morphinans and Neoplasms

Sinomenine (SIN) is a bioactive alkaloid compound extracted from a Chinese medicinal plant Sinomenium acutum. It is a multitarget antitumor natural substance. Various mechanisms have been proposed for the antitumor effects of SIN, such as direct cytotoxicity, induction of apoptosis, sensitization attenuating radiotherapy and chemotherapy, reversal of drug resistance, resistance to distant metastasis, and antiangiogenesis. SIN can be used as a tumor cell killer and an adjuvant to radiotherapy and chemotherapy. However, recent studies are mostly limited to the basic experimental stage; no systematic clinical studies have yet been reported. Therefore, this paper aimed to review the mechanism underlying the antitumor effects of SIN by consulting relevant domestic and foreign studies and to provide a relevant reference for further development, use, and exploration of SIN.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Chemotherapy, Adjuvant; Humans; Morphinans; Neoplasms; Plants, Medicinal; Radiotherapy, Adjuvant; Signal Transduction

Topics: Analgesics; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Drug Tolerance; Humans; Morphinans; Morphine; Narcotics; Neoplasms; Opioid-Related Disorders; Pain; Parasympatholytics; Psychotropic Drugs; Substance-Related Disorders

Topics: Administration, Oral; Analgesics, Opioid; Cancer Pain; Double-Blind Method; Family; Feasibility Studies; Hospice Care; Humans; Morphinans; Narcotic Antagonists; Neoplasms; Opioid-Induced Constipation; Palliative Care; Patient Selection; Polyethylene Glycols

Oxycodone is a µ-opioid receptor agonist widely used in the treatment of cancer pain. The predominant metabolic pathway of oxycodone is CYP3A4-mediated N-demethylation to noroxycodone, while a minor proportion undergoes 3-O-demethylation to oxymorphone by CYP2D6. The aim of this study was to investigate the effects of the mild CYP3A4 inhibitor aprepitant on the pharmacokinetics of orally administered controlled-release (CR) oxycodone.. This study design was an open-label, single-sequence with two phases in cancer patients with pain who continued to be administered orally with multiple doses of CR oxycodone every 8 or 12 hours. Plasma concentration of oxycodone and its metabolites were measured up to 8 hours after administration as follows: on day 1, CR oxycodone was administered alone; on day 2, CR oxycodone was administered with aprepitant (125 mg, at the same time of oxycodone dosing in the morning). The steady-state trough concentrations (Css) were measured from day 1 to day 3.. Aprepitant increased the area under the plasma concentration-time curve (AUC0-8) of oxycodone by 25% (p<0.001) and of oxymorphone by 34% (p<0.001), as well as decreased the AUC0-8 of noroxycodone by 14% (p<0.001). Moreover, aprepitant increased Css of oxycodone by 57% (p = 0.001) and of oxymorphone by 36% (p<0.001) and decreased Css of noroxycodone by 24% (p = 0.02) at day 3 compared to day 1.. The clinical use of aprepitant in patients receiving multiple doses of CR oxycodone for cancer pain significantly altered plasma concentration levels, but would not appear to need modification of the CR oxycodone dose.. UMIN.ac.jp UMIN000003580.

Topics: Adult; Aged; Analgesics, Opioid; Aprepitant; Area Under Curve; Delayed-Action Preparations; Female; Humans; Male; Middle Aged; Morphinans; Morpholines; Neoplasms; Oxycodone; Oxymorphone; Pain

