morphinans and Pain

Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit/risk ratio of currently available opioids, together with the current 'opioid crisis', warrant consideration on new opioid analgesic discovery strategies. Targeting peripheral opioid receptors as effective means of treating pain and avoiding the centrally mediated side effects represents a research area of substantial and continuous attention. Among clinically used analgesics, opioids from the class of morphinans (i.e., morphine and structurally related analogues) are of utmost clinical importance as analgesic drugs activating the mu-opioid receptor. In this review, we focus on peripheralization strategies applied to

Topics: Analgesics; Analgesics, Opioid; Humans; Morphinans; Morphine; Pain; Receptors, Opioid, mu

Due to the increased use of opioids for pain and their abuse globally, the rate of restrictive side effects is elevating. Opioid-induced constipation (OIC) is probably the most widespread, underdiagnosed, and yet common adverse effect. Naloxegol, as an opioid antagonist, is associated with beneficial impacts in OIC. Indeed, blocking mu (μ)-opioid receptors in the gastrointestinal tract (GI) may lead to neutralization of the GI adverse events of opioids.. This review is based on a PubMed and Clinicaltrials.gov search for studies undertaken over the past 20 years (2000-2020) using the following keywords: Movantik®, Moventig®, Naloxegol, Opioids, Opioid-induced constipation and Opioid antagonists.. Similar to the management of functional constipation, non-pharmacological therapies are applied as the first step of the procedure. However, in most cases, laxative therpaies with or without stool softeners, which may not result in satisfactory relief are applied. In these instances, administration of prokinetic agents is recommended. Furthermore, studies have shown that the best second-line therapy option is a peripherally acting μ-opioid receptor antagonist (PAMORA), which antagonizes GI adverse events.

Topics: Analgesics, Opioid; Humans; Laxatives; Morphinans; Narcotic Antagonists; Opioid-Induced Constipation; Pain; Polyethylene Glycols; Receptors, Opioid, mu

Opioid-induced constipation (OIC) is a major side effect of opioid use. Centrally acting antagonists result in opioid withdrawal or worsening of pain and lead to use of peripherally acting mu-opioid receptor antagonists (PAMORAs). The required doses of the PAMORAs, methylnaltrexone and naloxegol, in the treatment of OIC are well established in chronic opioid users. OIC may occur after short duration of opioid treatment; the required doses of naloxone, naltrexone, and PAMORAs in opioid-naïve subjects (with no opioid use for at least 3 months) are unclear. The aim of this review was to evaluate the PAMORA dose required for opioid-naïve subjects to achieve similar beneficial effects on symptoms or valid surrogates to those observed in chronic opioid users.. A PubMed search of μ-opioid antagonists to counter μ-opioid effects included terms: naloxone, naltrexone, methylnaltrexone, alvimopan, and naloxegol, as well as OIC and colonic transit.. The approved dose of methylnaltrexone in chronic opioid users, 0.3 mg/kg subcutaneous (SQ), did not affect motility in opioid-naïve subjects. Trials investigating the required dose of alvimopan showed 0.5-1 mg dose was efficacious in treating OIC; a 10-fold higher dose (12 mg) of alvimopan is needed to block effects of codeine on small bowel and colonic transit in opioid-naïve subjects compared to chronic opioid users. Opioid-naïve users need 125 mg of naloxegol to reverse the effects of opioids on transit; this is in contrast to the 12.5 to 25 mg needed to treat OIC in chronic opioid users.. Opioid-naïve subjects require a higher dose of PAMORA than chronic opioid users to achieve μ-opioid antagonist effect.

Topics: Analgesics, Opioid; Constipation; Dose-Response Relationship, Drug; Gastrointestinal Agents; Humans; Morphinans; Narcotic Antagonists; Pain; Piperidines; Polyethylene Glycols; Receptors, Opioid, mu; Treatment Outcome

The opioid pain market is a lucrative one, but is experiencing significant challenges in the U.S. as the country grapples with prescription opioid addiction, overdose and fatalities. The situation has been declared a national Public Health Emergency and the Food and Drug Administration (FDA) has introduced several measures intended to reduce opioid abuse. The development of abuse-deterrent prescription opioids is one such measure, but although abuse-deterrent formulations of opioids reduce drug liking and abuse, concerns have been highlighted by an Institute of Clinical and Economic Review (ICER) report regarding the insufficiency of currently available data to determine the effects of these formulations at the population level. However, the low abuse liability but effective analgesic efficacy reported for drugs such as NKTR-181 and difelikefalin highlight the potential of novel abuse-deterrent opioids.

Topics: Abuse-Deterrent Formulations; Analgesics, Opioid; Drug Combinations; Drug Compounding; Humans; Inappropriate Prescribing; Morphinans; Opioid-Related Disorders; Pain; Prescription Drug Misuse

Opioid-related bowel dysfunction is a common and potentially severe adverse effect from treatment with opioid analgesics. Its development is not dose related, nor do patients develop tolerance. Opioid-induced constipation (OIC) can lead to fecal impaction, bowel obstruction, and bowel perforation as well as noncompliance with opioid analgesics and poor quality of life. Routine administration of laxatives is necessary to maintain bowel function, and, in refractory cases, other modalities must be pursued. Available options are limited but include peripherally acting μ-opioid receptor antagonists (PAMORAs), including methylnaltrexone. Naloxegol is a newly developed PAMORA that is available through the oral route. At the therapeutic dose of 25 mg daily, naloxegol is effective and safe, with a limited side effect profile and is associated with preservation of centrally mediated analgesia. In this article, we discuss the pharmacokinetics, pharmacodynamics, adverse effects, clinical trials, and cost considerations of naloxegol. Finally, we discuss its potential role as a novel key treatment for OIC in palliative medicine patients.

Topics: Analgesics, Opioid; Constipation; Drug Interactions; Humans; Morphinans; Naltrexone; Narcotic Antagonists; Pain; Polyethylene Glycols; Quality of Life; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic

The 14-position of natural opiates (e.g. morphine) are unsubstituted, however synthetic approaches have uncovered that functionalizing position 14 gives rise to a wide range of diverse activities. This review focuses on SAR of the position, with the aim of aiding in the search for opioid analgesics with improved clinical profiles.

Topics: Animals; Humans; Morphinans; Narcotic Antagonists; Pain; Receptors, Opioid; Structure-Activity Relationship

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

Butorphanol (Stadol) is a synthetic agonist-antagonist analgesic from the 14-hydroxymorphinan series. Animal studies display analgesia, antitussive effects, low gastrointestinal activity, limited respiratory depression, some cardiovascular and skeletal muscle actions, diuresis, slight miosis and opiate antagonism. Butorphanol is metabolized in the liver with renal excretion, yielding a half-life of 3-4 h. Pain relief is good to excellent with parenteral administration in 90% of patients with moderate to severe pain. Surgical anesthetic indications involve preoperative and preinduction supplementation, balanced anesthesia and postoperative pain. Side effects are sedation, nausea, elevated pulmonary vascular pressures and rarely CNS excitation. Limited respiratory depression exists. Butorphanol is a potent analgesic agent with a favorable side effect profile.

Topics: Anesthesia; Animals; Antitussive Agents; Butorphanol; Chemical Phenomena; Chemistry; Depression, Chemical; Diuretics; Dose-Response Relationship, Drug; Humans; Morphinans; Morphine; Naloxone; Nausea; Oxymorphone; Pain; Pulmonary Wedge Pressure; Rats; Respiration; Substance-Related Disorders

Topics: Analgesics; Blood Circulation; Fentanyl; Humans; Intestines; Levallorphan; Meperidine; Methadone; Methotrimeprazine; Morphinans; Morphine; Nalorphine; Narcotic Antagonists; Nausea; Pain; Pentazocine; Psychopharmacology; Respiration; Substance-Related Disorders; Urinary Tract; Vomiting

This report-the second of a series on codeine and its alternates for pain and cough relief-contains a detailed evaluation of experimental and clinical data on newer substances having analgesic properties comparable to and in approximately the same range as those of codeine. The data are discussed under the headings: analgesic effects in animals; clinical usefulness; side-effects with particular reference to dependence and abuse liability.

Topics: Amides; Analgesics; Animals; Antitussive Agents; Azepines; Carisoprodol; Cats; Chickens; Codeine; Cough; Cyclazocine; Dextropropoxyphene; Diphenylacetic Acids; Dogs; Ducks; Guinea Pigs; Humans; Indenes; Indoles; Isoquinolines; Mice; Morphinans; Nalorphine; Narcotic Antagonists; Pain; Pentazocine; Phenethylamines; Pyrrolidines; Rats; Substance-Related Disorders; Thalidomide

Naloxegol is a PEGylated, oral, peripherally acting μ-opioid receptor antagonist approved in the United States for treatment of opioid-induced constipation in patients with noncancer pain. Naloxegol is metabolized by CYP3A, and its properties as a substrate for the P-glycoprotein (PGP) transporter limit its central nervous system (CNS) permeability. This double-blind, randomized, 2-part, crossover study in healthy volunteers evaluated the effect of quinidine (600 mg PO), a CYP3A/PGP transporter inhibitor, on the pharmacokinetics and CNS distribution of naloxegol (25 mg PO). In addition, the effects of quinidine on morphine (5 mg/70 kg IV)-induced miosis and exposure to naloxegol were assessed. Coadministration of quinidine and naloxegol increased naloxegol's AUC 1.4-fold and Cmax 2.5-fold but did not antagonize morphine-induced miosis, suggesting that PGP inhibition does not increase the CNS penetration of naloxegol. Naloxegol pharmacokinetics was unaltered by coadministration of morphine and either quinidine or placebo; conversely, pharmacokinetics of morphine and its metabolites (in the presence of quinidine) were unaltered by coadministration of naloxegol. Naloxegol was safe and well tolerated, alone or in combination with quinidine, morphine, or both. The observed increase in exposure to naloxegol in the presence of quinidine is primarily attributed to quinidine's properties as a weak CYP3A inhibitor.

Topics: Adult; Analgesics, Opioid; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Central Nervous System; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Morphinans; Morphine; Pain; Polyethylene Glycols; Quinidine; Receptors, Opioid, mu

Opioid-induced constipation is common and debilitating. We investigated the efficacy and safety of naloxegol, an oral, peripherally acting, μ-opioid receptor antagonist, for the treatment of opioid-induced constipation.. In two identical phase 3, double-blind studies (study 04, 652 participants; study 05, 700 participants), outpatients with noncancer pain and opioid-induced constipation were randomly assigned to receive a daily dose of 12.5 or 25 mg of naloxegol or placebo. The primary end point was the 12-week response rate (≥3 spontaneous bowel movements per week and an increase from baseline of ≥1 spontaneous bowel movements for ≥9 of 12 weeks and for ≥3 of the final 4 weeks) in the intention-to-treat population. The key secondary end points were the response rate in the subpopulation of patients with an inadequate response to laxatives before enrollment, time to first postdose spontaneous bowel movement, and mean number of days per week with one or more spontaneous bowel movements.. Response rates were significantly higher with 25 mg of naloxegol than with placebo (intention-to-treat population: study 04, 44.4% vs. 29.4%, P=0.001; study 05, 39.7% vs. 29.3%, P=0.02; patients with an inadequate response to laxatives: study 04, 48.7% vs. 28.8%, P=0.002; study 05, 46.8% vs. 31.4%, P=0.01); in study 04, response rates were also higher in the group treated with 12.5 mg of naloxegol (intention-to-treat population, 40.8% vs. 29.4%, P=0.02; patients with an inadequate response to laxatives, 42.6% vs. 28.8%, P=0.03). A shorter time to the first postdose spontaneous bowel movement and a higher mean number of days per week with one or more spontaneous bowel movements were observed with 25 mg of naloxegol versus placebo in both studies (P<0.001) and with 12.5 mg of naloxegol in study 04 (P<0.001). Pain scores and daily opioid dose were similar among the three groups. Adverse events (primarily gastrointestinal) occurred most frequently in the groups treated with 25 mg of naloxegol.. Treatment with naloxegol, as compared with placebo, resulted in a significantly higher rate of treatment response, without reducing opioid-mediated analgesia. (Funded by AstraZeneca; KODIAC-04 and KODIAC-05 ClinicalTrials.gov numbers, NCT01309841 and NCT01323790, respectively.).

Topics: Adult; Analgesics, Opioid; Constipation; Defecation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Morphinans; Narcotic Antagonists; Pain; Polyethylene Glycols; Receptors, Opioid, mu

Opioid-induced constipation (OIC) is a common adverse effect of opioid therapy.. To evaluate the long-term safety and tolerability of naloxegol, an oral, peripherally acting μ-opioid receptor antagonist (PAMORA), in patients with noncancer pain and OIC.. A 52-week, multicenter, open-label, randomised, parallel-group phase 3 study was conducted in out-patients taking 30-1000 morphine-equivalent units per day for ≥4 weeks. Patients were randomised 2:1 to receive naloxegol 25 mg/day or usual-care (UC; investigator-chosen laxative regimen) treatment for OIC.. The safety set comprised 804 patients (naloxegol, n = 534; UC, n = 270). Mean exposure duration was 268 days with naloxegol and 297 days with UC. Frequency of adverse events (AEs) was 81.8% with naloxegol and 72.2% with UC. Treatment-emergent AEs occurring more frequently for naloxegol vs. UC were abdominal pain (17.8% vs. 3.3%), diarrhoea (12.9% vs. 5.9%), nausea (9.4% vs. 4.1%), headache (9.0% vs. 4.8%), flatulence (6.9% vs. 1.1%) and upper abdominal pain (5.1% vs. 1.1%). Most naloxegol-emergent gastrointestinal AEs occurred early, resolving during or after naloxegol discontinuation and were mild or moderate in severity; 11 patients discontinued due to diarrhoea and nine patients owing to abdominal pain. Pain scores and mean daily opioid doses remained stable throughout the study; no attributable opioid withdrawal AEs were observed. Two patients in each group had an adjudicated major adverse cardiovascular event unrelated to study drug; no AEs were reported nor adjudicated as bowel perforations.. In patients with noncancer pain and opioid-induced constipation, naloxegol 25 mg/day up to 52 weeks was generally safe and well tolerated.

