Immediate-release Morphine Sulfate Research Articles

Analgesic efficacy of morphine sulfate immediate release vs. oxycodone/acetaminophen for acute pain in the emergency department.

Previous research demonstrated that administration of Morphine Sulfate Immediate Release (MSIR) results in similar analgesic efficacy to Oxycodone but with significantly lesser degrees of euphoria and reward. The purpose of this study sit to investigate if MSIR combined with Acetaminophen can serve as an opioid analgesic alternative to Oxycodone combined with acetaminophen (Percocet) for acute pain in the Emergency Department (ED). A prospective, randomized, double-blind trial of ED patients aged 18 to 64years presenting with moderate to severe acute pain as defined by an 11-point numeric rating scale (NRS) with an initial score of ≥5 (0=no pain and 10=very severe pain). Patients were randomized to receive either 15mg MSIR combined with 650mg of Acetaminophen or 10mg Oxycodone combined with 650mg Acetaminophen. Patients were assessed at baseline, 30, 45 and 60min. The primary outcome was reduction in pain at 60min. Secondary outcomes include drug likeability and adverse events. 80 patients were enrolled in the study (40 per group). Demographic characteristics were similar between the groups (P>0.05). Mean NRS pain scores at baseline were 8.44 for the MSIR group and 8.53 for the Percocet group (P=0.788). Mean pain scores decreased over time but remained similar between the groups: 30min (6.03 vs. 6.43; P=0.453), 45min (5.31 vs. 5.48; P=0.779), and 60min (4.22 vs. 4.87; P=0.346). Reduction in mean NRS pain scores were statistically significant from baseline to 30, 45 and 60min within each group (P<0.0001 at each time point for both groups). The largest NRS mean difference was from baseline to 60min: 4.2 (95% CI: 3.43 to 5.01) for MSIR group and 3.61 (95% CI: 2.79 to 4.43) for Percocet group. No clinically significant changes or any serious adverse events were observed in either group. MSIR provides similar analgesic efficacy as Percocet for short-term pain relief in the ED, similar rates of nausea/vomiting, and lower rates of likeability of the drug.

Analgesic Efficacy of MSIR/Acetaminophen vs. Oxycodone/Acetaminophen (Percocet) for Pain

Several research papers demonstrated that administration of Morphine Sulfate Immediate Release (MSIR) results in similar analgesic efficacy to Oxycodone but with significantly lesser degree of euphoria and reward. By identifying a safer alternative to oxycodone, our study may influence opioid prescribing practices nationwide, which has the potential to reduce the considerable morbidity and mortality related to misuse and abuse of prescription opioids. The purpose of this study is to investigate if Morphine Sulfate Immediate Release (MSIR) combined with Acetaminophen can serve as an opioid analgesic alternative to Oxycodone combined with acetaminophen (Percocet) for acute pain in the ED setting.

The ALERRT® instrument: a quantitative measure of the effort required to compromise prescription opioid abuse-deterrent tablets

ABSTRACTBackground: US FDA guidance recommends measuring the degree of effort needed to manipulate abuse-deterrent (AD) opioids. The ALERRT® instrument (PinneyAssociates; Bethesda, MD) uses visual analog scales to assess the labor, effort, and resources necessary to physically compromise AD product candidates in standardized settings. Objective: Use the ALERRT® instrument for testing morphine abuse-deterrent, extended-release, injection-molded tablets (ADER-IMT) 60 and 100 mg and the comparators immediate-release (IR) morphine sulfate 30 mg and extended-release (ER) morphine sulfate 60 mg. Methods: Four technicians tested the products using 10 household tools. The ALERRT instrument quantified effort (all tools) and time (3 preselected tools) required for manipulation. Results: Morphine-ADER-IMT 60 and 100 mg were difficult to manipulate, as demonstrated by high scores (mean range, 71.0−99.0 and 77.0−99.5, respectively). IR and ER morphine sulfate were easy to manipulate (low scores; mean range, 2.0−14.8 and 2.3−17.5, respectively). Statistically significant mean differences between morphine-ADER-IMT and comparators’ ALERRT scores were observed. Manipulations of morphine-ADER-IMT 60 and 100 mg for 300 seconds failed to produce substantial powdering. Manipulations of IR morphine sulfate (mean range, 65.5−175.8 seconds) and ER morphine sulfate (49.3−163.0 seconds) produced substantial to complete powdering in 92% of tablets. Conclusions: Morphine-ADER-IMT was extremely difficult to manipulate versus non-AD formulations of morphine. The ALERRT system differentiated the degree of effort for manipulation of morphine-ADER-IMT and non-AD morphine formulations, indicating sensitivity of this instrument as part of Category 1 testing. By measuring the degree of effort required for manipulation, the ALERRT instrument provides an empirical assessment into the relative difficulty of manipulating opioid analgesics for abuse.

