Narcotic Antagonist Analgesics Research Articles

Comparative study of haemodynamic responses of butorphanol and fentanyl while surgeries

Background: In spite of several new airway devices emerging in recent times, direct laryngoscopy and endotracheal intubation still reigns as the gold standard in airway management, Butorphanol is a morphinan chemically related to levorphanol and has mixed agonist-antagonist properties. It is more potent and it has advantage of producing less addiction and respiratory depression. Fentanyl is µ, receptor agonist, structurally related to phenylpiperidines having clinical potency ratio 50 – 100 times of morphine. It is more potent. Butorphanol tartarate is a totally synthetic narcotic antagonist analgesic, which does not require opium alkaloids for its synthesis. Aim and objectives: Comparing the haemodynamic parameters (pulse, SBP, DBP, MAP, SpO2) during general anaesthesia in patients receiving butorphanol and fentanyl. Material and Methods: This is a double-blind randomised study comparing the two opioids, fentanyl and butorphanol, was carried out in Muzaffarnagar Medical College & Hospital, Muzaffarnagar, Uttar Pradesh, India. In our study 62 cases were divided randomly into two groups. Group A patients received inj .butorphanol tartarate and Group B patients received inj fentanyl citrate. The complete data was recorded by a single observer regarding haemodynamic parameters (systolic blood pressure, diastolic blood pressure, heart rate etc.) intraoperatively as well as postoperatively.

Analgesic and other pharmacological activities of a new narcotic antagonist analgesic (-)-1-(3-methyl-2-butenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine and its enantiomorph in experimental animals

Of 1-chclohexyl-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine (I) and its 1-(3-methyl-2-butenyl) derivative (II), the S(+)-isomers were analgesically more active than either their +(-)-isomers or their racemates, having 15 to 44 times the potency of morphine in mice and rats. R(-)-I had comparable analgesic activity to morphine R(-)-II to pentazocine in mice, rats and dogs and they were nearly equipotent with pentazocine in reversing some actions of morphine. The S(+)-isomers and racemates lacked this action. R(-)-II required about 10 times more naloxone to reverse its analgesic activity than was needed to antagonise the S(+)-isomers, morphine and pentazocine. The S(+)-isomers and racemates produce a typical Straub tail reaction and increased spontaneous locomotor activity in mice, but the R(-)-isomers did not. R(-)-II had no significant physical dependence liability in mice, rats and monkeys. From these results, it is suggested that the compounds show an uncommon steroselectivity in comparison with morphine and its surrogates, and that R(-)-II is worth investigating further as a narcotic antagonist analgesic.

Morphine-receptor dissociation constant and the stimulus-effect relation for inhibition of gastrointestinal transit in the rat

The dissociation constant (K A) of morphine for its receptor was determined by the method of partial irreversible blockade of the receptor population using inhibition of gastrointestinal transit of a forced charcoal meal as the pharmacological endpoint. The anti-motility effects of morphine was antagonized when rats were pretreated with buprenorphine (0.3 mg/kg s.c.), a narcotic antagonist analgesic, 30 min before morphine and the extent of gastrointestinal transit was estimated a further 45 min later. With this schedule of drug administration, the agonist action of buprenorphine is minimal and its antagonist action predominates. The value of K A was (1.1±0.2)×10 −5 mol/kg, a value close to that previously reported (2.9×10 −5 mol/kg) by us with these compounds in the rat tail flick test. The value of [A 50] found here was 2.15×10 −6 mol/kg, approximately 1 5 of that of K A. Also, the stimulus-effect relation of the tissue, defined in Stephenson's theory, was plotted and found to be nonlinear. This result, when coupled with the inequality of K A and [A 50], argues against the application of classical drug-receptor theory to this system. The apparent agreement between K A values for anticiception and inhibition of gastrointestinal transit is interesting, but does not necessarily prove equivalent receptors mediating the two different effects.

Physical dependence liability of TR5379, a novel narcotic antagonist analgesic

AbstractTR5379 is a novel morphinan with potent antinociceptive activity in the mouse abdominal constriction procedure. It is a narcotic antagonist with a potency similar to that of butorphanol. In rats and monkeys, TR5379 does not appear to induce any physical dependence. Following a 6‐day chronic administration of TR5379 to rats, no indications of withdrawal were observed. TR5379 did not substitute for morphine in either the physically dependent rat or the physically dependent monkey. In the chronically morphinized rat, an acute dose of TR5379 caused the rapid onset of a marked withdrawal syndrome.