Topics: Adult; Aged; Analgesics, Opioid; Constipation; Female; Humans; Laxatives; Male; Middle Aged; Morphinans; Morphine; Narcotic Antagonists; Pain; 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

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

Nalbuphine and meperidine were compared as analgesic components of intravenous conscious sedation in a double-blind, prospective trial of 47 patients undergoing elective oral surgery. Subjects were evaluated for pain intensity, pain relief, anxiety, sedation, recall, and vital signs at systematic observation points intraoperatively and postoperatively. At the conclusion of surgery 83% of patients who had received nalbuphine and 86% of patients treated with meperidine indicated complete pain relief. One observed adverse reaction was attributed to meperidine and another to the sedative component diazepam. No statistically significant differences were observed between nalbuphine and meperidine treatments.

Topics: Adult; Anesthesia, Dental; Anesthesia, Local; Anxiety; Diazepam; Double-Blind Method; Female; Humans; Infusions, Intravenous; Male; Meperidine; Middle Aged; Morphinans; Nalbuphine; Pain; Preanesthetic Medication

This double-blind study compared the analgesic effects of morphine with those of butorphanol in patients who presented with pain because of sickle cell crisis. Patients were placed at bed rest, administered IV hydration, and randomly assigned on each visit to receive either 2 mg IM butorphanol or 6 mg IM morphine every 30 to 60 minutes as needed to produce a pain intensity of 50 mm or less on the linear analog pain scale until the patient was discharged. Linear analog scale for pain and pain relief, level of alertness, and vital signs were assessed at 60 and 120 minutes after each study drug dose, before additional doses, and at discharge. Eighteen patients (12 men, six women; mean age, 29.3 +/- 7.7 years) were studied. Six received only morphine, six received only butorphanol, and six received each treatment at some time during the study period, resulting in 45 randomizations to treatment. The two therapies did not differ significantly (P greater than .40) with respect to pain or relief of pain scores, level of alertness, or vital signs. The discharge rate was 69.6% and 68.2% with morphine and butorphanol, respectively (P = .92). The incidence of adverse effects was 13% and 23% with morphine and butorphanol, respectively (P = .46). We conclude that morphine and butorphanol are equally effective in the treatment of sickle cell crisis pain.

Topics: Adolescent; Adult; Anemia, Sickle Cell; Butorphanol; Double-Blind Method; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Morphinans; Morphine; Pain; Random Allocation

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 narcotic agonist-antagonist nalbuphine is reported to act as a strong analgesic with only minor respiratory depressant side-effects. Even in the postoperative period, the pain-relieving properties of analgesic drugs are reported to continue if the respiratory side-effects are being antagonized by administering nalbuphine. It was the aim of this study to investigate the analgesic properties of nalbuphine as compared to those of fentanyl, in suppressing the hemodynamic responses due to endotracheal intubation and skin incision. Furthermore, we are interested in studying postoperative analgesia and respiratory depression after using the two drugs during anesthesia.. Forty-one patients undergoing general surgical procedures were randomly assigned to two groups in a double-blind study. The patients were between 18 and 70 years old and belonged to ASA classes I-III. Patients with chronic obstructive pulmonary disease, cerebral vascular disorders, hepatic or renal failure, or those treated with monoamine oxidase inhibitors and tricyclic antidepressants were excluded from the study, as were patients with a drug dependency. All patients were premedicated with 25-50 mg each promethazine and pethidine. Anesthesia was induced with either 60-70 mg nalbuphine or 0.3-0.35 mg fentanyl, 2 mg alcuronium, 0.01 mg/kg flunitrazepam, and 1-2 mg/kg thiopental. All patients were intubated following 1-2 mg/kg succinylcholine. Five minutes following intubation they received another 30-40 mg nalbuphine or 0.15-0.2 mg fentanyl intravenously. Anesthesia was maintained with N2O:O2 2:1, alcuronium, and either nalbuphine or fentanyl and enflurane up to 1 vol.% or halothane up to 0.5 vol.%. Blood pressure, pulse rate, and arterial blood gases were measured at certain intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Anesthesia, Endotracheal; Blood Pressure; Clinical Trials as Topic; Cognition; Double-Blind Method; Fentanyl; Heart Rate; Hemodynamics; Humans; Middle Aged; Morphinans; Nalbuphine; Pain; Postoperative Period; Respiration

Topics: Buprenorphine; Clinical Trials as Topic; Double-Blind Method; Humans; Morphinans; Pain; Pain, Postoperative

Sixty patients suffering from moderate to severe pain following either orthopaedic or gynaecological surgery were treated with intramuscular buprenorphine (0.3 mg) or an intramuscular combination of buprenorphine (0.3 mg)/naloxone (0.2 mg) and the analgesic efficacy and safety of the two treatments was compared. The evaluation of efficacy showed that both treatments provided good analgesia which was apparent at the first assessment time (10 minutes) and continued for approximately 10 hours. Only seven patients suffered from unwanted side-effects with only drowsiness/sleepiness and nausea being reported by more than one patient. Over-all analysis of the results showed that there were no significant differences between the two treatments with regard to efficacy and safety.

Topics: Adolescent; Adult; Aged; Analgesia; Buprenorphine; Drug Therapy, Combination; Female; Humans; Kinetics; Male; Middle Aged; Morphinans; Naloxone; Pain; Postoperative Complications

The relative performance of three analgesic rating scales--visual pain analog, verbal pain intensity, and verbal pain relief--was assessed in clinical trials with 1,497 patients and a variety of pain models. The scales correlated strongly with one another, with inconsistent and generally minimal differences in sensitivity. Overall, the verbal relief scale tended to be slightly more sensitive than the pain analog rating, which in turn showed a small advantage over the verbal pain intensity assessment. When the scores derived from the categorized ratings 1 hour after drug dosing (generally the time of peak effect) were analyzed, there was little difference whether a parametric or nonparametric approach was taken. When the cumulative measures of overall effect over 6 hours were considered, however, the nonparametric approach was decidedly more powerful. There was a similar pattern when the analog scores were analyzed. This unanticipated finding appears to be due to the cumulative measures (from all three scales) being more skewed toward the lower end of their respective ranges than are the 1-hour scores. A composite efficacy variable was defined, incorporating data from the three primary scales; this measure was found to be generally comparable in sensitivity to the individual scales and may be useful as a global summary of response. While our investigation provides evidence that any of the ratings considered will accurately reflect analgesic response, the verbal relief scale was the most sensitive and might be the best choice if a single measure is desired.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Butorphanol; Clinical Trials as Topic; Cycloparaffins; Double-Blind Method; Humans; Morphinans; Morphine; Pain; Pain, Postoperative; Tetrahydronaphthalenes

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

Topics: Buprenorphine; Clinical Trials as Topic; Epidural Space; Humans; Injections; Morphinans; Morphine; Narcotics; Pain; Time Factors

Morphine chlorhydrate and buprenorphine chlorhydrate are given intramuscularly at increasing doses to patients suffering from intense pain in the facial or trigeminal nerves territory. No other drugs are used. The diverses groups of ten patients received respectively: --morphine: 0.100, 0.150, 0.200 mg/kg; --buprenorphine: 0.0015, 0.003, 0.006 mg/kg. On the whole, the analgesia is induced after a short time and is more durable, more intense as the dose is increased. Yet, concerning buprenorphine, the analgesia is not more intense with the 0.006 mg/kg dose, than with the 0.003 mg/kg dose. This phenomenon, if confirmed, would be an important limitation for the clinical use of this drug. For equianalgesic doses buprenorphine and morphine give an analgesia similar in time of initiation and in duration.

Topics: Aged; Buprenorphine; Female; Humans; Male; Middle Aged; Morphinans; Morphine; Pain

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

Butorphanol tartrate (4 mg and 8 mg) was compared to codeine phosphate (60 mg) and placebo for oral analgesic activity and side-effects employing a double-blind design in ninety-three out-patients suffering from moderate to very severe musculoskeletal pain. The study duration was 72 hours with medication administered every 4 to 6 hours (four times daily) for a total of twelve doses per patient. The results demonstrate that both the 4 mg and 8 mg doses of butorphanol were significantly better (p less than 0.u5) than placebo. While codeine 60 mg also proved active, it appears to be less efficacious than the high dose of butorphanol. The peak effect appeared to be evident in 1 to 2 hours. Butorphanol may be at least seven times more potent than codeine on a milligram basis. Although no serious side-effects were observed, butorphanol appeared to present a greater incidence of side-effects than codeine and placebo in this study.

Topics: Adolescent; Adult; Aged; Analgesics; Bone Diseases; Clinical Trials as Topic; Codeine; Double-Blind Method; Female; Humans; Male; Middle Aged; Morphinans; Muscular Diseases; Pain; Placebos

Topics: Administration, Oral; Adult; Analgesics; Clinical Trials as Topic; Codeine; Double-Blind Method; Episiotomy; Female; Humans; Morphinans; Pain; Placebos

Buprenorphine was used as an analgesic medication for patients at the pain clinic. Clinical observations on its long term administration for intractable pain are reported. A good analgesic activity was noted in most of the patients. Nausea and vomiting was the mean reason for cancellation of the therapy.

Topics: Administration, Oral; Adult; Aged; Analgesics; Clinical Trials as Topic; Confusion; Depression; Drug Evaluation; Female; Humans; Male; Middle Aged; Morphinans; Nausea; Pain; Sleep; Sweating; Time Factors; Vomiting

Topics: Administration, Oral; Analgesics; Aspirin; Azepines; Caffeine; Clinical Trials as Topic; Codeine; Dextropropoxyphene; Drug Therapy, Combination; Ethers, Cyclic; Humans; Morphinans; Pain; Pentazocine; Pentobarbital; Promazine

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: Adolescent; Adult; Aged; Blood Pressure; Cholecystectomy; Female; Humans; Isonipecotic Acids; Male; Meperidine; Middle Aged; Morphinans; Nausea; Nitriles; Pain; Piperidines; Pulse; Respiration; Vomiting

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

Topics: Adult; Analgesics; Clinical Trials as Topic; Humans; Isonipecotic Acids; Middle Aged; Morphinans; Pain; Postoperative Care; Postoperative Complications

Previous pharmacological data have shown the possible existence of functional interactions between μ- (MOP), κ- (KOP), and δ-opioid receptors (DOP) in pain and mood disorders. We previously reported that MOP knockout (KO) mice exhibit a lower stress response compared with wildtype (WT) mice. Moreover, DOP agonists have been shown to exert antidepressant-like effects in numerous animal models. In the present study, the tail suspension test (TST) and forced swim test (FST) were used to examine the roles of MOP and DOP in behavioral despair. MOP-KO mice and WT mice were treated with KNT-127 (10 mg/kg), a selective DOP agonist. The results indicated a significant decrease in immobility time in the KNT-127 group compared with the saline group in all genotypes in both tests. In the saline groups, immobility time significantly decreased in MOP-KO mice compared with WT mice in both tests. In female MOP-KO mice, KNT-127 significantly decreased immobility time in the TST compared with WT mice. In male MOP-KO mice, however, no genotypic differences were found in the TST after either KNT-127 or saline treatment. Thus, at least in the FST and TST, the activation of DOP and absence of MOP had additive effects in reducing measures of behavioral despair, suggesting that effects on this behavior by DOP activation occur independently of MOP.

Topics: Analgesics, Opioid; Animals; Antidepressive Agents; Female; Male; Mice; Morphinans; Pain; Receptors, Opioid, mu

Nalfurafine has been used clinically in Japan for treatment of itch in kidney dialysis patients and in patients with chronic liver diseases. A one-year post-marketing study showed nalfurafine to be safe and efficacious without producing side effects of typical KOR agonists such as anhedonia and psychotomimesis. In this chapter, we summarize in vitro characterization and in vivo preclinical studies on nalfurafine. In vitro, nalfurafine is a highly potent and moderately selective KOR full agonist; however, whether it is a biased KOR agonist is a matter of debate. In animals, nalfurafine produced anti-pruritic effects in a dose range lower than that caused side effects, including conditioned place aversion (CPA), hypolocomotion, motor incoordination, consistent with the human data. In addition, nalfurafine showed antinociceptive effects in several pain models at doses that did not cause the side effects mentioned above. It appears to be effective against inflammatory pain and mechanical pain, but less so against thermal pain, particularly high-intensity thermal pain. U50,488H and nalfurafine differentially modulated several signaling pathways in a brain region-specific manners. Notably, U50,488H, but not nalfurafine, activated the mTOR pathway, which contributed to U50,488H-induced CPA. Because of its lack of side effects associated with typical KOR agonists, nalfurafine has been investigated as a combination therapy with an MOR ligand for pain treatment and for its effects on opioid use disorder and alcohol use disorder, and results indicate potential usefulness for these indications. Thus, although in vitro data regarding uniqueness of nalfurafine in terms of signaling at the KOR are somewhat equivocal, in vivo results support the assertion that nalfurafine is an atypical KOR agonist with a significantly improved side-effect profile relative to typical KOR agonists.

Topics: Animals; Humans; Morphinans; Pain; Receptors, Opioid, kappa; Spiro Compounds

Opioid-induced constipation is the most prevalent adverse effect of opioid drugs. Peripherally acting mu opioid receptor antagonists (PAMORAs), including naloxegol, are indicated for the treatment of opioid-induced constipation. The aim of this study was the in vitro and in vivo pharmacological characterization of naloxegol in comparison with naloxone. In vitro experiments were performed to measure calcium mobilization in cells coexpressing opioid receptors and chimeric G proteins and mu receptor interaction with G protein and β-arrestin 2 using bioluminescence resonance energy transfer. In vivo experiments were performed in mice to measure pain threshold using the tail withdrawal assay and colonic transit using the bead expulsion assay. In vitro, naloxegol behaved as a selective and competitive mu receptor antagonist similarly to naloxone, being 3-10-fold less potent. In vivo, naloxone was effective in blocking fentanyl actions when given subcutaneously (sc), but not per os (po). In contrast, naloxegol elicited very similar effects with sc or po administration counteracting in a dose dependent manner the constipating effects of fentanyl without interfering with the fentanyl mediated analgesia. Thus, a useful PAMORA action could be obtained with naloxegol both after po and sc administration.