This study evaluated the plasma concentrations of oxycodone and its demethylates and opioid-induced adverse effects based on cachexia stage in cancer patients receiving oxycodone. Seventy patients receiving oxycodone for cancer pain were enrolled. Cachexia was evaluated using the Glasgow Prognostic Score (GPS). Predose plasma concentrations of oxycodone, oxymorphone, and noroxycodone were determined at the titration dose. Opioid-induced adverse effects were monitored for 2 weeks after the titration. Plasma concentrations of oxycodone and oxymorphone but not noroxycodone in patients with a GPS of 2 were significantly higher than that with a GPS of 0. The metabolic ratios of noroxycodone but not oxymorphone to oxycodone in patients with a GPS of 1 and 2 were significantly lower than in those with a GPS of 0. A higher GPS was associated with a higher incidence of somnolence, while the GPS did not affect the incidence of vomiting. Plasma concentrations of oxycodone and oxymorphone were not associated with the incidence of adverse effects. In conclusion, cancer cachexia raised the plasma exposures of oxycodone and oxymorphone through the reduction of CYP3A but not CYP2D6. Although the cachexia elevated the incidence of somnolence, alterations in their pharmacokinetics were not associated with the incidence.

Topics: Aged; Analgesics, Opioid; Cachexia; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Female; Humans; Male; Middle Aged; Morphinans; Neoplasms; Oxycodone; Oxymorphone; Pain

Oxycodone is widely used for the treatment of cancer pain, but little is known of its pharmacokinetics in cancer pain patients. The aim of this study was to explore the relationships between ordinary patient characteristics and serum concentrations of oxycodone and the ratios noroxycodone or oxymorphone/oxycodone in cancer patients.. Four hundred and thirty-nine patients using oral oxycodone for cancer pain were included. The patients' characteristics (sex, age, body mass index [BMI], Karnofsky performance status, "time since starting opioids", "oxycodone total daily dose", "time from last oxycodone dose", use of CYP3A4 inducer/inhibitor, "use of systemic steroids", "number of medications taken in the last 24 h", glomerular filtration rate (GFR) and albumin serum concentrations) influence on oxycodone serum concentrations or metabolite/oxycodone ratios were explored by multiple regression analyses.. Sex, CYP3A4 inducers/inhibitors, total daily dose, and "time from last oxycodone dose" predicted oxycodone concentrations. CYP3A4 inducers, total daily dose, and "number of medications taken in the last 24 h" predicted the oxymorphone/oxycodone ratio. Total daily dose, "time from last dose to blood sample", albumin, sex, CYP3A4 inducers/inhibitors, steroids, BMI and GFR predicted the noroxycodone/oxycodone ratio.. Women had lower oxycodone serum concentrations than men. CYP3A4 inducers/inhibitors should be used with caution as these are predicted to have a significant impact on oxycodone pharmacokinetics. Other characteristics explained only minor parts of the variability of the outcomes.

Topics: Analgesics, Opioid; Cross-Sectional Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dose-Response Relationship, Drug; Female; Humans; Linear Models; Male; Middle Aged; Morphinans; Neoplasms; Oxycodone; Oxymorphone; Pain; Sex Factors

The aim of this study was to evaluate the plasma dispositions of oxycodone and its demethylates and dose escalation based on genetic polymorphisms of CYP2D6, CYP3A5, ABCB1, and OPRM1 in cancer patients receiving oxycodone. Sixty-two Japanese cancer patients receiving oxycodone extended-release tablets were enrolled. Predose plasma concentrations (C(12)) of oxycodone, noroxycodone, and oxymorphone were determined at the titrated dose. Daily oxycodone escalation rate was evaluated as the opioid escalation index (OEI). Genetic variants did not significantly alter oxycodone C(12). Oxymorphone C(12) and its ratio to oxycodone C(12) were significantly higher in CYP2D6 extensive metabolizers than in intermediate metabolizers but did not affect dose escalation. In contrast, noroxycodone C(12) and its ratio to oxycodone C(12) were significantly higher in the CYP3A5*1 carrier group than in the *3/*3 group. The OEI was significantly higher in the CYP3A5*3/*3 group than in the *1 carrier group. No significant difference was observed in the OEI in the other genetic variants. Noroxycodone C(12) was higher in the dose escalation group as compared to the nonescalation group and significantly affected the incidence of dose escalation. In conclusion, CYP3A5*3 altered the plasma disposition of noroxycodone, which was inversely affecting the dose escalation in cancer patients receiving oxycodone.

