFL/plasma concentration relationship is too variable for reliable approximation results.

Palliative Care and Essential Drug Availability: Thailand National Survey 2012

Palliative care in Thailand was not well established in the past, but it is better supported by many organizations at present. Despite the change in the situation, the availability of essential drugs for palliative care has not been well studied. Our aim was to update the medical community on the current situation of essential drug availability for palliative care in Thai hospitals. The International Association for Hospice and Palliative Care (IAHPC) list of 34 essential drugs for palliative care was used in this survey. Five hundred and fifty-five hospitals replied to the questionnaire (response rate 57%). Eleven of the 24 nonopioid drugs were available above 90% in all hospitals. However, nonopioid drugs generally were less available in community hospitals (CH) and general hospitals (GH) than in large hospitals (LH). Tramadol was the most available weak opioid. Injectable morphine was the most available form of strong opioid in Thailand (96.9%). For the overall picture of oral morphine, immediate-release morphine was a less available form than the controlled-release form (32.2% versus 51.0%). Controlled-release oral morphine had a nearly two-fold better availability than immediate-release oral morphine in CH, GH, and LH, that is, cancer centers (CC), medical school hospitals (MH), regional hospitals (RH), and other government hospitals. In contrast, in private hospitals (PH), there was no difference between the availability of the controlled-release form and the immediate-release form. Transdermal fentanyl and methadone were also less available in Thailand (14.6% versus 16.5%, respectively). LH and PH have better overall nonopioid and opioid medication availability than CH and GH.

The effects of a single mild dose of morphine on chemoreflexes and breathing in obstructive sleep apnea

The effect of morphine on breathing and ventilatory chemoreflexes in obstructive sleep apnea (OSA) is unknown. It has been assumed that acute morphine use may induce deeper respiratory depression in OSA but this has not been investigated. We evaluated awake ventilatory chemoreflexes and overnight polysomnography on 10 mild-moderate OSA patients before and after giving 30mg oral controlled-release morphine. Morphine plasma concentrations were analysed. We found a 30-fold range of morphine plasma concentrations with the fixed dose of morphine, and a higher plasma morphine concentration was associated with a higher CO2 recruitment threshold (VRT) (r=0.86, p=0.006) and an improvement in sleep time with SpO2<90% (T90) (r=−0.87, p=0.005) compared to the baseline. The improvement in T90 also significantly correlated with the increase of VRT (r=−0.79, r=0.02). In conclusion, in mild-to-moderate OSA patients, a single common dose of oral morphine may paradoxically improve OSA through modulating chemoreflexes. There is a large inter-individual variability in the responses, which may relate to individual morphine metabolism.

Association of UGT2B7 and ABCB1 genotypes with morphine-induced adverse drug reactions in Japanese patients with cancer

To investigate the effects of genetic polymorphisms on morphine-induced adverse events in cancer patients. We examined the relation of morphine-related adverse events to polymorphisms in UDP-glucuronosyltransferase (UGT) 2B7, ATP-binding cassette, sub-family B, number 1 (ABCB1), and μ-opioid receptor 1 genes in 32 Japanese cancer patients receiving oral controlled-release morphine sulfate tablets. The T/T genotype at 1236 or TT/TT diplotype at 2677 and 3435 in ABCB1 was associated with significantly lower frequency of fatigue (grades 1-3) (P = 0.012 or 0.011, Fisher’s exact test). The UGT2B7*2 genotype was associated with the frequency of nausea (grades 1-3) (P = 0.023). The frequency of nausea was higher in patients without UGT2B7*2 allele than others. The diplotype at 2677 and 3435 in ABCB1 was associated with the frequency of vomiting (grades 1-3) (P = 0.011). No patient whose diplotype was consisted of no GC allele at 2677 and 3435 suffered from vomiting. Our findings suggest that pharmacogenetics can be used to predict the risk of morphine-induced adverse events.

Pain Relief from Baclofen Analgesia in a Neuropathic Pain Patient Who Failed Opioid and Pharmacotherapy

A case report and discussion of a 64-year-old white female who presented with uncontrolled pain in several body areas despite massive oral controlled release morphine use is presented. Her pain was not associated with much spasticity. This patient responded remarkably to intrathecal baclofen even after the opioid was tapered and discontinued. The potential usefulness of baclofen in seemingly opioid-resistant chronic pain is discussed.

