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Biomedical subjects

R F Kaiko

Publications and source records attributed to R F Kaiko.

At least 19 recordsLinked to original sources
PubMed1999

Efficacy and safety of controlled-release versus immediate-release oxycodone: randomized, double-blind evaluation in patients with chronic back pain.

OBJECTIVE: To compare the efficacy and safety of controlled-release oxycodone given every 12 hours with immediate-release oxycodone given four times daily in patients with persistent back pain. DESIGN: Randomized, double-blind, active-controlled, two-period crossover trial. PATIENTS: Fifty-seven adult outpatients with stable, chronic, moderate-to-severe low back pain despite analgesic therapy were enrolled; 47 were randomized; 11 discontinued for side effects, most commonly nausea and vomiting. INTERVENTIONS: Controlled-release oxycodone tablets given every 12 hours; immediate-release oxycodone tablets given four times daily; dose titration with controlled-release or immediate-release for up to 10 days; double-blind treatment for 4-7 days each. OUTCOME MEASURES: Patients' pain scores (0 = none, 1 = slight, 2 = moderate, 3 = severe). RESULTS: Pain intensity decreased from moderate to severe at baseline to slight at the end of titration with both oxycodone formulations. The daily oxycodone dose was 40 mg or less in 68% of patients. During double-blind treatment, mean pain intensity was maintained at 1.2 (0.1 SE) with controlled-release and at 1.1 (0.1 SE) with immediate-release oxycodone. The most common adverse events were constipation, nausea, pruritus, somnolence, and dizziness. CONCLUSIONS: Controlled-release oxycodone given every 12 hours was comparable with immediate-release oxycodone given four times daily in efficacy and safety, and it provides convenient, twice-daily, around-the-clock treatment for selected patients with persistent back pain that is inadequately controlled by nonopioids or as-needed opioid therapy.

Analgesics, Opioid↗
PubMed1998

The use of controlled-release oxycodone for the treatment of chronic cancer pain: a randomized, double-blind study.

To compare the effectiveness and safety of controlled-release (CR) oxycodone tablets with immediate-release (IR) oxycodone in patients with chronic cancer pain, a multicenter, randomized, double-blind, parallel-group study was performed in 111 patients with cancer pain. Patients were treated with 6 to 12 tablets or capsules of fixed-combination opioid/nonopioid analgesics per day at study entry. Patients received 30 mg of CR oxycodone tablets every 12 hr or 15 mg of IR oxycodone four times daily for 5 days. No titration or supplemental analgesic medications were permitted. The mean (+/- SE) baseline pain intensity (0 = none, 1 = slight, 2 = moderate, 3 = severe) was 1.5 +/- 0.1 for the CR oxycodone-treated group and 1.3 +/- 0.1 for the group given IR oxycodone (P > 0.05). The 5-day mean pain intensity was 1.4 +/- 0.1 and 1.1 +/- 0.1 for the CR and IR groups, respectively (P > 0.05). Discontinuation rates were equivalent (33%). There was no significant difference between treatment groups in the incidence of adverse events. This study demonstrates that cancer pain patients given 6 to 12 tablets or capsules of fixed-dose combination analgesics can be equally well treated with CR oxycodone administered every 12 hr or IR oxycodone four times daily at the same total daily dose. CR oxycodone offers the benefits of twice daily dosing.

Adult↗
PubMed1998

Controlled-release oxycodone compared with controlled-release morphine in the treatment of cancer pain: a randomized, double-blind, parallel-group study.

Controlled-release oral formulations of oxycodone and morphine are both suitable analgesics for moderate to severe pain. They were compared in cancer-pain patients randomized to double-blind treatment with controlled-release oxycodone (n = 48) or controlled-release morphine (n = 52) every 12 h for up to 12 days. Stable analgesia was achieved by 83% of controlled-release oxycodone and 81% of controlled-release morphine patients in 2 days (median). Following titration to stable analgesia, pain intensity (0=none to 3=severe) decreased from baseline within each group (p </= 0.005), from 1.9 (0.1) to 1.3 (0.1), mean (SE), with controlled-release oxycodone, and from 1.6 (0.1) to 1.0 (0.1) with controlled-release morphine (no significant between-group differences). Typical opioid adverse experiences were reported in both groups. Hallucinations were reported only with controlled-release morphine (n = 2). Visual analog scores (VAS) for 'itchy' and 'scratchin' were lower with controlled-release oxycodone (p </= 0.044), as was peak-to-trough fluctuation in steady-state plasma concentration (p = 0.004). The correlation between plasma concentration and dose was stronger (p = 0.026) for oxycodone (0.7) than morphine (0.3). The relationship between pain intensity (VAS) and plasma concentration was more positive for oxycodone (p = 0.046). There was a positive relationship between morphine-6-glucuronide concentrations and urea nitrogen and creatinine levels (p = 0.001). Controlled-release oxycodone was as effective as controlled-release morphine in relieving chronic cancer-related pain, and as easily titrated to the individual's need for pain control. While adverse experiences were similar, controlled-release oxycodone was associated with less itching and no hallucinations. Controlled-release oxycodone provides a rational alternative to controlled-release morphine for the management of moderate to severe cancer-related pain.

