Analgesic efficacy and potency of two oral controlled-release morphine preparations.

MS Contin tablets and Oramorph SR tablets are two forms of oral controlled-release morphine sulfate available for the alleviation of pain. Our objective was to compare their analgesic effects in a relative potency assay. In this study, 151 patients undergoing caesarean section or abdominal hysterectomy and reporting moderate or severe postoperative pain received a 30 or 90 mg dose of either drug in a balanced, randomized, double-blind, parallel-group, single-dose experimental design. Patients provided self-ratings of analgesia. Relative potency for pain relief were calculated from log dose-effect curves. For total pain relief (rated by visual analog scales) over 12 hours, the log dose relative potency estimate for MS Contin tablets/Oramorph SR tablets was 1.9 (95% confidence limits, 0.89 to 11.1); for peak pain relief (visual analog scales) the relative potency estimate was 1.7 (95% confidence limits, 0.65 to 48.3). Overall, the 90 mg dose of MS Contin was more effective than 30 or 90 mg doses of Oramorph SR and the 30 mg dose of MS Contin at hours 6 to 12. Adverse experiences (mainly drowsiness) were mostly mild to moderate, with no significant differences in their overall incidence or severity between equivalent doses. MS Contin tablets provided greater peak, total, and duration of analgesia, without higher incidence of adverse experiences.

Ibuprofen interferes with the efficacy of antihypertensive drugs. A randomized, double-blind, placebo-controlled trial of ibuprofen compared with acetaminophen.

STUDY OBJECTIVE: To assess the effects of ibuprofen on blood pressure control in patients being treated with antihypertensive drugs. DESIGN: Randomized, blinded, placebo-controlled, parallel trial of ibuprofen compared with acetaminophen and with placebo in 3-week treatment periods. SETTING: A general internal medicine clinic at a university hospital. PATIENTS: Forty-five patients with essential hypertension controlled by treatment with at least two antihypertensive drugs were enrolled. Of these, 41 completed the study; treatment was discontinued in 3 of the 15 patients in the ibuprofen group due to breakage of the drug capsules, and after randomization in 1 of the 14 patients in the placebo group due to unstable angina. All 15 patients in the acetaminophen group completed the study. INTERVENTIONS: All previous antihypertensive regimens were continued. During the 3-week treatment, ibuprofen, 400 mg, was administered orally every 8 hours; acetaminophen, 1 g, orally every 8 hours; or placebo, 2 capsules, orally every 8 hours. MEASUREMENTS AND MAIN RESULTS: In the ibuprofen group, the mean increase from baseline after 3 weeks of treatment was significant in the average supine diastolic blood pressure (6.4 mm Hg; 95% confidence interval [CI], 1.05 to 11.75; p = 0.0239); supine mean arterial pressure (6.6 mm Hg; 95% CI, 1.25 to 11.95; p = 0.0205); and sitting mean arterial pressure (5.8 mm Hg; 95% CI, 1.57 to 10.04; p = 0.0123). The mean increase in blood pressure variables in the ibuprofen group was significantly different compared with the mean increase in the variables in the placebo group after 3 weeks of treatment: supine systolic blood pressure (7.1 mm Hg compared with -4.5 mm Hg; 95% CI for the difference in means, 2.5 to 20.6; p = 0.0133); supine diastolic pressure (6.4 mm Hg compared with 0.0; 95% CI for difference in means, 0.87 to 12.4; p = 0.0250); supine mean arterial pressure (6.6 mm Hg compared with -1.5; 95% CI for difference in means, 2.0 to 14.2; p = 0.0110); sitting systolic pressure (6.8 mm Hg compared with -3.7; 95% CI for difference in means, 2.0 to 19.0; p = 0.0169); sitting diastolic pressure (5.3 mm Hg compared with -1.1; 95% CI for difference in means, 0.76 to 12.1; p = 0.0273); and sitting mean arterial pressure (5.8 mm Hg compared with -2.0; 95% CI for difference in means, 1.5 to 14.1; p = 0.0169).(ABSTRACT TRUNCATED AT 400 WORDS)

Anirolac vs. naproxen for postpartum uterine pain.

