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PubMed1985

[General pharmacologic studies on the analgesic flupirtine].

In the present study the general pharmacological properties of ethyl-N-[2-amino-6-(4-fluor-phenylmethylamino)pyridin-3-yl]carbama te (flupirtine, D 9998), a structural new analgesic, are described. In several tests with mice flupirtine shows a centrally depressant component of action. However, regarding undesirable side effects as ataxia, inhibition of motor activity etc. this action is, with respect to the analgesic effective doses less pronounced than those of comparable analgesics, for instance phenacetin. In relatively low doses flupirtine antagonizes tremor induced by oxotremorine in mice. This activity is probably not caused by a central anticholinergic action, because other anticholinergic effects have not been observed. It should be pointed out that flupirtine antagonizes the morphine-induced tail phenomenon in mice in relatively low doses. This action obviously differentiates flupirtine from opiates. Up to high doses flupirtine does not cause catalepsia in mice, consequently its centrally depressant activity does not resemble that of reserpine and also is not comparable with those of neuroleptic agents. The corneal and pinnal reflexes are not influenced by flupirtine and the righting reflex is slightly delayed in high doses. The anticonvulsive activity of flupirtine observed in the pentetrazol shock test (mouse) after high doses probably cannot be considered to occur within the analgesic dose range. Inhibition of amphetamine toxicity in mice observed in doses near the hypnotic doses may be caused by non-specific effects. In vitro tests with isolated trachea or ileum of guinea pigs show that flupirtine possesses no or very weak antagonism against histamine-induced spasms. In spasms caused by barium chloride flupirtine shows a weak musculotropic-spasmolytic activity. Investigations on the circulatory system of dogs do not indicate any incompatibilities with flupirtine. No evidence of antiarrhythmic activity was found in rats. Flupirtine has no local anesthetic activity in mice but some weak effects on the cornea of rabbits. Like several other analgesics flupirtine shows in rats a reversible antidiuretic action including sodium and chloride retention which is of relatively short duration and is not observed in long-term studies in rats and dogs. In contrast to many stronger antiinflammatory compounds, flupirtine does not possess ulcerogenic activity in rats up to high doses. A minimal inhibition of intestinal motility (mouse) is observed only in doses higher than the analgesic effective doses.

Aminopyridines↗
PubMed1973

[The analgesic effects of tetrazolo-(5,4-a)-6-methyluracil and tetrazolo(5,4-a)-6-propyluracil].

Tetrazolo-(5,4-a)-6-METHyl-uracil (compound VMI-502) and tetrazolo (5,4-a)-6-propyl-uracil (compound VMI-510) posses a marked sedative-hypnotic and analgesic action and a slightly expressed central skeletal muscles relaxant and anticonvulsant action. The analgesic (antinociceptive) action has been demonstrated by meens of 5 algesimetric methods. The compounds depress the pain reactions in case of stimulation of the superficial as well as of the deep nociceptors, too. Its analgesic action is about 3 times more intense then the action of codeine, about 20 times more intense then the action of amidopyrin and maetamizole, and about 2 times slighter then the action of morphine. The obtained results give the possibility of excluding the so called "false positive reaction". The studied compounds potentiate the analgesic action of the morphine and amidopyrine, applied in subanalgesic dose. It is assumed that by the mechanisme of his analgesic action the compounds VMI-502 and VMI-510 probably approach the non-narcotic analgesics.

Aminopyrine↗
PubMed1966

A double-blind comparison of two analgesics with placebo control.

The value of adding a sedative to commonly used analgesic agents to promote further the relief of pain was studied by a double-blind procedure in 90 post-surgical patients during 188 pain episodes. In moderate pain episodes, no statistically significant difference between the analgesic-sedative combination (Fiorinal-C(1/4)) and the analgesic (APC-C) was observed, although both compounds were superior to placebo (p <0.001). In severe pain episodes, the analgesic-sedative combination was superior to the analgesic alone; the analgesic, in turn, was superior to placebo (p <0.001).It is concluded that analgesia is more effective if associated apprehension is relieved by sedation.

Adolescent↗
PubMedDate not supplied

Brain and plasma levels of methadone and their relationships to analgesic activity of methadone in rats.

