Investigations on drug produced and subjectively experienced discriminative stimuli: 1. The fentanyl cue,a tool to investigate subjectively experienced narcotic drug actions.

Fentanyl is reported to produce a discriminative stimulus that can control food-reinforced lever pressing in rats. Other narcotics (i.e. dextromoramide, morphine, phenoperidine and piritramide) are found to be generalized with fentanyl injection, whereas the neuroleptic haloperidol is not. The subjectively experienced narcotic cue is effectively controlled by the experimental procedures described.     

The synthesis and preliminary pharmacological evaluation of 4-methyl fentanyl

The synthesis of 4-methyl fentanyl, a prototype of a novel class of fentanyl analogues has been effected in 5 steps, starting from N-ethoxycarbonyl-4-piperidone (approximately 20% overall yield). In the key step, N-phenylation of secondary aliphatic amide intermediare was achieved by a novel reaction, using diphenyliodonium chloride for the phenyl group transfer. Preliminary pharmacological results indicate that 4-methyl fentanyl is a super potent narcotic analgesic, about four times more potent than fentanyl.     

Selective interaction of drugs with a discriminable stimulus associated with narcotic actions

Rats were trained to bar press on either one of two levers depending on whether they received an injection of morphine (10 mg/kg) or saline. The rats responded on the morphine-correct lever when injected with another narcotic, fentanyl, but responded on the saline-correct lever when injected with a narcotic antagonist or another CNS active, but non-narcotic, drug (e.g., amphetamine, apomorphine). The narcotic antagonist, naloxone, prevented the occurrence of the narcotic discriminable stimulus, but the rats responded on the morphine-correct lever when injected with morphine plus any of a number of potent CNS active, but non-narcotic compounds. These results are discussed with reference to the specificity of this procedure for detecting drugs with narcotic agonist or antagonist properties.     

Inhibition of ganglionic transmission by narcotic analgesics; an effect antagonized by naloxone, nalorphine and calcium

Methadone, azidomorphine, oxycodone and fentanyl inhibit synaptic transmission in isolated sympathetic ganglia of the frog and rat, just as did morphine and pethidine in our previous investigations. This inhibitory effect can be antagonized not only by naloxone and nalorphine but also by increasing calcium concentration of the perfusion fluid of the ganglia. The inhibitory effect on transmission of narcotic analgesics takes place on specific opiate receptors of the peripheral ganglia.     

瑞芬太尼、芬太尼对小儿扁桃体切除术中应激反应和苏醒期躁动的影响

目的：探讨瑞芬太尼、芬太尼对小儿扁桃体切除术中应激反应以及苏醒期躁动的影响。方法：选择2012年1月至2012年12月期间择期行扁桃体切除手术的患儿80例为研究对象,将其分随机为瑞芬太尼组（40例）和芬太尼组（40例）,比较两组患者不同时间应激反应指标（ACTH、COR、IL-6）、苏醒时间、躁动评分、躁动发生率以及RamSay镇静评分,探讨两种麻醉药物的临床应用价值。结果：两组术前ACTH、COR、IL-6的基础应激指标比较,差别无统计学意义（P〉0．05）。瑞芬太尼组及芬太尼组术毕该三项指标较术前升高,术后1d较术毕有回落,差别有统计学意义（P〈0．05）;瑞芬太尼组术毕睐后1d的各项指标均远远低于芬太尼组,差别有统计学意义（P〈0．05）。瑞芬太尼组苏醒时间明显少于芬太尼组,躁动评分明显低于芬太尼组,躁动发生率明显低于芬太尼组,RamSay镇静评分明显高于芬太尼组,差别有统计学意义（P〈0．05）。结论：瑞芬太尼引起的应激反应明显弱于芬太尼组,且其苏醒期躁动情况明显优于芬太尼组,值得进一步推广应用。     