Anirolac, a new nonsteroidal anti-inflammatory drug, was evaluated for relative efficacy, safety, and time course of analgesia. In a stratified, randomized, parallel, double-blind trial, 120 hospitalized women with moderate or severe postpartum uterine pain were treated with single oral doses of anirolac, 50 or 100 mg, naproxen sodium, 550 mg, or placebo. Using verbal scales, patients rated pain intensity, pain relief, and side effects at regular intervals for 6 hours. Highest summed analgesic ratings over placebo were induced by anirolac, 100 mg (P less than or equal to 0.001), and naproxen (P less than or equal to 0.001), followed by anirolac, 50 mg (P less than or equal to 0.005). At each assessment after the first hour, anirolac, 50 and 100 mg, and naproxen induced significantly stronger analgesia than did placebo. Statistically significantly more drowsiness was reported with all three active agents than with placebo. Our results suggest that, for postpartum uterine pain, analgesia with anirolac, 50 or 100 mg, is equivalent to that with naproxen, 550 mg.

Ketorolac versus aspirin for postpartum uterine pain.

Ketorolac tromethamine, a new nonsteroidal antiinflammatory analgesic, was evaluated for relative efficacy, safety and time course of analgesia in a stratified, randomized, parallel, double-blind trial. The study involved 120 hospitalized women (4 groups of 30) with moderate or severe postpartum uterine pain treated with single oral doses of ketorolac 5 mg and 10 mg, aspirin 650 mg or placebo. At regular interviews for 6 hours patients rated pain intensity, pain relief and side effects. Significant differences (p less than or equal to 0.05, two-tailed) occurred among the 4 treatments for various measurements of summed and peak analgesia. Ketorolac 10 mg was significantly superior to placebo in 5 of 5 major efficacy measurements, and aspirin was significantly superior in 3 of 5. Ketorolac 10 mg gave the highest mean rating for summed pain intensity differences (13.6, p = 0.0002 versus placebo), followed by aspirin (11.9, p = 0.012), ketorolac 5 mg (10.9, p = 0.072) and placebo (8.6). With ketorolac 10 mg and 5 mg and aspirin, analgesia lasted 6 hours, with peak efficacy at 3 hours. Side effects were not significant. Our results suggested a positive dose-response relationship for ketorolac. Compared to aspirin, ketorolac 10 mg induced equal or more analgesia, whereas ketorolac 5 mg was near the minimum effective dose and seemed less effective than aspirin.

Flurbiprofen, aspirin, codeine, and placebo for postpartum uterine pain.

Flurbiprofen (Ansaid, Upjohn), a substituted phenyl propionic acid, is a new analgesic/anti-inflammatory agent. To evaluate its relative efficacy in noninflammatory pain, 159 hospitalized women with moderate or severe postpartum uterine cramps were given single oral doses of 50 mg of flurbiprofen, 650 mg of aspirin, 60 or 120 mg of codeine sulfate, or placebo in a parallel, stratified, randomized block, placebo-controlled, double-blind trial. Patients rated pain intensity, pain relief, and side effects in uniform interviews for six hours after treatment. All measures of peak and summed analgesia exhibited significant differences among the five treatments. Flurbiprofen and aspirin showed the greatest analgesic response and were significantly superior to placebo. Results of codeine treatment were equivocal with no evidence of a positive dose response. Side effects were unremarkable except for dizziness and drowsiness after the 120-mg codeine dose. These findings suggest that flurbiprofen as an analgesic for patients with postpartum uterine pain is equivalent to aspirin and superior to codeine.

Multicenter clinical evaluation of long-term efficacy and safety of labetalol in treatment of hypertension.