Topics: Administration, Oral; Analgesics, Opioid; Animals; Behavior, Animal; Calcium; CHO Cells; Constipation; Cricetulus; Fentanyl; Injections, Subcutaneous; Male; Mice; Morphinans; Morphine; Naloxone; Narcotic Antagonists; Pain; Polyethylene Glycols; Receptors, Opioid, mu

Premature and ill neonates undergo painful but medically necessary procedures while hospitalized. Although opiate drugs are administered as analgesics, problems associated with their side effects, tolerance, and potential dependence necessitate research into alternative pain-relieving medications. Here we test two plant-derived compounds in infant rats: sinomenine, which targets the Mas-related G-protein-coupled receptor member X2 opioid receptor; and salvinorin A, which is a κ opioid receptor agonist. In adult animals both sinomenine and salvinorin A are analgesic, but neither has been tested in infants.. We used the formalin and thermal plantar tests in rats 7 and 21 days of age (PN7 and PN21) for behavioral signs of pain. In addition, brain sections were stained using Fos immunohistochemistry to examine patterns of brain activation in the midbrain periaqueductal gray and the paraventricular nucleus of the hypothalamus.. Sinomenine was analgesic in both the formalin and thermal tests on animals 21 days of age. At PN7 only the highest dose elevated response latencies in the thermal test and there were no effects of sinomenine in the formalin test. Analysis of Fos expression in the sinomenine-treated animals showed no drug effect, in contrast to the behavioral results. Salvinorin A was analgesic in the formalin test only at the highest dose at 21 days of age but not in the thermal test at either age.. The increased modest effectiveness of sinomenine in older animals and the minimum salvinorin A drug effect suggest that the compounds act on sites that develop during the preweaning period (sinomenine) or after weaning (salvinorin A).

Topics: Analgesics; Analgesics, Opioid; Animals; Behavior, Animal; Diterpenes, Clerodane; Hot Temperature; Humans; Infant; Infant, Newborn; Morphinans; Pain; Pain Measurement; Phytotherapy; Plant Extracts; Rats, Long-Evans; Receptors, Opioid; Receptors, Opioid, kappa; Salvia; Sinomenium

Pain management is a challenging and unmet medical need. Despite their demonstrated efficacy, currently used opioid drugs and nonsteroidal anti-inflammatory drugs are frequently associated with several adverse events. The identification of new and safe analgesics is therefore needed. MP1104, an analogue of 3'-iodobenzoyl naltrexamine, is a potent nonselective full agonist at mu (MOR), kappa (KOR), and delta (DOR) opioid receptors, respectively. It was shown to possess potent antinociceptive effects in acute thermal pain assays without aversion in mice. In this study, we investigated MP1104 in the formalin test, a model of tonic pain. MP1104 (0.05, 0.1, and 1.0 mg/kg) reduced pain-like behaviors in phases I and II of the formalin test in male and female ICR mice. Pretreatment with KOR antagonist (norbinaltorphimine 10 mg/kg) and DOR antagonist (naltrindole 10 mg/kg) abolished the antinociceptive effects of MP1104 in the formalin test. These findings support the development of MP1104 for further testing in other pain models.

Topics: Analgesics; Analgesics, Opioid; Animals; Female; Male; Mice; Mice, Inbred ICR; Morphinans; Narcotic Antagonists; Pain; Pain Management; Pain Measurement; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa

Many patients on chronic opioid therapy suffer from constipation, one of the most common side effect of opioids. Movantik™ (naloxegol) is an opioid antagonist that is recently introduced in the market to treat opioid-induced constipation and contains naloxegol as the active ingredient. Naloxegol is a pegylated (polyethylene glycol-modified) derivative of α-naloxol. Detection of naloxone in the patients urine after consumption of naloxegol was not reported by the manufacturer and may mislead the prescribing clinicians. This study was conducted to investigate the presence of naloxone in the urine of patients that consume movnatik in pain management clinics.. The presence of naloxone and naloxol in the urine of 45 patients that consumed naloxegol and 25 patients that consumed suboxone™ were investigated using a liquid chromatography mass spectrometry (LCMS) method. The urinary concentration of naloxone, naloxol, and their glucuronide conjugates were evaluated in five volunteers that took one pill of naloxegol for one day and one volunteer who took the pill for three days.. Naloxone was detected in the urine of 45 individuals that were prescribed naloxegol. Urinary concentration of naloxone showed a distribution with a mean of 25 ± 18 ng/ml. Consumption of one pill of 25 mg naloxegol resulted in the detection of naloxol and naloxone in the urine of 5 volunteers 1 h after taking the pill. Evaluation of urine specimens from 25 patients that consumed suboxone™, resulted in the detection of naloxone (180 ± 187 ng/ml) and naloxol (6.3 ± 7.2 ng/ml).. This study demonstrated that consumption of naloxegol leads to appearance of naloxone in the urine of patients receiving opioid therapy in pain management clinics.

Topics: Adult; Female; Humans; Male; Middle Aged; Morphinans; Naloxone; Pain; Polyethylene Glycols; Retrospective Studies; Substance Abuse Detection

The paper describes a case report of a patient with a significant history of opioid-induced dysfunction of the sphincter of Oddi, who required morphine sulfate to manage oral mucositis pain, and who was successfully treated with concomitant oral naloxegol (Moventig: Kyowa Kirin, Galashiels, UK).

Topics: Administration, Oral; Analgesics, Opioid; Carcinoma, Squamous Cell; Humans; Male; Middle Aged; Morphinans; Morphine; Mucositis; Narcotic Antagonists; Pain; Polyethylene Glycols; Spasm; Sphincter of Oddi Dysfunction; Tonsillar Neoplasms

Nalfurafine is a G protein signaling-biased kappa opioid receptor (KOR) agonist approved in Japan for second-line treatment of uremic pruritus. Neither nalfurafine nor any other KOR agonist is currently approved anywhere for treatment of pain, but recent evidence suggests that G protein signaling-biased KOR agonists may have promise as candidate analgesics/antipruritics with reduced side effects compared to nonbiased or ß-arrestin-signaling-biased KOR agonists.. This study compared nalfurafine effects in rats using assays of pain-stimulated and pain-depressed behavior used previously to evaluate other candidate analgesics. Nalfurafine effects were also examined in complementary assays of itch-stimulated and itch-depressed behavior.. Intraperitoneal lactic acid (IP acid) and intradermal serotonin (ID 5HT) served as noxious and pruritic stimuli, respectively, in male Sprague Dawley rats to stimulate stretching (IP acid) or scratching (ID 5HT) or to depress positively reinforced operant responding in an assay of intracranial self-stimulation (ICSS; both stimuli).. Nalfurafine was equipotent to decrease IP acid-stimulated stretching and ID 5HT-stimulated scratching; however, doses of nalfurafine that decreased these pain/itch-stimulated behaviors also decreased control ICSS performance. Moreover, nalfurafine failed to alleviate either IP acid- or ID 5HT-induced depression of ICSS.. These results suggest that nalfurafine-induced decreases in pain/itch-stimulated behaviors may reflect nonselective decreases in motivated behavior rather than analgesia or antipruritus against the noxious and pruritic stimuli used here. This conclusion agrees with the absence of clinical data for nalfurafine analgesia and the weak clinical data for nalfurafine antipruritus. Nalfurafine bias for G protein signaling may not be sufficient for clinically safe and reliable analgesia or antipruritus.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Depression; Dose-Response Relationship, Drug; Japan; Male; Morphinans; Pain; Pruritus; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Self Stimulation; Spiro Compounds

BACKGROUND The purpose of this study was to investigate the effects of sinomenine (SIN) on CFA-induced inflammatory pain in rats, and to explore the underlying molecular mechanisms. MATERIAL AND METHODS To determine the potential influences of SIN in the pathogenesis of inflammatory pain, an inflammatory pain (IP) mouse model was established and rats were treated with SIN (30 mg/kg). Behavioral tests were used to assess the MWT and TWL of the rats. ELISA assay was used to detect the level of inflammation cytokines. Western blotting and qRT-PCR were carried out to measure the related protein and mRNA expression level, respectively. RESULTS We found that the MWT and TWL of the CFA-treated rats were markedly lower than that of the control rats, and they were significantly increased by SIN administration. The results suggest that IP rats had higher levels of TNF-α, IL-1β and IL-6 compared with the control rats. SIN administration decreased the levels of TNF-α, IL-1β, and IL-6. In addition, we found that p-p65 and p-p38 expression notably decreased after SIN treatment in IP rats. Moreover, the results showed that SIN inhibited Cox-2 and PGE2 expression in IP rats. CONCLUSIONS The data indicate that SIN had a protective role in inflammatory pain through repressing inflammatory mediators via preventing the p38MAPK-NF-κB pathway.

Topics: Animals; Cyclooxygenase 2; Cytokines; Freund's Adjuvant; Inflammation; Interleukin-1beta; Male; Morphinans; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Pain; Rats; Rats, Sprague-Dawley; Signal Transduction; Tumor Necrosis Factor-alpha

Sinomenium acutum has been used in traditional medicine to treat a painful disease such as rheumatic arthritis and neuralgia. Sinomenine, which is a main bioactive ingredient in Sinomenium acutum, has been reported to have an analgesic effect in diverse pain animal models. However little is known about the detailed mechanisms underlying peripheral analgesic effect of sinomenine. In the present study, we aimed to elucidate its cellular mechanism by using formalin-induced acute inflammatory pain model in mice. We found that intraperitoneal (i.p.) administration of sinomenine (50mg/kg) suppressed formalin-induced paw licking behavior in both the first and the second phase. Formalin-induced c-Fos protein expression was also suppressed by sinomenine (50mg/kg i.p.) in the superficial dorsal horn of spinal cord. Whole-cell patch-clamp recordings from small-sized dorsal root ganglion (DRG) neurons revealed that sinomenine reversibly increased the spike threshold and the threshold current intensity for evoking a single spike and decreased firing frequency of action potentials evoked in response to a long current pulse. Voltage-gated sodium currents (I

Topics: Animals; Antirheumatic Agents; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Formaldehyde; Ganglia, Spinal; Inflammation; Male; Mice; Mice, Inbred C57BL; Morphinans; Neuralgia; Pain; Pain Measurement; Patch-Clamp Techniques; Proto-Oncogene Proteins c-fos; Sensory Receptor Cells; Sodium; Voltage-Gated Sodium Channels

Sinomenine hydrochloride (SH) is an ideal drug for the treatment of rheumatoid arthritis and osteoarthritis. However, high plasma concentration of systemically administered SH can release histamine, which can cause rash and gastrointestinal side effects. Topical delivery can increase SH concentration in the synovial fluid without high plasma level, thus minimizing systemic side effects. However, passive diffusion of SH was found to be inefficient because of the presence of the stratum corneum layer. Therefore, an effective method is required to compensate for the low efficiency of SH passive diffusion. In this study, transdermal experiments in vitro and clinical tests were utilized to explore the optimized parameters for electroporation of topical delivery for SH. Fluorescence experiment and hematoxylin and eosin staining analysis were performed to reveal the mechanism by which electroporation promoted permeation. In vitro, optimized electroporation parameters were 3 KHz, exponential waveform, and intensity 10. Using these parameters, transdermal permeation of SH was increased by 1.9-10.1 fold in mice skin and by 1.6-47.1 fold in miniature pig skin compared with passive diffusion. After the electroporation stimulation, the intercellular intervals and epidermal cracks in the skin increased. In clinical tests, SH concentration in synovial fluid was 20.84 ng/mL after treatment with electroporation. Therefore, electroporation with optimized parameters could significantly enhance transdermal permeation of SH. The mechanism by which electroporation promoted permeation was that the electronic pulses made the skin structure looser. To summarize, electroporation may be an effective complementary method for transdermal permeation of SH. The controlled release of electroporation may be a promising clinical method for transdermal drug administration.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Delayed-Action Preparations; Drug Delivery Systems; Electroporation; Female; Humans; Male; Mice; Middle Aged; Morphinans; Pain; Swine; Swine, Miniature; Synovial Fluid; Transcutaneous Electric Nerve Stimulation

κ-Opioid receptor agonists with high selectivity over the μ-opioid receptor and peripheral selectivity are attractive targets in the development of drugs for pain. We have previously attempted to create novel analgesics with peripheral selective κ-opioid receptor agonist on the basis of TRK-820. In this study, we elucidated the biological properties of 17-hydroxy-cyclopropylmethyl and 10α-hydroxy derivatives. These compounds were found to have better κ-opioid receptor selectivity and peripheral selectivity than TRK-820.

Topics: Acetic Acid; Analgesics; Animals; Dose-Response Relationship, Drug; Drug Discovery; Male; Mice; Mice, Inbred ICR; Models, Molecular; Molecular Conformation; Morphinans; Pain; Receptors, Opioid, kappa; Spiro Compounds; Structure-Activity Relationship

Topics: Analgesics; Arthritis, Rheumatoid; Humans; Hyperalgesia; Hypersensitivity; Morphinans; Pain; Rats, Sprague-Dawley

We designed and synthesized pentacyclic propellane derivatives with a 6-amide side chain to afford compounds with higher MOR/KOR ratio and lower sedative effects than nalfurafine. The obtained etheno-bridged derivative with a β-amide side chain, YNT-854, showed a higher MOR/KOR ratio than nalfurafine. YNT-854 also exhibited a higher dose ratio between the sedative effect and the analgesic effect than observed with nalfurafine, which may guide the future design of useful analgesics with a weaker sedative effect than nalfurafine.