Clinical Trial↗
PubMed1998

Comparison of controlled-release and immediate-release oxycodone tablets in patients with cancer pain.

PURPOSE: This study compared the clinical efficacy of oxycodone hydrochloride controlled-release (CR) tablets administered every 12 hours with immediate-release (IR) oxycodone tablets administered four times daily in patients with cancer-related pain. PATIENTS AND METHODS: Cancer patients who required therapy for moderate to severe pain were randomized to CR oxycodone every 12 hours (n=81) or IR oxycodone four times daily (n=83) for 5 days in a multicenter, double-blind study. Pain intensity was assessed four times daily (categorical scale of none, slight, moderate, and severe); acceptability of therapy was assessed twice daily (categorical scale of very poor, poor, fair, good, and excellent). RESULTS: Pain intensity remained slight during the study, with mean oxycodone doses of 114 mg/d (range, 20 to 400 mg/d) for CR and 127 mg/d (range, 40 to 640 mg/d) for IR. Acceptability of therapy was fair to good with both treatments. While standard conversion ratios provided an acceptable dose for many patients, a protocol amendment that allowed initial titration and use of rescue medication reduced the discontinuation rate for lack of acceptable pain control (from 34% to 4% with CR and from 31% to 19% with IR before and after amendment, respectively) without increasing the discontinuation rate for adverse events (from 8% to 7% with CR and from 13% to 11% with IR). Fewer adverse events were reported with CR (109) than with IR (186) oxycodone (P=.006). CONCLUSION: CR oxycodone every 12 hours was as effective as IR oxycodone four times daily in managing moderate to severe cancer-related pain and was associated with fewer reports of adverse events.

Analgesics, Opioid↗
PubMed1998

Long-term administration of controlled-release oxycodone tablets for the treatment of cancer pain.

We conducted a study of the safety of controlled-release (CR) oxycodone tablets (OxyContin Tablets) administered chronically to patients with cancer-related pain in a usual clinical setting. These patients had participated in 1 of 2 double-blind, active-control studies. Our study was an open, 3-month treatment study that included 87 patients. Patients received CR oxycodone tablets every 12 hr in a manner that reflected typical clinical practice. Supplemental immediate-release (IR) oxycodone was available PRN for breakthrough pain. Patients recorded medication use, adverse events, and evaluations of pain intensity and acceptability of therapy in a daily diary. Forty-four patients (51%) completed all 12 weeks of study; 43 patients (49%) discontinued participation. At baseline and throughout the study period, the overall mean pain-intensity score was slight to moderate. A comparison of initial and final doses showed a significant but modest increase in total daily CR oxycodone dose. An increase or decrease in titration of the oxycodone dose occurred for 66 patients (84%) at least once during the 12-week study period, primarily for increased pain. Forty-four patients (56%) did not undergo dose titration when the latter was indicated. Half of the patients used IR oxycodone rescue almost daily; the mean number of rescue doses per day was 1.5. Despite stable pain control and an increasing total daily CR oxycodone dose, the percentage of patients reporting common opioid-related adverse events decreased over the course of the study. CR oxycodone tablets administered every 12 hr were successfully used to manage cancer pain over a 12-week period. Importantly, side effects diminished over time without a concomitant change in efficacy.

Administration, Oral↗
PubMed1997

Pharmacokinetics and pharmacodynamics of controlled-release opioids.