The long-term efficacy and safety of labetalol, an antihypertensive agent with combined beta- and alpha-blocking activity, were evaluated alone (number = 193) and in combination with a diuretic (number = 144) in an open-label multicenter trial of 337 hypertensive patients aged 21 to 75 years, including initially 205 (61 percent) men and 219 (65 percent) Caucasians. There were 219 (65 percent) mild, 85 (25 percent) moderate, and 33 (10 percent) severe hypertensive patients. Labetalol (100 to 1,200 mg twice a day) alone or in combination with a diuretic reduced the mean standing blood pressure by 13/11 and 25/16 mm Hg to 135/88 and 130/91 mm Hg, respectively (p less than 0.01), and supine blood pressure by 6/7 and 18/13 mm Hg to 141/86 and 138/90 mm Hg (p less than 0.01), respectively. Blood pressure reductions observed at one month were maintained after one year; 206 (62 percent) patients had 10 mm Hg or greater reductions and 184 (56 percent) patients were maintained at diastolic blood pressures less than 90 mm Hg. Most frequently reported drug-related side effects included fatigue (14 percent), dizziness (12 percent), nausea (11 percent), nasal stuffiness (8 percent), headache (4 percent), and male sexual dysfunction (14 percent). Side effects were generally of mild to moderate intensity and often transient. In addition, in 27 (8 percent) patients reversible asymptomatic transaminase elevations to greater than twice normal developed at some time during the study. In 13 (4 percent) patients these alterations resolved during continued labetalol therapy, but in five (2 percent) patients these marked elevations led to discontinuation of the drug. A total of 32 (9.5 percent) patients were terminated prematurely due to side effects (most commonly genitourinary or gastrointestinal) possibly attributable to the drug. These findings indicate that labetalol with or without a diuretic is a potentially effective, safe, and relatively well-tolerated long-term antihypertensive therapy.

Step II treatment with labetalol for essential hypertension.

Labetalol, a new alpha- and beta-adrenergic blocking agent, was administered to 57 patients with essential hypertension whose standing diastolic blood pressure was 105 to 120 mm Hg after three and four weeks of placebo therapy and greater than 90 mm Hg after three to four weeks of therapy with hydrochlorothiazide, 25 mg twice a day. Patients were then randomly assigned on a double-blind basis to receive either labetalol, 100 mg twice a day, or placebo combined with hydrochlorothiazide. Thereafter, the dose of labetalol was titrated weekly in both groups to a maximum of 400 mg twice a day to achieve a standing diastolic blood pressure of less than 90 mm Hg that was also decreased from the hydrochlorothiazide baseline by 10 mm Hg or more (therapeutic goal). Labetalol was abruptly discontinued after four weeks of treatment and patients were given hydrochlorothiazide alone for two additional weeks. After one week of labetalol therapy, 100 mg twice a day (added to hydrochlorothiazide), there was a significantly greater reduction in supine systolic/diastolic blood pressure (6/5 mm Hg, p less than 0.04/less than 0.03) and standing blood pressure (9/7 mm Hg, p less than 0.01/less than 0.01) than with placebo therapy (3/0.5 and 3/1 mm Hg, respectively). The blood pressure reduction in the labetalol-treated group was associated with a 4 and 5 beats per minute reduction in the supine and standing heart rates, respectively. The median labetalol dose required to achieve the standing diastolic blood pressure goal was 400 mg twice a day. After four weeks of labetalol treatment, the mean reduction in blood pressure from the hydrochlorothiazide baseline was 12/13 mm Hg (p less than 0.01/0.01) in the standing position and 8/8 mm Hg (p less than 0.01/0.01) in the supine position. These blood pressure reductions were accompanied by a mean reduction in heart rate of 7 beats per minute. The most frequently reported complaints other than thiazide-induced nocturia included dizziness, fatigue, nausea, rash, and/or pruritus. Most of these complaints were reported at a similar incidence while patients were receiving placebo or hydrochlorothiazide alone as when receiving labetalol with hydrochlorothiazide. After abrupt withdrawal of labetalol, no evidence of rebound hypertension was observed. Labetalol is a safe and effective step II drug when added to hydrochlorothiazide for the treatment of patients with moderate to moderately severe hypertension.

Codeine and aspirin analgesia in postpartum uterine cramps: qualitative aspects of quantitative assessments.

