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Biomedical subjects

R F Kaiko

Publications and source records attributed to R F Kaiko.

At least 37 records · Page 2Linked to original sources
PubMed1989

The United States experience with oral controlled-release morphine (MS Contin tablets). Parts I and II. Review of nine dose titration studies and clinical pharmacology of 15-mg, 30-mg, 60-mg, and 100-mg tablet strengths in normal subjects.

The results of nine US multicenter, sequential crossover, dose titration studies of controlled-release oral morphine (MS Contin 30 mg tablets [MSC], Purdue Frederick, Norwalk, CT) are reviewed in Part I. The studies demonstrated the prolonged analgesic efficacy of the preparation in the treatment of patients with moderate to severe cancer-related pain. Approximately 93% of the patients achieved satisfactory to excellent analgesia on a 12-hour regimen when appropriate dose titration was allowed. The remaining patients were successfully maintained on an 8-hour regimen. The preparation was well-tolerated and comparable in safety to immediate-release oral morphine. In global evaluations, MSC was judged to be significantly (P less than 0.05) more effective, and with significantly (P less than 0.05) fewer side effects than both the prestudy opioid analgesics and 4-hour immediate-release oral morphine. Patients had a broad range of morphine requirements (mean daily MSC dose, 240 mg; range, 60 mg/day to 1800 mg/day); therefore various MSC tablet strengths were developed. Part II presents three studies in which the MSC formulations (15-mg, 60-mg, and 100-mg tablets) were compared to the 30-mg tablet within three randomized, single-dose, two-way crossover, analytically blinded bioavailability protocols, to determine bioequivalence and dose proportionality. The maximum morphine concentration, time of maximum morphine concentration, and area under the plasma morphine versus 12-hour and 24-hour time curve (AUC 0.12; AUC 0.24) were determined in each study. There were no significant differences between the values associated with MSC 1 X 30 mg tablet and 2 X 15 mg tablets (study 1), MSC 2 X 30 mg tablets and 1 X 60 mg tablet (study 2), and MSC 3 X 30 mg tablets and 1 X 100 mg tablet (study 3, values adjusted to dose of 90 mg), except for one marginally significant difference in study 3 (AUC 0.24; P = 0.04) which was not clinically or biopharmaceutically significant. The results showed that MSC 15-mg, 30-mg, 60-mg, and 100-mg dosage strengths are bioequivalent and dose proportional, and, therefore, therapeutically interchangeable. It was concluded that with routine assessment of the patient and adherence to the principles of analgesic dosing, MSC can be successfully used to control cancer-related pain. Furthermore, the availability of various MSC tablet strengths can be expected to facilitate the analgesic management of a patient population with widely differing opioid requirements.

Administration, Oral↗
PubMed1989

Cancer pain management with a controlled-release oral morphine preparation.

An open-label pilot study was conducted to assess the efficacy and acceptability of a controlled-release oral morphine formulation, MS Contin tablets, when administered "by the clock" two to three times daily as a substitute for opioids given on request to patients with pain caused by advanced cancer. Initially, four-hourly does of standard "immediate-release" oral morphine sulfate tablets were substituted for the patients' prior analgesic medication and titrated to individual needs. Forty of the 47 patients enrolled in the study were subsequently switched to an eight-hourly MS Contin regimen (three patients became too ill to continue the study, and four left the study during the immediate-release titration phase because of adverse reactions that may have been drug related). Small "rescue" doses of standard oral morphine were available to the patients, but they were taken infrequently. Twenty-one of the 37 patients maintained on the eight-hourly schedule consented to be treated with, and were subsequently stabilized on, MS Contin administered every 12 hr, with a reduction of over 20% in their average daily morphine dose. Most of the patients rated the controlled-release medication superior to the standard oral morphine tablets in terms of both convenience and adequacy of relief.

Administration, Oral↗
PubMed1987

Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain.