While pharmacokinetic/pharmacodynamic relationships for opioids have not been consistently demonstrable or sufficiently predictive, there remain compelling reasons to pursue such relationships. Among the reasons for pursuing pharmacokinetic/ pharmacodynamic relationships is the prospect of predicting the time-action characteristics of new therapeutics on the basis of early studies in normals using pharmacodynamic surrogates for analgesia. The realization of such a model could improve the efficiency of development of analgesics. Four studies involving 98 normals were conducted to determine whether significant and reproducible relationships existed for oxycodone in the form of an oral controlled-release tablet. All studies were analytically blinded and utilized a validated gas chromatographic/mass spectrometric, sensitive (0.2 ng/ml), and specific method for oxycodone (four studies) and oxymorphone (two studies) quantitation in 17 to 20 serial plasma samples over 36 to 48 hours following a single 20 mg (or 40 mg) dose in each study. Concurrent assessments included vital signs and opioid effect VAS questionnaires. The studies demonstrated significant relationships between plasma oxycodone (but not oxymorphone) and pharmacodynamic surrogates (particularly VAS "drug effect") and were predictive of the 12-hour duration of pain control and prompt onset of analgesia subsequently demonstrated in multiple clinical studies involving patients with various pathological pain syndromes. The results suggest that investigators can make earlier, accurate predictions of opioid analgesic pharmacodynamics in patients based on pharmacokinetic/pharmacodynamic studies in normal volunteers.

Administration, Oral↗
PubMed1996

Analgesic efficacy of controlled-release oxycodone in postoperative pain.

The efficacy and safety of graded doses (10, 20, and 30 mg) of controlled-release (CR) oxycodone was compared with that of immediate-release (IR) oxycodone (15 mg), immediate-release oxycodone 10 mg in combination with acetaminophen 650 mg (APAP), and placebo in a single-dose, double-blind, randomized, parallel-group study. The participants, 182 inpatients experiencing moderate to severe pain after abdominal or gynecologic surgery, provided hourly ratings of pain intensity and relief for 12 hours after administration. All active treatments were significantly superior to placebo for many hourly measurements and for the sum of pain intensity differences (SPID) and total pain relief (TOTPAR). A dose response was found among the three levels of CR oxycodone for pain relief and peak pain intensity difference (PID), with the 20- and 30-mg doses being significantly better than the 10-mg dose. For all active treatments, peak PID and peak pain relief occurred approximately 2 to 4 hours after administration. The median time to onset of relief was 32 minutes for oxycodone plus APAP, 41 minutes for IR oxycodone, and 46 minutes for CR oxycodone 30 mg. Duration of pain relief showed that the 10-, 20-, and 30-mg doses of CR oxycodone had durations of action of 10 to 12 hours compared with IR oxycodone and oxycodone plus APAP (both approximately 7 hours). Typical adverse events, particularly somnolence, occurred in all active treatment groups. Treatment with CR oxycodone was safe and effective in this study, and its characteristics will be beneficial in the treatment of pain.

Acetaminophen↗
PubMed1996

Pharmacokinetic-pharmacodynamic relationships of controlled-release oxycodone.

Plasma concentrations of oxycodone, oxymorphone, and noroxycodone were determined after administration of 20 mg oral controlled-release oxycodone tablets to four subject groups: young (aged 21 to 45 years) men, elderly (aged 65 to 79 years) men, young women, and elderly women. Area under the oxycodone and noroxycodone concentration-time curve (AUC) values were comparable among the four groups. Compared with oxycodone, the oxymorphone AUC values were small, with significant differences between subject groups. AUC values were also calculated for the pharmacodynamic variable "drug effect," scored on a 100 mm visual analog scale. The two groups with the highest oxycodone AUC values (young and elderly women) had the lowest oxymorphone AUC values and the greatest drug effect AUC values. The two groups with the lowest oxycodone AUC values (young and elderly men) had the highest oxymorphone AUC values and the lowest drug effect AUC values. These results support oxycodone, and not oxymorphone, as being primarily responsible for pharmacodynamic and analgesic effects.

Administration, Oral↗
PubMed1996

Differential effects of food on the bioavailability of controlled-release oxycodone tablets and immediate-release oxycodone solution.

The effects of a high-fat meal on the bioavailability of oxycodone hydrochloride, administered as a recently developed 40 mg controlled-release (CR) tablet or a 20 mg immediate-release (IR) solution, were evaluated in a randomized crossover study in 22 normal male and female subjects. Serial blood samples were collected for 36 h after dosing and analyzed for oxycodone by a validated method using gas chromatography/mass spectrometry. There was no significant food effect with CR oxycodone as judged by 90% confidence interval (CI) analysis of AUC0-infinity and Cmax values under fed and fasted conditions. For the IR solution, both oxycodone bioavailability and peak plasma oxycodone concentration were significantly altered by consumption of the high-fat meal, with the mean value for AUC0-infinity increasing to 120% (CI = 109-132%) and the mean value for Cmax decreasing to 82% (CI = 47-91%) of values observed in the fasted condition. Adverse events reported for both formulations were mostly mild to moderate in severity and typical of those observed with opioids.

Adult↗
PubMed1996

Characterization and validation of a pharmacokinetic model for controlled-release oxycodone.

