Randomized evaluation of controlled-release codeine and placebo in chronic cancer pain.

Codeine is widely used in combination with acetaminophen and aspirin for the management of mild to moderate pain. However, there are few controlled clinical trials of single-entity codeine in chronic cancer pain. The purpose of this study was to evaluate the clinical efficacy and safety of controlled-release codeine given every 12 hr in patients with cancer pain. Thirty-five patients with chronic cancer pain were randomized in a double-blind crossover study to controlled-release (CR) codeine or placebo, for 7 days each. Pain intensity was assessed at 0800 hr and 2000 hr using a visual analogue scale (VAS) and a five-point categorical scale, and the use of "rescue" acetaminophen-plus-codeine (300 mg/30 mg every 4 hr as needed) was recorded. Thirty patients completed the study (17 male, 13 female; mean age, 64.4 +/- 9.8 years) with a mean daily CR codeine dose of 277 +/- 77 mg (range, 200-400 mg). CR codeine treatment resulted in significantly lower overall VAS pain intensity scores (22 +/- 18 mm versus 36 +/- 20 mm, P = 0.0001), categorical pain intensity scores (1.2 +/- 0.8 versus 1.8 +/- 0.8, P = 0.0001), and pain scores when assessed by day of treatment and by time of day. Daily "rescue" analgesic consumption was significantly lower on CR codeine, compared to placebo treatment (2.2 +/- 2.3 versus 4.6 +/- 2.8 tablets per day, P = 0.0001). Both patients and investigators preferred CR codeine to placebo (80% versus 3%, P = 0.0014 and 73% versus 7%, P = 0.0160, respectively). These data indicate that CR codeine, given every 12 hr results in significant reductions in pain intensity and the use of "rescue" acetaminophen-plus-codeine in patients with cancer pain. CR codeine provides the benefits of a flexible single entity codeine formulation and the convenience of 12-hr duration of action, which allows patients uninterrupted sleep and improved compliance.

Repeated dosing of Uniphyl tablets under fed and fasting conditions: comparison of serum theophylline levels, pulmonary function, and asthma symptoms.

In order to determine the effects of repeated administration under fed and fasting conditions on the bioavailability and clinical efficacy of Uniphyl tablets, 22 adult asthmatics took the drug immediately following their evening meal for seven consecutive days and under fasting conditions for an additional seven consecutive days. For each patient, the daily theophylline dose remained constant throughout the study. Peak and trough serum theophylline concentrations (STC), spirometry, asthma symptoms, side effects and use of beta-agonist inhalers were recorded daily at 0730 and 1900 hours. The mean daily theophylline dose was 818.2 +/- 213.0 mg. The mean peak STC when Uniphyl was taken with food was 14.4 +/- 4.5 mg/L and was 13.1 +/- 3.6 mg/L when taken under fasting conditions (P less than .05). The trough STC was 7.4 +/- 2.8 mg/L with food and 6.9 +/- 2.1 mg/L while fasting (NS). There were no significant differences between the two dosing conditions in terms of spirometry, asthma symptom scores, side effects or use of beta-agonist inhalers. There was no significant difference between the patients' morning and evening FEV1 under either dosing condition. Since the differences in STC between fed and fasting conditions were not clinically significant, we conclude that there is no need to restrict patients to a rigid relationship between Uniphyl dosing and meal conditions. On the basis of patient preference and compatibility with a normal lifestyle, we recommend that patients should generally be instructed to take the drug with or shortly following their evening meal.

The role of theophyllines in a preventive approach for subjects with both mild and severe asthma.

Theophyllines continue to have a definite place in asthma therapy. With careful attention to therapeutic serum theophylline concentrations they are effective to improve spirometry and prevent symptoms. Theophyllines provide an additional benefit when prescribed with beta 2 agonists, and oral or inhaled steroids. Evening dosing with the once-daily, 24 hour formulation of theophylline 400 mg (Uniphyl) improves early morning function and prevents all or most of the early morning symptom exacerbation. Whereas there has been considerable focus on the potential side effects and theophylline toxicity, if subjects are introduced slowly to theophyllines, particularly in naive patients, and with careful attention to patient tolerance and serum theophylline concentrations, a majority of patients can be satisfactorily introduced to the products. With clinical experience, and when introduced with care, most patients will receive significant therapeutic benefit from theophyllines, with minimal or no side effects. Most patients readily accept the products, particularly the once daily 24 hour formulation.

Potential cost-avoidance with oral extended-release morphine sulfate tablets versus morphine sulfate solution.

The costs of acquiring, preparing, and administering morphine sulfate extended-release tablets and morphine sulfate solution were compared. Pharmacists at an acute-care community hospital timed the pharmacy and nursing components of the process of preparing and administering single doses of morphine sulfate extended-release tablets 60 mg and morphine sulfate solution 5 mg/mL. The labor cost of each step was determined by multiplying the mean time required to perform the task by the median of the wage scale for the person performing it. Acquisition costs and ancillary supply costs were determined, and the overall cost of each therapy was calculated. The total time required for providing single doses did not differ substantially. However, assuming a total daily morphine sulfate dosage of 120 mg, the time required for administering extended-release morphine sulfate tablets 60 mg twice daily was determined to be 8.90 minutes, compared with 23.44 minutes for solution (4 mL of 5-mg/mL solution) six times daily. Thus, although the cost of acquiring extended-release tablets was considerably higher than that of solution, the total daily cost of therapy with tablets was less than half that of therapy with solution. The potential for cost avoidance and the clinical advantages associated with extended-release morphine sulfate tablets make this formulation an attractive therapeutic alternative.