Prolonged Oral Morphine Therapy for Severe Angina Pectoris

Patients with intractable angina pectoris despite optimal drug therapy, who are not candidates for revascularization procedures, pose a very difficult problem. We evaluated the role of chronic opioid therapy in four such patients. The patients (mean age 79.5 years) were treated by low doses (mean 40 mg/day) of controlled-release oral morphine (CRM) for 1 to 5 years. The treatment was followed by a marked decline in the rate of admissions and hospitalization periods. The number of admissions decreased from a mean of 6 during the year prior to CRM therapy to 1.5 the following year. The duration of hospitalization for angina pectoris during these periods decreased from a mean of 42 ± 35 days to 6 ± 10 days (p < 0.05). Side effects were negligible and consisted mainly of lactulose-responsive constipation. We suggest that prolonged oral morphine therapy may be administered with good efficacy and no significant side effects in selected patients with intractable angina pectoris.

A Pharmacokinetic and Tolerability Evaluation of Two Continuous Subcutaneous Infusion Systems Compared to an Oral Controlled-Release Morphine

The pharmacokinetic profiles, safety, and tolerability of continuous subcutaneous infusion with a novel drug deliver system (the MEDIPAD system) was compared to a standard infusion pump (the CADD-Micro) and to controlled-release tablets (MS Contin) for the administration of morphine sulfate. This was a single-center, open-label, three-treatment study conducted in 24 male and female healthy volunteers. The mean age was 40.6 yr (SD = ± 12.27). A three treatment design was chosen to compare differences between modes of administration within each subject to minimize the impact of intersubject variability: Treatment A was a continuous 48-hr subcutaneous infusion of morphine sulfate (165.6 mg at a rate of 3.45 mg/hr) with the MEDIPAD system attached to the chest, Treatment B was a series of four oral doses of morphine sulfate (120 mg each) at 12-hr intervals, and Treatment C was a continuous 48-hr subcutaneous infusion of morphine sulfate (163.2 mg at a rate of 3.40 mg/hr) with the CADD-Micro device attached to the chest. Subjects began treatment after eligibility was established and informed consent was obtained. The primary pharmacokinetic parameters (AUC, C max) for the two devices were similar; 90% confidence intervals showed that the MEDIPAD system was bioequivalent to the CADD-Micro in terms of both rate and extent of morphine absorption. The mean morphine plasma concentration versus time plot suggested that plasma concentrations rise more rapidly with the MEDIPAD device than with the CADD-Micro or oral administrations. The MEDIPAD system showed mild application and injection site reactions; there were no site reactions for the CADD-Micro or oral doses. As expected nausea, somnolence, and abdominal pain occurred more frequently in the oral treatment than the two infusion devices. These data suggest that the MEDIPAD system, which is currently undergoing clinical evaluation, is an acceptable alternative to the traditional oral treatment of morphine sulfate for delivery of analgesics as it allows rapid absorption of morphine; is small, easy to use, and disposable; and achieves plasma levels that are essentially equal to other standard infusion pumps.

Randomised trial of oral morphine for painful episodes of sickle-cell disease in children

Oral controlled-release morphine can provide effective analgesia through a non-invasive route and may facilitate outpatient management of severe episodes of sickle-cell pain. We compared the clinical efficacy and safety of oral morphine with continuous intravenous morphine in children with severe episodes of sickle-cell pain, by a double-blind, randomised, parallel-group design. 56 children aged 5-17 years received loading doses of intravenous morphine of up to 0.15 mg/kg, followed by randomly assigned oral morphine 1.9 mg/kg every 12 h plus intravenous placebo (saline), or intravenous morphine 0.04 mg kg-1 h-1, plus placebo tablet. Breakthrough pain was treated with oral, immediate-release morphine 0.4 mg/kg every 2-3 h as required. Pain was assessed daily at 0900 h, 1300 h, 1700 h, and 2100 h with a picture face scale, a pictorial scale (Oucher), a behavioural-observational scale (CHEOPS), and by an investigator. 50 children completed the study (28 boys, 22 girls; mean age 11.2 years [SD 3.5]; mean oral morphine dose 2.99 mg/kg daily [0.75]; mean intravenous morphine dose, 0.81 mg/kg daily [0.30]). Mean overall pain scores were similar for oral and intravenous morphine (CHEOPS, 6.3 [1.5] vs 6.4 [1.4], p = 0.8; Oucher, 31.5 [25.4] vs 39.2 [21.7], p = 0.3; Faces, 2.2 [1.4] vs 2.4 [1.3], p = 0.6; clinical rating, 1.7 [0.7] vs 1.9 [0.5], p = 0.3). Opioid analgesia was required for a mean of 4.2 days (1.7) and 5.4 days (2.6), respectively (p = 0.0591). Pain scores from all scales correlated significantly (r = 0.5865-0.8980, p = 0.0001). Frequency of rescue analgesia did not differ significantly between the oral and intravenous morphine groups (0.7 [0.8] vs 0.9 [0.7] doses daily, p = 0.2). Frequency and severity of adverse events did not differ significantly. Oral, controlled-release morphine is a reliable, non-invasive alternative to continuous intravenous morphine for the management of painful episodes of sickle-cell disease in children.

