Double-blind, randomized comparison of the analgesic and pharmacokinetic profiles of controlled- and immediate-release oral oxycodone in cancer pain patients.

Thirty patients with cancer pain completed a double-blind crossover study comparing controlled-release (CR) and immediate-release (IR) oxycodone. In open-label titration (2 to 21 days), these patients were stabilized on IR oxycodone qid. They were then randomized to double-blind treatment with CR oxycodone q12h or IR oxycodone qid for 3 to 7 days followed by crossover at the same daily dose. Mean (+/- SD) pain intensity (0 = none to 10 = severe) decreased from a baseline of 6.0 +/- 2.2 to 2.7 +/- 1.1 after titration with IR oxycodone dosed qid. Pain intensity remained stable throughout double-blind treatment: 2.7 +/- 1.9 with CR oxycodone and 2.8 +/- 1.9 with IR oxycodone. Acceptability of therapy and pain scores correlated with plasma oxycodone concentrations for each interval and were similar for both medications (IR and CR oxycodone). Adverse events were similar for both formulations. Following repeat dosing under double-blind conditions, oral CR oxycodone administered q12h provided analgesia comparable to IR oxycodone given qid.

The combination of ibuprofen and oxycodone/acetaminophen in the management of chronic cancer pain.

Thirty subjects with chronic moderate to severe pain who were receiving oxycodone/acetaminophen (oxy/APAP) for analgesia were initially evaluated for at least 7 days for oxy/APAP requirements for pain control. Each subject then received, in a randomized double-blind fashion, either 600 mg ibuprofen or placebo for an additional 7 days while hospitalized. Oxy/APAP usage was recorded daily along with efficacy and toxicity parameters. Overall global evaluations were also recorded on completion of the study. Comparison of mean differences before and after treatment with ibuprofen or placebo indicated a marked decrease in oxy/APAP use with ibuprofen (p less than 0.01) and a slight increase in use in the placebo group. Reduction in oxy/APAP usage occurred within 24 hours and maximized at 5 days. Overall global scores showed a marked preference for the ibuprofen combination over placebo (p less than 0.01). Daily pain intensity (p less than 0.05) and pain relief scores (p less than 0.05) also improved with the addition of ibuprofen. This study indicates that ibuprofen is efficacious in the management of chronic cancer pain, resulting in both enhanced analgesia and a reduction in concomitant narcotic use.

Comparison of intramuscular dezocine with butorphanol and placebo in chronic cancer pain: a method to evaluate analgesia after both single and repeated doses.

Sixty hospitalized subjects with chronic moderate to severe pain as a result of advanced cancer were enrolled in a randomized, parallel, double-blind trial comparing single doses and multiple doses of intramuscular dezocine (10 mg) with butorphanol (2 mg) and placebo. During the initial 6-hour efficacy evaluation, analgesia was measured using verbal and visual scriptors and vital signs, and acute toxicity information was recorded. Subjects with initial pain relief entered the 7-day multidose portion of the trial, and efficacy and toxicity data were recorded daily. After the initial dose the peak analgesia of the active agents was similar, but the duration of analgesia was longer with dezocine. After multiple doses, dezocine was superior to butorphanol in terms of length of treatment. Dezocine had less toxicity than had butorphanol after both single and repeated doses, further suggesting that dezocine may be beneficial in managing chronic cancer pain. The described study design is unique in that it compares the analgesic efficacy and toxicity of several analgesics with placebo after both single and multiple doses in the same subject. This method may prove to be an alternative pain model to evaluate chronic cancer pain.

Comparison of the analgesic efficacy and safety oral ciramadol, codeine, and placebo in patients with chronic cancer pain.