Topics: Aged; Asian People; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Delayed-Action Preparations; Female; Humans; Male; Middle Aged; Morphinans; Neoplasms; Oxycodone; Oxymorphone; Polymorphism, Genetic; Receptors, Opioid, mu

We prospectively investigated the efficacy of opioid rotation from oral morphine to oral oxycodone in cancer patients who had difficulty in continuing oral morphine treatment because of inadequate analgesia and/or intolerable side effects.. Twenty-seven patients were enrolled and 25 were evaluated. The rate of patients who achieved adequate pain control, which provided an indication of treatment success, was evaluated as primary endpoint. The acceptability and pharmacokinetics of oxycodone were evaluated in addition to the assessment of analgesic efficacy and safety during the study period.. In spite of intense pain, the morphine daily dose could not be increased in most patients before the study because of intolerable side effects. However, switching to oral oxycodone allowed approximately 1.7-fold increase as morphine equivalent dose. Consequently, 84.0% (21/25) of patients achieved adequate pain control. By the end of the study, all patients except one had tolerated the morphine-induced intolerable side effects (i.e. nausea, vomiting, constipation, drowsiness). Common side effects (>10%) that occurred during the study were typically known for strong opioid analgesics, and most were mild to moderate in severity. A significant negative correlation between creatinine clearance (CCr) value and the trough concentrations of the morphine metabolites was observed. On the other hand, no significant correlation was found between CCr value and the pharmacokinetic parameters of oxycodone or its metabolites.. For patients who had difficulty in continuing oral morphine treatment, regardless of renal function, opioid rotation to oral oxycodone may be an effective approach to alleviate intolerable side effects and pain.

Topics: Administration, Oral; Aged; Analgesics, Opioid; Constipation; Drug Administration Schedule; Female; Humans; Linear Models; Male; Middle Aged; Morphinans; Morphine; Morphine Derivatives; Nausea; Neoplasms; Oxycodone; Pain; Prospective Studies; Renal Insufficiency, Chronic; Sleep Stages; Treatment Outcome; Vomiting

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.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Biological Availability; Chronic Disease; Cross-Over Studies; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Morphinans; Neoplasms; Oxycodone; Oxymorphone; Pain; Pain Measurement; Therapeutic Equivalency; Vomiting

Oxycodone is an opioid analgesic that closely resembles morphine. Oxymorphone, the active metabolite of oxycodone, is formed in a reaction catalyzed by CYP2D6, which is under polymorphic genetic control. The role of oxymorphone in the analgesic effect of oxycodone is not yet clear. In this study, controlled-release (CR) oxycodone and morphine were examined in cancer pain. CR oxycodone and morphine were administered to 45 adult patients with stable pain for 3-6 days after open-label titration in a randomized, double-blind, cross-over trial. Twenty patients were evaluable. Both opioids provided adequate analgesia. The variation in plasma morphine concentrations was higher than that of oxycodone, consistent with the lower bioavailability of morphine. Liver dysfunction affected selectively either oxycodone or morphine metabolism. Three patients with markedly aberrant plasma opioid concentrations are presented. Significant individual variation in morphine and oxycodone metabolism may account for abnormal responses during treatment of chronic cancer pain.

Topics: Administration, Oral; Adult; Aged; Analgesics, Opioid; Cross-Over Studies; Cytochrome P-450 CYP2D6; Debrisoquin; Delayed-Action Preparations; Double-Blind Method; Female; Humans; Male; Middle Aged; Morphinans; Morphine; Morphine Derivatives; Neoplasms; Oxycodone; Pain; Pain Measurement; Phenotype

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.