The analgesic response to codeine of patients with postpartum uterine-cramp pain has recently met with controversy. To readdress this question, we conducted a new study comparing codeine sulfate, 60 mg (N = 32) and 120 mg (N = 31), with aspirin, 650 mg (N = 34), and placebo (N = 32) in hospitalized women with moderate or severe postpartum uterine cramps treated with single oral doses in a parallel, stratified, randomized, double-blind trial. Subjective reports were used as indices of response, and patients rated pain intensity, pain relief, and side effects at periodic, uniformly conducted interviews for 6 hr. Most measures of analgesia exhibited important differences among the treatments. In patients with undifferentiated pain (N = 129) and in a subset of patients with pure uterine cramps (N = 56; i.e., no concomitant episiotomy), aspirin showed the greatest response, whereas codeine responses were equivocal with no evidence of a positive dose response. In contrast, in a subset of patients with mixed episiotomy-uterine pain (N = 73), 120 mg codeine showed good separation from placebo and compared favorably with aspirin. Codeine, 60 mg, showed a similar trend, and there was a strong suggestion of dose-dependent analgesia. Side effects were not remarkable except for dizziness and drowsiness after 120 mg codeine in all sets and subsets of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Metkephamid and meperidine analgesia after episiotomy.

Metkephamid is an analog of methionine enkephalin. The efficacy, safety, and time course of analgesia with 70 or 140 mg metkephamid were compared with those of 100 mg meperidine and placebo in 59 hospitalized women with severe postpartum episiotomy pain. There were two separate trials with single intramuscular doses and identical designs, including parallel groups, randomized blocks, and double-blind conditions. Using subjective reports as indexes of response, patients rated pain intensity, pain relief, and side effects at periodic interviews for 6 hr. Almost all measures of summed and peak analgesia exhibited important differences among the three treatments in both trials. Metkephamid at the 140-mg dose was the most effective and meperidine, 100 mg, was next, whereas metkephamid, 70 mg, and placebo were least effective. Only metkephamid, 140 mg, and meperidine were measurably superior to placebo. Both treatments took effect within 30 min and peaked at 1 to 2 hr; with 140 mg metkephamid, maximum analgesia was sustained 6 hr, i.e., 2 hr longer than with meperidine. Metkephamid, 70 mg, could not be distinguished from placebo throughout its entire time course. Although dizziness was experienced with meperidine, the two metkephamid doses induced other side effects, including sensation of heavy limbs, dry mouth, eye redness, and nasal stuffiness. None were distressing. Our results suggest that 140 mg metkephamid compares favorably with 100 mg meperidine for analgesia after episiotomy, but it induces minor side effects more frequently.

Labetalol: a review of its pharmacology, pharmacokinetics, clinical uses and adverse effects.

Labetalol is a combined alpha- and beta-adrenoceptor blocking agent for oral and intravenous use in the treatment of hypertension. It is a nonselective antagonist at beta-adrenoceptors and a competitive antagonist of postsynaptic alpha 1-adrenoceptors. Labetalol is more potent at beta that at alpha 1 adrenoceptors in man; the ratio of beta-alpha antagonism is 3:1 after oral and 6.9:1 after intravenous administration. Labetalol is readily absorbed in man after oral administration, but the drug, which is lipid soluble, undergoes considerable hepatic first-pass metabolism and has an absolute bioavailability of approximately 25%. There are no active metabolites, and the elimination half-life of the drug is approximately 6 hours. Unlike conventional beta-adrenoceptor blocking drugs without intrinsic sympathomimetic activity, labetalol, when given acutely, produces a decrease in peripheral vascular resistance and blood pressure with little alteration in heart rate or cardiac output. However, like conventional beta-blockers, labetalol may influence the renin-angiotensin-aldosterone system and respiratory function. Clinical studies have shown that the antihypertensive efficacy of labetalol is superior to placebo and to diuretic therapy and is at least comparable to that of conventional beta-blockers, methyldopa, clonidine and various adrenergic neuronal blockers. Labetalol administered alone or with a diuretic is often effective when other antihypertensive regimens have failed. Studies have shown that labetalol is effective in the treatment of essential hypertension, renal hypertension, pheochromocytoma, pregnancy hypertension and hypertensive emergencies. In addition, preliminary studies indicate that labetalol may be of value in the management of ischemic heart disease. The most troublesome side effect of labetalol therapy is posture-related dizziness. Other reported side effects of the drug include gastrointestinal disturbances, tiredness, headache, scalp tingling, skin rashes, urinary retention and impotence. Side effects related to the beta-adrenoceptor blocking effect of labetalol, including asthma, heart failure and Raynaud's phenomenon, have been reported in rare instances.