瑞芬太尼、芬太尼对小儿扁桃体切除术中应激反应和苏醒期躁动的影响

目的:探讨瑞芬太尼、芬太尼对小儿扁桃体切除术中应激反应以及苏醒期躁动的影响。方法:选择2012年1月至2012年12月期间择期行扁桃体切除手术的患儿80例为研究对象,将其分随机为瑞芬太尼组(40例)和芬太尼组(40例),比较两组患者不同时间应激反应指标(ACTH、COR、IL-6)、苏醒时间、躁动评分、躁动发生率以及RamSay镇静评分,探讨两种麻醉药物的临床应用价值。结果:两组术前ACTH、COR、IL-6的基础应激指标比较,差别无统计学意义(P0.05)。瑞芬太尼组及芬太尼组术毕该三项指标较术前升高,术后1d较术毕有回落,差别有统计学意义(P0.05);瑞芬太尼组术毕﹑术后1d的各项指标均远远低于芬太尼组,差别有统计学意义(P0.05)。瑞芬太尼组苏醒时间明显少于芬太尼组,躁动评分明显低于芬太尼组,躁动发生率明显低于芬太尼组,RamSay镇静评分明显高于芬太尼组,差别有统计学意义(P0.05)。结论:瑞芬太尼引起的应激反应明显弱于芬太尼组,且其苏醒期躁动情况明显优于芬太尼组,值得进一步推广应用。     

Steric interactions and the activity of fentanyl analogs at the mu-opioid receptor

Fentanyl is a highly potent and clinically widely used narcotic analgesic. The synthesis of its analogs remains a challenge in the attempt to develop highly selective mu-opioid receptor agonists with specific pharmacological properties. In this paper, the use of flexible molecular docking in a study of the formation of complexes between a series of active fentanyl analogs and the mu-opioid receptor is described. The optimal position and orientation of fourteen fentanyl analogs in the binding pocket of the mu-receptor were determined. The major receptor amino acids and the ligand functional groups participating in the complex formation were identified. Stereochemical effects on the potency and binding are explained. The proposed model of ligand-receptor binding is in agreement with point mutation experiments explaining the role of the amino acids: Asp147, Tyr148, Asn230, His297, Trp318, His319, Cys321, and Tyr326 in the complex formation. In addition, the following amino acids were identified as being important for ligand binding or receptor activation: Ile322, Gly325, Val300, Met203, Leu200, Val143, and Ile144.     

IV. Discriminative stimulus effects of narcotics: Evidence for multiple receptor-mediated actions

Results of studies on the discriminative stimulus effects of narcotics are consistent with the hypothesis that multiple receptors mediate the effects of these compounds. In the rat, at least three subsets of discriminative effects exist, although some drugs appear to have effects that transcend more than one subset. The discriminative effects of morphine-like narcotics (μ agonists), for example, are often clearly distinguishable from the discriminative effects produced by κ agonists, such as ketazocine, and from those produced by phencyclidine-like agonists, such as SKF-10,047 and cyclazocine. Cyclazocine, however, has been reported to have discriminative effects in common with morphine (45) and fentanyl (17) and appears to have κ-like, in addition to phencyclidine-like, discriminative effects. The relative ability of pure narcotic antagonists to block the discriminative effects of these compounds also provides evidence for distinct pharmacologic actions of these drugs. In the rat, the discriminative effects of morphine are blocked by doses of naloxone that are considerably smaller than those that are needed to block the discriminative effects of cyclazocine (44). The discriminative effects of phencyclidine are not altered at all by naltrexone (63).     

Narcotic dependence, narcotic action and dopamine receptors.