The levels of methadone in brain and plasma of rats after acute administration of several different doses of methadone were measured at several time points and relationships to analgesic activity were examined. Both brain and plasma levels of methadone as well as the analgesic activity of methadone, expressed as analgesic area and as percentage of maximum possible effect, were all increased by increasing dosage. All these measurements dropped rapidly after reaching the peak levels 30 min after administration of methadone. At the time of maximal analgesia, the analgesic effect of methadone was quantitatively related to both brain and plasma levels of methadone with 50% of the analgesic maximum possible effect corresponding to the concentrations of 1.44 nmol/g and 0.52 nmol/ml of methadone in brain and plasma, respectively. Our data suggest that measurement of changes in the plasma concentration of methadone at the time of maximal analgesia reflects changes in the brain concentration of methadone and may provide an index of changes in the analgesic effect of methadone.

Analgesics, Opioid↗
PubMed1981

Studies on synthesis and relationship between analgesic activity and receptor affinity for 3-methyl fentanyl derivatives.

In the present paper, the synthesis and analgesic activity (mice, i.p. hot plate test) of the derivatives of 3-methyl fentanyl are briefly described. Compound 7302, cis-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropionamide (cis: 3-methyl/4-N-phenylpropionamide) is found to be the most potent analgesic agent in this series synthesized by our laboratory (ED50 = 0.0022 mg/kg). The analgesic activity of 7302 is 28 times more potent than that of fentanyl and 6300 times more than that of morphine. The partition coefficients of 10 compounds in the series are determined by high performance liquid chromatography (HPLC) and their log p values are about 3. There are no regular relationships between the analgesic activity and partition coefficients. Study on the specific binding of 8 out of the above 10 compounds to crude synaptic plasma membrane (P2-fraction) of mouse brain demonstrates that there is an excellent statistical linear correlation (r = 0.998) between the analgesic potency and the specific binding affinity. The result shows that the analgesic potency of the derivatives of this series is mainly dependent on binding affinity for opiate receptor.

Analgesics↗
PubMed1984

[Inhalation provocation test with lysine acetylsalicylic acid (Aspisol)--a useful method for the diagnosis of analgesic asthma].

In patients with analgesics induced asthma (AIA) provocation tests by inhalation are less dangerous than oral provocation. Bianco et al. and Schmitz-Schumann et al. described an inhalation provocation test (IPT) with Lysine-acetylsalicylic-acid (Lys-ASA). We found analgesics induced asthma in 5 p.c. of our patients with bronchial asthma. The results of 41 IPT with Lys-ASA are reported. In 26 of 29 patients with analgesics intolerance in the history the test was positive after a threshold dose of 18,0 mg (9,3-53,3 mg) Lys-ASA. 3 patients believed to have analgesics intolerance. It could be excluded by negative IPT and following negative oral provocation. In a control group of 12 patients with intrinsic asthma, nasal polyps and sinusitis, but without analgesics intolerance in the history, the test was positive too in 2 patients. They didn't use analgesics in the past years. The diagnosis could be confirmed by oral provocation. In our opinion IPT with Lys-ASA is very useful to find an AIA or to exclude it. It is better controllable than oral provocation. The induced bronchospasm is good reversible by inhalation of beta-mimetics or injection of methylxanthines. Intraindividual variations of bronchial tolerance can be supposed. All patients with AIA tolerated oral provocation with salicyclamide.

Airway Resistance↗
PubMed1984

Comparative analysis of drug distribution costs for controlled versus noncontrolled oral analgesics.

Total costs for controlled substance oral analgesics and non-controlled analgesics were compared for patients at a 548-bed university hospital. During 1983, all cost elements involved in drug delivery (excluding large-volume parenterals) were identified. Direct and indirect pharmacy labor costs were determined. Personnel costs were calculated from time studies of nurses (in 1979-80) and pharmacy technicians (in 1982). Other pharmacy costs, based on the hospital's 1982 data, included inventory holding costs, computer services, supplies, and drug acquisition costs. Costs were calculated for four oral analgesics--acetaminophen with codeine, aspirin with codeine, ibuprofen, and zomepirac sodium--used during a 30-day period in 1981. For all medications, total average cost per dose for 1,949,418 doses was $2.44, of which 41% was drug acquisition cost. Personnel costs for pharmacy and nursing accounted for 43% and 11%, respectively, of total costs. For 46% of 5111 oral analgesic doses, frequency of administration was at least four times daily. Average purchase cost per dose for the oral analgesics was $0.15, while total costs for the controlled and non-controlled drugs were $1.02 and $0.50, respectively. For the four oral analgesics in this study, cost was affected by dosage schedule and controlled or noncontrolled status. Calculation of the total average cost per dose is useful in projecting annual costs and in identifying areas for cost reduction.