Pilot study on disposition and pain relief after i.m. administration of meperidine during the day or night.

Two groups (four patients each) of sickle cell anemia patients with severe pain were studied. One group comprised patients admitted to emergency unit in the morning (5:40 to 9:15) and the other patients admitted in the evening (18:53 to 22:50). All patients received intramuscular meperidine (1.5 mg/kg). Pain intensity and pain relief were followed for 4 h; blood samples were taken up to 6 h after drug administration. Significant differences in drug disposition were found between the day and night groups, as the elimination half-life was 46% shorter during the night and the total serum clearance was 70% greater during the night. Whereas a positive correlation was found between drug concentration and pain relief for the day group, no such correlation was found for th night group. Even though peak concentrations were higher during the night, analgesia was lower. This pilot study suggests that much higher meperidine doses might be required during the night to achieve equieffective analgesia.

Antihypertensive effects of lofexidine in patients with essential hypertension.

1 Single oral doses of lofexidine, 0.1, 0.3, and 0.6 mg produced dose related decreases in supine and standing arterial pressure and heart rate in nineteen patients with essential hypertension. 2 A mean oral antihypertensive threshold dose of less than 0.1 mg was estimated. 3 Lofexidine decreased mean urinary noradrenaline excretion 28% and caused significant retention of sodium and water. 4 The most prominent side effects were sedation and orthostatic dizziness. 5 Lofexidine is pharmacologically similar to, but apparently less potent than clonidine as an antihypertensive agent.

Propiram and codeine in episiotomy pain.

To evaluate relative efficacy, safety, and time course of analgesia, propiram fumarate (50 and 100 mg), a new narcotic agonist-antagonist, was compared with codeine sulfate (60 mg) and placebo in a clinical trial with a single peroral dose, parallel, stratified, randomized, and double-blind design involving 80 hospitalized postpartum women with medium or severe episiotomy pain. Using verbal subjective reports as index of response, patients rated pain intensity and side effects at periodic interviews for 6 h. Relative efficacy findings based on peak effects and summed pain-intensity differences suggested dose-dependent analgesia with propiram and also that 60 mg codeine lay between 50 mg propiram and placebo. Moreover, after 50 or 100 mg propiram, 8 of 20 patients reported greater than 50% reduction of initial pain compared with 7 of 20 after 60 mg codeine and 2 of 20 after placebo. After each of the propiram doses, distinct analgesia began within 1/2 h and reached peak effect between 1 h (p less than 0.02) and 2 h (p less than 0.05). After f60 mg codeine, onset was slower and peak later (4 h, p less than 0.05). All three active drugs continued to act until the 5th or 6th h. Drowsiness was the only statistically significant side effect reported after propiram. These results suggest that single 50 or 100 mg doses of propiram were effective in episiotomy pain, induced stronger analgesia than 60 mg codeine, and took effect more rapidly.

Bioavailability of naproxen sodium and its relationship to clinical analgesic effects.

1 In the first of a series of trials with naproxen sodium it was shown that patients achieved significantly earlier and higher plasma levels of naproxen when naproxen sodium was administered. 2 In a second study comparing naproxen with naproxen sodium in patients with post-partum pain, pain intensity was consistently lower for the group receiving naproxen sodium. However, statistically significant differences were not seen until 4 to 5 h after medication. 3 A final study documented that a more frequent dosage schedule of every 6 h led to clearly higher plasma levels than those achieved with an every 8 h regimen; plasma levels did not plateau. Doses up to 1,375 mg/day were well tolerated. 4 In conclusion, naproxen sodium appears to be an improved form of naproxen for use as a analgesic agent.

