Controlled-release Morphine Tablets Research Articles

Clinical Efficacy of Controlled-Release Morphine Tablets Combined with Celecoxib in Pain Management and the Effects on WNK1 Expression

OBJECTIVES:This study was designed to evaluate the clinical efficacy of controlled-release morphine tablets combined with celecoxib in relieving osteocarcinoma-related pain and the effects of the combination on WNK1 expression.METHODS:A total of 110 patients with osteocarcinoma-related pain were selected and divided into two groups based on the treatment administered, including the control group (treated with controlled-release morphine tablets alone) and the study group (treated with a combination of controlled-release morphine tablets and celecoxib). We compared the treatment efficacy, pain level (visual analog scale (VAS)), time of onset of breakthrough pain (BTP), dose of morphine, incidence of adverse events, quality of life (QOL) score, and With-no-lysine 1 (WNK1) expression in the peripheral blood (PB) as determined with qRT-PCR before and after treatment, of the two groups.RESULTS:The total effective rate of the study group was higher than that of the control group, while the VAS score, time of onset of BTP, dose of morphine, incidence of adverse events, QOL score, and relative WNK1 expression in the PB were lower than those of the control group (p<0.05).CONCLUSION:Combination treatment with controlled-release morphine tablets and celecoxib can be extensively used in the clinical setting because it effectively improves the symptoms, QOL score, and adverse effects in patients with osteocarcinoma-related pain.

Clinical Efficacy and Safety of Once-Daily Dosing of a Novel, Prolonged-Release Oral Morphine Tablet Compared With Twice-Daily Dosing of a Standard Controlled-Release Morphine Tablet in Patients With Cancer Pain: A Randomized, Double-Blind, Exploratory Crossover Study

Recently, a new oral prolonged-release formulation of morphine sulfate for once-daily dosing has been developed based on an injection-molded matrix (abuse-deterrent, prolonged-release erodible matrix [ADPREM]). The objective of this double-blind, randomized, exploratory crossover study was to assess the efficacy and safety of once-daily ADPREM compared with twice-daily controlled-release morphine (CRM; MST ContinusNapp Pharmaceuticals, Cambridge, UK). Thirty-eight adult cancer pain patients participated in the study, which consisted of a run-in period for stabilization and two consecutive fixed-dose treatment periods of two weeks' duration each. Rescue medication, immediate-release morphine sulfate, was available during the entire study for treatment of breakthrough pain (BTP). There was no difference between the treatments in use of rescue medication. The medians of the average number of rescue doses per day were 1.0 and 0.7 during the ADPREM and CRM treatment periods, respectively, with an estimated median difference of 0.07 dose/day (95% confidence interval: -0.21, 0.29). Likewise, no differences between treatments were found for the number of BTP episodes per day or morning and evening ratings of pain intensity (current, average, minimum, and maximum). Median assessment of the drugs was "good" for both treatments, and neither of the treatments was preferred. Steady-state trough concentrations of morphine and its metabolites in plasma before morning dosing were similar after either treatment period. The adverse events were as expected in an opioid-treated cancer population and showed no differences between ADPREM and CRM. In this study, dosing with ADPREM at intervals of 24 hours was therapeutically equivalent to CRM dosed at intervals of 12 hours.

In a precautionary move, ratiopharm is initiating a voluntary recall of a number of lots of controlled-release morphine tablets in Canada.

In a precautionary move, ratiopharm is initiating a voluntary recall of a number of lots of controlled-release morphine tablets in Canada.

Controlled-release morphine tablets in patients with chronic cancer pain: a narrative review of controlled clinical trials.

Controlled-release (CR) morphine tablets have become routine therapy in the management of cancer pain. Compared with immediate-release (IR) morphine, this formulation provides the benefit of dosing every 12 hours. This study reviewed the 10 published, well controlled, repeated-dose, comparative studies with CR morphine tablets administered every 12 hours to patients with cancer pain. CR morphine tablets were uniformly effective; 98% of patients completed a treatment course of every-12-hours therapy. Although the effective analgesic dose varied considerably from study to study (range, 90-330 mg per day), pain was well controlled with CR morphine tablets as the primary analgesic. Mean pain scores, converted to a common 10-point scale, ranged from 1.1-2.9 across all studies. There was only occasional need for IR morphine rescue medication (range, 2-39 mg per day). The mean discontinuation rate because of side effects or lack of every-12-hours efficacy was 2%. In seven studies that used IR morphine as the comparative agent, CR morphine tablets were found to be equally effective as IR morphine. Twice-daily dosing of CR morphine provides convenient, safe, and effective relief of cancer pain.