Administration, Oral↗
PubMed1980

Suprofen, a new peripheral analgesic.

The antinociceptive properties of suprofen [alpha-methyl-4-(thienylcarbonyl)benzene acetic acid] are described in a pathologically induced hyperalgesic model, the rat adjuvant arthritis flexion test. By using this assay, suprofen was characterized as an orally effective, non-narcotic analgesic with a rapid onset and 4-hr duration of activity. Suprofen is 50 times more potent than acetaminophen, five times more potent than codeine and equipotent to the new peripheral analgesics, zomepirac and diflunisal. In combination experiments, suprofen potentiates the analgesic effects of acetaminophen and, unlike morphine, the analgesic effect of suprofen is not blocked by naloxone. In other hyperalgesic assays, suprofen is an extremely potent inhibitor of arachidonate-induced writhing and is equipotent to morphine in the yeast-induced paw edema (Randall-Selitto) assay. Additionally, suprofen is inactive on the normal paw in the Randall-Selitto test, the mouse Eddy hot-plate test and the tail withdrawal reflex assay induced by warm water in rats, all sensitive tests capable of detecting central (narcotic) but not peripheral analgesics. Activity on prostaglandin biosynthesis from several species and tissues suggests that suprofen is a tissue selective inhibitor of prostaglandin synthesis. These experiments suggest that suprofen represents a new class of potent, orally effective, peripheral (non-narcotic) analgesics with potential usefulness in a variety of clinical pain situations formerly reserved for narcotics.

Acetaminophen↗
PubMed1982

Analgesic effects of intraventricular morphine and enkephalins in nondependent and morphine-dependent rats.

The analgesic effects of i.c.v. morphine and the enzyme-resistant enkephalin analogs, D-Ala2-Leu- and D-Ala2-Met-enkephalinamide, measured in the tail-flick test, were compared in nondependent and morphine-dependent rats. Dependence was induced and maintained by scheduled access to 0.05% morphine solution for at least 8 weeks before testing. In the nondependent rats, 1.0 to 10 micrograms of each drug injected into the lateral ventricle produced a dose-related increase in analgesia; on a molar basis, morphine was 1.3 (1.0-1.7) times more potent than the enkephalins. Naloxone (0.3 and 1.0 mg/kg) antagonized the analgesic effect of the three compounds: the effect of morphine was competitively antagonized, whereas the interaction between naloxone and the enkephalins did not appear to be competitive. Chronic morphine treatment produced different changes in the analgesic effects of morphine and the enkephalins. In contrast to the tolerance that was observed after s.c. injection of morphine in morphine-dependent rats, the analgesic effect of i.c.v. morphine was enhanced in these animals. The analgesic effect of D-Ala2-Leu-enkephalinamide was also enhanced in morphine-dependent animals, whereas tolerance developed to the effect of D-Ala2-Met-enkephalinamide. Thus, the analgesic effect of morphine and enkephalins are differentially altered in the presence of naloxone and in morphine-dependent animals. These results could reflect an allosteric interaction between neuronal binding sites for enkephalins and opiate alkaloids.

Analgesics↗
PubMed1980

A quantitative analgesic assay in the rabbit based on the response to tooth pulp stimulation.

A DC ramp voltage was used to stimulate rabbit tooth pulps. Thresholds to elicit chewing movements were extremely stable in the absence of drug treatment. Using cumulative dosing of analgesic drugs, potency and efficacy measurements could be readily obtained. Narcotic analgesics were the most effective analgesics on this test, followed by two centrally acting non-narcotics (nefopam and baclofen). Antipyretic/anti-inflammatory analgesics and centrally acting non-analgesic drugs elevated thresholds by lesser amounts or were inactive. It is concluded that the rabbit tooth pulp assay is suitable for the qualitative and quantitative determination of analgesic activity.

Analgesics↗
PubMed1976

Analgesic nephropathy.

Analgesic nephropathy occurs most commonly in Australia, where it is the second most frequent cause of renal failure. Whilst the reasons for widespread abuse of analgesics are poorly understood, the consequences of abuse are now well recognised. Increasing emphasis is being placed on the analgesic syndrome and on the accelerated atherosclerosis seen in these patients. Attention in the article is drawn to ways in which the analgesic syndrome can be recognised and analgesic abuse ceased. A therapeutic approach is presented which allows the successful withdrawal of analgesic in almost all patients.