Fentanyl pectin nasal spray for breakthrough cancer pain.

Fentanyl pectin nasal spray for breakthrough cancer pain.

A 44-Year-Old Woman With Excessive Sleepiness

A 44-year-old woman was referred by her primary care physician for a polysomnogram for further workup of excessive daytime sleepiness. She reported a 6-month history of uncontrollably falling asleep. She frequently dozed off while watching television, sitting inactive in public places, and talking to people. She had dozed off while driving, but had not had any driving accidents. Her Epworth Sleepiness Scale score was 21 of 24. She admitted to snoring, but no apneas were witnessed by her bed partner. She denied symptoms of morning headaches, gasping for air, leg jerking during sleep, cataplexy, sleep paralysis, hypnagogic hallucinations, gastroesophageal reflux during sleep, or insomnia. She usually went to bed at 10:00pmand woke up at 9:00am. She reported three to four nocturnal awakenings per night. She denied taking naps. Medical history included chronic pain from cervical spinal stenosis, hypothyroidism, hyperlipidemia, depression, restless legs, migraines, and gastroesophageal reflux disease. She had no known cardiac illnesses. Medications included levothyroxine, 50 μg daily; duloxetine, 60 mg daily; cyclobenzaprine, 10 mg tid; omeprazole, 20 mg daily; trazodone, 50 mg daily; gabapentin, 600 mg daily; tolterodine, 2 mg bid; cetirizine, 10 mg daily; extended-release oral morphine sulfate, 15 mg bid; and immediate-release oral morphine sulfate, 15 mg qid as needed for pain.

Relationship between onset of pain relief and patient satisfaction with fentanyl pectin nasal spray for breakthrough pain in cancer.

Satisfaction with pain relief in patients with breakthrough pain in cancer (BTPc) has typically been assessed by overall efficacy without consideration of the rapidity of that response. To determine the relationship between speed of onset of pain relief and patient satisfaction for treated BTPc episodes overall and for individual treatments. Pooled data from two randomized, double-blinded crossover studies. Patients having 1-4 BTPc episodes per day on ≥60 mg/day oral morphine or equivalent. Episodes treated with fentanyl pectin nasal spray (FPNS; 100-800 μg), immediate-release morphine sulfate (IRMS), or placebo. Pain intensity was measured on an 11-point scale (5-60 minutes posttreatment); satisfaction was measured on a 4-point scale (30 and 60 minutes). The primary analysis assessed the overall relationship of time to onset of pain relief (pain intensity difference [PID]≥1) or time to clinically meaningfully reduction in pain (PID≥2) versus patient satisfaction and overall pain intensity (summed pain intensity difference at 30 [SPID30] and 60 minutes [SPID60]) assessed by analysis of variance (ANOVA). A secondary analysis assessed whether satisfaction was different between treatments using a within-patient comparison. Eight hundred thirty-one FPNS-treated, 368 IRMS-treated, and 200 placebo-treated episodes were analyzed. Overall, within the pool there was a statistically significant relationship between time to onset of pain relief (PID≥1 and PID≥2) and patient satisfaction (both speed of relief and overall) at 30 and 60 minutes (p<0.001); this relationship was also true within individual treatment groups (p<0.01). Similar results were found for overall pain intensity reduction. When treatment groups were compared using within-patient data, FPNS provided earlier onset of pain relief than IRMS or placebo (p<0.05), which translated into better satisfaction at 60 minutes (p<0.01). Earlier onset of pain relief resulted in greater patient satisfaction and overall relief of pain; between-treatment comparisons showed that FPNS provided earlier pain relief and greater satisfaction than IRMS or placebo.

