Twenty-four patients with severe pain related to cancer completed a randomised, double-blind, double-dummy, crossover study examining morphine pharmacokinetics and pharmacodynamics when the same 24-h morphine dose was administered using two modified release oral morphine formulations; either one dose of Kapanol (a new sustained release polymer coated pellet formulation administered in capsule form, Glaxo Wellcome group of companies) per 24 h, or MS Contin (Purdue Frederick Company, Connecticut, USA) administered at 12-h intervals. The morphine dose was optimised for each patient using an immediate release morphine solution in the lead-in period to provide the most favourable balance between pain relief and side-effects. Patients were then randomly allocated to receive their 24-h morphine dose as either Kapanol or MS Contin in period 1. Patients recorded daily measures of pain relief and morphine related side-effects (morphine pharmacodynamics) in a diary. Patients were admitted to the Pain Management Unit on the morning of day 7 (+/- 1 day) and frequent blood samples were collected for 24 h following the 10:00 h dose to fully characterise the pharmacokinetic profile for morphine and its metabolites at steady state. Morphine pharmacodynamics and the amount and timing of rescue medication (dextromoramide) were also recorded during this time. Period 2, which commenced at 10:00 h on day 8, was identical to period 1 except the modified release formulations were changed. The pharmacokinetic profile of Kapanol exhibited a significantly higher Cmin (minimum plasma morphine concentration), less fluctuation in plasma morphine concentration throughout the dosing interval, a longer Tmax (time associated with the maximum morphine concentration) and a greater time that the plasma morphine concentration was > or = 75% of Cmax (an index of the control the formulation exerts over the morphine release rate) compared to that of MS Contin. Some of these pharmacokinetic differences (e.g., Cmin and fluctuation in plasma morphine concentration) were surprising given that the dosing interval for Kapanol (24 h) was double that of MS Contin (12 h). There was no significant difference between the Kapanol and MS Contin treatment phases in any of the pharmacodynamic parameters, morphine related side-effects, the percentage of patients taking rescue medication as well as the amount or time to the first dose of rescue analgesia on day 7 in periods 1 and 2, patient or investigator assessments of global efficacy at the end of periods 1 and 2, or patient treatment preference at the end of the study. Once a day Kapanol provided the same degree of pain relief and morphine related side-effects as 12-h MS Contin.

Sustained release morphine formulations are now generally accepted as the formulations of choice in the treatment of severe cancer pain. Kapanol™/Kadian™ (Glaxo/Faulding), a new sustained release formulation consisting of polymer coated pellets in a capsule, has recently been shown to have a superior morphine release profile compared to the standard tablet, MS Contin. If fact, the release characteristics of morphine from Kapanol suggested the possibility that one oral dose of Kapanol per 24 hours could effectively treat severe cancer pain. Twenty four patients completed a randomised, double-blind, two period, crossover study comparing 24-hourly Kapanol to 12-hourly MS Contin. The morphine dose per 24 hours was identical for the two formulations and morphine pharmacokinetics were determined over 24 hours at steady state for each formulation (i.e. after 7 days). The Cmax, Cmin, AUC and fluctuations in plasma morphine concentrations were not significantly different between the two formulations (P > 0.05, repeated measures ANOVA). Kapanol had significantly longer Tmax values (P < 0.001) than MS Contin. These results indicate that one Kapanol dog per 24 hours should at least be as efficacious as 12 hourly MS Contin in die treatment of severe cancer pain from the pharmacokinetic perspective. Sustained release morphine formulations are now generally accepted as the formulations of choice in the treatment of severe cancer pain. Kapanol™/Kadian™ (Glaxo/Faulding), a new sustained release formulation consisting of polymer coated pellets in a capsule, has recently been shown to have a superior morphine release profile compared to the standard tablet, MS Contin. If fact, the release characteristics of morphine from Kapanol suggested the possibility that one oral dose of Kapanol per 24 hours could effectively treat severe cancer pain. Twenty four patients completed a randomised, double-blind, two period, crossover study comparing 24-hourly Kapanol to 12-hourly MS Contin. The morphine dose per 24 hours was identical for the two formulations and morphine pharmacokinetics were determined over 24 hours at steady state for each formulation (i.e. after 7 days). The Cmax, Cmin, AUC and fluctuations in plasma morphine concentrations were not significantly different between the two formulations (P > 0.05, repeated measures ANOVA). Kapanol had significantly longer Tmax values (P < 0.001) than MS Contin. These results indicate that one Kapanol dog per 24 hours should at least be as efficacious as 12 hourly MS Contin in die treatment of severe cancer pain from the pharmacokinetic perspective.