Topics: Amides; Analgesics, Opioid; Animals; CHO Cells; Cricetinae; Cricetulus; Guinea Pigs; Male; Mice; Mice, Inbred ICR; Morphinans; Pain; Protein Binding; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spiro Compounds; Structure-Activity Relationship

Oxycodone is an opioid analgesic metabolized to oxymorphone and noroxycodone by cytochrome P450 (CYP) 2D6 and 3A4/5, respectively. This was a retrospective study to evaluate sex, age, urinary pH and concurrent medication use on oxycodone, oxymorphone and noroxycodone distributions. Urine specimens obtained from patients on chronic opioid therapy were analyzed by LC-MS-MS. There were 108,923 specimens from a subject's first or single visit, who were at least 18 years of age, and had documented physician-reported oxycodone use. The majority of specimens had detectable oxycodone urine concentrations (n = 106,852) resulting in oxycodone mole fractions (arithmetic mean ± SD) of 0.44 ± 0.27. Ninety-eight percent (n = 106,229) and 49% (n = 53,394) had detectable oxymorphone and noroxycodone, respectively. Oxycodone and oxymorphone mole fractions were lower in women compared with men (P < 0.0001). Mean ± SD age was 49.1 ± 12.9 years. Noroxycodone mole fractions were highest in the 65 years and older age group. Concurrent use of a CYP2D6 inhibitor, but not a CYP3A4/5 inhibitor, altered oxycodone and oxymorphone mole fractions. Dual inhibition of CYP2D6 and CYP3A4/5 did not result in a statistical difference upon comparison with CYP2D6 inhibitor or CYP3A4/5 inhibitor use. Patient factors affect oxycodone and metabolite mole fractions and suggest increased awareness of each contribution when attempting to monitor therapy with urine drug testing.

Topics: Adolescent; Adult; Age Factors; Aged; Analgesics, Opioid; Chromatography, Liquid; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Female; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Morphinans; Oxycodone; Oxymorphone; Pain; Retrospective Studies; Sex Factors; Specimen Handling; Tandem Mass Spectrometry; Young Adult

Mu opioid receptor (MOR) selective antagonists and partial agonists have been used for the treatment of opioid abuse and addiction. Our recent efforts on the identification of MOR antagonists have provided several novel leads displaying interesting pharmacological profiles. Among them, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[(3'-isoquinolyl)acetamido]morphinan (NAQ) showed sub-nanomolar binding affinity to the MOR with significant selectivity over the delta opioid receptor (DOR) and the kappa opioid receptor (KOR). Its central nervous system penetration capacity together with marginal agonism in the MOR-GTPγS binding assay made it a very interesting molecule for developing novel opioid abuse and addiction therapeutic agents. Therefore, further pharmacological characterization was conducted to fully understand its biological profile. At the molecular and cellular level, NAQ not only induced no translocation of β-arrestin2 to the MOR, but also efficaciously antagonized the effect of DAMGO in MOR-βarr2eGFP-U2OS cells in the β-arrestin2 recruitment assay. At the in vivo level, NAQ displayed a potent inhibition of the analgesic effect of morphine in the tail-flick assay (ID50=1.19 mg/kg). NAQ (10 mg/kg) also significantly decreased the hyper-locomotion induced by acute morphine without inducing any vertical jumps. Meanwhile NAQ precipitated lesser withdrawal symptoms in morphine dependent mice than naloxone. In conclusion, NAQ may represent a new chemical entity for opioid abuse and addiction treatment.

Topics: Analgesics; Animals; Arrestins; Behavior, Animal; beta-Arrestins; Cell Line, Tumor; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Humans; Isoquinolines; Ligands; Male; Mice, Inbred ICR; Morphinans; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Receptors, Opioid, mu

The aim of this study is to evaluate the pharmacokinetic profile of oxycodone and three of its metabolites, noroxycodone, oxymorphone and noroxymorphone after intravenous administration in Chinese patients with pain.. Forty-two subjects were assigned to receive intravenous administration of oxycodone hydrochloride of 2.5, 5 or 10 mg. Plasma and urine samples were collected for up to 24 h after intravenous administration of oxycodone hydrochloride.. Pharmacokinetic parameters showed that mean values of C(max), AUC(0-t) and AUC(0-∞) of oxycodone were dose dependent, whereas Tmax and t(1/2) were not. The mean AUC(0-t) ratio of noroxycodone to oxycodone ranged from 0.35 to 0.42 over three doses, and those of noroxymorphone, or oxymorphone, to oxycodone were ranging of 0.06-0.08 and 0.007-0.008, respectively. Oxycodone and its three metabolites were excreted from urine. Approximately 10% of unchanged oxycodone was recovered in 24 h. Most adverse events (AEs) reported were mild to moderate. The frequently occurred AEs were dizziness, nausea, vomiting, drowsiness and fatigue. No dose-related AEs were found.. Our pharmacokinetics of oxycodone injection in Chinese patients with pain strongly support continued development of oxycodone as an effective analgesic drug in China.

Topics: Adult; Analgesics, Opioid; Area Under Curve; Female; Humans; Injections, Intravenous; Male; Middle Aged; Morphinans; Oxycodone; Oxymorphone; Pain

Topics: Analgesics, Opioid; Female; Humans; Male; Morphinans; Oxycodone; Oxymorphone; Pain

Topics: Analgesics, Opioid; Female; Humans; Male; Morphinans; Oxycodone; Oxymorphone; Pain

We previously reported that the κ agonists with mixed μ activity could attenuate heroin self-administration with less potential to develop tolerance. The present study further investigated the effects of (-)-3-N-Ethylamino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride (ATPM-ET), a κ agonist and μ agonist/antagonist, on the acquisition and reinstatement of morphine-induced conditioned place preference (CPP), heroin self-administration and heroin-primed reinstatement of drug-seeking behavior. We found that ATPM-ET produced a longer duration of potent antinociceptive effects with less side effect of sedation. More importantly, ATPM-ET attenuated the acquisition of morphine-induced CPP, without affecting the reinstatement of morphine CPP. Furthermore, ATPM-ET significantly inhibited heroin self-administration and the reinstatement of heroin primed drug-seeking behavior. Taken together, ATPM-ET, a novel κ agonist and μ agonist/antagonist may have utility for the treatment of drug dependence.

Topics: Analgesics, Opioid; Animals; Conditioning, Psychological; Drug-Seeking Behavior; Heroin Dependence; Male; Mice; Morphinans; Morphine; Narcotic Antagonists; Pain; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Receptors, Opioid, mu; Self Administration

Activation of δ opioid (DOP) receptors regulates pain and emotional responses, and also displays ligand-biased agonism. KNT-127 (1,2,3,4,4a,5,12,12a-octahydro-2-methyl-4aβ,1β-([1,2]benzenomethano)-2,6-diazanaphthacene-12aβ,17-diol) is a novel DOP receptor agonist inducing analgesia and antidepressant effects in mice. Here, we have assessed KNT-127 for (i) analgesia against chronic inflammatory pain; (ii) effects on depression, locomotion and DOP receptor internalization; and (iii) for cross-tolerance to analgesic and antidepressant effects of acute treatment by other DOP receptor agonists.. Inflammatory pain was induced by complete Freund's adjuvant injection into tail or hindpaw, and thermal and mechanical sensitivities were determined in mice. Locomotor and antidepressant-like effects were measured using actimetry and forced swim test respectively. In vivo KNT-127 selectivity and internalization were assessed using DOP receptor knockout mice and knock-in mice expressing fluorescent-tagged DOP receptors. KNT-127 was injected acutely at 0.1-10.0 mg·kg(-1) or administered chronically at 5 mg·kg(-1) daily over 5 days.. Acute treatment with KNT-127 reversed inflammatory hyperalgesia, produced an antidepressant-like effect but induced neither hyperlocomotion nor receptor sequestration. Chronic treatment with KNT-127 induced tolerance and cross-tolerance to SNC80-induced analgesia, but no tolerance to SNC80-evoked hyperlocomotor or antidepressant-like effects.. The DOP receptor agonist KNT-127 induced agonist-specific acute and chronic responses, at both behavioural and cellular levels. It displays activities similar to the other recently reported DOP agonists, AR-M1000390, ADL5747 and ADL5859, and differs from SNC80. SNC80 differs from the other DOP receptor agonists including KNT-127, by exhibiting ligand-biased tolerance at this receptor.

Topics: Analgesics; Animals; Antidepressive Agents; Behavior, Animal; Benzamides; Depression; Drug Tolerance; Freund's Adjuvant; Hot Temperature; Hyperalgesia; Male; Mice, Inbred C57BL; Mice, Knockout; Morphinans; Motor Activity; Pain; Piperazines; Receptors, Opioid, delta

The synthesis and the effect of a combination of 6-glycine and 14-phenylpropoxy substitutions in N-methyl- and N-cycloproplymethylmorphinans on biological activities are described. Binding studies revealed that all new 14-phenylpropoxymorphinans (11-18) displayed high affinity to opioid receptors. Replacement of the 14-methoxy group with a phenylpropoxy group led to an enhancement in affinity to all three opioid receptor types, with most pronounced increases in δ and κ activities, hence resulting in a loss of μ receptor selectivity. All compounds (11-18) showed potent and long-lasting antinociceptive effects in the tail-flick test in rats after subcutaneous administration. For the N-methyl derivatives 13 and 14, analgesic potencies were in the range of their 14-methoxy analogues 9 and 10, respectively. Even derivatives 15-18 with an N-cyclopropylmethyl substituent acted as potent antinociceptive agents, being several fold more potent than morphine. Subcutaneous administration of compounds 13 and 14 produced significant and prolonged antinociceptive effects mediated through peripheral opioid mechanisms in carrageenan-induced inflammatory hyperalgesia in rats.

Topics: Analgesics; Animals; Binding, Competitive; Guanosine 5'-O-(3-Thiotriphosphate); Magnetic Resonance Spectroscopy; Morphinans; N-substituted Glycines; Pain; Rats; Receptors, Opioid; Spectrometry, Mass, Electrospray Ionization; Spectroscopy, Fourier Transform Infrared; Structure-Activity Relationship

Urine drug testing of pain patients provides objective information to health specialists regarding patient compliance, diversion, and concurrent illicit drug use. Interpretation of urine test results for semi-synthetic opiates can be difficult because of complex biotransformations of parent drug to metabolites that are also available commercially and may be abused. Normetabolites such as norcodeine, norhydrocodone and noroxycodone are unique metabolites that are not available commercially. Consequently, detection of normetabolite in specimens not containing parent drug, provides conclusive evidence that the parent drug was consumed. The goal of this study was to evaluate the prevalence and patterns of the three normetabolites, norcodeine, norhydrocodone and noroxycodone, in urine specimens of pain patients treated with opiates. Urine specimens were hydrolyzed with beta-glucuronidase and analyzed by a validated liquid chromatography tandem mass spectrometry (LC/MS/MS) assay for the presence of codeine, norcodeine, morphine, hydrocodone, norhydrocodone, hydromorphone, dihydrocodeine, oxycodone, noroxycodone, and oxymorphone. The limit of quantitation (LOQ) for these analytes was 50ng/mL. The study was approved by an Institutional Review Board. Of the total specimens (N=2654) tested, 71.4% (N=1895) were positive (>or=LOQ) for one or more of the analytes. The prevalence (%) of positive results for codeine, hydrocodone and oxycodone was 1.2%, 26.1%, and 36.2%, respectively, and the prevalence of norcodeine, norhydrocodone and noroxycodone was 0.5%, 22.1%, and 31.3%, respectively. For specimens containing normetabolite, the prevalence of norcodeine, norhydrocodone and noroxycodone in the absence of parent drug was 8.6%, 7.8% and 9.4%, respectively. From one-third to two-thirds of these specimens also did not contain other metabolites that could have originated from the parent drug. Consequently, the authors conclude that inclusion of norcodeine, norhydrocodone and noroxycodone is useful in interpretation of opiate drug source and reduces potential false negatives that would occur without tests for these unique metabolites.

Topics: Analgesics, Opioid; Chromatography, Liquid; Codeine; False Negative Reactions; Forensic Toxicology; Humans; Hydrocodone; Medication Adherence; Morphinans; Oxycodone; Oxymorphone; Pain; Tandem Mass Spectrometry

Neuronal events leading to development of long-term potentiation (LTP) in the nociceptive pathways may be a cellular mechanism underlying hyperalgesia. In the present study, we examine if induction of spinal LTP may be associated with functional changes in the supraspinal opioidergic system. The opioid receptors (ORs) play a key role in nociceptive processing and controlling the descending modulatory system to the spinal cord.. Spinal LTP was induced by electrical high-frequency stimulation (HFS) conditioning applied to the sciatic nerve, and the excitability at spinal level was verified by spinal field potential recordings. To study supraspinal changes in opioid neurotransmission following the same HFS conditioning, we used small animal positron emission tomography (PET) and [(11)C]Phenethyl-Orvinol ([(11)C]PEO). All rats included in the PET study were scanned at baseline and 150 min after HFS, and specific binding was calculated with a reference tissue model.. A clear C-fibre LTP, i.e. increased C-fibre response and reduced C-fibre threshold, was observed 150 min after HFS conditioning (t-test, P<0.05, n = 6). Moreover, increased OR binding, relative to baseline, was observed after the same type of HFS conditioning ipsilaterally in the amygdala, hippocampus, somatosensory cortex and superior colliculus, and bilaterally in the nucleus accumbens, caudate putamen and hypothalamus (paired t-test, HFS>baseline, P<0.05, n = 8).. HFS conditioning of the sciatic nerve resulted in both spinal LTP and functional changes in supraspinal opioidergic signalling. Our findings suggest that induction of spinal LTP may be associated with reduced opioid neurotransmission in brain regions involved in pain modulation and affective-emotional responses.