Ciramadol is a new opioid agonist-antagonist analgesic with low potential for dependency. Forty-three patients with moderate to severe chronic pain from primary or metastatic malignancy of the bone or major organs were enrolled in a randomized double-blind study that compared orally administered ciramadol (30 mg or 90 mg) to codeine (60 mg) and placebo. A single-dose, four-way crossover design, with a randomized Latin-square treatment sequence, was used. Data for 40 patients who received the above four study medications were included in the final statistical analysis of efficacy. Analgesic efficacy was measured at 0, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, and 6.0 hours, using standard visual and verbal pain relief and pain intensity scales. All active therapies provided greater pain relief than placebo (P less than .05). Ciramadol 30 mg and codeine 60 mg demonstrated equal analgesic activity, whereas ciramadol 90 mg was superior to both therapies. The predominant adverse experiences associated with ciramadol were nausea and drowsiness, which were apparently not dose related. Ciramadol appears to be an effective analgesic at the doses tested, with tolerable gastrointestinal central nervous system side effects at both the 30-and 90-mg dose levels.

Dose ranging evaluation of the antiemetic efficacy and toxicity of intramuscular levonantradol in cancer subjects with chemotherapy-induced emesis.

A phase II double-blind placebo-controlled, randomized dose-ranging trial was undertaken to determine the antiemetic efficacy and toxicity of the synthetic cannabinoid levonantradol at doses of 0.5, 1.0, 1.5, and 2.0 mg. Intramuscular levonantradol was prophylactically administered in random dosing to 20 subjects with a documented history of refractory emesis due to chemotherapy in advanced cancer. The selected dose was administered prior to the chemotherapy and was serially repeated over 12 hours, and efficacy and toxicity data were evaluated for 24 hours. Significant (P less than 0.01) antiemetic activity over placebo was observed with all doses of levonantradol administered, and a dose-effect response was not observed. Doses up to 2.0 mg were well tolerated, and observed toxicity increased with increased doses and with repeated dosing. Psychomimetic effects were mild and tolerable, and the limiting side effects were somnolence and hypotension.

Analgesic efficacy and pharmacokinetic evaluation of meperidine and hydroxyzine, alone and in combination.

As part of a study to evaluate the analgesic efficacy of meperidine and hydroxyzine, alone and in combination, a double-blind complete crossover study of meperidine (50 mg IM), hydroxyzine (100 mg IM), meperidine (50 mg IM) plus hydroxyzine (100 mg IM), and saline placebo was conducted. Thirty patients with chronic moderate to severe pain due to metastatic cancer were evaluated as to pain relief following administration of all four study medications. All of the treatment groups showed statistically significant analgesic activity as compared to placebo. Hydroxyzine provided sustained pain relief to six hours, whereas meperidine produced analgesia up to two hours. The combination produced additive analgesia only during the first 2 hr. The pharmacokinetics of meperidine and hydroxyzine were compared to observed analgesia. Significant correlation between serum drug levels of meperidine and hydroxyzine and pain relief resulted and the serum levels of meperidine and hydroxyzine necessary for analgesia were calculated to be 0.10-0.15 mg/ml and 60-70 ng/ml; respectively. The observed analgesia of the meperidine/hydroxyzine combination was correlated with the analgesia of the individual agents and the limited additive analgesia observed with the addition of meperidine to hydroxyzine does not justify the added toxicity of the narcotic.

Analgesic efficacy of zomepirac sodium in patients with pain due to cancer.

In a single-dose, a double-blind crossover study in 40 patients with chronic pain due to advanced cancer, zomepirac sodium (Zomax), a new, single-entity, non-narcotic analgesic, was compared to oxycodone with APC (Percodan) and placebo. Both a verbal and a curvilinear visual analog scale were used in the study, and the results obtained were comparable. Zomepirac sodium, 100 mg, provided analgesia equal to oxycodone with APC in all assessments of pain intensity and pain relief. The analgesic activity of zomepirac sodium was apparent by 1 hour, reached a peak between 3 and 4 hours after administration, and lasted at least 6 hours. Zomepirac sodium, 100 mg, appears to be an acceptable alternative to narcotic combinations such as oxycodone with APC in the management of moderate to severe cancer pain. The visual analog scale presented appears to be useful in the evaluation of analgesic efficacy and appears to be acceptable as an alternative to the more conventional verbal scale.

Pharmacokinetics and mechanisms of action of analgesics in clinical pain.