徐方性モルヒネ錠内包坐剤投与によるモルヒネの患者血中濃度と鎮痛効果

In preparation for a study, we prepared a morphine suppository (MS-C suppository) that contained controlled-release morphine tablet (MS Contin®) in the suppository base.We then investigate plasma morphine concentrations and the analgesic effect produced following rectal MS-C suppository were investigated in three patients with cancer pain. Plasma morphine concentrations subsequent to this rectal administration were found to be much higher than those predicted from the morphine concentration administered orally.The elimination half-life of morphine (t1/2) after rectal administration was 2.5-4 times longer than that after oral administration of MS Contin®. The clinically desirable analgesic effect was obtained in all patients tested. Though side effect of drowsiness was observed in two patients.These results indicated that the MS-C suppository is a desirable treatment for ameliorating cancer pain.

Morphine and morphine-6-glucuronide plasma concentrations and effect in cancer pain

The relationships between plasma morphine and metabolite (M3G and M6G) concentrations and analgesic efficacy were investigated in an open study of 39 cancer pain patients receiving chronic oral morphine therapy with either morphine sulfate solution or controlled-release morphine tablets. There were no differences in morphine, metabolite kinetics, or analgesic efficacy between equivalent doses of conventional or controlled-release formulations. The increase in morphine plasma concentration after a dose (1 hr for normal release, 2 hr for controlled release) was correlated significantly with the dose of morphine (r = 0.914, P < 0.001). There was a significant reduction in pain intensity (P < 0.05) and increase in pain relief (P < 0.001) after the dose of morphine administration, when compared with the predose score. One-half of the patients had mild and tolerable adverse effects. Patients were classified by mean pain relief between doses as having optimal, moderate, or poor pain control. No simple relationship was found between morphine plasma concentration and pain control. Morphine plus M6G concentrations in the “optimal control” group (751.2 ± 194 nmol/L), however, were more than twice those found in the “moderate control” group (276.9 ± 41.9 nmol/L) (P < 0.05), and no patient in the moderate control group had a morphine plus M6G concentration greater than 405 nmol/L. These results support the importance of M6G in morphine analgesia. For these hospitalized patients, there appeared to be a therapeutic range of morphine plus M6G plasma concentrations for optimal pain control with a lower limit of 400 nmol/L predose.

大学病院におけるモルヒネ製剤使用量の推移

We surveyed the amount of morphine preparations used at our hospital, the Hospital of Toyama Medical and Pharmaceutical University, including both marketed preparations and the sustained release suppository which we prepare here at our pharmacy. For oral dosage, the amount of controlled release morphine tablet used rapidly increased, while morphine HC1 powder decreased dramatically. As for the amount of suppositories being used, the morphine HCl suppository as well as that of the sustaind release suppository tends toward a slight increase. Since more morphine is expected to be used, it is essential for pharmacists to contribute to a more appropriate clinical use of morphine.

A comparative study of controlled-release morphine (CRM) suspension and CRM tablets in chronic cancer pain

This study compared the efficacy and the adverse effects of controlled-release morphine (CRM) suspension (SAR 213) and CRM tablets (Moscontin) in the treatment of cancer pain. This multicenter, randomized, double-blind, double-dummy, crossover study was carried out on 52 patients. Each patient received both study treatments given at an equivalent dosage of morphine during each of two 7-day periods. The primary outcome variable was the severity of pain assessed three times daily by means of a visual analogue scale. Secondary criteria of efficacy were the severity of pain assessed by verbal rating scale, the need for “rescue” doses of immediate-release morphine, treatment preference, and indices of quality of life (activity, mood, sleep). There were no statistically significant differences in the parameters assessed when comparing the two groups. This study shows that, when prescribed at the same doses, CRM suspension and CRM tablets have similar efficacy and adverse effects, as well as the same duration of action. The results of this first clinical study carried out on CRM suspension are especially relevant for patients with cancer pain who have difficulty swallowing.

Bioavailability of morphine in rabbits after rectal administration of suppository containing controlled release morphine tablet.