Topics: Animals; Brain; Electric Stimulation; Evoked Potentials; Female; Long-Term Potentiation; Morphinans; Nerve Fibers, Unmyelinated; Neural Pathways; Pain; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Sciatic Nerve; Synaptic Transmission; Time Factors

The aim of this study was to establish the effect of lidocaine, a local anesthetic, on pain and itch using formalin-induced nociception and kappa opioid antagonist-induced scratching models in mice. We investigated if local intradermal pretreatment (at -10 min) with lidocaine N-ethyl bromide (lidocaine, 2%, 0.1 ml) antagonizes behavioral responses and prevents c-fos expression induced by pain and itch. Male, Swiss Webster mice (25-30 g, n=6-10) were used. Formalin (5%, 20 microl, s.c.) or saline was administered to the right dorsal hindpaw and the time spent licking this paw was recorded at 0-10 min and 20-35 min. For itching, mice were challenged with 5'-guanidinonaltrindole (GNTI, 0.3mg/kg, s.c., behind the neck) or saline and the number of neck-directed scratches with hindpaws was counted for 30 min. C-fos immunohistochemistry was performed in lumbar (for pain) and cervical (for scratching) spinal sections 2h after the respective treatments. We found that lidocaine (a) antagonizes both formalin-induced pain and GNTI-induced scratching and (b) prevents c-fos expression evoked by pain (medial side of the superficial layer and deeper layers of the dorsal horn) and itch (lateral side of the superficial layer of the dorsal horn). Additionally, GNTI caused c-fos activation in mice wearing an Elizabethan collar (to prevent scratching of the neck) suggesting that GNTI provokes c-fos expression by inducing an itch sensation. Our results highlight the antipruritic properties of lidocaine and argue for its comprehensive clinical testing against pruritic states.

Topics: Animals; Behavior, Animal; Formaldehyde; Gene Expression Regulation; Guanidines; Lidocaine; Male; Mice; Morphinans; Naltrexone; Neurons; Pain; Proto-Oncogene Proteins c-fos; Pruritus; Receptors, Opioid, kappa

Peripheral micro-opioid receptors (MOR) have emerged as important components of inhibitory nociceptive pathways. Here, the antinociceptive effects of MOR agonists, the 6beta-glycine derivative of 14-O-methyloxymorphone (HS-731), DAMGO and morphine were evaluated in a mouse model of visceral pain. The abdominal acetic acid-induced writhing test was used to examine the peripheral, preemptive antinociceptive opioid action on visceral nociception. HS-731 administered subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) dose-dependently and completely inhibited writhing, being 24-598-fold more potent, depending on the administration route, than two selective MOR agonists, the enkephalin analogue [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]enkephalin (DAMGO) and morphine. A longer duration of action (2-3 h) was induced by HS-731 given before acetic acid, while shorter effect was produced by morphine (30-60 min) and DAMGO (30-45 min). The antinociceptive effects of systemic opioids were reversed by the s.c. opioid antagonist, naloxone. Blocking of central MOR by the selective MOR antagonist D-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP, i.c.v.) resulted in a significant reduction of antinociception of s.c. morphine, whereas it completely failed to antagonize the effects of systemic HS-731 or DAMGO. In in vitro studies, HS-731 and DAMGO, but not morphine showed high intrinsic efficacy, naltrexone-sensitive agonist effect at MOR of the rat vas deferens. These data demonstrate that selective activation of peripheral MOR by systemic s.c. HS-731 or DAMGO produces potent peripheral, preemptive visceral antinociception, while morphine's effects are mediated primarily through central mechanisms. Our findings support the role of peripheral MOR in the pathology of pain states involving sensitization of peripheral nociceptors.

Topics: Acetic Acid; Analgesics, Opioid; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Administration Schedule; Drug Interactions; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Epoxy Compounds; In Vitro Techniques; Male; Mice; Morphinans; Morphine; Pain; Pain Measurement; Peptide Fragments; Peptides; Rats; Rats, Wistar; Somatostatin; Time Factors; Vas Deferens

Opioids induce analgesia by activating opioid receptors not only within the central nervous system but also on peripheral sensory neurons. This study investigated peripherally mediated antinociception produced by the mu-opioid receptor agonist 2-[(4,5alpha-epoxy-3-hydroxy-14beta-methoxy-17-methylmorphinan-6beta-yl)amino]acetic acid (HS-731) after s.c. and oral administration in rats with carrageenan-induced hindpaw inflammation. Antinociceptive effects after s.c. administration were assessed 3 h after intraplantar carrageenan injection and compared with those of centrally acting mu-opioid agonists 14-methoxymetopon and morphine. Opioid agonists caused dose-dependent increases in inflamed paw withdrawal latencies to mechanical and thermal stimulation. The time course of action was different, in that HS-731 (20 microg/kg s.c.) produced significant long-lasting effects up to 4 h after administration, whereas 14-methoxymetopon (20 microg/kg) and morphine (2 mg/kg) reached their peak of action at 10 to 30 min, and their effect declined rapidly thereafter. Subcutaneous administration of the peripherally selective opioid antagonist naloxone methiodide inhibited antinociception elicited by HS-731 (20 microg/kg s.c.), whereas it was ineffective against 14-methoxymetopon (20 microg/kg s.c.). Moreover, the antinociception produced by 100 microg/kg s.c. HS-731 was dose-dependently reversed by s.c. naloxone methiodide. This indicates that HS-731 preferentially activates peripheral opioid receptors, whereas 14-methoxymetopon mediates analgesia via central mechanisms. Orally administered HS-731 significantly reduced hyperalgesia in the inflamed paw induced by carrageenan, which was reversible by s.c. administered naloxone methiodide. These results show that systemic (s.c. and oral) treatment with the mu-opioid agonist HS-731 produces potent and long-lasting antinociception through peripheral mechanisms in rats with carrageenan-induced hindpaw inflammation.

Topics: Administration, Oral; Analgesics, Opioid; Animals; Carrageenan; Dose-Response Relationship, Drug; Epoxy Compounds; Hindlimb; Inflammation; Injections, Subcutaneous; Male; Morphinans; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu

The analgesic effects of opioid agonists and the expression of mu- and kappa-opioid receptors were compared between mice with herpetic pain and those with postherpetic pain induced by herpetic virus inoculation. Morphine inhibited herpetic pain more effectively than postherpetic pain. Intrathecal injection reduced the analgesic effects of morphine on postherpetic pain, but intracerebroventricular injection did not. The kappa-opioid receptor agonist nalfurafine suppressed herpetic and postherpetic pain to similar degrees. mu-Opioid receptor-like immunoreactivities in the lumbar dorsal horn were markedly decreased at the postherpetic, but not herpetic, stage of pain. In the dorsal root ganglia, the expression of mu-opioid receptor mRNA was significantly decreased in mice with postherpetic pain, whereas the kappa-opioid receptor mRNA level was not altered. These results suggest that specific down-regulation of the mu-opioid receptor in the primary sensory neurons is responsible for the reduced analgesic action of morphine on postherpetic pain. The kappa-opioid receptor may be a useful target for the analgesic treatment of postherpetic neuralgia.

Topics: Analgesics, Opioid; Animals; Down-Regulation; Female; Fluorescent Antibody Technique; Ganglia, Spinal; Herpesvirus 1, Human; Hyperalgesia; Immunohistochemistry; Injections, Intraventricular; Injections, Spinal; Mice; Mice, Inbred BALB C; Morphinans; Morphine; Neuralgia, Postherpetic; Pain; Pain Measurement; Posterior Horn Cells; Receptors, Opioid, kappa; Receptors, Opioid, mu; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spine; Spiro Compounds

In the search for opioid agonists with delayed antagonist actions as potential treatments for substance abuse, the bridged morphinan BU74 (17-cyclopropylmethyl-3-hydroxy-[5beta,7beta,3',5']-pyrrolidino-2'[S]-phenyl-7alpha-methyl-6,14-endoetheno morphinan) (3f) was synthesized. In isolated tissue and [35S]GTPgammaS opioid receptor functional assays BU74 was shown to be a potent long-lasting kappa opioid receptor agonist, delta opioid receptor partial agonist and mu opioid receptor antagonist. In antinociceptive tests in the mouse, BU74 showed high efficacy and potent kappa opioid receptor agonism. When its agonist action had waned BU74 became an antagonist of kappa and mu opioid receptor agonists in the tail flick assay and of delta, kappa and mu opioid receptor agonists in the acetic acid writhing assay. The slow onset, long-duration kappa opioid receptor agonist effects of BU74 suggests that it could be a lead compound for the discovery of a treatment for cocaine abuse.

Topics: Acetic Acid; Analgesics; Animals; Benzomorphans; Binding, Competitive; Bridged-Ring Compounds; Cell Line, Tumor; Guanosine 5'-O-(3-Thiotriphosphate); Guinea Pigs; Hot Temperature; Ileum; In Vitro Techniques; Male; Mice; Mice, Inbred ICR; Morphinans; Narcotic Antagonists; Pain; Pain Measurement; Radioligand Assay; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Sulfur Radioisotopes; Vas Deferens

(-)-17-Cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-6beta-[N-methyl-3-trans-3-(3-furyl) acrylamido] morphinan hydrochloride (TRK-820) is a kappa-opioid receptor agonist that has pharmacological characteristics different from typical kappa-opioid receptor agonists. This study was conducted to determine the antiallodynic and antihyperalgesic effects of TRK-820 in a mouse model of acute herpetic pain and to compare them with those of the kappa-opioid receptor agonist enadoline and the mu-opioid receptor agonist morphine. Percutaneous inoculation with herpes simplex virus type-1 induced tactile allodynia and mechanical hyperalgesia in the hind paw on the inoculated side. TRK-820 (0.01-0.1 mg/kg p.o.), enadoline (1-10 mg/kg p.o.) and morphine (5-20 mg/kg p.o.) dose dependently inhibited the allodynia and hyperalgesia, but the antiallodynic and antihyperalgesic dose of enadoline markedly decreased spontaneous locomotor activity. The antinociceptive action of TRK-820 (0.1 mg/kg) was completely antagonized by pretreatment with norbinaltorphimine, a kappa-opioid receptor antagonist, but not by naltrexone, a mu-opioid receptor antagonist. Repeated treatment with morphine (20 mg/kg, four times) resulted in the reduction of antiallodynic and antihyperalgesic effects, whereas the inhibitory potency of TRK-820 (0.1 mg/kg) was almost the same even after the fourth administration. There was no cross-tolerance in antinociceptive activities between TRK-820 and morphine. Intrathecal and intracerebroventricular, but not intraplantar, injections of TRK-820 (10-100 ng/site) suppressed the allodynia and hyperalgesia. These results suggest that TRK-820 inhibits acute herpetic pain through kappa-opioid receptors in the spinal and supraspinal levels. TRK-820 may have clinical efficacy in acute herpetic pain with enough safety margins.

Topics: Animals; Gene Expression; Mice; Morphinans; Morphine; Pain; Receptors, Opioid, kappa; Receptors, Opioid, mu; RNA, Messenger; Spiro Compounds

The development of buprenorphine as a treatment for opiate abuse and dependence has drawn attention to opioid ligands that have agonist actions followed by long-lasting antagonist actions. In a search for alternatives to buprenorphine, we discovered a bridged pyrrolidinomorphinan (BU72). In vitro, BU72 displayed high affinity and efficacy for mu-opioid receptors, but was also a partial delta-opioid receptor agonist and a full kappa-opioid receptor agonist. BU72 was a highly potent and long-lasting antinociceptive agent against both thermal and chemical nociception in the mouse and against thermal nociception in the monkey. These effects were prevented by mu-, but not kappa- or delta-, opioid receptor antagonists. Once the agonist effects of BU72 had subsided, the compound acted to attenuate the antinociceptive action of morphine. BU72 is too efficacious for human use but manipulation to reduce efficacy could provide a lead to the development of a treatment for opioid dependence.

Topics: Analgesics; Animals; Binding, Competitive; Buprenorphine; Cell Line, Tumor; CHO Cells; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Female; Guanosine 5'-O-(3-Thiotriphosphate); Guinea Pigs; Ileum; In Vitro Techniques; Macaca mulatta; Male; Mice; Mice, Inbred ICR; Morphinans; Morphine; Muscle Contraction; Pain; Pain Measurement; Pyrroles; Radioligand Assay; Rats; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Sulfur Radioisotopes; Time Factors; Tritium; Vas Deferens

This report concerns the synthesis and preliminary pharmacological evaluation of a novel series of kappa agonists related to the morphinan (-)-cyclorphan (3a) and the benzomorphan (-)-cyclazocine (2) as potential agents for the pharmacotherapy of cocaine abuse. Recent evidence suggests that agonists acting at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. We describe the synthesis and chemical characterization of a series of morphinans 3a-c, structural analogues of cyclorphan [(-)-3-hydroxy-N-cyclopropylmethylmorphinan S(+)-mandelate, 3a], the 10-ketomorphinans 4a,b, and the 8-ketobenzomorphan 1b. Binding experiments demonstrated that the cyclobutyl analogue 3b [(-)-3-hydroxy-N-cyclobutylmethylmorphinan S(+)-mandelate, 3b, MCL-101] of cyclorphan (3a) had a high affinity for mu, delta, and kappa opioid receptors in guinea pig brain membranes. Both 3a,b were approximately 2-fold more selective for the kappa receptor than for the mu receptor. However 3b (the cyclobutyl analogue) was 18-fold more selective for the kappa receptor in comparison to the delta receptor, while cyclorphan (3a) had only 4-fold greater affinity for the kappa receptor in comparison to the delta receptor. These findings were confirmed in the antinociceptive tests (tail-flick and acetic acid writhing) in mice, which demonstrated that cyclorphan (3a) produced antinociception that was mediated by the delta receptor while 3b did not produce agonist or antagonist effects at the delta receptor. Both 3a,b had comparable kappa agonist properties. 3a,b had opposing effects at the mu receptor: 3b was a mu agonist whereas 3a was a mu antagonist.