Concentrations of methadone in plasma, estimates of pain relief, and pupillary size were determined after a single intravenous dose (10 to 30 mg) of methadone hydrochloride to eight patients with chronic pain, five of whom had cancer. The pharmacokinetic parameter estimates reveal rapid and extensive distribution (Varea) and a slow apparent elimination half-life (t1/2) (mean Varea = 3.59 L/kg and harmonic mean t1/2 = 23 hours). The harmonic mean blood clearance is 106 ml/min, the harmonic mean renal clearance is 3.9 ml/min, the mean hepatic extraction ratio is 0.089, and plasma protein binding is 86% to 89%. These results suggest that only the free (unbound) fraction of methadone present in blood is extracted by the liver and that methadone can be classified as a low (hepatic)-extraction drug. The data were fit to a pharmacokinetic-pharmacodynamic model to obtain estimates of the steady-state plasma methadone concentration required to produce 50% of the maximum pain relief. This value varied from 0.04 to 1.13 micrograms/ml (mean = 0.29 micrograms/ml). These results indicate substantial interindividual variation in the relationship between changes in plasma methadone concentration and analgesia in patients with chronic pain receiving opioids. A pharmacokinetic-pharmacodynamic model may be useful for the individualization of analgesic dosage and therefore the optimization of pain management in patients with chronic pain.

Adult↗
PubMed1985

Epidural and intrathecal opiates: cerebrospinal fluid and plasma profiles in patients with chronic cancer pain.

We studied the cerebrospinal fluid (CSF) and plasma concentration-time profiles of morphine, methadone, and beta-endorphin after lumbar epidural or intrathecal injection in 17 patients with cancer. After epidural injection, all three drugs reached peak levels in lumbar CSF within 34 minutes that were 50 to 1300 times higher than free drug concentrations in plasma. The rate of decline of CSF levels correlated with drug lipid solubility (methadone [t1/2 = 73 minutes] greater than morphine [126 minutes] greater than beta-endorphin [317 minutes]). Plasma levels were comparable with those after intragluteal injection of the same dose. In four patients given intrathecal morphine or methadone, CSF at the C1-2 level contained high levels of morphine as early as 1 hour after injection, but levels of methadone were lower or undetectable. Three of 17 patients reported improved analgesia initially, but none were improved at 2 weeks after chronic therapy. We conclude that analgesia induced by intrathecal or epidural morphine injections is caused by drug acting at both spinal and supraspinal sites. The use of spinal opiates such as morphine is of limited value in patients whose pain is not adequately managed by high systemic doses of morphine-like drugs.

Adult↗
PubMed1985

Intramuscular meptazinol and morphine in postoperative pain.

Meptazinol is an agonist-antagonist opioid analgesic believed to be unique in its selectivity for mu1 (high affinity) receptors and its cholinergic activity. Our objectives were to determine the relative analgesic potency of intramuscular meptazinol and morphine and to compare mood and side effects in 102 patients with cancer who have postoperative pain. Meptazinol (50, 100, and 200 mg) and morphine (4, 8, and 16 mg) were given for moderate to severe pain in a double-blind, randomized but balanced, incomplete block design. Serial multiple assessments of pain, relief, mood, and side effects were made. The most precise estimates of relative analgesic potency indicate that meptazinol is equivalent to 10 mg morphine at 120 mg (95% confidence interval 80 to 170 mg) for peak effect and at 175 mg (95% confidence interval 125 to 270 mg) for total effect. Mean (+/- SE) times to peak effect and to remedication were 0.9 +/- 0.1 and 3.6 +/- 0.2 hours for meptazinol and 1.4 +/- 0.1 and 4.8 +/- 0.4 hours for morphine at equianalgesic peak effects. The percentages of subjects with one or more side effects were 18, 49, and 73 for graded meptazinol doses and 32, 49, and 65 for graded morphine doses. Mean numbers of side effects per subject were 0.3, 1.5, and 3.5 for meptazinol and 0.5, 0.7, and 1.7 for morphine. Profiles of side effects differed. Mood improvement and overall satisfaction were dose related and greater for morphine than for meptazinol. Side effects may limit the use of meptazinol in doses that relieve severe postoperative pain.

Adolescent↗
PubMed1984

Ibuprofen in the treatment of postoperative pain.

The site and type of operation and the age of the patient help determine the intensity of postoperative pain and the level of medication necessary for relief. Controlled clinical trials have shown that ibuprofen (Motrin) is an effective and safe analgesic for patients with mild to moderate postoperative pain. In a study of 120 patients with postoperative orthopedic pain, ibuprofen was more effective than acetaminophen-codeine and had a longer duration of action.

Acetaminophen↗
PubMed1983

Central nervous system excitatory effects of meperidine in cancer patients.