Postthyroidectomy analgesia: Morphine, buprenorphine, or bupivacaine?

Study Objective: To compare three analgesic regimens for pain relief after thyroidectomy. Design: Randomized, double-blind, placebo-controlled study. Setting: Inpatient anesthesia in a university department of endocrine surgery. Patients: 342 patients scheduled for elective thyroidectomy with nitrous oxide-oxygen-isoflurane anesthesia in addition to fentanyl. Interventions: Group 1 received preoperative oral controlled release morphine 10 mg, and Group 2 received postoperative sublingual buprenorphine 0.2 mg. Group 3 received 0.25% bupivacaine (10 ml) wound infiltration before skin closure. Eight hours after tracheal extubation, patients received a second dose of the same drug in each group except in Group 3, where medication was changed to sublingual buprenorphine 0.2 mg. Measurements and Main Results: Patients in Group 2 required fewer additional analgesics: 0.54 ± 0.68 vs. 0.96 ± 0.84 in Group 1 and 0.79 ± 0.78 in Group 3. Patients in Group 2 demonstrated a better pain score and this group showed a higher percentage of satisfied patients: 96% vs. 85% in Group 1 and 91 % in Group 3. Group 2 also included more patients requiring no analgesics: 56% vs. 32% in Group 1 and 42 % in Group 3. The side effects in all three groups did not differ. Conclusion: The administration of sublingual buprenorphine after thyroidectomy provides better analgesia than small doses of oral controlled-release morphine or than 0.25% bupivacaine wound infiltration at the end of surgery.

Preclinical study of a controlled release oral morphine system in rats

The efficiency of a new controlled release oral system containing morphine hydrochloride elaborated by introducing the drug into the polymeric structure of Eudragit® L30D is evaluated. Its in vitro dissolution behaviour and its effectiveness using the tail flick test model of pain in rats are investigated. A significant reduction in the drug release rate from the morphine-Eudragit® L30D complex as well as a very high efficiency in the dissolution process have been found. The tested morphine complex has an analgesic effect in rats. This effect is very clear from 30 min to 8 h. At 12 h the effect remains clear but with a lower level of statistical significance. Furthermore, there are no significative differences between the different doses tested.

Pharmacokinetics of two novel rectal controlled-release morphine formulations

Administration of morphine by the oral route is not possible in cancer patients who are unable to swallow or are intolerant of oral morphine. Thus, there is a need for reliable alternate routes of drug administration. We compared the bioavailability of two prototype 30-mg morphine sulfate controlled-release suppository formulations (high and low viscosity) with 30-mg oral controlled-release morphine sulfate tablets in a 14-subject single-dose randomized, three-way crossover study. Venous blood samples were obtained immediately prior to and for 24 hr following each dose. Morphine concentrations were determined by radioimmunoassay. Compared with oral controlled-release morphine, the high- and low-viscosity suppository formulations had significantly greater bioavailability (AUC 0–24 72.7± 13.2 for the oral preparation versus 98.6±35.7 and 105.8±37.3 ng · hr/mL for the suppositories, respectively, P < 0.05), later peak concentration (t max 2.3±0.8 versus 3.1±2.3 and 5.0±1.5 hr, respectively, P < 0.05), and longer half-value duration (4.3±1.6 versus 10.4±5.5 and 9.5±4.3 hr, respectively, P < 0.05). Peak concentration for the high-viscosity suppository formulation (C max 7.75±2.66 ng/mL) was significantly lower than the low-viscosity suppository (C max 9.23±2.85 ng/mL) and the oral tablet (C max 10.4±2.78 ng/mL) formulations ( P < 0.05). The increased bioavailability observed with the two controlled-release suppositories may be the result of partial avoidance of hepatic biotransformation with rectal administration.

Controlled-release oral morphine

Controlled-release oral morphine

Comparison of controlled-release oral morphine to continuous intravenous morphine infusion in the control of pain in sickle cell crisis

Comparison of controlled-release oral morphine to continuous intravenous morphine infusion in the control of pain in sickle cell crisis

Controlled-Release Oral Morphine (MS Contin Tablets, MSC) in Post-Operative Pain

Controlled-Release Oral Morphine (MS Contin Tablets, MSC) in Post-Operative Pain