1. Oxycodone is a strong opioid agonist that is currently available in immediate-release (IR) formulations for the treatment of moderate to severe pain. Recently, controlled-release (CR) oxycodone tablets were developed to provide the benefits of twice-a-day dosing to patients treated with oxycodone. The purpose of this investigation was to develop and validate a pharmacokinetic model for CR oxycodone tablets in comparison with IR oxycodone solution. 2. Twenty-four normal male volunteers were enrolled in a single-dose, randomized, analytically blinded, two-way crossover study designed to compare the pharmacokinetics of two 10 mg CR oxycodone tablets with 20 mg IR oxycodone oral solution. Pharmacokinetic models describing the oxycodone plasma concentration vs time profiles of CR tablets and IR solution were derived using NONMEM version IV. The predictive performance of the models was assessed by comparison of predicted oxycodone plasma concentrations with actual oxycodone plasma concentrations observed in a separate group of 21 volunteers who received repeated doses of IR and CR oxycodone for 4 days. 3. The unit impulse disposition function of oxycodone was best described by a one-compartment model. Absorption rate of the IR solution was best described by a mono-exponential model with a lag time, whereas absorption rate of the CR tablet was best described using a bi-exponential model. The absorption profile of the CR tablets was characterized by a rapid absorption component (t1/2abs = 37 min) accounting for 38% of the available dose and a slow absorption phase (t1/2abs = 6.2 h) accounting for 62% of the available dose. Two 10 mg tablets of oral CR oxycodone hydrochloride were 102.7% bioavailable relative to 20 mg of IR oxycodone hydrochloride oral solution. The population model derived after administration of a single dose accurately predicted both the mean and range of oxycodone concentrations observed during 4 days of repeated dosing. The mean prediction error was 2.7% with a coefficient of variation of 54%. 4. The absorption characteristics of CR oxycodone tablets should allow effective plasma concentrations of oxycodone to be reached quickly and for effective concentrations to be maintained for a longer period after dosing compared with the IR oral solution. The CR dosage form has pharmacokinetic characteristics that permit 12 hourly dosing.

Adult↗
PubMed1995

A bioequivalence study of oral controlled-release morphine using naltrexone blockade.

Twenty-three normal volunteers who received morphine sulphate (MS Contin) with naltrexone completed this randomized, analytically blinded, two-way crossover comparison of the bioavailability of one 200-mg oral controlled-release morphine sulfate tablet with two 100-mg MSC tablets. Morphine effects were blocked by three 100-mg doses of naltrexone. The first dose of naltrexone was given 24 hours before MSC dosing, followed by a second dose at the time of MSC dosing and a third dose 24 hours after MSC administration. Compared with two 100-mg MSC tablets, the 200-mg tablet was 96% bioavailable (90% confidence interval, 88.14-105.74%). The 90% confidence intervals for mean Cmax and AUC0-24 for one 200-mg MSC tablet were within +/- 20% of the Cmax and AUC0-24 of two 100-mg tablets, indicating the two dosage forms are bioequivalent. Single 200-mg doses of MSC given with the naltrexone blockade were generally well tolerated, and adverse effects were similar to those reported for naltrexone alone and for lower doses of morphine without naltrexone. Naltrexone proved safe and effective in blocking the effects of controlled-release morphine, permitting bioequivalence studies of a high dose of morphine in normal volunteers.

Administration, Oral↗
PubMed1995

Relative bioavailability of controlled-release oral morphine sulfate during naltrexone blockade.

The effect of naltrexone hydrochloride on the bioavailability of 60 mg controlled-release oral morphine sulfate in normal volunteers was determined using a randomized, 2-way crossover, analytically blinded study design. Although naltrexone did not qualitatively alter the concentration-time curve for controlled-release morphine, the area under the plasma morphine concentration-time curve from 0-24 h (AUC0-24) was significantly greater (p < 0.01) for morphine given with naltrexone (265 ng x h/ml) than for morphine given alone (215 ng x h/ml). Compared to morphine given alone, the apparent absorption half-life of morphine was decreased from 0.94-0.58 h (p = 0.01) and Cmax was increased from 28.17 ng/ml to 32.26 ng/ml (p = 0.04) during naltrexone blockade, whereas the Tmax and apparent elimination half-life of morphine were not significantly affected. The minimal differences in morphine bioavailability indicate naltrexone may be useful in comparative bioavailability studies of high-dose opioids in opioid-naive normal volunteers.

Adult↗
PubMed1993

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.

Administration, Oral↗
PubMed1992

The bioavailability of morphine in controlled-release 30-mg tablets per rectum compared with immediate-release 30-mg rectal suppositories and controlled-release 30-mg oral tablets.