Topics: Adult; Aged; Aged, 80 and over; Analgesics; Bridged Bicyclo Compounds, Heterocyclic; Butorphanol; Chronic Disease; Clinical Trials as Topic; Cycloparaffins; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Morphinans; Neoplasms; Pain; Random Allocation; Tetrahydronaphthalenes

The analgesic efficacy and tolerability of a morphine agonist-antagonist buprenorphine are evaluated. The drug is compared to pentazocin. For this purpose, the drugs were randomly administered to 42 patients suffering from pain caused by advanced cancer. Buprenorphine demonstrated a significantly higher analgesic effect than pentazocin and was better tolerated.

Topics: Buprenorphine; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Male; Morphinans; Neoplasms; Pain, Intractable; Pentazocine

Sublingual tablets of buprenorphine (Temgesic sublingual) were given in a controlled trial of 41 patients for 2804 patient-days. With a mean starting dose of 1.09 mg and a final dose of 1.53 mg buprenorphine daily there was a good pain-relieving effect. The interval between doses was six to eight hours. The trial did not reveal any direct pointers as to tolerance or addictiveness after long-term intake of the drug. Because of its effectiveness and good duration of action, as well as the absence of negative long-term effects, the drug can be recommended in the long-term management of cancer pain.

Topics: Buprenorphine; Clinical Trials as Topic; Drug Evaluation; Humans; Long-Term Care; Morphinans; Neoplasms; Pain, Intractable; Palliative Care

Topics: Analgesia; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Injections, Intramuscular; Morphinans; Morphine; Neoplasms; Palliative Care

Topics: Adult; Aged; Analgesics, Opioid; Buprenorphine; Clinical Trials as Topic; Female; Humans; Male; Meperidine; Middle Aged; Morphinans; Morphine Derivatives; Neoplasms; Pain, Intractable; Palliative Care

Twenty-eight cancer patients were treated with intramuscular butorphanol tartrate, a new non-narcotic analgesic, for investigating its clinical benefits in controlling cancer pain. Remarkable analgesic effects were observed approximately 30 minutes after administration by the single dose of either 1 or 2 mg of butorphanol. The effects lasted actively for 3 to 4 hours. Tolerance or drug dependency was rarely recognized even in the cases receiving repeated injections of the drug. Adverse effects, such as dizziness, nausea, thirst, numbness of the hands etc, observed in 5 patients were transient and required no medication. The above results may warrant a long-term administration of the drug for controlling varieties of pain in the cancer patients.

Topics: Aged; Butorphanol; Clinical Trials as Topic; Dose-Response Relationship, Drug; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Morphinans; Neoplasms; Pain, Intractable; Time Factors

Buprenorphine appears to have an analgesic effect (evaluated after a week of treatment) statistically superior to that of the comparative drug. On the whole, during buprenorphine treatment the normal activities of life of the individual patient improved. The percentage incidence of the side-effects is similar for the two drugs. Buprenorphine, however, caused less intense side-effects than pentazocine.

Topics: Adult; Aged; Buprenorphine; Humans; Middle Aged; Morphinans; Neoplasms; Pain; Pentazocine; Time Factors

1 Twenty-seven patients with moderate to severe chronic pain of malignant origin received buprenorphine (0.3 mg) and morphine (10 mg) intramuscularly in a double-blind, single dose within patient study. 2 Efficacy analysis demonstrated no significant differences in the peak analgesic effects or in the time to reach these effects. However, buprenorphine had a significantly longer duration of action than morphine. 3 Sedation was the most frequent unwanted effect with a similar incidence following each treatment. Buprenorphine was associated with a significantly higher incidence, greater severity, earlier onset, and longer duration of dizziness, nausea and vomiting than morphine. 4 Following both treatments there were small but significant decreases in pulse rate, blood pressure, and respiratory rate.

