piperidines and picenadol

1. The analgesic efficacy and safety of a single 50 mg intramuscular dose of rac-picenadol, a centrally acting agonist-antagonist opioid analgesic, were compared with pethidine (meperidine) 100 mg and placebo in 60 patients with moderate to severe postoperative pain using hourly pain intensity and relief measurements for up to 6 h following injection of the study medications. 2. Both picenadol and pethidine were statistically significantly (P < 0.05) more effective than placebo in reducing pain intensity and in increasing total relief. Patients receiving picenadol and pethidine had higher frequency of somnolence than patients receiving placebo. In addition, patients receiving picenadol 50 mg experienced a higher incidence of confusion (30%), speech disorders (30%), and tremors (25%) than the patients receiving either pethidine or placebo. 3. These results were compared with those of a similar study which investigated the effects of a 25 mg intramuscular dose of picenadol vs pethidine and placebo. This comparison suggests that 25 mg of picenadol is a more acceptable dosage since both 25 and 50 mg were effective dosages.

Topics: Adult; Analgesics; Female; Humans; Injections, Intramuscular; Male; Pain Measurement; Pain, Postoperative; Piperidines

A double-blind, parallel study was conducted to evaluate the analgesic effect and safety of a single 25 mg oral dose of picenadol, a centrally acting analgesic, and to compare it with a 60 mg dose of codeine and a placebo in patients with postoperative pain. Two sites using similar protocols enrolled a total of 178 inpatients with postoperative pain. Pain intensity, relief, and adverse experiences were then measured for up to 6 hours after administration of the test medications. Both picenadol and codeine were significantly more effective than placebo in reducing pain intensity (mean sum of pain intensity difference scores: picenadol 5.21, codeine 5.19, and placebo 2.82) and increasing total relief (mean total pain relief: picenadol 10.21, codeine 11.07, and placebo 6.96). Adverse experience profiles were similar among the three treatment groups.

Topics: Adult; Analgesics; Clinical Trials as Topic; Codeine; Female; Humans; Male; Middle Aged; Pain, Postoperative; Piperidines

Picenadol (LY 150720) is a racemic mixture of an N-methyl-4-phenylpiperidine derivative, with agonist-antagonist opiate properties. Preclinical animal pharmacology and toxicology studies demonstrated analgesic activity and a low order of toxicity. Clinical pharmacology studies have demonstrated its safety in man. Hospitalized post-cesarean section patients with postoperative pain were blindly given an intramuscular dose of picenadol, 25 mg, meperidine, 100 mg, or placebo. Analgesia and side effects of picenadol and meperidine were similar.

Topics: Adolescent; Adult; Analgesics; Cesarean Section; Double-Blind Method; Drug Evaluation; Female; Humans; Meperidine; Pain, Postoperative; Piperidines; Placebos; Pregnancy; Random Allocation

The absolute configurations of the enantiomers of the opioid picenadol [cis-1,3-dimethyl-4-propyl-4-(3-hydroxyphenyl)piperidine; cis-3-methyl, 4-propyl] have been determined by an X-ray crystallographic study of the chloride salt of the (+)-enantiomer. The agonist (+)-enantiomer and the antagonist (-)-enantiomer were found to have the 3R,4R and 3S,4S absolute configurations, respectively. The conformational properties of the enantiomers were also examined with MM2-87 calculations. There was good agreement between the computed global minimum and the crystallographic structure with the phenyl ring approximately bisecting the piperidine ring by both methods. This orientation of the phenyl ring differs from that of related opioids such as the phenylmorphans, prodines, meperidine, and ketobemidone in which the phenyl ring tends to eclipse one edge of the piperidine ring. Because the phenyl ring bisects the piperidine ring in picenadol, there is little difference in the three-dimensional orientations of the phenyl rings of the two enantiomers when one superimposes the piperidine rings. The agonist (+)-enantiomer is ambiguous with respect to an opioid ligand model, which suggests that agonist activity requires a specific range of dihedral angles for the phenyl ring. While the global minimum of the agonist is not consistent with the model, a second conformer that is only 1.2 kcal/mol above the global minimum is consistent. An alternative explanation is that agonist or antagonist activity is solely due to the presence of the 3-methyl group on the different edges of the piperidine ring.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analgesics; Crystallography, X-Ray; Molecular Conformation; Narcotic Antagonists; Piperidines; Receptors, Opioid; Stereoisomerism