Acidosis↗
PubMed1994

Analgesics for cardiac surgery patients in critical care: describing current practice.

BACKGROUND: In the last 10 years, the American Association of Critical-Care Nurses has twice ranked pain management as a priority issue for research and practice. Recent research findings suggest that undermedication of patients continues both in and out of critical care. Postoperative cardiac surgery patients have reported detailed recollections of pain experiences while in critical care, yet little is known about management of postoperative cardiac surgery pain. OBJECTIVE: The purpose of this study was to describe current practice related to analgesic prescription and administration for postoperative cardiac surgery patients in critical care. METHODS: Medical records of 80 adults undergoing cardiac surgery in two hospitals were randomly selected for review. Data pertaining to pain medications prescribed and doses administered for the day of surgery, first and second postoperative days were recorded for 66 eligible subjects. RESULTS: All but one patient had a prescription for intravenous morphine, hourly as needed. In addition, all patients had prescriptions for one or more oral analgesics as needed. Gender and age effects were noted for analgesic prescriptions. The average total amount of intravenous morphine given over the 3 days was 13.9 +/- 13.5 mg in an average of 4 +/- 3.7 doses. The average total number of acetaminophen with oxycodone tablets given over the 3 days was 5.8 +/- 5.4 tablets in an average of 3.6 +/- 3.0 doses. Age and hospital effects were noted in the administration of analgesics. CONCLUSIONS: The finding of small and infrequent analgesic doses is consistent with other studies conducted in and out of critical care. Important inconsistencies, or variations in practice, exist in both the prescription and administration of analgesics for postoperative cardiac surgery patients in the critical care setting.

Administration, Oral↗
PubMed1977

Flunixin meglumine: a non-narcotic analgesic.

The N-methyl-d-glucamine salt of flunixin (flunixin meglumine) is a potent non-narcotic analgesic agent after parenteral administration in mice, rats and monkeys. It is significantly more potent than pentazocine, meperidine and codeine in the rat yeast paw test after subcutaneous administration in saline. Activity on intramuscular administration is comparable to that after subcutaneous administration and is enhanced when dissolved in buffered saline as compared to nonbuffered saline. In addition, flunixin meglumine also had oral activity and differs from indomethacin in having more analgesic activity per unit of anti-inflammatory activity. In mice, flunixin meglumine is equipotent to pentazocine and more potent than meperidine and codeine in the abdominal constriction test. In primates, flunixin meglumine at 10 mg/kg i.m., produced a degree of analgesic efficacy comparable to that of a clinically effective dose of morphine (0.3 mg/kg). In contrast to codeine, tolerance to the analgesic action of flunixin meglumine was not observed. Furthermore, flunixin meglumine retained its activity in rats made tolerant to codeine. Unlike narcotics, the analgesic effect of flunixin meglumine is not antagonized by naloxone after acute administration in rats. These results indicate that flunixin meglumine is a parenterally and orally effective analgesic in animals and is unlikely to have narcotic or drug dependence liability.

Analgesics↗
PubMed1995

[Analgesic effect of morphine and its metabolites administered by an intracerebroventricular route].

Intraventricular morphine administration is indicated, in some selected cases, to alleviate intractable cancer pain. Our pharmacokinetics data in cerebro-spinal fluid allowed us to formulate the theory of "Front de Recrutement". Then we were able to determine in cisternal and ventricular cerebrospinal fluid the morphine 6-glucuronide concentrations. Morphine 6-glucuronide is the main analgesic metabolite of morphine and its presence in cerebro-spinal fluid could be due to a metabolism of morphine in the central nervous system. Our animal studies showed that the analgesic activity of morphine 6-glucuronide was 27 to 67 times higher than that of morphine. By demonstrating the 6-monoacetyl morphine potency (analgesic metabolite of heroin that is 20 times more potent than morphine), we showed the involvement of the 6 position in the analgesic effect of these opioids. When we compared the morphine-6 concentrations in human cerebro-spinal fluid with the analgesic potency of this metabolite, the morphine-6 glucuronide was responsible of 33% to 67% of the supra-spinal analgesic effect. As heroin, morphine must be considered as a precursor whose metabolites have pharmacologic effects.