Intravenous Flurbiprofen Axetil To Relieve Cancer-Related Multiple Breakthrough Pain: A Clinical Study

To compare the treatment effect reducing cancer-related multiple breakthrough pain (BTP) between immediate release morphine sulfate (IRMS) and flurbiprofen axetil. Eligible patients with refractory BTP were divided into two groups; the control group received IRMS for rescue care; the flurbiprofen group received intravenous flurbiprofen axetil. Patients were asked to assess the effect of rescue medication on their most severe pain. The study assessed 217 patients, 122 in the control group and 95 in the flurbiprofen group. The average time to meaningful pain relief following the administration of rescue medication in the two groups was 27.3 minutes (control group) and 16.0 minutes (flurbiprofen group, P<0.01). A significant reduction in pain intensity was found in both groups; the average visual analog scale (VAS) score was reduced from 7.8 to 3.0 in the control group and from 7.9 to 2.2 in the flurbiprofen group (P<0.01). Flurbiprofen axetil can relieve BTP quickly and effectively.

Opioid therapy for refractory dyspnea in patients with advanced chronic obstructive pulmonary disease: patients' experiences andoutcomes.

Dyspnea that is refractory to conventional treatments affects up to 50% of patients with advanced chronic obstructive pulmonary disease (COPD). Although professional societies recommend opioids in this setting, evidence supporting their use over months is limited. We conducted a multicentre mixed-methods study to understand patients' experiences when opioids are added to optimized conventional treatments for advanced COPD. A total of 44 patients (median age 74, range 51-89 years) agreed to participate in this 6-month study. After baseline assessments, immediate-release morphine sulfate syrup (initially 0.5 mg twice daily) was slowly titrated upward based on weekly assessments of symptoms. We conducted semistructured interviews and collected contemporaneous measures of health-related quality of life, severity of dyspnea, anxiety, depression, global ratings of opioid "helpfulness" and adverse effects before, at 2 months and at 4-6 months after opioids were started. Of the 44 patients, 32 (73%) completed the trial; 27 (90%) of 30 patients reported the opioid treatment as very (43%) or somewhat (47%) helpful. Three main themes emerged from the patients' overall positive experiences: small gains have big impact; realign hopes with reality; and "try it." Significant improvements were observed in median (interquartile range) scores between baseline and 4-6 months' assessment for health-related quality of life (Chronic Respiratory Questionnaire: 3.5 [2.8-4.0] v. 4.2 [3.6-4.8]; and Chronic Respiratory Questionnaire-Dyspnea domain: 2.8 [2.3-3.6] v. 3.9 [2.8-4.5]) and decreases in severity of dyspnea (numerical rating scale: 7.0 [5.0-8.0] v. 5.0 [4.0-6.0]). Adverse effects were minimal for most patients. Opioids were a helpful and acceptable intervention for refractory dyspnea in patients with advanced COPD. Many of the patients experienced sustained benefits over months, which supports recent recommendations to consider opioids in this setting. ClinicalTrial.gov, no. NCT00982891.

Efficacy and Safety of Fentanyl Pectin Nasal Spray Compared with Immediate-Release Morphine Sulfate Tablets in the Treatment of Breakthrough Cancer Pain: A Multicenter, Randomized, Controlled, Double-Blind, Double-Dummy Multiple-Crossover Study

Immediate-release morphine sulfate (IRMS) remains the standard treatment for breakthrough cancer pain (BTCP), but its onset of effect does not match the rapid onset and short duration of most BTCP episodes. This study will evaluate the efficacy/tolerability of fentanyl pectin nasal spray (FPNS) compared with IRMS for BTCP. Patients (n = 110) experiencing one to four BTCP episodes/day while taking ≥ 60 mg/day oral morphine (or equivalent) for background cancer pain entered a double-blind, double-dummy (DB/DD), multiple-crossover study. Patients completing a titration phase (n = 84) continued to a DB/DD phase: 10 episodes of BTCP were randomly treated with FPNS and oral capsule placebo (five episodes) or IRMS and nasal spray placebo (5 episodes). The primary end point was pain intensity (P < .05 FPNS vs. IRMS) difference from baseline at 15 minutes (PID(15)). Secondary end points were onset of pain intensity (PI) decrease (≥ 1-point) and time to clinically meaningful pain relief (CMPR, ≥ 2-point PI decrease). Safety and tolerability were evaluated by adverse events (AEs) and nasal assessments. By-patient and by-episode analyses were completed. Compared with IRMS, FPNS significantly improved mean PID(15) scores. 57.5% of FPNS-treated episodes significantly demonstrated onset of PI improvement by 5 minutes and 95.7% by 30 minutes. CMPR (≥ 2-point PI decrease) was seen in 52.4% of episodes by 10 minutes. Only 4.7% of patients withdrew from titration (2.4% in DB/DD phase) because of AEs; no significant nasal effects were reported. FPNS was efficacious and well tolerated in the treatment of BTCP and provided faster onset of analgesia and attainment of CMPR than IRMS.