Topics: Adult; Dose-Response Relationship, Drug; Humans; Male; Morphine Dependence; Narcotic Antagonists; Piperidines; Substance-Related Disorders

Picenadol is a unique opioid mixed agonist-antagonist analgesic currently under clinical evaluation. Structurally, picenadol is a 4-phenylpiperidine derivative and a racemic mixture whose mixed agonist-antagonist properties are a consequence of the d-isomer being a potent opiate agonist, whereas the l-isomer is an opioid antagonist. In the mouse writhing and rat tail heat tests, the analgesic potency of picenadol is estimated to be 1/3 that of morphine. Picenadol itself has weak antagonist activity, whereas the antagonist potency of the l-isomer is approx. 1/10 that of nalorphine. Evaluation of picenadol's affinity for opioid receptors reveals that picenadol, unlike other mixed agonist-antagonists has high affinity for both the mu and delta receptors but a markedly lower affinity for the kappa receptor. Extensive pharmacological investigations show picenadol to have a low potential to produce opiate-like side effects, including a low liability for abuse and physical dependence.

Topics: Animals; Chemical Phenomena; Chemistry; Columbidae; Dogs; Drug Tolerance; Female; Guinea Pigs; Male; Mice; Morphine; Motor Activity; Naloxone; Pain; Piperidines; Rats; Rats, Inbred Strains; Receptors, Muscarinic; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine

The mixed-action opioid picenadol (LY150720) is a racemic mixture whose resolution results in a stereoselective separation of agonist and antagonist activity. The effects of picenadol, its dextrorotatory isomer (LY136596) and morphine were studied alone and in combination with naloxone in squirrel monkeys responding under a schedule of electric shock titration. Shock intensity was scheduled to increase at 15-sec intervals in 30 steps from 0 to 5.5 mA. Completion of a fixed ratio 5-response requirement terminated the shock for a 15-sec time-out period after which shock resumed at the next lower intensity. Picenadol (0.1-17.5 mg/kg), the d-isomer (0.3-3.0 mg/kg) and morphine (0.3-5.6 mg/kg) produced dose-related increases in the intensity at which monkeys maintained the shock without decreasing responding in the presence of shock. Shock intensity increases produced by picenadol occurred over a broader dose range than with either the d-isomer or morphine. Increases in shock intensity produced by picenadol, the d-isomer and morphine were blocked by naloxone (0.001-1.0 mg/kg), although the effects of picenadol were less susceptible to antagonism. The effects of the levorotatory isomer of picenadol (LY136595) were also examined alone and in combination with morphine. The l-isomer (0.1-10.0 mg/kg) did not alter shock intensity when administered alone; however, in combination with morphine it produced a dose-dependent antagonism of the effects of morphine. The l-isomer was less potent than naloxone in this respect. These data support previous suggestions that the antinociceptive properties of picenadol arise from mu agonist actions of the dextrorotatory isomer and that the levorotatory isomer acts to limit the efficacy of the racemate.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Electroshock; Male; Morphine; Naloxone; Narcotic Antagonists; Piperidines; Saimiri; Stereoisomerism

The mixed agonist-antagonist analgesics buprenorphine, butorphanol, nalbuphine, pentazocine and picenadol were compared to the prototype mu and kappa agonists morphine and Mr 2033, respectively, in the following tests in rhesus monkeys: overt behavioral effects upon acute administration in drug-naive animals; discriminative stimulus properties in monkeys trained to respond to either etorphine or ethylketazocine; self-administration of the test agent relative to codeine; single dose suppression and precipitation in withdrawn and non-withdrawn morphine-dependent monkeys, respectively; and primary addiction studies in drug-naive animals. Whereas both buprenorphine and nalbuphine precipitate withdrawal in morphine-dependent monkeys, withdrawal following chronic administration of buprenorphine resulted in no observable signs of abstinence, while nalbuphine withdrawal was similar to that seen in morphine-dependent monkeys. Butorphanol, pentazocine and picenadol all produced mild dependence of the kappa-type; that is, natural withdrawal behavior similar to that seen following chronic Mr 2033 administration.