Nefopam and propoxyphene in episiotomy pain.

To evaluate relative efficacy, safety, and time course of analgesia, nefopam (45 and 90 mg), a new centrally acting nonnarcotic analgesic, was compared with propoxyphene (65 mg) and placebo in a single oral dose, parallel, stratified, randomized, double-blind trial with 100 hospitalized postpartum women with medium or severe episiotomy pain. Using subjective reports as indices of response, patients rated pain intensity and side effects at periodic interviews for 6 hr. After 45 and 90 mg nefopam, 21 of 25 and 20 of 25 patients (p less than 0.01) reported more than 50% reduction of pain, whereas after 65 mg propoxyphene 18 of 25 (p less than 0.05) and after placebo 11 of 25 reported reduction in pain. Relative efficacy, based on summed pain intensity differences, showed measurable but modest dose-dependent analgesia with nefopam, suggesting that the effectiveness of 65 mg propoxyphene lay between 45 mg nefopam and placebo. Side effects included mild dizziness and hypothermia after nefopam and mild elevation of diastolic arterial pressure after nefopam and propoxyphene. Our results suggest that 45- and 90-mg doses of nefopam induced more analgesia than 65 mg propoxyphene in the relief of episiotomy pain.

Fendosal and aspirin in postpartum uterine pain.

The analgesic efficacy of fendosal, a new nonsteroidal anti-inflammatory agent structurally related to salicylic acid, was compared with that of aspirin and placebo in 100 patients with postpartum uterine pain in a single oral dose, parallel, stratified, randomized, double-blind design. With 650 mg aspirin and with 200 or 400 mg fendosal, but not with 100 mg, analgesic effects, as measured subjectively by mean pain intensity scores, began within 1 hr and had similar time-effect patterns for the first 4 or 5 hr. Thereafter with the 2 higher doses of fendosal analgesia contimued to increase, reaching a peak at 6 hr (p less than 0.05) and persisting beyond 7 hr (p less than 0.01), whereas there was no aspirin analgesia after the fifth hour. With 100 mg fendosal time of onset tended to be delayed 2 hr or more, and duration was short. The most effective treatment (largest mean 7-hr sum of pain intensity difference [SPID] scores) was 400 mg fendosal (p less than 0.01); 200 mg fendosal was rated second (p less than 0.01), 650 mg aspirin, third (p less than 0.05), 100 mg fendosal, fourth, and placebo, fifth. There was no significant side effects. These results demonstrate the efficacy of single doses of fendosal as well as the dose-dependent magnitude and time course of effects on postpartum uterine pain.

Naproxen, aspirin, and codeine in postpartum uterine pain.

The analgesic efficacy of oral naproxen and its sodium salt was compared with that of aspirin and codeine in two separate trials involving 140 and 90 patients, respectively, with postpartum uterine pain in a single-dose, parallel, stratified, randomized, placebo-controlled, double-blind design. With 300 or 600 mg naproxen and with 275 mg naproxen sodium, significant analgesia, measured subjectively by pain intensity differences (PID), was prolonged at least 7 or 8 hr; onset tended to be delayed 2 hr or more. With 650 mg aspirin analgesia began within 1 hr and continued until the fifth hour, while with 60 mg codeine responses were indistinguishable from placebo responses throughout the 8-hr time course. Although time-effect patterns with naproxen sodium and aspirin were different, summed analgesic effects (SPID) showed equal efficacy and superiority over placebo (p less than 0.005). With each of the 2 doses of naproxen, SPID separation from placebo was comparable to that above (p less than 0.02 and 0.005, respectively), but analgesic dose response, though measurable, was not significant. Side effects were not significant with any of the treatments. It appears that naproxen and naproxen sodium are analgesics with efficacy equal to aspirin and may prove to be rational substitutes for currently available analgesics in some painful states in which longer pain relief would be desireable.