A simple, reliable method for predicting the physical dependence liability of narcotic antagonist analgesics in the rat

The rat intraperitoneal infusion procedure was used to chronically administer drugs for evaluation of the physical dependence liability of narcotic antagonist analgesics. Three methods were used to assess dependence liability: presence of withdrawal signs upon abrupt cessation of chronic infusion (primary dependence), attenuation of the withdrawal signs produced by cessation of chronic morphine infusion (morphine substitution), and production of withdrawal signs when chronically morphine-infused rats were administered the drugs (precipitated withdrawal). Butorphanol, nalbuphine and pentazocine all caused a mild withdrawal in the rat primary dependence model which agrees with the conclusions from experiments with monkey and man. None of these agents substituted for morphine in the rat and all three appeared to precipitate withdrawal. Two experimental drugs, Codorphone and TR5400, did not induce primary dependence in the rat, and in chronic-morphinized rats, they precipitated a withdrawal syndrome comparable to naloxone. Another experimental drug, TR5257, substituted for morphine. The correlation between these observations in the rat and previously published data from the monkey are excellent. It is proposed that the rat could be used as a reliable indicator of potential physical dependence liability for the narcotic antagonist analgesics.

P-70 - Analgesic activity of the new narcotic antagonist analgesics, R(-)-1-(3-methyl-2-butenyl or cyclohexyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine dihydrochloride, and their enantiomorphs in experimental animals

P-70 - Analgesic activity of the new narcotic antagonist analgesics, R(-)-1-(3-methyl-2-butenyl or cyclohexyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine dihydrochloride, and their enantiomorphs in experimental animals

Morphine training dose: A determinant of stimulus generalization to narcotic antagonists in the rat

Rats were trained to discriminate between saline and either 1.75 or 5.6 mg/kg of morphine in a two-choice discrete-trial avoidance paradigm. Both groups of rats generalized completely to higher doses of morphine as well as to profadol and pentazocine, analgesics with narcotic antagonist properties. The dose of each test drug required to elicit drug-appropriate responding was about one-half log-unit higher in the rats trained with 5.6 mg/kg of morphine than in the rats trained with 1.75 mg/kg. Rats trained with the lower dose of morphine also generalized completely to the narcotic antagonist nalbuphine and to the non-opioid drug d-amphetamine, and generalized partially to the narcotic antagonist cyclazocine. In contrast, rats trained with the higher dose of morphine showed only partial generalization to nalbuphine and virtually none to cyclazocine and d-amphetamine. The degree of stimulus generalization to the narcotic antagonists and to d-amphetamine in the two groups of rats corresponds well with the known similarities and differences between the syndromes of subjective effects engendered by these drugs and morphine in man. These results indicate that systematic variation of the morphine training dose can facilitate characterization of the discriminative stimulus properties of narcotic antagonist analgesics and enhance the value of drug discrimination procedures as a model for predicting the subjective effects of these drugs.

Sodium-induced alterations of opiate effects on the binding of 3H-dihydromorphine to mouse brain homogenates

Abstract The inhibitory potency of opiate agonists on the stereo-specific binding of 3H-dihydromorphine in mouse brain homogenates was not affected by the presence of sodium ions. That of pure antagonists was greatly enhanced by NaCl whereas the inhibitory effects of mixed agonist-antagonists were reduced by NaCl, indicating that sodium ions might affect the agonist component more than the antagonist component of narcotic-antagonist analgesics. The inhibitory potency of the opiates tested in our system agrees with their potency in reducing the stereospecific binding of 3H-naloxone to rat membranes, the contractions of co-axially stimulated guinea pig ileum and their analgesic potency in animals and humans.

AGONIST AND ANTAGONIST PROPERTIES OF BUPRENORPHINE, A NEW ANTINOCICEPTIVE AGENT

1. Buprenorphine is a highly lipophilic derivative of oripavine. In rodent antinociceptive assays (writhing, tail pressure), buprenorphine had an action which was rapid in onset and of long duration; it was 25-40 times more potent than morphine after parenteral injection and 7-10 times more potent after oral administration. 2. The log dose-response relationship for buprenorphine was curvilinear in mouse and rat tail flick tests with the antinociceptive effect decreasing at higher, non-toxic doses. 3. Tolerance developed to the antinociceptive activity of buprenorphine in mice. 4. No signs of abstinence were observed on naloxone challenge or after abrupt withdrawal in monkeys receiving buprenorphine chronically for one month. 5. Buprenorphine antagonized the antinociceptive actions of morphine in mouse and rat tail flick tests but was an ineffective antagonist in the rat tail pressure test. 6. Buprenorphine precipitated signs of abstinence in morphine-dependent mice and monkeys but not in morphine-dependent rats. 7. Buprenorphine produced Straub tails in mice. This effect was not antagonized when the animals were pretreated with naloxone. However, in the rat tail pressure test high doses of diprenorphine antagonized established antinociceptive effects of buprenorphine. 8. It is concluded that buprenorphine represents a definite advance in the search for a narcotic antagonist analgesic of low physical dependence potential.