The bioavailability of controlled-release morphine 30-mg tablets (MSC) administered orally or rectally and immediate-release morphine (RMS) 30-mg suppositories per rectum, was compared in this 14-subject, randomized, single-dose, analytically blinded, crossover study. Rectal MSC plasma morphine area under the curve from 0-24 hours (AUC0-24) was 50.8% of RMS and was similar for MSC administered by either route (rectal MSC = 90% oral MSC). Rectal MSC had a significantly delayed time to peak plasma level (5.4 vs 1.07 and 2.5 hrs for rectal MSC vs RMS and oral MSC, respectively) and a significantly attenuated time to maximum concentration (6.1 vs 25.4 and 9.7 ng/ml, respectively). Proctoscopy 24 hours after insertion revealed seven instances of mild, transient mucosal erythema or edema with rectal MSC and 12 with RMS. The number of nonlocal adverse effects was 14 with rectal MSC, 19 with RMS, and 18 with oral MSC. Further studies must determine the therapeutic consequences of pharmacokinetic differences and establish guidelines for rectal MSC use. The product is currently not recommended by the manufacturer for rectal administration.

Administration, Oral↗
PubMed1991

Relationships between opioid disposition and their pharmacological effects--an overview.

The understanding of the metabolic disposition and pharmacokinetics of opioid analgesics and their relationship to therapeutic and adverse effects has been an area of considerable research activity in the past two decades and has provided the beginning of an applied science in this area. Given the experimental nature and complexity of pharmacokinetic/pharmacodynamic relationships and the state of the art in this area, the most meaningful therapeutic conclusions and extrapolations remain those based on the results of the most adequate and well-controlled therapeutic evaluations. In contrast, advances in analytical methodology and an understanding of the pharmacokinetics of opioid analgesics in specific patient populations (e.g. severe hepatic cirrhosis, renal failure) have provided clinically useful guidance towards the appropriate precautions for the use of opioid analgesics.

Analgesics, Opioid↗
PubMed1990

Controlled-release morphine bioavailability (MS Contin tablets) in the presence and absence of food.

The bioavailability of a single, orally administered, 30-mg controlled-release morphine tablet (MS Contin Tablet; The Purdue Frederick Company, Norwalk, Conn.) was compared after fasting or a high fat meal in this single dose, randomized, crossover study involving 24 healthy male subjects. There was no significant (p greater than 0.05) difference in the mean extent of morphine absorption over 24 hours in the presence or absence of food (area under the plasma concentration vs. time curve [AUC(0,24)], fed = 107% of fasted). Time to maximal concentration (Tmax) was similar (p greater than 0.05) in the two treatment groups; the mean Tmax for fed volunteers was 2.5 hours versus 2.4 hours for fasted volunteers. The two regimens did not differ significantly (p greater than 0.05) with regard to maximal morphine concentration (Cmax); mean Cmax for fed subjects was 8.22 ng/ml whereas mean Cmax for fasted subjects was 8.53 ng/ It was concluded that consumption of a high fat meal did not affect either the rate or extent of morphine absorption, or any of the other pharmacokinetic parameters tested, following administration of MSC.

Administration, Oral↗
PubMed1989

Oral controlled-release morphine sulfate. Analgesic efficacy and side effects of a 100-mg tablet in cancer pain patients.

Fifty-one cancer pain patients with limited opioid exposure participated in a randomized, double-blind, repeated-dose, parallel-group comparison of two dosage strengths of the controlled-release morphine preparation, MS Contin tablets (The Purdue Frederick Company, Norwalk, CT). The patients were first stabilized on immediate-release oral morphine 30 mg every 4 hours, with 15 mg available every 2 hours as needed for breakthrough pain ("rescue" dose). Each patient then received either one 100 mg MS Contin tablet or three 30-mg MS Contin tablets every 12 hours, with rescue medication as needed, for 3 days. Analysis of study power revealed sufficient sensitivity to detect clinically relevant differences in pain intensity and use of rescue medication. The two tablet strengths yielded similar pain relief, use of rescue medication, and frequency of side effects. In addition, pain and use of rescue medication did not change from the beginning to the end of the 12-hour dosing intervals in either group. In the study population as a whole, pain intensity was lower and total morphine intake higher during the period on controlled-release morphine. These data establish comparable analgesic efficacy and side effect potential of these two dosage strengths and confirm a 12-hour duration of effect for both. The improved analgesia on the controlled-release morphine may be attributable to increased consumption of drug resulting from improved compliance.

Administration, Oral↗