Topics: Adult; Aged; Buprenorphine; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Morphinans; Morphine; Neoplasms; Pain, Intractable; Time Factors

The therapeutic value of buprenorphine was investigated in 31 patients suffering from moderate to severe cancer pain by intramuscular administration at the single doses of 0.2 mg and 0.3 mg in comparison with pentazocine 30 mg. Analgesic effect of buprenorphine 0.3 mg was significantly superior to buprenorphine 0.2 mg and pentazocine 30 mg. The duration of analgesia with buprenorphine was 9 hours at 0.2 mg and 11 hours at 0.3 mg, which were markedly longer than pentazocine's 6 hours. Side effects most commonly observed in the three groups were nausea, vertigo, oral dryness, urinary retention, vomiting, sweating, and headache. The frequency of side effects was 54.8% for buprenorphine 0.2 mg, 50.0% for buprenorphine 0.3 mg and 58.3% for pentazocine 30 mg respectively, indicating no significant difference between the three groups. Blood pressure, heart rate and respiratory rate did not change appreciably, thereby suggesting a little effect of buprenorphine on the respiratory and cardiovascular systems. Buprenorphine was found a useful or extremely useful in 58% at 0.2 mg and 87.5% at 0.3 mg. As the result it was concluded that buprenorphine could be valuable as an analgesic for cancer pain.

Topics: Adolescent; Adult; Aged; Blood Pressure; Buprenorphine; Female; Humans; Male; Middle Aged; Morphinans; Neoplasms; Pain, Intractable; Pentazocine; Pulse; Respiration

1 Buprenorphine is a new antagonist analgesic which was offered sublingually to 141 patients with moderate cancer pain as an alternative to their current analgesic. These patients were not on regular strong morphine-like analgesics. 2 Forty-seven patients used the drug on demand in unit doses ranging from 0.15-0.8 mg for an average of 12 weeks. A full-time nurse-observer was used throughout the studies. 3 Good analgesic results were obtained. Certain difficult chronic dull aching pains in the head and neck were especially helped by the drug. There was no indication of dependence or tolerance in this study. 4 The main side-effect was drowsiness which lessened with usage of the drug. A major advantage of the drug was the absence of constipation as a side-effect. 5 This sublingual preparation seems worthy of addition to the commercially available range of analgesics in clinical practice.

Topics: Buprenorphine; Clinical Trials as Topic; Humans; Morphinans; Neoplasms; Pain

Topics: Administration, Oral; Adult; Aged; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Tolerance; Female; Heroin; Humans; Infusions, Parenteral; Male; Middle Aged; Morphinans; Neoplasms; Pain; Substance-Related Disorders; Terminal Care; Time Factors

Topics: Analgesics; Animals; Clinical Trials as Topic; Injections, Intramuscular; Morphinans; Nalorphine; Neoplasms; Pain; Palliative Care; Respiration; Terminal Care

Opioid-induced constipation (OIC) is one of the most common adverse events of opioid therapy and can severely reduce quality of life (QOL). Naldemedine is the orally available peripheral-acting μ-opioid receptor antagonist approved for OIC treatment. However in daily clinical practice, some cancer patients show insufficient control of OIC even while receiving naldemedine.. To identify factors associated with non-response to naldemedine in cancer patients.. This study retrospectively analyzed 127 cancer patients prescribed naldemedine at Seirei Hamamatsu General Hospital in Japan between November 2016 and June 2021. For the regression analysis of factors associated with OIC, variables were extracted manually from electronic medical records. Naldemedine had been prescribed by the attending physician after the presence of OIC had been defined with reference to Rome IV diagnostic criteria. Naldemedine was evaluated as "effective" in cases where the number of defecations increased at least once in the first 3 days after starting naldemedine. Multivariate logistic regression analysis was performed to identify factors associated with non-response to naldemedine. The data used were from the group of patients who received naldemedine in our previous study.. Factors significantly associated with non-response to naldemedine included chemotherapy with taxanes within 1 month of evaluation of naldemedine effect (odds ratio [OR] = 0.063; 95% confidence interval [CI] = 0.007-0.568), and addition of or switching to naldemedine due to insufficient efficacy of prior laxatives (OR = 0.352, 95% CI = 0.129-0.966).. The identification of factors associated with non-response to naldemedine prescribed for OIC may help improve QOL among cancer patients.