The role of the morphine metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in the analgesia observed following morphine administration is controversial. There is greater acceptance of the analgesic role ascribed to M6G while M3G is alternatively considered to be inactive or result in functional antagonism. Kapanol™/Kadian™ (Glaxo/Faulding) is a new sustained release morphine formulation consisting of polymer coated pellets in a capsule. Twenty-four patients completed a randomized, double-blind, two period, crossover study comparing 24 hourly Kapanol to 12 hourly MS Contino. The morphine metabolite profile was determined in a randomly selected subset of those patients (n = 8). The Cmax, Cmin, AUC, time that the plasma morphine concentration was ≥ 0.75 Cmax (for that metabolite) and fluctuations in plasma morphine concentrations were not significantly different (P > 0.05, repeated measures ANOVA) between the two formulations for either metabolite. However, the Tmax for both M6G (P

Twenty-eight patients with severe pain due to cancer, who could no longer obtain acceptable pain relief from optimised doses of oral opioids, were entered into a study which compared pain relief, satisfaction with pain therapy and estimates of neuropsychological functioning during treatment with spinally administered (i.e., epidural and intrathecal) morphine as either repeated bolus doses or as a continuous infusion. These measures of efficacy and side effects were repeated every 2 weeks until either the patient died (82% of patients), withdrew from the study or were no longer able to complete the tests due to deterioration of their condition. The mean (range) duration of treatment was 169 (6-537) days for those patients receiving continuous infusion and 140 (28-378) days for those patients receiving repeated bolus doses. There was no significant difference in visual analogue pain scores, pain relief scores and satisfaction scores between the bolus and infusion groups. Furthermore, low pain scores and high pain relief scores indicated that both treatment modalities provided effective pain control. Similarly, there was no significant difference between the two groups in the various tests used to assess depression or neuropsychological function (i.e., memory, vigilance, attention and processing). There was a significantly greater degree of dose escalation in patients receiving continuous infusion compared to patients receiving repeated bolus doses. For 6 patients in the infusion group the catheter was sited in the intrathecal space, as the dose requirements by the epidural route exceeded the delivery capacity of the pump. For 4 patients in the bolus group the catheter was similarly sited, due to pain on injection and leakage/blockage.(ABSTRACT TRUNCATED AT 250 WORDS)

Records of 313 patients who had been treated with spinal morphine via an implanted Port-A-Cath were reviewed. In 284 cases the Port-A-Cath was implanted for epidural delivery of morphine in patients with cancer-related pain. These patients were treated for a mean of 96 (range 1-1215) days. There was a wide variation in dose requirements, minimum daily dose ranging from 0.5 to 200 mg and maximum daily dose from 1 to 3072 mg. However, there was no clear trend to increasing dose as period of epidural morphine administration increased. The most frequent complications were pain on injection (12.0% incidence), occlusion of the portal system (10.9%), infection (8.1%) and leakage of administered morphine such that it did not all reach the epidural space (2.1%). In all but 1 case infections were limited to the area around the portal or along the catheter track. All infections resolved without sequelae following removal of the portal and/or administration of antibiotics. In 17 patients Port-A-Caths were implanted for the intrathecal delivery of morphine to control cancer-related pain. These patients also exhibited wide variations in morphine dose requirements. Port-A-Caths were also implanted for delivery of spinal morphine in 12 patients with chronic pain which was not related to cancer and which failed to respond to other therapies. These patients were treated for a mean of 155 (range 2-575) days. Port-A-Caths were removed from 7 of these patients, primarily due to infection (2 cases) and inadequate pain relief and pain on injection (2 cases).

Study Objectives: To explore the influence of liposomes on the pharmacodynamic action of bupivacaine and to determine whether postsurgical analgesic advantages can be obtained from epidural delivery of liposomal bupivacaine compared with the current formulation.Design: Open, nonrandomized study.Setting: Physiopathology laboratory, general operating theaters, and intensive care units of Reine Fabiola Hospital and Institut Médical de Traumatologie et Revalidation.patients: 26 ASA physical status II and III patients who had undergone major surgery (abdominal, vascular, urologic, thoracic, orthopedic).Interventions: After completion of the operation, the patients were divided into 2 groups to receive 1 of 2 bupivacaine preparations epidurally for postsurgical pain: Group 1 (n = 12) received plain 0.5 % bupivacaine with 1:200, 000 epinephrine; Group 2 (n = 14) received liposomal 0.5% bupivacaine.Measurements and Main Results: The following observations were made: onset and quality of analgesia, quality of motor block according to the Bromage scale, and sympathetic block. Onset time of sensory block averaged 15 minutes in both groups. Pain relief durations were 3.2 ± 0.4 hours with plain bupivacaine and 6.25 ± 1.13 hours with the liposomal preparation (p < 0. 05). In the liposomal bupivacaine group, no motor block was recorded. Low sympathetic block occurred in all patients. Analgesia in a subset of patients following abdominal aortic surgery increased from 2.4 ± 0.35 hours to 10.6 ± 1.4 hours by encapsulation of bupivacaine (p < 0.01). There was no neurotoxicity or cardiotoxicity.Conclusions: The liposomal formulation of bupivacaine increased duration of analgesia without motor block or adverse side effects.