Determining the clinically important difference in visual analog scale scores in abuse liability studies evaluating novel opioid formulations

This study determined how the magnitude of change in positive subjective responses predicts clinical outcome in a treatment setting. Specifically, we attempted to define what constitutes a clinically important difference (CID) in subjective responses. A 100-mm visual analog scale (VAS) measured subjective ratings of drug "high," calculated via an anchor-based method with published data from participants receiving sustained-release naltrexone (NTX) and heroin in a laboratory setting. The data were then compared to clinical outcomes in a treatment trial with sustained-release naltrexone. A distribution-based method subsequently analyzed data from participants who received ALO-01 (extended-release morphine with sequestered NTX) to predict its abuse liability. Differences in ratings of drug high of approximately 10 mm on a 100-mm line were clinically significant. By extrapolation, CIDs were also found between crushed or intact ALO-01 and immediate-release morphine sulfate (IRMS). No CIDs were found between intact and crushed ALO-01. From laboratory and treatment trial data involving naltrexone, calculation of CIDs in subjective ratings of high is possible. Consequently, crushing/swallowing or injecting ALO-01 produces clinically significantly less drug high than oral or intravenous morphine alone, suggesting that ALO-01 has lower abuse liability by those routes than morphine formulations.

Dose titration of fentanyl pectin nasal spray in a broad range of patients for the treatment of breakthrough pain in cancer.

e19659 Background: Randomized controlled studies have demonstrated that fentanyl pectin nasal spray (FPNS) provides superior pain relief compared with placebo and immediate-release morphine sulfate for the treatment of patients with breakthrough pain in cancer (BTPc). An ideal BTPc agent should also be easily titratable across a wide range of patient types. This report details the successful dose titration of FPNS in the clinical trial program. Methods: The FPNS clinical trial program enrolled 523 patients experiencing 1–4 BTPc episodes/day while taking ≥60 mg/day oral morphine (or equivalent) for background pain. The open-label titration phase was designed to find an effective dose that successfully treated 2 consecutive episodes of BTPc without unacceptable adverse events (AEs). Results: Across the FPNS clinical trial program, a total of 2,417 episodes of BTPc were treated with FPNS in the dose-titration phase. This included a broad range of patient types: >28% were >60 years of age (mean age, 54.2), 48% were female, 55% were white, 56.6% had an Eastern Cooperative Oncology Group (ECOG) score = 1, and 21% were undergoing chemotherapy. Patients were successfully titrated to either 100 µg (17.7%), 200 µg (21.8%), 400 µg (32.0%), and 800 µg (28.5%) in a minimal number of steps (mean, 2.7). Successful titration was consistent across the 3 multinational, multicenter studies at sites across 13 countries and 4 continents. Dose distribution did not vary by age or by weight, although there was a slight tendency for men to titrate to higher doses. Titration failed for FPNS-related reasons in 42 (8.0%) patients: 15 (2.9%) because of AEs and 27 (5.2%) because of inadequate efficacy. Treatment-related AEs leading to withdrawal were primarily headache, nausea, and vomiting, consistent with the known effects of fentanyl; they were not dose related. Conclusions: FPNS provides an easy-to-use and convenient method of administration for the treatment of BTPc. Furthermore, FPNS is easily titrated to an effective dose in a broad range of opioid-tolerant cancer patients, with only 8.0% unable to titrate for FPNS-related reasons.