Topics: Acetic Acid; Animals; Benzomorphans; Brain; Dose-Response Relationship, Drug; Ethylketocyclazocine; Guinea Pigs; In Vitro Techniques; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Morphinans; Morphine; Narcotic Antagonists; Pain; Pain Measurement; Reaction Time; Receptors, Opioid, kappa; Receptors, Opioid, mu

Topics: Aged; Aged, 80 and over; Alfentanil; Combined Modality Therapy; Electric Stimulation Therapy; Female; Humans; Intraoperative Care; Laser Therapy; Male; Middle Aged; Morphinans; Pain; Pain Management; Pain, Intractable; Propofol; Rectal Neoplasms; Sigmoid Neoplasms

Intravenous (i.v.) administration of morphine produces a dose-dependent inhibition of the tail-flick (TF) reflex, depressor response, and bradycardia in the rat. Some of these effects depend on interactions of i.v. morphine with peripheral opioid receptors and the integrity of cervical vagal afferents. The present studies used the relatively specific mu, delta, and kappa opioid receptor agonists (DAGO, DPDPE or U-50,488H) and the relatively specific mu, delta, and kappa opioid receptor antagonists (beta-FNA, naloxonazine, naltrindole or nor-BNI) in either intact rats or rats with bilateral cervical vagotomy (CVAG) to delineate the vagal afferent/opioid-mediated components of these effects. I.v. administration of DAGO in intact rats produced a dose-dependent inhibition of the TF reflex, depressor response, and bradycardia virtually identical to those produced by i.v. morphine. All of these effects of either i.v. DAGO or i.v. morphine were significantly attenuated by either bilateral CVAG or pre-treatment with the mu 2 opioid receptor antagonist beta-FNA. Pre-treatment with the mu 1 opioid receptor antagonist naloxonazine affected i.v. DAGO-induced inhibition of the TF reflex and bradycardia, but had no significant effects on i.v. morphine-produced responses. I.v. administration of DPDPE produced a dose-dependent pressor response, but had no marked effects on the either the TF reflex or heart rate (HR). The pressor response was unaffected by either bilateral CVAG or pre-treatment with naltrindole, naloxone, hexamethonium, or bertylium. i.v. administration of U-50,488H produced a depressor response and bradycardia, but had no significant effect on the TF reflex. The depressor response and bradycardia produced by i.v. U-50,488H were unaffected by bilateral CVAG, but could be antagonized by pre-treatment with either nor-BNI or naloxone. These studies suggest that the vagal afferent-mediated antinociceptive and cardiovascular effects of i.v. morphine are primarily mediated by interactions with low affinity mu 2 opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analysis of Variance; Animals; Blood Pressure; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Heart Rate; Hexamethonium; Hexamethonium Compounds; Indoles; Injections, Intravenous; Male; Morphinans; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Pain; Pyrrolidines; Rats; Rats, Sprague-Dawley; Reference Values; Time Factors; Vagotomy; Vagus Nerve

Previous work has demonstrated that 3 pharmacologically and neuroanatomically distinct analgesia systems can be sequentially activated by increasing numbers of transcutaneous tail-shock. To date, the categorization of the early (after 2 tail-shocks) and late (after 80-100 tail-shocks) analgesias as opiate-mediated has been based on the ability of systemic naltrexone and morphine tolerance to block these effects. In contrast, the analgesia observed after 5-40 tail-shocks is unaffected by these manipulations, leading to its categorization as non-opiate. The preceding companion paper and the present work were aimed at identifying the neuroanatomical loci at which opiates exert their analgesic effects in this tail-shock paradigm and, further, to identify which opiate receptor subtypes are involved. The 8 experiments included in the present paper examined the effect of microinjecting either naltrexone (a relatively non-selective opiate receptor antagonist), binaltorphimine (kappa receptor antagonist), Cys2-Tyr3-Orn5-Pen7-amide (CTOP) (mu receptor antagonist), or naltrindole (delta receptor antagonist) either into the third ventricle or over the frontal cortex. Taken together, these experiments demonstrate that the late (80-100 shock) opiate analgesia is mediated by delta opiate receptors located within subcortical structures rostral to the 4th ventricle. No evidence for supraspinal opiate involvement in the early (2 shock) opiate analgesia was found.

Topics: Analysis of Variance; Animals; Cerebral Ventricles; Dose-Response Relationship, Drug; Electroshock; Indoles; Injections, Intraventricular; Injections, Spinal; Male; Morphinans; Naltrexone; Narcotic Antagonists; Pain; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Spinal Cord

When administered repeatedly, in conjunction with hot plate testing, naloxone and naltrexone have the paradoxical effect of producing antinociception in rats and mice. Recently, we have found that the sub-acute selective blockade of mu opioid receptors leads to the development of antinociception and an augmentation of kappa receptor-mediated antinociception. In this study, acute delta/kappa antagonist treatment produced a significant decrease in paw lick latency in rats displaying antinociception induced by sub-acute mu blockade, however, the response level of these animals was still significantly above the baseline. In addition, rats receiving sub-acute combined mu and delta antagonist treatment took longer to develop an antinociceptive response than those treated with a mu antagonist alone. Sub-acute selective blockade of kappa or delta opioid receptors had no overall effect on paw lick latency during the course of 5 days of hot plate testing. The results indicate that delta receptor activity may play a role in the antinociception induced by sub-acute mu blockade. However, while delta antagonist treatment effected the expression, it did not completely attenuate the antinociception induced by sub-acute mu blockade suggesting that there is still a significant non-opioid component to this analgesic response. The results of a final experiment, in which acute delta antagonist treatment had no effect on antinociception induced by repeated systemic injections of naloxone, supported this hypothesis.

Topics: Animals; Indoles; Male; Morphinans; Naltrexone; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Sensitivity and Specificity

Previous work has demonstrated that 3 pharmacologically and neuroanatomically distinct analgesia systems can be sequentially activated by increasing numbers of transcutaneous tail-shock. To date, the categorization of the early (after 2 tail-shocks) and late (after 80-100 tail-shocks) analgesias as opiate-mediated has been based on the ability of systemic naltrexone and morphine tolerance to block these effects. In contrast, the analgesia observed after 5-40 tail-shocks is unaffected by these manipulations, leading to its categorization as non-opiate. The present work and the following companion paper were aimed at identifying the neuroanatomical loci at which endogenous opiates exert their analgesic effects in this tail-shock paradigm and, further, to identify which opiate receptor subtypes are involved. The 3 experiments included in the present paper focus on the role of spinal opiates in tail-shock induced analgesia. The first experiment demonstrates that the tail-shock parameters used do not directly activate pain suppressive circuitry within the spinal cord, but rather activate centrifugal pain modulation circuitry originating within the brain. The last two experiments examine the effect of intrathecal microinjection of either naltrexone (a relatively non-selective opiate receptor antagonist), binaltorphimine (kappa receptor antagonist), Cys2-Tyr3-Orn5-Pen7-amide (CTOP) (mu receptor antagonist), or naltrindole (delta receptor antagonist). Taken together, these latter 2 experiments demonstrate that both the early (after 2 shocks) and late (after 80-100 shocks) opiate analgesias are mediated by kappa opiate receptors within the spinal cord.

Topics: Analysis of Variance; Animals; Dose-Response Relationship, Drug; Electroshock; Indoles; Injections, Spinal; Male; Morphinans; Naltrexone; Narcotic Antagonists; Pain; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Somatostatin; Spinal Cord

The modulatory effects of intrathecally (i.t.) administered dynorphin A(1-17) and dynorphin A(1-13) on morphine antinociception have been studied previously in rats by other investigators. However, both potentiating and attenuating effects have been reported. In this study, the modulatory effects of i.t. administered dynorphin A(1-17) as well as the smaller fragment, dynorphin A(1-8), were studied in mice. In addition, nor-binaltorphimine (nor-BNI), a highly selective kappa opioid receptor antagonist, and naltrindole (NTI), a highly selective delta opioid receptor antagonist, were used to characterize the possible involvement of spinal kappa and delta opioid receptors in the modulatory effects of the dynorphins. Dynorphin A(1-17) and dynorphin A(1-8) administered i.t. at doses that did not alter tail-flick latencies, were both able to antagonize in a dose-dependent manner, the antinociceptive action of s.c. administered morphine sulfate. The antinociceptive ED50 of morphine sulfate was increased 3.9- and 5.3-fold by 0.4 nmol/mouse of dynorphin A(1-17) and dynorphin A(1-8), respectively. Injections of 0.4 and 0.8 nmol/mouse of nor-BNI i.t., but not its inactive enantiomer (+)-1-nor-BNI, inhibited dose-dependently the antagonistic effects of the dynorphins. These doses of nor-BNI alone did not affect the antinociceptive action of morphine sulfate. Intrathecal administration of 5 nmol/mouse of NTI also did not affect the modulatory effects of dynorphins. These observations that dynorphins exert their antagonistic effects on morphine-induced antinociception stereoselectively through spinal kappa opioid receptors may suggest a coupling between spinal kappa and mu opioid receptors.

Topics: Animals; Dynorphins; Indoles; Male; Mice; Morphinans; Morphine; Naltrexone; Pain; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Spine; Stereoisomerism

Topics: Humans; Morphinans; Morphine; Morphine Dependence; Pain; Receptors, Opioid

Until recently the only pharmacological probes for delta-receptors have been peptide enkephalin analogues. These suffer from a number of limitations including high cost, partial agonist effects and a propensity for neurotoxicity. A stable non-peptide antagonist, naltrindole, has recently become available. We have explored its intrinsic actions and found that it attenuated swim stress-induced antinociception, a model for endogenous delta-receptor activation. Naltrindole may therefore be a useful alternative to presently available delta-receptor antagonists.

Topics: Animals; Behavior, Animal; Indoles; Male; Morphinans; Naltrexone; Narcotic Antagonists; Pain; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Stress, Psychological

Nalbuphine reverses opioid-induced respiratory depression, but the effect on analgesia is unclear. The analgesic interaction between subcutaneous (sc) nalbuphine and intrathecal morphine in conscious, male, Sprague-Dawley rats implanted with chronic intrathecal catheters was investigated. Nalbuphine (10 mg/kg) injected 30 min after intrathecal morphine (4 micrograms) significantly antagonized the effect of morphine in the tail flick test. The antagonism was rapid in onset and persisted beyond the experimental period of 240 min. The magnitude and the duration of the effect were comparable to that observed with sc naloxone (1 mg/kg). In contrast to the results in the tail flick test, nalbuphine enhanced the effect of intrathecal morphine in the noninflamed paw pressure test. Nalbuphine (10 mg/kg) alone had no effect on the time course of tail flick latency but significantly increased paw pressure threshold during the 15-90 min interval after sc injection. Nalbuphine (0.5 mg/kg, sc) alone had no antinociceptive effect in either pain test and did not antagonize the antinociceptive effect of intrathecal morphine (4 micrograms) in the tail flick test. However, sc nalbuphine (0.5 mg/kg), injected 30 min after intrathecal morphine (1.5 micrograms), significantly enhanced the effect of morphine in the paw pressure test compared with intrathecal morphine + sc saline-treated rats. The results indicate a complex analgesic interaction between intrathecal morphine and sc nalbuphine. The net analgesic effect during the interaction was determined by the following: 1) the doses of morphine and nalbuphine; 2) the time after nalbuphine administration; and 3) the nature of the nociceptive stimulus. At lower doses, sc nalbuphine appeared to potentiate the effect of intrathecal morphine in the noninflamed paw pressure test.

Topics: Analgesics; Animals; Drug Interactions; Injections, Spinal; Injections, Subcutaneous; Male; Morphinans; Morphine; Nalbuphine; Pain; Pain Measurement; Rats; Rats, Inbred Strains; Reaction Time; Sensory Thresholds

Forty-six patients with moderate to severe pain caused by orthopedic injuries, burns, multiple trauma, or intraabdominal conditions were treated with intravenous (IV) nalbuphine hydrochloride (Nubain; DuPont Pharmaceuticals, Wilmington, DE) by paramedics before arrival at the hospital. Patients who weighed less than 60 kg received 15 mg nalbuphine, and patients weighing greater than 60 kg received 20 mg nalbuphine. Forty-one of 46 patients (89%) experienced pain relief from nalbuphine, with maximum relief occurring within 15 minutes after the administration of the drug. Two addicted patients received no pain relief. There were no untoward side effects following nalbuphine administration, and the patients' heart rates, mean arterial pressures, and respiratory rates remained constant and stable throughout the study period. Repeated assessment of the patient by paramedics in the field was not impaired by nalbuphine treatment. In summary, nalbuphine hydrochloride is a useful and safe analgesic drug for IV use by paramedics in the prehospital setting.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Emergencies; Emergency Medical Technicians; Female; Humans; Male; Middle Aged; Morphinans; Nalbuphine; Pain; Wounds and Injuries

In order to examine the pharmacokinetics and excretion of nalbuphine (Nubain 20) in breast milk, patients suffering from postpartum pain were given a single dose of 20 mg nalbuphine intramuscularly. During a 24-h period, the total amount of nalbuphine excreted in the breast milk was 2.3 micrograms (mean value), which is equivalent to 0.012% of the dosage. The mean milk/plasma quotient was calculated using the AUC from the milk and plasma time curves at 1.2:1. An oral intake of 2.3 micrograms nalbuphine would not show any measurable plasma concentrations in the neonate. Adverse opioid reactions, e.g. respiratory depression are not to be expected even if one assumes a lack of glucuronide production in the neonate.

Topics: Adult; Female; Half-Life; Humans; Injections, Intramuscular; Milk, Human; Morphinans; Nalbuphine; Pain; Postpartum Period; Pregnancy

The present study compared the effects of two opioid antagonists, beta-funaltrexamine (beta-FNA) and 16-methyl cyprenorphine (RX8008M) on the antinociception produced by a range of opioid agonists in the abdominal constriction test in the mouse and the paw pressure test in the guinea-pig. Both antagonists produced large shifts in the dose-response curves to the mu-agonists, morphine and fentanyl, confirming their mu-antagonist activity. Neither antagonist produced any antagonism of the antinociceptive effects of the selective kappa-agonists U50488, U69593 and tifluadom, in the mouse. However, RX8008M produced small shifts in the dose-response curves to these agonists in the guinea-pig, which seems more likely to reflect mu-receptor activity of the agonists in the guinea-pig than lack of selectivity of the antagonists. Both beta-FNA and RX8008M produced some antagonism of bremazocine, ethyl-ketocyclazocine, proxorphan and butorphanol, indicating that these agonists have a prominent mu-receptor component to their antinociceptive actions.