The effects of narcotic analgesics and narcotic antagonists on ganglionic transmission in the rat

The effects of narcotic analgesics, narcotic-antagonist analgesics and narcotic antagonists on ganglionic transmission in the superior cervical ganglia of the rat were studied in vivo and in vitro . In vivo administration of morphine, meperidine, methadone, pentazocine or naltrexone blocked ganglionic transmission. Levorphanol, cyclazocine, nalorphine and naloxone had no effect on ganglionic transmission in this procedure. In vitro studies confirmed the in vivo results with the exception of levorphanol, cyclazocine and nalorphine, which were also found to block ganglionic transmission in vitro . In both preparations, naloxone did not antagonize the effect of morphine, suggesting that the effects of morphine and the other opiates were nonspecific. Similar potency of d - and l -isomers of pentazocine and cyclazocine support this conclusion. The observation that naltrexone blocked ganglionic transmission, but the other pure narcotic antagonist, naloxone, was inactive is somewhat unique to this test procedure and possibly significant.

Stereospecificity of intraventricularly administered acetylmethylcholine antinociception

We have previously reported that the intraventricular injection of acetylcholine increases latency in the mouse tail-flick test, the ED50 being 7.3 ug (1). This effect was reversed by five narcotic-antagonist analgesics in the same order of potency in which they antagonized morphine, and was found to be due to muscarinic receptor stimulation. It was also pointed out at that time that the intraventricular injection of acetylcholine would block the writhing response to intraperitoneally administered p-phenyl-quinone. In this preliminary communication, we present our results of the effect of the intraventricular injection of acetyl-choline on writhing induced by intraperitoneally administered acetylcholine. In addition, we present results of our studies in which we demonstrated stereospecificity of intravetricularly administered ministered acetylmethylcholines in causing antinociception.

Measurement of analgesia using a spatial preference test in the rat

Using a rectangular tilt cage, the aversive threshold to grid shock was defined as that intensity avoided 75% of the time. Each shock intensity (30, 60, 90, 120, and 150 μA) was presented for 10 min during the 50-min daily session. Various narcotic (codeine sulfate, meperidine hydrochloride) and narcotic antagonist (pentazocine, cyclazocine) analgesics, as well as a sedative hypnotic (sodium pentobarbital), were assayed using this procedure. Both the narcotic and narcotic antagonist analgesics reliably elevated the aversive threshold in a dose dependent manner. These results could not be accounted for in terms of drug induced sedation. Sodium pentobarbital, in agreement with the clinical literature, demonstrated poor analgesic properties and was able to reliably elevate the aversive threshold only in doses that severely hampered the execution of the escape response. This technique appears to be specifically sensitive to the analgesic properties of drugs. As such, it should be useful as a screening procedure in the development of new analgesics and for the investigation of possible mechanisms underlying drug addiction.

Narcotic and narcotic antagonist analgesics: Their effect on rat brain monoamine oxidase in vitro

Morphine, codeine, normorphine, norcodeine, nalorphine, methadone, pentazocine, cyclazocine, meperidine and levallorphan were tested in vitro for activity as inhibitors of rat brain monoamine oxidase. Beta-phenylisopropylhydrazine and chlorpromazine were used, respectively, as strong and weak inhibitors to define the upper and lower limits of inhibitory activity. All test compounds, with the exception of methadone, were found to be weaker monoamine oxidase inhibitors than chlorpromazine. The log dose-response curve for methadone stretches across four orders of magnitude in concentration and, at low molar concentrations, the monoamine oxidase inhibitory activity of methadone is equivalent to the monoamine oxidase inhibitory activity of betaphenylisopropylhydrazine at equally low concentrations.

Some agonistic actions of the morphone antagonist levallorphan on behavior and brain monoamines in the rat.

The effects of levallorphan, a narcotic-antagonist analgesic, were studied on locomotor activity, operant behavior (continuous avoidance schedule), and brain monoamine content in the rat. Levallorphan produced an increase in locomotor activity and in the rate of avoidance responding. Brain norepinephrine was significantly decreased 1 h after 256 mg/kg of levallorphan. Brain dopamine (DA) levels were lowered by 64 and 256 mg/kg of levallorphan. There was no effect on brain serotonin levels. The stimulant effects of levallorphan on operant behavior were blocked by simultaneous administration of naloxone. A clear antagonism of the effects of levallorphan on locomotor activity by naloxone could be demonstrated for low doses of levallorphan but not for doses above 16 mg/kg. Naloxone also failed to prevent the depletion of brain catecholamines produced by levallorphan. Naloxone alone had no consistent effect on either of the behaviors under observation or on brain monoamine content. These findings indicate that levallorphan is a stimulant of behavior in the rat, and that the stimulant action is mediated by at least two mechanisms: one which is blocked by naloxone, and one which is not. Furthermore, it is suggested that the rat should be considered as a possible animal model in which to study the agonistic properties of certain narcotic-antagonist analgesics on behavior.