Analgesics, Opioid↗
PubMed1998

Use and abuse of over-the-counter analgesic agents.

Pain and discomfort in everyday life are often treated with over-the-counter (OTC) analgesic medications. These drugs are remarkably safe, but serious side effects can occur. Up to 70% of the population in Western countries uses analgesics regularly, primarily for headaches, other specific pains and febrile illness. It is not known whether the patterns of use are consistent with good pain management practices. OTC analgesics are also widely used to treat dysphoric mood states and sleep disturbances, and high levels of OTC analgesic medication use are associated with psychiatric illness, particularly depressive symptoms, and the use of alcohol, nicotine and caffeine. More than 4 g per day of acetylsalicylic acid (ASA) or acetaminophen over long periods is considered abuse. People using excessive amounts of OTC analgesics may need more effective treatments for chronic pain, depression or dysthymia. The possibility that these drugs have subtle reinforcing properties needs to be investigated. Certainly phenacetin, which was taken off the market in the 1970s, had intoxicating effects. A better understanding of patterns of use is needed to determine the extent of problem use of OTC analgesics, and whether health could be improved by educating people about the appropriate use of these drugs.

Analgesics↗
PubMed1998

The postoperative analgesic efficacy and safety of piroxicam (FDDF) and naproxen sodium.

The aim of the present study was to compare the analgesic efficacy of piroxicam-FDDF (fast dissolving dosage form) with naproxen sodium, following bilateral removal of impacted third molars. A double-blind, randomized, crossover, analgesic trial was carried out on 40 patients undergoing surgical removal of one lower third molar at each visit. The analgesic efficacy of a single dose regimen of piroxicam-FDDF (40 mg, Feldene Flash, Pfizer, Turkey) was compared with naproxen sodium (550 mg, Anaprotab, Sanli, Turkey). Pain intensity was measured on a category-rating scale during the 8-h period after drug administration. Each patient evaluated the efficacy of the study medication at 15, 30, 45, 60, 90 and 120 min, and then hourly for up to 8 h of drug ingestion. Additional key efficacy measures were also determined (pain intensity difference [PID], sums of pain intensity difference [SPID], total pain relief [TOTPAR], peak pain relief, number of observations at which pain was half-relieved, overall evaluation of study medication effectiveness, and time to medication with a back-up analgesic). The data were analyzed by paired Student's t-test and one-way analysis of variance (ANOVA). Results are expressed as means +/- SEM, and p < 0.05 was taken as statistically significant. The PID and pain relief scores of the piroxicam-FDDF group were significantly greater than those for the naproxen sodium group at 15, 30, 45 and 60 min (p < 0.01). After 90 min to 8 h, no statistical significance was revealed among the two test groups (p > 0.05). The peak pain relief, maximal analgesic effect, SPID, TOTPAR values, adjusted mean number of observations with pain at least half-relieved, and the final overall evaluation records were all superior for piroxicam-FDDF (p < 0.05). The results of this study clearly show that the analgesic efficacy of piroxicam-FDDF is superior to naproxen sodium in the treatment of pain following oral surgery for the removal of impacted third molars.

Adolescent↗
PubMed1998

The effect of location of transcutaneous electrical nerve stimulation on postoperative opioid analgesic requirement: acupoint versus nonacupoint stimulation.