Two kinds of sustained release morphine suppositories have been prepared; one is an oleaginous base suppository (MSC) containing a controlled release morphine tablet (MST: MS Contin), and the other is a hollow-type suppository (MSCH) containing MST and morphine powder packed in its hollow space. In vitro release tests and in vivo rectal absorption experiments in rabbits were performed. The profiles of morphine release from MST and MSC in vitro were similar, and revealed that suppository bases had no effect on the release profile of morphine from the preparation. Morphine release from MSCH was rapid in the early phase, and then enclosed morphine was slowly and continuously released from MST. Phamacokinetics of morphine from the suppository were compared with the orally administered MST, and it was found that there was no difference in the maximum plasma concentration (Cmax) and the peak time (Tmax) between MSC and MST, but the mean residence time (MRT) of MSC was approximately three times longer than that of MST, and the extent of bioavailability (BA) of MSC was significantly larger than that of MST (71.6 +/- 14.2% and 11.9 +/- 4.0%, respectively). Cmax can be altered arbitrarily by changing the morphine content in the hollow space of MSCH. As in the case of MSC, the plasma concentration of morphine from MSCH was maintained. It is concluded from the above results that MSC is a satisfactory sustained release morphine suppository for the treatment of cancer pain, administering it twice a day, and that MSCH is effective due to its fast analgesic effect and sustained release nature not only for cancer pain but also for surgical operations.

ウサギに３種類の坐剤を投与した際のモルヒネの体内動態

We prepared three kinds of morphine suppositories: HE was based on the equivalent mixture of Witepsol H-15 and E-75; S was based on Witepsol S-55 alone; MSC contained controlled-release morphine tablet (MS Contin) in the same base as HE. The pharmacokinetics after rectal administration of the preparations was investigated in rabbits. We found that HE had short Tmax (10min) and that the sustained release continued around 6hr after administration. The extent of bioavailability (BA) of HE was 43.4%, and the plasma concentration of morphine was higher than orally administered MS Contin tablet, throughout the observation period. S had a high BA (95.1%) but Cmax (446.2ng/ml) was too high judged from some risk of adverse effect or dependence. Thus we considered it is not appropriate for clinical use. On the other hand, MSC had longer Tmax (150min). The plasma concentration 12hr after administration was around half the Cmax and the sustained release was found to be good. The MSC's BA also showed high value and only a little dispersion (78.3±6.6%). The cumulative absorption-time profiles of MSC in vivo approximated to the morphine-release behavior of MS Contin tablets in vitro.From the facts described above we conclude:1. We can expect the same or more analgesic effect from HE than oral MS Contin tablets.2. MSC is a good sustained-release morphine suppository which can be expected to be useful for cancer pain therapy, through every 12-hr administration.

Controlled-Release Morphine Bioavailability (MS Contin® Tablets) in the Presence and Absence of Food

The bioavailability of a single, orally administered, 30-mg controlled-release morphine tablet (MS Contin Tablet; The Purdue Frederick Company, Norwalk, Conn.) was compared after fasting or a high fat meal in this single dose, randomized, crossover study involving 24 healthy male subjects. There was no significant (p greater than 0.05) difference in the mean extent of morphine absorption over 24 hours in the presence or absence of food (area under the plasma concentration vs. time curve [AUC(0,24)], fed = 107% of fasted). Time to maximal concentration (Tmax) was similar (p greater than 0.05) in the two treatment groups; the mean Tmax for fed volunteers was 2.5 hours versus 2.4 hours for fasted volunteers. The two regimens did not differ significantly (p greater than 0.05) with regard to maximal morphine concentration (Cmax); mean Cmax for fed subjects was 8.22 ng/ml whereas mean Cmax for fasted subjects was 8.53 ng/ It was concluded that consumption of a high fat meal did not affect either the rate or extent of morphine absorption, or any of the other pharmacokinetic parameters tested, following administration of MSC.

The role of oral controlled-release morphine for pain relief in children with cancer

Effective pain control is a key part of the care of children with cancer. We report our experience with controlled-release morphine tablets (MST Continus, NAPP) given as analgesia to 60 children who were terminally ill from a range of malignant diseases. MST was given over periods ranging from 1-165 days (median 14 days). We found that the appropriate initial dose was 1 mg/kg/dose for children whose pain was not controlled by mild analgesics or weak opioids. Maximum doses up to 41.6 mg/kg/dose were needed to maintain analgesia. Provision of a short-acting opioid is essential for breakthrough pain. The main side-effects were temporary drowsiness and constipation. Careful education of parents and health-care professionals in the correct use of MST is important. MST proved an effective and acceptable strong analgesic for children, particularly convenient for the terminally ill at home.