Topics: Analgesics, Opioid; Constipation; Gastrointestinal Agents; Humans; Morphinans; Naltrexone; Narcotic Antagonists; Neoplasms; Opioid-Induced Constipation; Quality of Life; Retrospective Studies

Naloxegol, an oral once-daily peripherally acting mu-opioid receptor antagonist, is indicated for the treatment of opioid-induced constipation (OIC) with inadequate response to laxative(s), in cancer and non-cancer patients. This study mainly aimed to assess in real-life conditions the efficacy and safety of naloxegol in cancer pain patients and the evolution of their quality of life.. A non-interventional, 4-week follow-up study was conducted in 24 French oncology and pain centers between 2018 and 2019. Eligible patients were aged ≥ 18 years, treated with opioids for cancer pain, and started naloxegol for OIC with inadequate response to laxatives. The rate of the response to naloxegol (primary criterion) was assessed at W4. The evolution of quality of life was measured using the Patient Assessment of Constipation Quality of Life (PAC-QOL).. A total of 124 patients were included (mean age, 62 ± 12 years; ECOG ≤ 2, 79%; primary cancer, lung 18%, breast 16%, prostate 11%, head and neck 9%, digestive 9%…; metastatic stage, 80%). At inclusion, the median opioid dosage was 60 mg of oral morphine or equivalent. At W4, the response rate was 73.4% (95% CI [63.7-83.2%]), and 62.9% (95% CI [51.5-74.2%]) of patients had a clinically relevant change in quality of life (decrease in PAC-QOL score ≥ 0.5 point). Adverse events related to naloxegol were reported in 8% of patients (7% with gastrointestinal events; one serious diarrhea).. This real-world study shows that naloxegol is effective and well tolerated in cancer pain patients with OIC and that their quality of life improves under treatment.

Topics: Aged; Analgesics, Opioid; Cancer Pain; Constipation; Follow-Up Studies; Humans; Male; Middle Aged; Morphinans; Neoplasms; Opioid-Induced Constipation; Polyethylene Glycols; Quality of Life

Bioactive compound design based on natural product (NP) structure may be limited because of partial coverage of NP-like chemical space and biological target space. These limitations can be overcome by combining NP-centered strategies with fragment-based compound design through combination of NP-derived fragments to afford structurally unprecedented "pseudo-natural products" (pseudo-NPs). The design, synthesis, and biological evaluation of a collection of indomorphan pseudo-NPs that combine biosynthetically unrelated indole- and morphan-alkaloid fragments are described. Indomorphane derivative Glupin was identified as a potent inhibitor of glucose uptake by selectively targeting and upregulating glucose transporters GLUT-1 and GLUT-3. Glupin suppresses glycolysis, reduces the levels of glucose-derived metabolites, and attenuates the growth of various cancer cell lines. Our findings underscore the importance of dual GLUT-1 and GLUT-3 inhibition to efficiently suppress tumor cell growth and the cellular rescue mechanism, which counteracts glucose scarcity.

Topics: Biological Products; Biological Transport; Cell Cycle; Cell Proliferation; Glucose; Glucose Transporter Type 1; Glucose Transporter Type 3; Glycolysis; Humans; Morphinans; Neoplasms; Tumor Cells, Cultured