UNLABELLED: Transcutaneous electrical nerve stimulation (TENS) has been used as a complementary (supplemental) therapy to opioid analgesics for pain relief after surgery. Simultaneous stimulation at a classical Chinese acupoint site and periincisional dermatomes significantly decreases the postoperative analgesic requirement. This sham-controlled study was designed to assess the relative effectiveness of acupoint versus nonacupoint stimulation on the postoperative hydromorphone (HM) requirement, the incidence of opioid-related side effects, and the overall recovery profile. One hundred women undergoing total abdominal hysterectomy or myomectomy procedures with a standardized general anesthesia were randomly assigned to one of four postoperative analgesic treatment regimens (n = 25 each): Group I = sham-TENS (no electrical current) at the Zusanli (ST36) acupoints, Group II = nonacupoint-TENS at the shoulders, Group III = dermatomal-TENS at the level of the surgical incision, and Group IV = acupoint-TENS at the Zusanli acupoints. The frequency of TENS was set in the standard dense-and-disperse mode of 2/100 Hz. The intensity of stimulation was set at 0 mA for patients in Group I and at 9-12 mA for patients in Groups II, III, and IV. A patient-controlled analgesia (PCA) device programmed to deliver bolus doses of HM 0.2-0.4 mg IV on demand with a minimal lockout interval of 10 min was used to quantify the postoperative opioid analgesic requirement. Standard 100-mm visual analog scales were used to assess pain, as well as sedation, fatigue, and nausea, at specific intervals after surgery. The numbers of PCA demands and delivered bolus doses, requirements for supplemental medication, and any opioid-related side effects were recorded. In the first 24 h postoperatively, the opioid requirements in Groups III and IV were decreased by 37% and 39%, respectively, compared with the control (sham) group and 35% and 38%, respectively, compared with Group II. The duration of PCA usage and the incidences of nausea and dizziness were also significantly decreased in Groups III and IV compared with Groups I and II. We conclude that periincisional dermatomal and Zusanli acupoint stimulation were equally effective in decreasing the postoperative opioid analgesic requirement and in reducing opioid-related side effects. Both of these positions were more effective than the nonacupoint (shoulder) location. IMPLICATIONS: The location of the stimulating electrodes seems to be an important determinant of the efficacy of transcutaneous electrical nerve stimulation in decreasing the need for opioid analgesics in the postoperative period. This study demonstrates that transcutaneous electrical nerve stimulation applied at the dermatomal level of the skin incision is as effective as Zusanli acupoint stimulation, and both were more effective than stimulation at a nonacupoint (shoulder) location.

Acupuncture Points↗
PubMed1999

Synthesis and analgesic activity of 2-methyl-2-[1-(3-benzoyl-4-substituted-1,4-dihydropyridyl)]acetic acid methyl esters, acetic acids, and acetamides.

A group of 2-methyl-2-[1-(3-benzoyl-4-substituted-1,4-dihydropyridyl)]acetic acid methyl esters (7), weak acetic acids (8), and acetamides (9) were designed for evaluation as less acidic non-ulcerogenic non-steroidal antiinflammatory drugs (NSAIDs). In this respect, the model compound 2-methyl-2-[1-(3-benzoyl-4-phenyl-1,4-dihydropyridyl)]acetic acid (8a), unlike traditional arylacetic acid NSAIDs, was shown to be a weak acid with a pKa of 9.17. In contrast to arylacetic acid NSAIDs, the alpha-methylacetic acid sodium salt of 8a, or the methyl alpha-methylacetate ester (7a) did not inhibit cyclooxygenase-1 (COX-1) or -2 (COX-2). In vitro stability studies showed that the methyl alpha-methylacetate ester (7a) acts as a prodrug to the alpha-methylacetic acid derivative (8a), undergoing rapid (< 10 minutes) and quantitative conversion upon incubation with rat plasma, or incubation with rat liver homogenate (t1/2 = 25 min). In contrast, the alpha-methylacetamide (9a) underwent negligible (< 2%) conversion to the alpha-methylacetic acid derivative (8a) upon incubation with either rat plasma, or rat liver homogenate, for incubation times up to 24 h. The effect of a C-3 para-substituted-benzoyl substituent (R1 = H, Cl, Me), a C-4 substituent (R2 = aryl, benzyl, cyclohexyl, alkyl), and the nature of the N1-acetic acid moiety [methyl ester (R3 = OMe), acetic acid (R3 = OH), acetamide (R3 = NH2)] on analgesic activity was determined using the 4% NaCl-induced abdominal constriction (writhing) assay. Compounds 7-9 inhibited writhing 27-95% relative to the reference drug aspirin (58% inhibition). The analgesic potency with respect to the para-benzoyl substituent was H > Cl or Me. Although the effect of the C-4 R2-substituent on analgesic activity was variable within the ester, acid and amide sub-groups of compounds, compounds having a R2-cyclohexyl substituent generally provided superior analgesic activity relative to those having a lipophilic alkyl substituent. The nature of the R3-substituent (OMe, OH, NH2) was a determinant of analgesic activity where the potency order was acetic acid methyl ester > acetic acid or acetamide, except when the C-4 R2-substituent was cyclohexyl or benzyl where the potency order was acetamide > acetic acid methyl ester or acetic acid. Reduction of the 5,6-olefinic bond of the 1,4-dihydropyridyl compound (9a, 94% inhibition) to the corresponding 1,2,3,4-tetrahydropyidyl derivative (10, 69% inhibition) reduced analgesic activity.

Acetamides↗