Analgesic response to single and multiple doses of controlled-release morphine tablets and morphine oral solution in cancer patients.

Immediate-release oral morphine, given every four hours in individually titrated doses, is effective in the control of severe cancer pain. To evaluate the analgesic efficacy of a controlled-release morphine sulfate preparation, MS Contin tablets (MSC, Purdue Frederick, Toronto, Ontario, Canada), after a single dose and under steady-state conditions, the authors compared MSC administered every 12 hours with morphine oral solution (MOS) administered every 4 hours in 17 adult cancer patients with chronic severe pain. In the single-dose evaluation, in which the patients were randomly assigned to receive MSC or MOS, there were no significant differences in analgesic efficacy or requirement for supplemental morphine between the two treatments. With both preparations, pain severity ratings increased toward the end of the 12-hour, single-dose observation period and were higher than the pain scores reported after dose titration. In the steady-state evaluation, which was a randomized crossover comparison, both preparations provided effective pain control with minimal side effects. There was no significant difference between MSC and MOS in overall pain scores or in pain scores analyzed by time of day and day of therapy. In conclusion, that an individualized twice-daily regimen of MSC is as effective as 4-hourly MOS for the control of chronic severe cancer pain. The twice-daily regimen has several advantages: it allows an uninterrupted night's sleep, it is substantially more convenient, and it can be expected to reduce both medication errors and noncompliance.

Control of severe pain with sustained-release morphine tablets v. oral morphine solution.

Recently a sustained-release morphine sulfate tablet (MS Contin [MSC]) was introduced in Canada. In a randomized double-blind crossover trial we compared MSC given every 12 hours with a morphine sulfate solution (MSS) given every 4 hours to 17 patients suffering from chronic severe pain. After titration of the morphine dosage to optimize the analgesic effect, each patient received 10 days of therapy with either MSC or MSS, then 10 days of therapy with an equal daily dose of the other formulation. Both preparations provided effective pain control, with minimal side effects. There was no significant difference between MSC and MSS in pain scores on a visual analogue scale (VAS), severity scores for tiredness and nausea, amount of supplemental morphine needed for break-through pain or patient preference. The plasma morphine concentrations tended to be greater during treatment with MSC. The study had an 89% probability of detecting a clinically significant difference in VAS pain scores. We conclude that an individualized, twice-daily regimen of MSC is as effective as MSS given every 4 hours for control of severe pain. The twice-daily regimen has several advantages: it provides for an uninterrupted night's sleep, it is substantially more convenient than the six doses per day required with MSS, and it should help reduce both medication errors and noncompliance.

The clinical significance of food-induced changes in the absorption of theophylline from Uniphyl tablets.

To determine the effects of food on the absorption of theophylline from Uniphyl tablets (a once-daily sustained-release theophylline formulation), we performed a crossover evaluation in 20 adults with asthma. After 5 days of continuous dosing (at 6 PM), all patients received their regular Uniphyl dose under specified fasting conditions, and serum theophylline concentrations were measured sequentially during the following 24 hours. The patients' next Uniphyl dose was administered immediately after ingestion of a standardized high-fat meal, and theophylline concentrations were again measured during 24 hours. Five days later, the procedure was repeated in the opposite order. The patients' mean daily theophylline dose was 890.0 +/- 229.2 mg. We found relatively minor, but in some cases statistically significant, differences in pharmacokinetic parameters between food and fasting administration. When Uniphyl was administered with food, bioavailability was increased by 10% (p less than 0.01), the time of maximum concentration occurred 3 hours later (p less than 0.01), and the minimum or "trough" theophylline concentration was 0.7 mg/L greater (p less than 0.01), as compared to administration while patients were fasting. There was no evidence of "dose dumping" after either food or fasting administration of Uniphyl, and there was no significant difference in the maximum theophylline concentration attained between the two dosing conditions. There was no evidence of a difference in therapeutic efficacy between the two dosing conditions. All patients tolerated the drug well throughout the trial.

Review of the North American experience with evening administration of Uniphyl tablets, a once-daily theophylline preparation, in the treatment of nocturnal asthma.

Increasing awareness of the exaggerated circadian rhythm in bronchomotor tone that causes most asthmatic patients to have increased respiratory symptoms in the early morning has resulted in a search for dosing strategies that will provide maximal bronchodilatory activity at the time of reduced bronchial patency. The purpose of this paper is to review briefly the published data on the North American experience with evening administration of the once-daily theophylline preparation, Uniphyl tablets. An increasing body of data demonstrates that this regimen produces peak concentrations of theophylline in the blood during the early morning hours, the time of maximal benefit for patients with nocturnal asthma. These data also show that once-daily Uniphyl administered in the evening is superior to both a once-daily morning Uniphyl schedule and to a conventional twice-daily sustained-release theophylline preparation in reducing early morning bronchoconstriction and associated symptoms.