Little is known about the pharmacokinetics (PKs) of oxycodone in patients with advanced cancer. There is considerable reluctance to subject these patients to non-essential tests including repeated venipuncture that has been necessary in PK studies to date. We investigated the possibility of using saliva sampling as a simple non-invasive test to investigate opioid PKs.. Patients with malignant disease receiving oral sustained release (SR) oxycodone at any dose were asked to provide saliva samples at the same time as blood samples. Samples were not taken within 6 h of a dose of immediate release oxycodone. Plasma and saliva oxycodone and metabolite concentrations were measured using HPLC coupled with tandem mass spectrometric detection.. One hundred and thirty-nine paired plasma/saliva samples were collected from 43 cancer patients who had been taking SR oxycodone for more than 5 days at doses ranging from 10 to 600 mg/day (median 40 mg/day). Plasma concentrations of oxycodone and noroxycodone ranged from 1.0 to 256.0 and 0.9-269.4 μg/L, respectively. Salivary concentrations of oxycodone (range 0.93-3,620, mean 336 μg/L) were much higher than plasma concentrations (mean 38.2 μg/L). There was a poor correlation between concentrations of both oxycodone and noroxycodone in plasma and saliva over a range of times following dosing (r (2) = 0.4641 and 0.3891, respectively). No correlation was shown between salivary pH and oxycodone or noroxycodone concentrations. The majority of patients questioned chose saliva sampling over plasma sampling as the preferred method.. High levels of both oxycodone and its major metabolite are present in saliva, but this does not provide a valid substitute for plasma when monitoring oxycodone levels for PK studies or therapeutic monitoring.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Chromatography, High Pressure Liquid; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Morphinans; Neoplasms; Oxycodone; Patient Preference; Saliva; Tandem Mass Spectrometry; Time Factors; Young Adult

Opioids are recommended by the World Health Organization for moderate to severe cancer pain. Oxycodone is one of the most commonly used opioids and is metabolized in the liver by CYP3A4 and CYP2D6 enzymes. The aim of this cross-sectional study was to assess the relationship between oxycodone pharmacokinetics, pharmacodynamics and the CYP2D6 genotypes "poor metaboliser" (PM), "extensive metaboliser" (EM) and "ultra-rapid metaboliser" (URM) in a cohort of patients with cancer pain.. The patients were genotyped for the most common CYP2D6 variants and serum concentrations of oxycodone and metabolites were determined. Pain was assessed using the Brief Pain Inventory (BPI). The EORTC QLQ-C30 was used to assess the symptoms of tiredness and nausea. Cognitive function was assessed by the Mini Mental State (MMS) examination. Associations were examined by analyses of variance (ANOVA) and covariance (ANCOVA), or ordinal logistic regressions with and without covariates.. The sample consisted of 27 PM, 413 EM (including heterozygotes) and 10 URM. PM had lower oxymorphone and noroxymorphone serum concentrations and oxymorphone to oxycodone ratios than EM and URM. No differences between PM, EM and URM in pain intensity, nausea, tiredness or cognitive function was found.. CYP2D6 genotypes caused expected differences in pharmacokinetics, but they had no pharmacodynamic consequence. CYP2D6 genotypes did not influence pain control, the adverse symptoms nausea and sedation or the risk for cognitive failure in this study of patients treated with oxycodone for cancer pain.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Biotransformation; Chronic Pain; Cohort Studies; Cross-Sectional Studies; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Drug Monitoring; Europe; Female; Genetic Association Studies; Humans; Male; Middle Aged; Morphinans; Neoplasms; Oxycodone; Oxymorphone; Polymorphism, Genetic; Severity of Illness Index

Topics: Adolescent; Butorphanol; Child; Drug Evaluation; Female; Humans; Infusions, Intravenous; Male; Morphinans; Neoplasms; Pain, Intractable

Topics: Butorphanol; Drug Evaluation; Humans; Morphinans; Neoplasms; Pain, Intractable; Time Factors

The efficacy of continuous subcutaneous infusion of buprenorphine for the treatment of terminal cancer pain was studied. Continuous subcutaneous administration of 4-8 micrograms/kg/day of buprenorphine, examined by the visual analogue scale was revealed to have satisfactory analgesic potency for control of every type of terminal cancer. This therapy can be undertaken by any member of the medical staff because of its safety and simplicity. The indications for this method are almost unlimited when the subcutaneous tissue can absorb the drug at a constant rate. Continuous subcutaneous buprenorphine administration via a portable infusion pump allows patients with severe pain from cancer the opportunity to move about freely.