Actions of morphine and narcotic antagonist analgesics on the spinal cord of acute and chronic spinal rats.

The present study shows that morphine and narcotic antagonist analgesics depress the electromyographic (EMG) response of tail muscles to a noxious stimulus in chronic spinal rats, whereas no significant action can he detected in route spinal rats.

Actions of Morphine and Narcotic Antagonist Analgesics on the Spinal Cord of Acute and Chronic Spinal Rats

The present study shows that morphine and narcotic antagonist analgesics depress the electromyographic (EMG) response of tail muscles to a noxious stimulus in chronic spinal rats, whereas no significant action can he detected in route spinal rats.

Studies on the receptors involved in the action of the various agents in the phenylbenzoquinone analgesic assay in mice

1. Tolerance to the activity of several narcotic analgesics (morphine, levorphanol, and methadone) and several narcotic-antagonist analgesics (pentazocine, cyclazocine, and nalorphine) was studied in the mouse phenylbenzoquinone stretching test. Virtually complete tolerance was induced by chronic treatment with each of the narcotic agents, while no apparent tolerance was induced by the narcotic antagonists.2. In morphine-tolerant mice there was a high degree of cross-tolerance to the effects of not only the other narcotic drugs but also to those of the narcotic antagonists, acetylsalicylic acid, and physostigmine.3. The effects of morphine and pentazocine were antagonized by naloxone but not by atropine, while the effects of physostigmine were antagonized by atropine but not by naloxone. Neither atropine nor naloxone antagonized the effect of acetylsalicylic acid.4. The results of the tolerance study suggest that there is a fundamental difference in the consequences of receptor interaction for the narcotic and the narcotic-antagonist analgesics. Morphine-tolerant mice exhibit cross-tolerance non-specifically. The selectivity of naloxone and atropine differentiates the narcotic and narcotic-analgesics from the other two agents used in this analgesic test.

Quantitative studies on the antagonism by naloxone of some narcotic and narcotic-antagonist analgesics.

1. Naloxone was used to study the antagonism of the analgesic effects of some narcotics (morphine sulphate, levorphanol tartrate, and methadone hydrochloride) and narcotic antagonists (pentazocine, cyclazocine, and nalorphine hydrochloride). The analgesic assay used was the mouse phenylbenzoquinone stretching test.2. The in vivo equivalent of a pA(2) value (apparent pA(2)) for naloxone was determined with each agonist. These values were found to be significantly larger with the narcotics than with the narcotic antagonists.3. The slopes in the apparent pA(2) plots were also found to be significantly different. It was concluded that this difference in slopes was probably not due to a lack of equilibrium in one of the two groups of analgesics.4. The results suggest that the narcotic and the narcotic-antagonist analgesics may inhibit stretching in this assay by interacting either with two different receptors or with the same receptor in a different manner.

Drug action on tail shock-induced vocalization in mice and its relevance to analgesia

Analgesia and related drugs were tested on both intact and neurally transected mice for inhibition of vocalization induced by repetitive tail shocks (mouse tail shock test: MTST). In intact mice, major narcotic and phenothiazine analgesics, e.g. morphine, methadone and methotrimeprazine, produced a marked dose-dependent inhibition; much higher doses of codeine and non-analgesic tranquilizers, e.g. chlorpromazine and hydroxyzine, were required to produce comparable effects. Narcotic-antagonist analgesics (nalorphine, cyclazocine, pentazocine) and the non-narcotic, non-analgesic, dextromethorphan, showed an early ceiling of the effect. Levallorphan, a non-analgesic narcotic antagonist, was inactive. Decortication and neutral transections, from the frontal pole to the pons, did not affect vocalization or the effect of drugs upon vocalization except for the strong narcotics whose potencies were reduced to about 1 4 following transections caudal to the anterior commissure. It was concludedv that: (1) drug effectiveness in the MTST does not consistently parallel clinical analgesic efficacy; (2) vocalization in the MTST is integrated at low brain stem levels, its inhibition by drugs not necessarily requiring participation of higher neural levels. The relevance of the MTST to pain and analgesia is thus rendered questionable.

Counteraction of narcotic antagonist analgesics by the narcotic antagonist Naloxone.

SummaryWhen the potent narcotic antagonist, naloxone, was injected subcutane-ously into mice and rats simultaneously with narcotic antagonist analgesics, naloxone counteracted the writhing test analgesic activity of the antagonists. Naloxone completely antagonized the potent analgesic activity of pentazocine, nalorphine, cyclazocine, and cy-clorphan, and also antagonized the weak analgesic activity of levallorphan.