Consistency of Efficacy, Patient Acceptability, and Nasal Tolerability of Fentanyl Pectin Nasal Spray Compared with Immediate-Release Morphine Sulfate in Breakthrough Cancer Pain

Context We recently reported that fentanyl pectin nasal spray (FPNS) provides superior pain relief from breakthrough cancer pain (BTCP) compared with immediate-release morphine sulfate (IRMS), with significant effects by five minutes and clinically meaningful pain relief from 10 minutes postdose. Objectives To report the consistency of efficacy, tolerability, and patient acceptability of FPNS vs. IRMS. Methods Patients ( n = 110) experiencing one to four BTCP episodes/day while taking ≥60 mg/day oral morphine (or equivalent) for background pain entered a double-blind, double-dummy (DB/DD), multiple-crossover study. Those who completed an open-label titration phase ( n = 84) continued to a DB/DD phase; 10 episodes were randomly treated with FPNS and overencapsulated placebo or IRMS and nasal spray placebo (five episodes each). Pain intensity (PI) and pain relief scores were assessed. Patient acceptability scores were assessed at 30 and 60 minutes. Safety and tolerability were assessed by adverse events (AEs) and nasal assessments. Results Per-episode analysis revealed that FPNS consistently provided relief from pain more rapidly than IRMS; by 10 minutes, there were significant differences in PI difference scores and in the percentages of episodes showing clinically meaningful pain relief ( P < 0.05). Overall acceptability scores were significantly greater for FPNS than for IRMS at 30 ( P < 0.01) and 60 ( P < 0.05) minutes. Patients were “satisfied/very satisfied” with the convenience (79.8%) and ease of use (77.2%) of FPNS. Only 4.7% of patients withdrew from titration because of AEs; no significant nasal effects were reported. Conclusion This study demonstrates that FPNS is efficacious, well accepted, and well tolerated by patients with BTCP.

A Comparison of Change in the 0–10 Numeric Rating Scale to a Pain Relief Scale and Global Medication Performance Scale in a Short-term Clinical Trial of Breakthrough Pain Intensity

Pain intensity is commonly reported using a 0-10 Numeric Rating Scale in pain clinical trials. Analysis of the change on the Pain Intensity Numerical Rating Scale as a proportion has most consistently correlated with clinically important differences reported on the patient's global impression of change. The correlation of data from patients with breakthrough pain with a Pain Relief Scale and a different global outcome measures will extend our understanding of these measures. Data were obtained from the open titration phase of a multiple crossover, randomized, double-blind clinical trial comparing oral transmucosal fentanyl citrate with immediate-release oral morphine sulfate for the treatment of cancer-related breakthrough pain. Raw and percentage changes in the pain intensity scores from 1,307 episodes of pain in 134 oral transmucosal fentanyl citrate-naïve patients were correlated with the clinically relevant secondary outcomes of Pain Relief Verbal Response Scale and the global medication performance scale. The changes in raw and percentage change were assessed over time and compared with the ordinal Pain Relief Verbal Response Scale and Global Medication Performance Scale. The P value of the interaction between the raw pain intensity difference was significant (P = 0.034) for four 15-min time periods but not for the percentage pain intensity difference score (P = 0.26). We found similar results in comparison with the ordinal Pain Relief Verbal Response Scale (P = 0.0048 and P = 0.36 respectively) and global medication performance categories (P = 0.048 and P = 0.45, respectively). The change in pain intensity in breakthrough pain was more consistent over time and when compared with both the Pain Relief Verbal Response Scale and the Global Medication Performance Scale when the percentage change is used rather than raw pain intensity difference.

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.

Unexpected Urine Drug Testing Results in a Hospice Patient on High-Dose Morphine Therapy

A 41-year-old African-American woman was admitted to an inpatient hospice facility with advanced, inoperable cervical cancer. The patient was experiencing severe pain secondary to extensive local tumor invasion, osseous pelvic metastases, and sacral decubitus ulcers. Her pain was treated with an escalating-dose schedule of morphine sulfate until satisfactory analgesia was achieved with stable doses of a combination of controlled-release morphine sulfate (MSContin®, Purdue Pharma LP) 400 mg orally every 8 h, and immediate-release morphine sulfate (MSIR®, Purdue Pharma LP), 180 mg orally every 4 h, as needed for breakthrough pain (average 2 to 3 doses per day). The patient experienced several episodes of life-threatening vaginal bleeding for which she was hospitalized for red blood cell transfusions and bilateral hypogastric artery embolizations. She spent the final 12 weeks of her life exclusively on the inpatient hospice unit. Approximately 3 weeks before her death, the patient underwent urine specimen collection and analysis of morphine and metabolites. GC-MS analysis revealed the presence of morphine as well as small quantities of hydromorphone. During the past 2 decades, chronic opioid analgesic therapy (COAT) for chronic nonmalignant pain has gained increasing clinical acceptance. An unintended consequence of more liberal opioid prescription practices has been a dramatic increase in the abuse and diversion of these drugs. According the most recent National Survey on Drug Abuse and Health (1), the number of new, past-year abusers of prescription opioids was 2 147 000—more than the number of new abusers of any other single class …