Are controlled release morphine tablets (Moscontin®)suitable for titrating the dose of morphine in far advanced cancer pain? a french multicentric study

Are controlled release morphine tablets (Moscontin®)suitable for titrating the dose of morphine in far advanced cancer pain? a french multicentric study

Controlled‐release morphine in cancer pain

Nineteen patients with pain from advanced cancer stabilised on oral 4-hourly aqueous morphine who were to be converted to twice daily controlled-release morphine tablets (MST Continus) completed this study. Patients were randomised to receive either their usual 4-hourly morphine dose or placebo with the first dose of MST tablets. There were no significant differences between the treatment groups in ratings of pain intensity, pain relief or side effects, or in any of the measured pharmacokinetic parameters. No patients in the placebo group experienced any breakthrough pain, and nursing staff were unable to identify which patients had received the active dose of morphine elixir. We conclude that there is no need for a loading dose when aqueous morphine is changed to MST tablets.

Guidelines for use of controlled-release oral morphine in cancer pain management Correlation with clinical experience

An open study of 47 patients with cancer pain treated with repeated doses of a controlled-release oral morphine tablet was conducted to assess the acceptability of this drug and develop guidelines for its use. Each patient kept a detailed record of pain, analgesic intake, side effects, and other medications. A nurse observer/clinician followed these patients on a daily basis and kept similar records. Of 47 patients who began the study, 37 were successfully stabilized with standard morphine sulfate tablets and then switched to controlled-release morphine (CRM). Twenty-one patients who completed the study took CRM every 12 h, and 16 patients received a dose every 8 h. Doses of the CRM ranged from 30 mg every 12 h to 360 mg every 8 h. Less frequent doses and uninterrupted sleep were reported advantages. All of the patients completing the study chose to continue this method of pain management and extended care data were obtained from each patient poststudy through continued monitoring.

硫酸モルヒネ徐放錠（ＭＳ‐Ｃ）の癌患者における薬物速度論的検討

硫酸モルヒネ徐放錠（ＭＳ‐Ｃ）の癌患者における薬物速度論的検討

RELATIVE BIOAVAILABILITY OF CONTROLLED RELEASE MORPHINE TABLETS (MST CONTINUS) IN CANCER PATIENTS

The bioavailability of oral controlled release morphine tablets (MST, Napp Laboratories) and oral morphine sulphate in aqueous solution (MSS) was compared in 10 patients with advanced cancer. Serum samples were analysed for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) using a specific HPLC assay. The relative bioavailability of morphine with MST was significantly less than that with MSS (mean 80%, range 50-110%) although there was no difference between the formulations in the relative availability of M3G and M6G. There was no significant difference between the formulations in the serum concentration of morphine at 12 h. The mean ratios morphine: M6G:M3G (comparing areas under the serum concentration-time curves) were 1:9:56. There was a highly significant linear relationship between the dose administered and AUC for morphine, M3G and M6G after MSS; and for morphine after MST. Median tmax for morphine was 0.5 h with MSS and 2.5 h with MST; for M3G 1.5 h with MSS and 3.0 h with MST; and for M6G 1.5 h with MSS and 3.25 h with MST. A secondary peak of unconjugated morphine, which may represent enterohepatic circulation, was seen in several patients 2-4 h after administration of elixir and 4-6 h after administration of MST.

CONTROLLED-RELEASE MORPHINE TABLETS: A double-blind trial in dental surgery patients

We report a randomized double-blind comparison of controlled-release morphine tablets (MST-1; 2 x 10 mg) and oral morphine sulphate in solution (20 mg) in 28 patients (20 females) who had undergone removal of impacted lower third molars or a dental clearance under general anaesthetic. The response in both groups was very poor: eight of 15 patients in MST-1 group and six of 13 patients in the standard group required "rescue" analgesics and were withdrawn from the study within the first 2h. No threshold plasma concentration of morphine corresponding to a particular analgesic effect was apparent. MST-1 produced significantly greater plasma concentrations at 8h compared with the standard preparation. Controlled-release morphine, or any oral formulation of morphine, may not be suitable for the treatment of acute pain after operation.