Acute systematic administration of narcotic analgesics increases the firing rate of nerve cells in the zona compacta of the substantia nigra, causes an increase in the rate of dopamine turnover in striatal and mesolimbic areas of the brain, stimulates prolactin release, inhibits brain self-stimulation and discriminated shock-avoidance, blocks cardiovascular effects of systemically injected dopamine, blocks aggression as well as compulsive jumping in mice treated with DOPA and amphetamine, antagonizes stereotypy induced by apomorphine or amphetamine, and blocks apomorphine-induced vomiting in dogs. Chronic administration of narcotic analgesics results in withdrawal signs upon the cessation of the drug administration. These signs include, tolerance to the increase in striatal dopamine turnover caused by narcotic analgesics or haloperidol, aggressive behaviors which are further stimulated by directly or indirectly acting dopamine-receptor agonists and are blocked by dopamine-receptor blockers, facilitation of recovery from the “lateral hypothalamic syndrome”, an increase in basal levels of striatal adenylate cyclase which shows greater sensitivity to dopamine, and, an enhanced sensitivity to apomorphine-induced reduction of dopamine turnover. It is therefore, concluded that acute administration of narcotic drugs results in an inhibition of dopamine-receptor activity while chronic administration of these drugs results in an increased response of these dopamine receptors to dopamine agonists. Recent experiments on the interaction of other drugs with narcotic analgesics suggest that, unlike the direct action of neuroleptics on the dopamine receptors, the narcotic action on dopamine receptors is indirect.     

A comparison of narcotic analgesics with neuroleptics on behavioral measures of dopaminergic activity.

Because of many practical difficulties which are encountered in obtaining direct evidence for the involvement of brain neurotransmitters in the action of narcotic drugs, several indirect procedures are often employed. One such method is to compare on the same measures of drug action the narcotic drugs with a non-narcotic drug having a known mechanism of action. Haloperidol is a prototype non-narcotic drug which blocks dopamine receptors and many of its actions are believed to be associated with this receptor blockade. In this paper we compare various actions of haloperidol or other neuroleptics with morphine or other narcotic analgesics using the same testing parameters. We hope that such a comparison would evaluate the role of dopamine receptors in narcotic action and narcotic dependence. This discussion is limited only to the behavioral measures as a comparison of neurochemical measures was recently reviewed in another paper (1).     

The clinical outcome of abdominoplasty performed under conscious sedation: increased use of fentanyl correlated with longer stay in outpatient unit

The objective of this study was to present data supporting the effectiveness of performing mini and full abdominoplasties under conscious sedation with local anesthesia. The authors performed 20 such operations between 1994 and 1996, using a combination of midazolam (Versed) and fentanyl instead of general anesthesia (without an anesthesiologist or nurse anesthetist present). At 5- to 10-minute intervals, the surgeon would order the injection of 1 cc (1 mg/ml) of midazolam and 1 cc (50 microg/ml) of fentanyl. The amount and the interval varied based on the patient's level of sedation. Blood pressure, oxygen saturation, and the patient's response to verbal and physical stimuli were used to assess the sedation level. Average operating time was 147.5 minutes, and mean length of stay in the outpatient recovery room was 235.5 minutes. The average amounts of midazolam and fentanyl used were 9.4 mg (6 to 12.5 mg) and 532 microg (300 to 800 microg), respectively. The average age of patients in this group was 41.7 years (28 to 63 years). Nineteen patients were discharged the same day. There were no surgical complications and no complication related to the sedation (such as respiratory or cardiac compromise). The average follow-up of these patients was 1.2 years (range, 3 to 21 months). Correlation coefficient rates and regression rates were calculated. The longer the procedure, the more midazolam was used intraoperatively (r = 0.5, p = 0.03). However, there was no correlation between the length of the procedure and the amount of fentanyl used. Rather, there was a positive correlation demonstrating that patients who received more fentanyl stayed longer in the outpatient recovery area after surgery (r = 0.6, p < 0.01). The age of the patients and the amount of midazolam did not correlate with how fast they went home from the outpatient area. In conclusion, full and mini abdominoplasties can be performed safely using conscious sedation without compromising patient care or surgical outcome. Second, the survey revealed that patient satisfaction with these procedures performed under conscious sedation was very high. Third, the increased use of fentanyl, not midazolam, resulted in a longer stay in the outpatient unit after surgery. Nausea is a known side effect of narcotic analgesics, and it correlated with a higher dose of fentanyl administration in the patients. The authors are now routinely administering a dose of either droperidol or odansetron (Zofran) preoperatively (both are antiemetics). Previously, the ratio of midazolam and fentanyl injection was 1:1 every 5 to 10 minutes, but now it is 2: 1 to 4: 1 every 5 to 10 minutes (a smaller dose of fentanyl is administered). The conscious sedation technique should be an option for patients and plastic surgeons in academic and community hospital settings if they desire.     