A new transmucosal drug delivery system for patients with breakthrough cancer pain: the fentanyl effervescent buccal tablet

Breakthrough pain, a transitory severe pain with the background of otherwise controlled persistent pain has a prevalence between 52% and 67% in outpatients with cancer. Medications for such sudden-onset pain require non-invasive delivery of a potent and short-acting opioid for rapid pain relief. Although oral transmucosal delivery of fentanyl citrate (OTFC) has been shown to provide better pain relief than a typical oral opioid administration such as morphine sulfate immediate release (MSIR) in the management of breakthrough pain in patients with cancer-related pain, newer delivery systems offer a potential for further enhancement of pain relief. The fentanyl effervescent buccal tablet (FBT) formulation employs a novel drug delivery system that relies on an effervescence reaction to improve buccal fentanyl absorption. Using the effervescence reaction results in the production and dissipation of carbon dioxide with a dynamic shift in pH as the tablet dissolves. The induced low pH favors dissolution of fentanyl citrate in saliva (higher water solubility). The subsequent increase in pH thereafter favors the buccal absorption of non-ionized fentanyl across the buccal mucosa. Such a pH "pumping" mechanism increases the permeation of fentanyl into and through the buccal to the vascular system from where the agent is transported to the specific opioid receptor sites in the CNS. Compared with OTFC, data in healthy volunteers show that the effervescence reaction employed in FBT increases the total amount and the speed of absorption of fentanyl being absorbed. Compared with OTFC there is an increase in peak fentanyl blood concentrations, and an enhancement of the amount of buccal delivery of fentanyl. Such favorable data are underlined by the results of clinical studies where the FBT technology was studied in patients with breakthrough pain in chronic malignant pathologies.

Effervescent Morphine Results in Faster Relief of Breakthrough Pain in Patients Compared to Immediate Release Morphine Sulfate Tablet

Morphine tablets have been formulated to produce an easily ingested effervescent solution when placed in water. It was hypothesized that an aqueous solution would result in fast gastrointestinal transit with a more rapid onset of action compared to immediate release morphine sulfate (IRMS), which would be especially beneficial in treating breakthrough pain (BTP). In an open-label safety and efficacy study, effervescent morphine was given to 76 chronic cancer pain patients for treatment of BTP evaluating time until pain relief, global satisfaction and side effects. Results were compared to those obtained using an IRMS formulation in a preceding run-in period. For BTP, a mean dose of 28 mg of effervescent morphine (range 10-80 mg) resulted in a highly significant reduction of pain score (mean 7.8 to mean 3.2; P < 0.001). Efficacy was not different from that observed with IRMS. However, mean time until sufficient pain relief was significantly shorter than with IRMS (13 +/- 5.6 vs. 27 +/- 4.4 minutes; P < 0.01). The incidence of side effects was similar with the new morphine formulation and with IRMS. There was no relationship between the previous dose of the daily opioid and the effective dose of effervescent morphine. The dose for treatment of BTP was determined by individual titration and not predicted by the dose taken with the basic pain medication. Compared to IRMS, overall satisfaction for effervescent morphine was rated "superior" by 16.7%, and "better" by 63.2% of patients. Effervescent morphine offers an alternative for management of breakthrough cancer pain compared with the commonly used IRMS.

Oral analgesia in the treatment of post-cesarean pain

Objective: Cesarean section is one of the most common operations. The new technologies of postoperative pain treatment such as patient-controlled analgesia, are expensive and may limit women caring for their newborns shortly after delivery. The present study assessed patient satisfaction with oral analgesia following cesarean section. Study design: An open prospective study was conducted on all women who had a cesarean section with epidural analgesia, during two consecutive periods of 3 months each. In the first group of 109 women, an oral solution of 1 g dipyrone was allowed every 4 h, upon patient request. Patients requesting additional analgesia were administered a tablet of 30 mg immediate-release morphine sulfate. In the second group of 90 women, the same protocol was used; however, oral morphine was the drug of choice and dipyrone was used for rescue analgesia. Pain intensity and satisfaction were self-evaluated by patients using a visual analog scale. Results: The results of each study period were independently evaluated. The demographic and obstetrical variables were similar in both groups. The duration of analgesic effect of dipyrone was 6.5 h and the satisfaction score was 90. The duration of analgesic effect of oral morphine was 5.05 h and the satisfaction score was 83.7. Overall, patients in both groups requested only 25% of the permissible dosage of analgesia. Conclusions: Oral analgesia following cesarean section provides satisfactory pain relief, is easily administered, and is a substantially less costly alternative to the new pain treatment technologies currently in use.