Topics: Abdomen; Animals; Guinea Pigs; Male; Mice; Morphinans; Muscle Contraction; Naltrexone; Narcotic Antagonists; Narcotics; Nociceptors; Pain

1. Activity of the mimetic muscles of the upper face were recorded from awake and anesthetized patients by surface electromyography (SEMG). 2. High amplitude SEMG accompanied ketamine anesthesia and/or the presentation of pain-provoking stimuli. 3. During periods of elevated facial muscle activity, fentanyl or butorphanol decreased SEMG amplitude. 4. The opioid-induced SEMG depression was not consistently associated with either lowered vigilance or analgesia but did provide an objective measure of drug effect.

Topics: Adult; Aged; Butorphanol; Electromyography; Evoked Potentials; Facial Muscles; Fentanyl; Humans; Middle Aged; Morphinans; Naloxone; Pain; Pain, Postoperative; Succinylcholine

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Female; Injections, Spinal; Macaca; Morphinans; Nalbuphine; Pain; Sensory Thresholds

Opioid antagonists selective for delta-, kappa- and mu-receptor subtypes were administered intrathecally in rats prior to determination of response thresholds to noxious heat, pressure and chemical visceral stimulation. All antagonists induced hyperalgesia differentially with two or more stimuli but delta- and mu-blockade failed to alter writhing activity. Thus, the extent of involvement of an opioid receptor subtype in antinociception depends on the type of noxious stimulation.

Topics: Analgesia; Animals; Benzomorphans; Enkephalin, Leucine; Hyperalgesia; Hyperesthesia; Injections, Spinal; Male; Morphinans; Naloxone; Narcotic Antagonists; Pain; Rats; Receptors, Opioid

Topics: Adult; Dreams; Humans; Male; Mental Disorders; Morphinans; Nalbuphine; Pain

Topics: Adult; Female; Heart Rate; Humans; Infant, Newborn; Male; Middle Aged; Morphinans; Morphine; Nalbuphine; Nausea; Pain; Postoperative Complications; Respiration

During a 2-year period, 150 patients were treated with epidural opioids for more than 7 days; 89 received morphine and 61 buprenorphine. In 16 cases, medication was changed from morphine to buprenorphine, and in 6 from buprenorphine to morphine. In 19 patients in each group, the disease process was benign. The median daily dose of morphine was 17 mg given by an average of 2.9 injections; the corresponding figures in the buprenorphine group were 1.3 mg and 2.6 injections. The mean duration of treatment was 49 days (7-397) in the morphine group and 53 days (7-262) in the buprenorphine group. Satisfactory pain relief was achieved in 40 (45%) patients who received morphine and 41 (67%) patients given buprenorphine. Altering medication from morphine to buprenorphine improved analgesia in 32% of patients, while the reverse improved pain relief in a further 46% of the patients. Side effects were reported in 46% of patients given morphine and 20% given buprenorphine. Seventy-one patients were treated on an outpatient basis. In these cases, buprenorphine was administered for 89% of the total duration of treatment and morphine chloride for 52%.

Topics: Buprenorphine; Chronic Disease; Epidural Space; Humans; Injections; Morphinans; Morphine; Pain; Retrospective Studies

The potent opioid peptide beta-endorphin is found in the brain and pituitary with two related fragments, beta-endorphin-(1-27) and beta-endorphin-(1-26). The fragments retain substantial opioid-receptor binding activity but are virtually inactive analgesically. beta-Endorphin-(1-27) inhibits beta-endorphin-induced and etorphine-induced analgesia when coinjected intracerebroventricularly into mice. Antagonism by competition at the same site(s) is suggested from parallel shifts of the dose-response curves of etorphine or beta-endorphin in the presence of beta-endorphin-(1-27). Its potency is 4-5 times greater than that of the opiate antagonist naloxone. beta-Endorphin-(1-26) does not antagonize the antinociceptive action of etorphine or beta-endorphin in doses up to 500 pmol per animal.

Topics: Animals; beta-Endorphin; Binding, Competitive; Dose-Response Relationship, Drug; Endorphins; Etorphine; Male; Mice; Morphinans; Naloxone; Pain; Peptide Fragments; Receptors, Opioid

A technique for the management of pain and anxiety during pacemaker implantation, electrophysiologic studies, and related procedures is described. The technique involves the intravenous administration of small amounts of the narcotic agonist-antagonist nalbuphine and the benzodiazepine diazepam. The small amounts of medication used induce relaxation while allowing the patient to interact and cooperate during the procedure. The absence of side effects facilitates outpatient treatment. This method of pain management not only improves the quality of patient care but also encourages earlier hospital discharge.

Topics: Adult; Aged; Anesthesia, Inhalation; Anesthesia, Local; Diazepam; Electrophysiology; Female; Humans; Infusions, Parenteral; Lidocaine; Male; Morphinans; Nalbuphine; Pacemaker, Artificial; Pain; Procaine

Topics: Buprenorphine; Humans; Morphinans; Pain; Terminal Care

Buprenorphine was administered as sublingual tablets to 70 patients suffering from chronic pain of malignant or non-malignant origin. Daily doses ranging from 0.4 mg to 3.2 mg were administered and good analgesia was reported by the majority of patients. The most common unwanted effects were drowsiness/sleepiness, nausea and/or vomiting and sweating which appeared to be dose related but the incidence of dizziness was not related to daily dose. The incidence of all these unwanted effects except drowsiness/sleepiness decreased after the first week's treatment. No buprenorphine related changes in vital signs or laboratory values were observed and no signs of tolerance or physical dependence were seen in the short term period after discontinuation of treatment. A significant positive correlation between buprenorphine plasma concentration and daily dose was observed but there was no correlation between plasma levels and pain relief.

Topics: Administration, Oral; Adult; Aged; Buprenorphine; Chronic Disease; Evaluation Studies as Topic; Female; Humans; Kinetics; Male; Middle Aged; Morphinans; Pain

Xorphanol is a new mixed agonist-antagonist from the morphinan class of analgesics. On the basis of animal experiments, the physical dependence liability of xorphanol is predicted to be of a low order in man. Conceptually, xorphanol is of interest since in vitro experiments have revealed anti-naloxone properties and resistance to antagonism by opioid antagonists. At the practical level, xorphanol is a well tolerated, orally active analgesic that provides effective pain relief clinically.

Topics: Animals; Chemical Phenomena; Chemistry; Humans; Male; Mice; Mice, Inbred Strains; Morphinans; Morphine; Pain; Rats; Rats, Inbred Strains; Substance-Related Disorders; Time Factors; Urination

The visceral analgesic, cardiorespiratory, and behavioral effects induced by xylazine, butorphanol, meperidine, and pentazocine were determined in 9 adult horses with colic. Colic was produced by inflating a balloon in the horses' cecum. Heart rate, respiratory rate, mean arterial blood pressure, and cardiac output increased after cecal balloon inflation. Xylazine and butorphanol decreased the hemodynamic response to cecal balloon inflation. Meperidine and pentazocine had minimal effects on the cardiorespiratory changes induced by cecal balloon inflation. Xylazine produced the most pronounced visceral analgesia. The duration of visceral analgesia was longest with xylazine (approx 90 minutes) followed by butorphanol (approx 60 min) and then by meperidine and pentazocine (approx 30 to 35 min). Accurate assessment of the effects of visceral analgesics is dependent upon the use of objective tests to evaluate pain.

Topics: Analgesia; Animals; Behavior, Animal; Butorphanol; Colic; Female; Heart; Horse Diseases; Horses; Male; Meperidine; Morphinans; Pain; Pentazocine; Respiration; Thiazines; Xylazine

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

Systemic (s.c.) administration of alpha 2 agonists clonidine (25-100 micrograms/kg) or guanfacine (50-400 micrograms/kg) elicited antinociception as assessed by the cat tail-flick model and potentiated in a dose-dependent manner the antinociceptive effect of etorphine (2.5 micrograms) administered directly into the periaqueductal gray. Conversely, systemic yohimbine (1 mg/kg) attenuated the effects of central etorphine, and diminished potentiation of etorphine by the alpha 2 agonists. Prior microinjection of clonidine (5 micrograms) or guanfacine (5 micrograms) into the locus coeruleus (LC) reduced the intensity of central etorphine antinociception whereas central yohimbine (20 micrograms) pretreatment increased peak antinociceptive activity and prolonged the duration of etorphine. Thus, systemic alpha 2 agonists are inherently antinociceptive and potentiate central narcotic antinociception; however, the site of interaction between alpha 2 agonists and opiates does not appear to be the LC inasmuch as alpha 2 agonists attenuate the antinociceptive effect of etorphine when administered directly into the LC. A spinal site of action is suggested based upon known LC-spinal projections and our experimental observations.

Topics: Adrenergic alpha-Agonists; Animals; Cats; Clonidine; Drug Interactions; Etorphine; Guanfacine; Guanidines; Kinetics; Male; Morphinans; Nociceptors; Pain; Phenylacetates; Yohimbine

Topics: Animals; Benzomorphans; Chemical Phenomena; Chemistry; Discrimination Learning; Haplorhini; Histamine H1 Antagonists; Mice; Morphinans; Pain; Papio; Rats; Substance-Related Disorders

The analgesic activity of the opiate agonists etorphine and sufentanil and the antagonistic effects of diprenorphine and naloxone have been related to the occupancy of 3 classes of opiate binding sites previously defined in vivo in order to establish their pharmacological significance. Sufentanil binds specifically in vivo to the first type of site (site 1), exhibiting approximately 1100-fold selectivity over site 2, whereas etorphine displays approximately 20-fold selectivity for site 1 over site 2. Neither agonist has a measurable affinity to the third type of binding site. The binding data suggest that site 1 is analogous to the mu site previously identified in vitro. Both agonists produce analgesia in the rat tail flick test at the same low fractional occupancy of site 1 (approximately 2% at the ED50) while they display much lower and quite different occupancies at site 2. Both of the opiate antagonists naloxone and diprenorphine reduce the potency of sufentanil and etorphine by a factor of 2 at 50% occupancy of site 1 alone. These results provide strong evidence that these 4 drugs exert their effects by interaction with site 1 (mu sites) which therefore may be regarded as the receptor responsible for analgesic action in this test. The assumption of a direct relationship between antagonistic effect and fractional occupancy appears to be valid for naloxone and diprenorphine at site 1, while the agonists exert their action at a very low fractional occupancy implying a non-linear binding-effect process.

Topics: Animals; Brain; Diprenorphine; Drug Interactions; Etorphine; Fentanyl; Morphinans; Naloxone; Pain; Rats; Receptors, Opioid; Sufentanil

Topics: Adult; Buprenorphine; Drug Tolerance; Epidural Space; Female; Humans; Injections; Morphinans; Pain; Spinal Neoplasms; Uterine Neoplasms

Platinum-oxide hydrogenation of 5-m-methoxyphenyl-2-methyl-9-oxomorphan (I) gave the 9 alpha-hydroxy racemate (II) whose phenolic analogue (III) is a strong antinociceptive agent, fully supportive of morphine dependence in rhesus monkeys. The di-O-acetyl derivative (VI) of III was similar to III in its profile of activity. The diastereoisomer of III (VII), obtained by hydrogenation of the methobromide of I (IV), extrusion of methyl bromide, and O-demethylation of the resultant free base (VIII), was almost inactive antinociceptively and did not suppress withdrawal symptoms in morphine-dependent monkeys. The orientation of the C-9 hydroxyl groups was deduced from spectral data and by analogy.

Topics: Analgesics; Animals; Benzoquinones; Chemical Phenomena; Chemistry; Humans; Macaca mulatta; Mice; Morphinans; Pain; Quinones; Reaction Time; Stereoisomerism; Substance Withdrawal Syndrome

One hundred twenty-one patients with postpartum pain caused by uterine cramp or episiotomy pain were the subjects of a randomized, double-blind, single-dose study of oral nalbuphine (N), 15 mg (N = 39); codeine (C), 60 mg (N = 42); and placebo (N = 40) for analgesia. Observations were made over 6 hr. There were significant differences for sum of pain intensity differences and total pain relief between the active drugs and placebo but not between N and C. Time to onset of analgesia favored N (mean = 0.65 min) over C (mean = 0.74 min), but the analgetic effect of N diminished more rapidly at this dose. Results were the same for both uterine cramp and episiotomy pain. Adverse effects were of the narcotic type and of the same incidence for the two active drugs. Two new parameters for determining analgetic effect are introduced: number of dropouts per dose and number of subjects with zero analgetic effect.

Topics: Administration, Oral; Adult; Codeine; Double-Blind Method; Drug Evaluation; Episiotomy; Female; Humans; Morphinans; Nalbuphine; Pain; Postpartum Period; Pregnancy; Random Allocation; Uterus

In barbiturate-anaesthetized cats, intravenous naloxone (0.025-0.10 mg/kg) increased the amplitude of monosynaptic reflexes produced by electrical stimulation of the nerves to the biceps-semitendinosus and gastrocnemius muscles and the complex reflexes to electrical stimulation of myelinated afferents of the sural and tibial nerves and reflexes to electrical stimulation of unmyelinated primary afferents of the tibial nerve. Increases in reflexes were also produced by the (-)- but not the (+)-isomer of the opiate antagonist N- furylmethylnormetazocine (both isomers being given in the dose range 0.03-0.20 mg/kg). The doses of naloxone increasing reflexes to C primary afferents had no effect on the responses of some dorsal horn neurones with cutaneous receptive fields to the same stimuli. The results suggest that, in anaesthetized cats, inhibition involving opioid peptides at some stage is present on many motoneurones. This inhibition may have relevance to animal behaviour after injury.