Nonspecific arousal with noloxone.

The use of naloxone, the first narcotic antagonist devoid of agonist properties, has become the standard way of treating narcotic-induced coma and respiratory depression. This report concerns a patient in whom a narcotic effect was unlikely, but who nevetheless showed arousal after naloxone administration.     

A systems and control theory approach to dynamic neurotransmitter balance in narcotic addiction and narcotic antagonism.

We have formulated a pharmacological-physiological systems analysis and control theory based on interactive neuronal feedback loops (the effects of endogenous neurochemical diseases and exogenous CNS drugs on neurotransmitter synthesis and release, reuptake and metabolism) for normal, abnormal and catastrophic situations.We set up the systems diagrams for neurotransmitter systems and in that single framework were able to describe endogenous neurochemical disorders, the effect that their drug treatment modalities had on the dynamic neurochemical balance and the effect other CNS drugs such as narcotics and narcotic antagonists had on neurochemical balance. This led to a hypothesis that narcotic addiction is caused by negative feedback induced increase in synthesis and release of certain neurotransmitters, tolerance arises in a related manner, narcotic withdrawal symptoms are caused by out-of-phase feedback and a major mechanism of antagonist action of narcotic antagonists is not merely competitive displacement of a narcotic from its “receptor site” but rather is due to an increase in the concentration of catecholamines in the synaptic cleft.     

A novel form of dependency of hepatic extraction ratio of opioids in vivo upon the portal vein concentration of drug: Comparison of morphine,diamorphine, fentanyl,methadone and buprenorphine in the chronically cannulated cow

In the chronically cannulated cow, the hepatic extraction ratio for intravenous boluses of morphine, diamorphine, fentanyl, methadone and buprenorphine increased towards a plateau value as portal vein drug concentration increased. An extraction ratio close to zero for morphine was observed at a portal vein plasma drug concentration of about 200 nanomol per litre, which is within the range for significant pharmacodynamic effects. The similar concentrations extrapolated for the other narcotics would be of less pharmacodynamic importance. The phenomenon did not depend with morphine on the history of drug delivery to the liver; measurement of hepatic blood flow showed the effect was not an artifact of unrepresentative blood sampling, and was not related to any action of the narcotics on hepatic blood flow. The existence of this novel type of concentration dependent hepatic extraction ratio in vivo can explain a number of anomalous observations on narcotic pharmacokinetics, especially for morphine. Furthermore, similar behaviour may be expected for non-opioid drugs having similar pharmacokinetic properties.     

Differential reduction of morphine-withdrawal body shakes by butaclamol enantiomers

Rats withdrawn from continuous morphine infusion showed reliable occurrence of withdrawal body shakes. This sign of narcotic withdrawal was inhibited by the neuroleptic drug, (+) butaclamol. (?) Butaclamol was inactive. (+) Butaclamol activity was not antagonized by naloxone (5 mg/kg). The anti-withdrawal mechanism of (+) butaclamol is discussed in terms of effects on dopamine and narcotic receptors.The butyrophenone neuroleptic, haloperidol, has been used successfully to reduce signs of narcotic withdrawal in laboratory animals (1–4) and human addicts (5). Other neuroleptics of the butyrophenone type also show anti-withdrawal action (6, 7). The mechanism of action of these neuroleptics in blocking narcotic withdrawal is not understood. Butaclamol is a new neuroleptic drug that is available in two enantiomers and only (+) butaclamol possesses neuroleptic activity (8–10). Because of its demonstrated stereo-specificity in producing its pharmacological action, we employed this drug to establish specificity of action of neuroleptics in blocking narcotic withdrawal.     