Topics: Animals; Behavior, Animal; Benzomorphans; Buprenorphine; Butorphanol; Codeine; Discrimination, Psychological; Humans; Macaca mulatta; Morphinans; Morphine; Morphine Dependence; Nalbuphine; Narcotic Antagonists; Pentazocine; Piperidines; Substance Withdrawal Syndrome

The opioid LY150720 is a racemic mixture whose resolution results in a highly stereospecific separation of agonist and antagonist activity. The effects of LY150720 (0.3-3.0 mg/kg), its agonist (dextro) isomer LY136596 (0.3-1.7 mg/kg) and morphine (0.03-1.0 mg/kg) were studied alone and in combination with naloxone (0.001-1.0 mg/kg) in squirrel monkeys whose responding was maintained under a multiple fixed-ratio 30-response fixed-interval 5-minute (mult FR-30 FI 5-min) schedule of food presentation. LY150720, LY136596 and morphine generally decreased responding under both schedule components, although in several instances increases in responding under the FI component were noted, particularly following LY150720 and LY136596. Naloxone (0.1-3.0 mg/kg) generally had little effect on responding, whereas the antagonist (levo) isomer LY136595 (0.3-10.0 mg/kg) decreased responding under both schedule components. The rate-decreasing effects of morphine, LY150720 and LY136596 were reversed by naloxone; doses of naloxone required to reverse the effects of all three drugs were comparable. When combined with morphine, naloxone restored rates and patterns of responding to control values, whereas combinations of LY150720 or LY136596 and naloxone increased responding under the FI component in excess of control values. These increases appear to be due to anticholinergic actions of LY150720 and LY136596, as they are reversed by physostigmine (0.01 mg/kg) and similar increases are produced by scopolamine (0.01-0.1 mg/kg).

Topics: Analgesics; Animals; Conditioning, Operant; Male; Naloxone; Physostigmine; Piperidines; Reinforcement Schedule; Saimiri; Scopolamine

The opioid mixed agonist-antagonist picenadol (LY150720) is a racemate whose resolution results in a highly stereospecific separation of opioid agonist and antagonist activity. Attenuation of the antinociceptive effects of the agonist (dextro) isomer LY136596 by the antagonist (levo) isomer LY136595 was evaluated quantitatively in squirrel monkeys responding under a schedule of electric shock titration through the use of a dose-ratio analysis. LY136596 (0.3-3.0 mg/kg) produced a dose-related increase in the intensity at which monkeys maintained the shock. Increases in shock intensity produced by LY136596 were antagonized by LY136595 (0.1-10.0 mg/kg); dose-response curves for LY136596 were shifted to the right in a parallel manner by increasing doses of LY136595. An apparent pA2 (Schild) plot obtained from these data yielded a line with a slope of -0.60 +/- 0.05 and an apparent pA2 value of 5.67 +/- 0.07. These data support previous suggestions that the antinociceptive activity of picenadol (LY150720) resides in the d-isomer (LY136596) and that the l-isomer (LY136595) acts to limit the analgesic efficacy of the racemate.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Electroshock; Male; Narcotic Antagonists; Piperidines; Saimiri; Stereoisomerism

The effects of picenadol and its (+)- and (-)-isomers were determined on the responding of pigeons under a multiple fixed-ratio (FR) 50-response, fixed-interval (FI) 5-min schedule of grain presentation. Picenadol decreased responding in both schedule components as a function of dose (0.64-10 mg/kg). Naloxone shifted to the right the picenadol dose-effect curve in the FR component (2.8-fold), but had little effect on the dose-effect curve for FI responding. Similarly, the (+)-isomer decreased responding in both schedule components, but naloxone was only able to shift to the right the dose-effect curve for the (+)-isomer on FR responding (2-fold). The effects of the (+)-isomer on FI responding were not affected by naloxone. The (-)-isomer decreased responding at high doses (20 and 40 mg/kg) and this effect was not antagonized by naloxone. The dose-effect curves for the (-)-isomer were shifted markedly to the left in animals maintained on daily doses (30 or 60 mg/kg p.o.) of methadone. Low doses (2.5-20 mg/kg) of the (-)-isomer antagonized the behavioral suppressant effects of 5 mg/kg of l-methadone. The (+)-isomer, but not the (-)-isomer, antagonized the complete behavioral suppression produced by 0.05 mg/kg of oxotremorine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Behavior, Animal; Columbidae; Dose-Response Relationship, Drug; Isomerism; Male; Methadone; Naloxone; Narcotic Antagonists; Parasympatholytics; Piperidines; Structure-Activity Relationship

Topics: Analgesics; Animals; Mice; Narcotic Antagonists; Piperidines; Rats; Receptors, Opioid; Respiration; Stereoisomerism