Due to recent interest in the development of drug assay techniques, the pharmacokinetics of many analgesics have been defined. In addition, mechanisms of action of the commonly used analgesics have been partly delineated, and currently accepted analgesic regimens and usages are being questioned. By considering both the pharmacokinetics and the mechanism of action of each of these analgesics, it would appear that only a few of the currently available agents are needed for the treatment of acute and chronic pain. Newer agents with reduced toxicity have been introduced but have resulted in little expansion of novel ways to interfere with pain. The recent discovery of the beta-endorphin system, the reevaluation of older agents, and the development of new agents that work at pain pathways other than the classical sites hold out the promise of alternative means of control of certain types of pain. An agent that has analgesic efficacy equivalent to morphine but with reduced toxicity is especially exciting in the development of new analgesics. An agent that, in addition, does not lead to intolerable psychomimetic reactions but instead addresses multiple aspects of treating the fear, pain, and tension triad of pain will be beneficial in acute pain but will especially enhance the spectrum of the control of chronic pain such as cancer, neuralgia and arthralgia.

Lymphangioma in four dogs.

Lymphangioma, a rare benign tumor of lymph vessels, was diagnosed in 4 dogs. The lesions were in the nasopharynx, retroperitoneum, axilla, and medial aspect of thigh. Treatment was either surgical excision or marsupialization.

A potentially toxic drug interaction between pethidine (meperidine) and phenobarbitone.

The concomitant administration of pethidine (meperidine) and phenobarbitone results in enhanced sedation in a patient previously tolerant of pethidine. A complete analysis of pethidine kinetics and metabolism was performed in this patient, in four additional patients undergoing similar treatment but not receiving phenobarbitone, and in a volunteer after placebo and phentobarbitone pretreatment. The results indicate that phentobarbitone enhances the production of the toxic metabolite norpethidine by increasing N-demethylation.

Fate of streptozotocin (NSC-85998)in patients with advanced cancer.

We have investigated the distribution, biotranformation, and excretion of streptozotocin and its 14C- and 3H-labeled metabolities in 15 patients with advanced cancer. Streptozotocin was detected in the plasma during the first 3 hours after administration while radioactive products were present for longer than 24 hours. No unchanged streptozotocin was detected in the cerebrospinal fluid (CSF); however, 14C-labeled metabolites were detected in the 2-hour CSF sample in a concentration equivalent to the 2-hour plasma level. H activity is the CSF was not detected at this time period. Radioactivity measured in biopsied tissues indicated that streptozotocin labeled with 14C and 3H or its metabolites penetrated tumor tissue. 14C tissue levels were found to approximate plasma levels; however, 3H levels were found to be greater than the corresponding plasma levels. Fifteen percent of the total dose of streptozotocin administered was recovered in the urine. 3H-labeled metabolites were recovered in excess of 60% in the urine, and approximately 30% of the 14C-labeled metabolites were recovered in the urine during a similar interval. Less than 1% of the administered 14C and 3H was recovered in the feces. 14C-labeled CO2 was also recovered, although quantitative recovery was not attained. At least three major metabolites of streptozotocin were detected in the urine by radiochromatography. Two metabolites contained only 3H and one metabolite contained both 14C and 3H in the same ratio as administered.

Absorption, distribution, and excretion of 5-azacytidine (NSC-102816) in man.

Patients with advanced cancer were given 5-azacytidine labeled at position 4 with radioactive carbon (14C) by either the intravenous (iv) or subcutaneous (sc) route. Absorption of the drug from the sc injection site was rapid and peak plasma levels were attained within one-half hour. Within 2 hours, the plasma level of radioactivity was approximately equal to that noted in the patients treated iv. The plasma half-life after iv injection was 3.5 hours; after sc administration, the plasma half-life was 4.2 hours. Patients receiving the drug sc excreted less drug in the urine than did those receiving the drug iv. No radioactivity was detected in the expired carbon dioxide when the drug was given by either route. Drug uptake into tumor tissue was always greater than uptake into surrounding normal tissue. The highest concentrations of radioactivity in the tissues were achieved when the drug had been given iv. Traces of radioactivity were still detectable in the tissues for as long as 6 days after administration of the drug. The incorporation of radioactivity into tumor RNA but not into DNA was demonstrated. The maximum level of radioactivity detected in the spinal fluid was equivalent to 0.2 microg of 5-azacytidine per milliliter of fluid.