873 Kadian TM/kapanol TM—A once daily morphine formulation

Although oral morphine remains the opioid of choice for the management of moderate to severe cancer pain, controlled-release morphine fonnulations have only enabled dosing every 8 to 12 hours. Kadian™/Kapanol™ (K) is novel polymer-coated morphine sulfate pellets (20, 50, 100 mg) in a capsule designed for 12 to 24 hourly dosing. This randomized, double-blind, double-dummy, parallel group study compared the efficacy and safety of K q12h or q24h to MS Conlin® tablets (MSC) q12h. Eligible patients with cancer pain were titrated to adequate analgesia with a stable dose of immediate-release morphine sulfate (IRMS) over a 3 to 14 day lead-in, then randomized to one of the three treatments for 7 ± 1 days. Rescue medication was IRMS tablets. Primary measures of efficacy on the final day were time to first rescue medication and total dose of rescue as a % of total daily dose (TDD) of morphine (%IRMS). Secondary measures were: daily—visual analogue scale (VAS) of pain intensity, quality of sleep, and incidence of morphine-related side effects; final day–VAS and verbal rating scale (VRS) of pain intensity, VRS of pain control, and patient global assessment of pain control and investigator global asssessment of efficacy. 152 patients completed final day assessments at 28 centres in the U.S.A.. Mean age was 61 yrs and TDD of morphine was 138 mg. 54 patients were treated with K q24h, 45 with K q12h, 53 with MSC. The number requiring rescue on the final day was K q24h 46%, K q12h 51%, MSC 55%. Time to first rescue was K q24h 6.8 h, K q12h 7.5 h, MSC 6.3 h. %IRMS was K q24h 39.2, K q12h 29.2, MSC 42.9. There were no significant differences for all measures. Patient global assessment (good or very good) significantly favoured K q24h over MSC (K q24h 89%, K q12h 76%, MSC 68%, P = 0.018). There were no significant differences for other secondary measures. Kadian™/Kapanol™ q24h and q12h had efficacy and safety similar to MSC q12h but had the added advantage of 12 to 24 hourly administration with a trend to less rescue medication use. Patient global assessment significantly favoured Kapanol™/KadianTM.

Evaluation of a cancer pain model for the testing of long-acting analgesics. The effect of MS Contin in a double-blind, randomized crossover design.

A double-blind, double-dummy, crossover study compared oral controlled-release morphine sulfate (MS Contin tablets [MSC], Purdue Frederick, Norwalk, CT) every 12 hours, and immediate-release morphine sulfate (IRMS) tablets, every 4 hours, in 14 evaluable patients with chronic cancer pain. The test model described showed assay sensitivity for steady-state analgesia, requiring relatively few subjects to yield statistical significance in pharmacologic potency estimates. Initial doses were the calculated equivalents of about one third the previous opioid requirements or at least 30 mg MSC every 12 hours or 15 mg IRMS every 4 hours. This was generally subtherapeutic; hence, additional IRMS was available for break-through pain. Doses of MSC and IRMS were titrated upwards until the requirement for rescue IRMS was less than 20% of the total daily amount of morphine. In both study phases, the total dose of morphine increased significantly from the first day to the last, on which it was significantly (34%) higher for IRMS than MSC. Pain was significantly less intense and frequent in the last 24 hours of each treatment arm than in the first, and equally well controlled by both regimens. The two treatments were equipotent in a pharmacologic assay using dosages and pain scores. The requirement for rescue analgesia was similarly comparable for both treatments, decreasing significantly with upward dose titration. The few side effects experienced (one with MSC and three with IRMS) did not include serious reactions such as respiratory depression. It is concluded that MSC, 12-hourly, controls cancer pain as effectively and safely as IRMS on a 4-hour schedule. MS Contin exhibits a 12-hour duration of action as previously shown in other well-controlled trials. A problem of pain exacerbation at the start of each study phase was found to be associated with the design of this study. It may be resolved with a higher initial study dose and/or use of a patient-controlled analgesia device for parenteral rescue doses.