Topics: Buprenorphine; Humans; Injections, Subcutaneous; Morphinans; Neoplasms; Pain, Intractable

Epidural opiates were administered to 139 patients with pain due to malignant diseases via a chronic indwelling catheter inserted percutaneously. So far, 9,716 days of treatment can be evaluated. In 87% of the patients whose pain previously could not be controlled with conventional analgesic approaches, epidural opiates resulted in remarkable pain relief. With a mean daily dose of 15.6 mg morphine (range 2-290 mg) or 0.86 mg buprenorphine (range 0.15-7.2 mg) half of the patients could be treated as outpatients. The mean duration of therapy was 72 days (range 1-700 days), 26 catheters being in place for more than 100 days and one catheter being in place for 510 days. Two severe side-effects (meningitis) were observed, both patients being free of symptoms after catheter removal and antibiotic therapy. Epidural opiates proved to be a valuable method of pain control in terminal illness. The method should be reserved for those patients, for whom oral opiates fail to produce effective pain relief.

Topics: Adult; Aged; Anesthesia, Epidural; Buprenorphine; Catheters, Indwelling; Female; Humans; Male; Middle Aged; Morphinans; Morphine; Neoplasms; Pain, Intractable

Topics: Adolescent; Buprenorphine; Child; Child, Preschool; Female; Humans; Male; Morphinans; Neoplasms; Pain; Retrospective Studies

Buprenorphine sublingual tablets (0.2 mg) were investigated in therapy of cancer pain. In 67 patients there was a good analgetic effect in 60%, even in those cases treated with other opiates before. The induction time was quite long (60 min.) but is no problem in chronic administration. Effective pain relief was obtained even in final stages of cancer. The mean daily dose of buprenorphine had been 1.2-1.7 mg, the mean duration of analgesia being 6-8 hours with a single dose of 0.2-1.0 mg buprenorphine. Typical opiate-side-effects were registered and well tolerated after some days' treatment. There was no respiratory depression. Buprenorphine sublingual tablets are certainly a good alternative in orally available opioids.

Topics: Administration, Oral; Adult; Aged; Buprenorphine; Female; Humans; Long-Term Care; Male; Middle Aged; Morphinans; Neoplasms; Pain, Intractable

Topics: Buprenorphine; Humans; Morphinans; Neoplasms; Pain, Intractable; Palliative Care; Postoperative Period; Respiration, Artificial

Topics: Butorphanol; Hemodynamics; Humans; Morphinans; Neoplasms; Pain, Postoperative; Respiration; Substance-Related Disorders

In that study we compared the analgesic effects of equianalgesic doses of buprenorphine and morphine taken as the narcotic of reference. The experiment has been undertaken in ten adults having severe cancer pain. The results have been analysed by statistical non parametric tests. We found that buprenorphine and morphine have the same pattern of action despite the fact that intramuscular buprenorphine has a clinical duration of approximately 9 hours.

Topics: Adolescent; Adult; Analgesics; Buprenorphine; Female; Humans; Male; Middle Aged; Morphinans; Morphine; Neoplasms; Pain; Statistics as Topic; Time Factors

Topics: Buprenorphine; Humans; Injections, Intramuscular; Morphinans; Neoplasms; Pain, Intractable

Topics: Acepromazine; Analgesics; Animals; Castration; Cesarean Section; Cyclopropanes; Dog Diseases; Dogs; Drug Combinations; Evaluation Studies as Topic; Female; Male; Morphinans; Neoplasms; Neuroleptanalgesia; Pentanols; Pregnancy; Tooth Extraction; Wounds and Injuries