The analgesic meperidine has been reported to produce signs of central nervous system excitation in human beings. To determine the relationship between signs and symptoms of central nervous system excitation and plasma levels of meperidine and normeperidine, we studied 67 patients receiving meperidine for the relief of postoperative or chronic pain. In 48 patients, excitatory effects ranging from mild nervousness to tremors, twitches, multifocal myoclonus, and seizures were directly correlated with accumulation of normeperidine in plasma. Evidence of compromised renal function occurred in only 14 of the 48 symptomatic patients, suggesting that renal dysfunction may contribute to but is not the sole factor in the accumulation of normeperidine or its relation to adverse neurological signs. In a second study we surveyed mood alterations in 47 patients receiving meperidine and 29 receiving other narcotic analgesics for postoperative pain. The repeated administration of meperidine was associated with adverse alterations in various elements of mood (e.g., apprehension, sadness, restlessness).

Adolescent↗
PubMed1983

Plasma levels and analgesia following deltoid and gluteal injections of methadone and morphine.

The objective was to determine whether deltoid as compared to gluteal injection of morphine and methadone produce differential plasma levels and analgesic effects. Thirty-two postoperative cancer patients received deltoid and gluteal injections of morphine, 8 and 16 mg, within a double-blind, twin crossover design. Forty-four patients received deltoid or gluteal methadone, 10 mg. Deltoid morphine resulted in peak plasma levels 1.8 times (P less than 0.05) those observed following gluteal morphine. Deltoid methadone resulted in peak levels 2.5 times (P less than 0.005) those following gluteal injection. Deltoid morphine resulted in an area under the drug level-time (0 to 4 hours) curve 1.4 times (N.S.) the area observed following gluteal injection. Deltoid methadone resulted in an area under the drug level-time (0 to 4 hours) curve 2.2 times (P less 0.001) the area observed following gluteal injection. Deltoid methadone, but not morphine, provided greater (1.7-fold, P less than 0.05) pain relief than gluteal injection. If more rapid and enhanced analgesia is indicated, then the deltoid site may be preferable over the gluteal site for standard doses of methadone and other lipid soluble analgesics. In addition, the relative potency of compounds of widely differing lipid solubility may depend upon the site of intramuscular injection.

Adult↗
PubMed1983

Sources of variation in analgesic responses in cancer patients with chronic pain receiving morphine.

Our objective was to identify and quantify sources of variation in the relief of chronic pain with morphine. Relief scores were extracted from records obtained during controlled trials of analgesics in cancer patients with chronic pain in which intramuscular morphine was the assay standard. Relief data from 715 patients after 565 8-mg and 538 16-mg doses were segregated according to age, race, sex, pre-drug pain intensity, character and site. Middle-aged patients obtained relief after 8 mg comparable to relief obtained by younger patients after 16 mg; oldest patients obtained relief after 8 mg comparable to relief obtained by middle-aged patients after 16 mg. Blacks receiving 8 mg obtained relief comparable to whites receiving 16 mg. Sex-related differences were not significant. Patients with moderate, as compared to severe, pre-drug pain obtained significantly greater relief only after 16 mg. Patients reporting dull pain obtained relief after 8 mg comparable to relief obtained with sharp pain after 16 mg. Patients with abdominal pain obtained relief after 8 mg comparable to relief of pain in the chest or arms after 16 mg. These results provide dose-related evidence of variation in relief with morphine in chronic cancer pain and establish particular patient and pain characteristics as variables for which controls should be provided in analgesic assays.

Adolescent↗
PubMed1982

Clinical analgesic assay of sublingual buprenorphine and intramuscular morphine.

A six-point, incomplete block assay of sublingual buprenorphine and intramuscular morphine has been carried out, providing valid relative potency estimates of the two drugs in terms of total relief on both categorical and visual analog scales. Sublingual buprenorphine was about 15.5 times as potent as intramuscular morphine in terms of these total relief estimates. Similar relative potency estimates were obtained using first-dose-only data. There was no evidence of interaction by day in the crossover data, and the crossover study proved more efficient and provided tighter confidence limits. Sublingual buprenorphine produced a lower peak effect than intramuscular morphine. At equivalent peak effects, it produced longer-lasting analgesia. Side effect occurrence was roughly comparable for the two drugs, and no evidence of narcotic antagonist activity was seen after buprenorphine. The six-point assay proved to be effective in defining the dose-effect curves and relative potencies of the two drugs.

Administration, Oral↗