Topics: Animals; Benzomorphans; Cats; Endorphins; Morphinans; Motor Neurons; Naloxone; Neural Inhibition; Pain; Reflex; Reflex, Monosynaptic; Spinal Cord

This case-report of a 78-year old patient, suffering from extreme pain caused by metastatic formation and pathological bone fractures, shows, that the epidural injection of buprenorphine is a good alternative compared to other means of pain-treatment. During almost four days heart rate, blood pressure and breathing frequency, as well as the general reactions of the patient, were observed. Few side effects and little discomfort make the method advisable for patients in poor general condition.

Topics: Aged; Anesthesia, Epidural; Breast Neoplasms; Buprenorphine; Chronic Disease; Epidural Space; Female; Femoral Neck Fractures; Humans; Injections; Morphinans; Neoplasm Metastasis; Pain

Topics: Adult; Buprenorphine; Humans; Male; Middle Aged; Morphinans; Pain; Substance-Related Disorders

The agonist and antagonist properties of bremazocine, ethylketazocine, Mr 2034 and Mr 2092, benzomorphans with the same pharmacological actions in vitro, were studied in vivo in rats. Overnight fasted animals were tested for nociceptive reaction on a 55 degrees C hot-plate and for the intestinal transit of a charcoal meal fed 5 min earlier. The antagonist activity was assessed by the drugs' ability to prevent morphine-induced constipation. Bremazocine was an agonist on the nociceptive reaction and a pure antagonist on intestinal propulsion; ethylketazocine and Mr 2034 were pure agonists in both tests and Mr 2092 was a mixed agonist-antagonist in the intestinal transit test. Thus the in vivo agonist-antagonist properties of opiates cannot always be predicted from their in vitro characteristics.

Topics: Analgesia; Animals; Benzomorphans; Constipation; Dose-Response Relationship, Drug; Gastrointestinal Motility; Male; Morphinans; Morphine; Pain; Rats; Structure-Activity Relationship

Topics: Adult; Analgesics; Anesthesia, Epidural; Anesthesia, Local; Butorphanol; Female; Humans; Intraoperative Complications; Morphinans; Pain; Pain, Postoperative; Pregnancy; Sterilization, Tubal

One hundred forty-two rats given intracerebral microinjections of 1 microgram of etorphine hydrochloride were observed for subsequent analgesia (flinch-jump technique) and catatonia (bar test). Neuroanatomical specificity of effect was demonstrated to the extent that behavioral effects did not result from injections into areas of low opiate receptor binding affinity, such as medial cerebral cortex and hippocampus, nor were positive results obtained from injections into fiber bundles, such as the corpus callosum and internal capsule. Positive results were obtained in a large number of areas, ranging from brain stem to telencephalon. Injections eliciting analgesia without catatonia were limited in number (9 animals) and were widely scattered throughout neuroanatomical loci. Microinjection more frequently elicited catatonia only (29 animals), and site of injection was limited to posterior cerebral cortex, posterior amygdala, dorsal reticular formation, and cerebral aqueduct. Dual behavioral effects were elicited in 28 of the animals and occurred most frequently upon injection into the periaqueductal gray, inferior colliculus, and cerebral aqueduct. (Injection into cerebral aqueduct produced 50% catatonia only and 50% dual effects). The study suggests that opiate-elicited analgesia and catatonia may be neuroanatomically distinct phenomena.

Topics: Animals; Brain; Brain Mapping; Catatonia; Etorphine; Female; Humans; Male; Morphinans; Pain; Rats; Rats, Inbred Strains

Topics: Buprenorphine; Humans; Morphinans; Pain; Palliative Care

To compare the respiratory depressant and analgesic effects of nalbuphine and morphine, six healthy male subjects were given the drugs as single 0.15-mg/kg doses, and as four successive doses of 0.15 mg/kg. Respiratory depression was monitored by ventilatory and mouth occlusion pressure responses during CO2 rebreathing, while analgesia to experimental pain was tested with the submaximal effort tourniquet ischemia test. When given as single 0.15 mg/kg doses, both drugs significantly increases the threshold and tolerance for experimental pain. The analgesic effect was similar for both drugs at this dosage, as was depression of the ventilatory and occlusion pressure responses to CO2. Morphine administered in multiple doses progressively increased pain tolerance from 30 +/- 13% above control with the first dose of 0.15 mg/kg to 107 +/- 13% above control after the fourth dose (cumulative total 0.60 mg/kg). Nalbuphine produced a 40 +/- 12% increase in pain tolerance with an initial dose of 0.15 mg/kg, but additional increments of nalbuphine did not result in significantly greater analgesia. The increasing morphine dosage was associated with progressive rightward displacements and ultimately decreases in the slope of the CO2 response curves. Nalbuphine produced an initial rightward displacement of the CO2 response curves similar to morphine, but continued administration of the drug did not result in further displacement or changes in slope. These findings demonstrate that nalbuphine, in contrast to morphine, exhibits a ceiling effect for respiratory depression which is paralleled by its limited analgesic effect on experimental pain.

Topics: Adult; Analgesics; Carbon Dioxide; Dose-Response Relationship, Drug; Humans; Male; Morphinans; Morphine; Nalbuphine; Pain; Respiration; Sensory Thresholds; Spirometry

Topics: Buprenorphine; Humans; Morphinans; Pain; Pentazocine

The action of the benzomorphan narcotic antagonists Mr-1452 and Mr-2266 and their respective (+) isomers Mr-1453 and Mr-2267 as well as the antimuscarinic agent atropine upon oxotremorine (OTMN)-induced analgesia, tremor, and hypothermia were investigated in mice. The (+) isomers Mr-1453 (1.0 mg kg-1 i.p.) and Mr-2267 (2.0 mg kg-1 i.p.), but not the (-) isomers (Mr-1452 and Mr-2266) in doses up to 2.0 mg kg-1 i.p. after 30 min pretreatment produced a significant and parallel shift in OTMN's analgesic dose-response line, assessed by the hot plate test (55 degrees C). None of the isomers tested produced any significant change in OTMN induced tremor or hypothermia. This contrasted with atropine (0.5 mg kg-1 i.p.) which antagonized all three pharmacological parameters. The present data indicate that OTMN-induced analgesia in mice may involve a neuronal substrate which, at least partly, differs from those subserving tremor and hypothermia. In addition it supports the notion that cholinergic analgesia exhibits stereospecific sensitivity to the (+) isomers of narcotic antagonists.

Topics: Animals; Atropine; Benzomorphans; Body Temperature; Drug Interactions; Male; Mice; Morphinans; Narcotic Antagonists; Nociceptors; Oxotremorine; Pain; Stereoisomerism; Time Factors; Tremor

Topics: Administration, Oral; Blood Gas Analysis; Buprenorphine; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Morphinans; Mouth Floor; Pain; Time Factors

Topics: Buprenorphine; Endorphins; Humans; Morphinans; Pain; Pentazocine

This open study evaluated the safety, tolerance and efficacy of multiple oral doses of butorphanol tartrate as long-term therapy for moderate to severe pain of various aetiologies. Twenty patients were given doses ranging from four to twelve 4 mg tablets per day for a period of 3 to 201 days (median 87 days). Median pain relief over the entire study was rated as good, very good or excellent in eleven patients (55%) and poor to fair in the remaining nine patients (45%). Global assessments were as follows: good to very good--twelve patients; poor to fair--eight patients. Ten of the twenty patients treated reported side-effects (sedation, light-headedness, dizziness, insomnia and headache) ranging from mild to severe. No drug-related abnormalities with respect to blood pressure, body-weight or laboratory data were evident.

Topics: Administration, Oral; Adolescent; Adult; Aged; Butorphanol; Drug Evaluation; Female; Humans; Male; Middle Aged; Morphinans; Outpatients; Pain; Time Factors

Topics: Butorphanol; Humans; Morphinans; Pain

Topics: Analgesics; Butorphanol; Drug Evaluation; Female; Humans; Legislation, Drug; Methods; Morphinans; Nalbuphine; Pain; Pregnancy; United States

Topics: Buprenorphine; Humans; Injections; Morphinans; Pain; Pain, Postoperative

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: Humans; Morphinans; Nalbuphine; Pain

Topics: Butorphanol; Humans; Injections, Intramuscular; Injections, Intravenous; Morphinans; Pain; Pain, Postoperative

Topics: Analgesics; Animals; Apomorphine; Behavior, Animal; Body Weight; Chlorpromazine; Dronabinol; Humans; Mice; Morphinans; Morphine; Pain; Pentobarbital; Rats; Substance Withdrawal Syndrome; Thyrotropin-Releasing Hormone

The narcotic antagonists naltrexone (1a) and naloxone (2a) were stereospecifically reduced to the corresponding 6beta-hydroxy epimers 1b and 2b, respectively, with formamidinesulfinic acid in an aqueous alkaline medium. The reaction products were obtained with no detectable quantity of the 6alpha epimers 1c and 2c. The products 1b and 2b were formed in yields of 88.5 and 40%, respectively, and characterized by spectral methods. Compared to 1a and 2a, the stereospecific reduction products 1b and 2b and their 6alpha epimers 1c and 2c are all significantly less potent as narcotic antagonists in mice. Only 1c and 2c also possess antinociceptive activity.

Topics: Animals; Cyclopropanes; Mice; Morphinans; Naloxone; Narcotic Antagonists; Pain; Quinones; Reaction Time; Stereoisomerism

The eight optically active stereoisomers and the corresponding four racemic forms of 5,9-dimethyl-2'-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphan (1) have been prepared. Depending on their configurations these compounds are potent analgesics or inactive substances in mice. The analgesics attain potencies up to about a hundred times that of morphine but they do not show morphine-like side effects in mice nor do they suppress abstinence in withdrawn morphine dependent monkeys. Their therapeutic ratios are favorable and, in the case of la-1 and la-2, exceptionally good. Configuration-activity relationships are discussed. R configuration of the N-tetrahydrofurfuryl group is a major prerequisite for high analgesic potency.

Topics: Analgesia; Analgesics; Animals; Benzomorphans; Female; Hot Temperature; Lethal Dose 50; Male; Mice; Molecular Conformation; Morphinans; Optical Rotation; Pain; Reaction Time; Stereoisomerism; Structure-Activity Relationship

A new non-narcotic analgesic, 2-[3-(p-fluorobenzoyl)-n-propy]-5alpha,9alpha-dimethyl-2'-hydroxy-6,7-benzomorphan (ID-1229) has been prepared from 5alpha,9alpha-dimethyl-2'-hydroxy-6,7-benzomorphan. The analgesic activities of ID-1229 were several times more potent than those of pentazocine in the acetic acid writhing test in mice, bradykinin test in rats, Randall-Selitto's test in rats, and the electrical stimulation test in mice, while, ID-1229 showed little activity in both the tail pinch test and the hot plate test. ID-1229 did not show anti-narcotic activity in the morphine-combined test, and the Straub tail phenomenon was not observed in ID-1229. ID-1229 showed CNS activities in some tranquilizing tests, but did not show activity in several other CNS tests. The CNS potency is condiserably weaker as compared with haloperidol or diazepam, and the pattern of CNS activities in ID-1229 is quite different from those of both compounds. ID-1229 is a potent non-narcotic analgesic with tranquilizing activity, which is quite free from the undersirable side effects of morphine or morphine-like compounds including pentazocine.

Topics: Analgesics; Animals; Behavior, Animal; Benzomorphans; Female; Male; Mice; Morphinans; Motor Activity; Narcotic Antagonists; Pain; Rabbits; Rats; Reaction Time

Topics: Blood Gas Analysis; Drug Combinations; Female; Fetus; Humans; Hydrogen-Ion Concentration; Infant, Newborn; Injections, Intramuscular; Labor, Obstetric; Male; Morphinans; Morphine Derivatives; Nalorphine; Nicotinic Acids; Pain; Pregnancy; Respiration

Topics: Analgesics; Codeine; Drug Prescriptions; Humans; Infusions, Parenteral; Meperidine; Morphinans; Morphine; Pain; Substance-Related Disorders; Time Factors

Topics: Analgesics; Anti-Bacterial Agents; Dental Care; Drug-Related Side Effects and Adverse Reactions; Humans; Infection Control; Infections; Morphinans; Pain

Topics: Acetaminophen; Acetanilides; Administration, Oral; Analgesics; Aspirin; Codeine; Dextropropoxyphene; Hemorrhage; Humans; Indomethacin; Morphinans; Pain; Phenacetin; Phenylbutazone; Substance-Related Disorders

Topics: Aminopyrine; Amobarbital; Analgesics; Animals; Aspirin; Blood; Cats; Codeine; Diazepam; Dogs; Drug Antagonism; Drug Synergism; Glutethimide; Guinea Pigs; Haplorhini; Methods; Mice; Morphinans; Morphine; Naphthalenes; Pain; Phenacetin; Pyrimidinones; Rabbits; Rats; Synaptic Transmission

Topics: Humans; Morphinans; Pain; Parasympatholytics; Pyrazoles; Spasm

Topics: American Medical Association; Female; Health Education; Heroin; Humans; Legislation, Drug; Methadone; Morphinans; Morphine; Morphine Dependence; Pain; Personality; Pregnancy; Pregnancy Complications; Socioeconomic Factors; Substance Withdrawal Syndrome; United States

Topics: Adrenal Cortex Hormones; Age Factors; Aniline Compounds; Animals; Animals, Newborn; Body Temperature; Brain Chemistry; Breeding; Crowding; Environment; Female; Hexobarbital; Male; Mice; Microsomes, Liver; Mixed Function Oxygenases; Morphinans; Oxidoreductases; Pain; Pharmacogenetics; Receptors, Drug; Sex Factors; Sleep; Species Specificity; Time Factors

Topics: Alkaloids; Analgesia; Biological Assay; Mice; Morphinans; Pain; Pharmacology; Promethazine; Research; Toxicology

Topics: Analgesia; Analgesics; Animals; Animals, Newborn; Dogs; Morphinans; Pain

Topics: Analgesics; Morphinans; Morphine; Morphine Derivatives; Pain; Pain, Postoperative