CHEMICAL STRUCTURE AND NARCOTIC POTENCY TO GRAIN WEEVILS. ALCOHOLS AND METHYL ESTERS OF FATTY ACIDS

The narcotic and toxic potencies of the first seven homologous alcohols and the methyl esters of the first seven homologous fatty acids have been determined using grain weevils (Calandra granaria). The experiments were designed as balanced incomplete blocks, and Finney's probit plane technique was applied to the results. In both series of compounds the narcotic and toxic potencies expressed in thermodynamic concentrations decreased with increasing number of carbon atoms. The margin between narcotic dose and toxic dose is greater in the alcohol series than in the ester series. The methyl esters of the fatty acids showed a stepwise descent in biological potency, the odd numbered series being more active than the even series. The penetration of these compounds into grain weevils and their biological action are discussed in relation to the coefficients of response to log concentration and log time of exposure.     

Validated GC-MS analysis for the determination of residual fentanyl in applied Durogesic reservoir and Durogesic D-Trans matrix transdermal fentanyl patches

The method development and validation characteristics are described of a simple gas chromatographic-mass spectrometric (GC-MS) analytical procedure to determine residual fentanyl in used Durogesic reservoir patches and Durogesic D-Trans matrix technology based systems to estimate the actual rate of transdermal fentanyl delivered in individual patients. The sample preparation protocol constituting a saline based extraction of sets of new patches of each nominal dose available, resulted in fentanyl extraction recoveries to increase steadily as a function of increasing extraction time. For the reservoir type transdermal therapeutic system (TTS), fentanyl extraction efficiencies at equilibrium (16 h) ranged from approximately 60% (100-microg/h TTS) to 95% (25-microg/h TTS), whereas for the matrix type system considerable lower recoveries were demonstrated for the highest nominal dose rates (35%-52%), while reaching 90% for the 25-microg/h system. For the latter type of fentanyl TTS, an optimized methanol based extraction protocol yielded virtually quantitative fentanyl recoveries for each matrix patch nominal dose level at substantially shorter extraction periods (15 min). The GC-MS analytical method using selected ion monitoring (SIM) and deuterated fentanyl as internal standard was shown to be adequately selective with regard to the presence of other compounds in the Durogesic patches. It was further demonstrated that the developed analytical protocols provided highly reproducible and accurate estimates of the initial fentanyl content of each patch type at all available nominal doses, with coefficients of variation and relative errors generally below 10%. These advantageous assay validation characteristics can be further transposed to the application of residual fentanyl level estimates in used patches, provided that with each batch of samples also a set of new TTSs with equal dose is assayed to perfectly mimic extraction phenomena. Finally, the presented GC-MS analytical protocol was successfully applied for the determination of residual fentanyl in a subset of 57 reservoir type patches obtained from four palliative patients.     

Lactic/glycolic acid polymers as narcotic antagonist delivery systems.

Lactic/glycolic acid polymers of several compositions were evaluated as the vehicle material for long term, controlled delivery of narcotic antagonists. L(+)-lactic, and glycolic acids-designated L(+), and G, respectively-were converted to polymers with weight ratios of 75 L(+)/25 G, 90 L(+)/10 G, and 100 L(+). Naltrexone base and naltrexone pamoate were incorporated into these polymers as a physical blend at several drug/polymer mass ratios. The mixtures were formed into small cylinders and spheres which were suitable for subcutaneous implantation by means of a trochar. $\text{In vitro}$ screening was carried out followed by $\text{in vivo}$ testing in mice. Radioactive assay and direct challenge with morphine using the tail-flick test were used to evaluate the drug release. The release rates approximated zero-order kinetics for most of the release period and the narcotic antagonist response to a challenge dose of morphine was maintained from one month to over six months depending on the formulation tested. Factors affecting narcotic antagonist delivery system design were polymer composition, narcotic antagonist solubility, drug loading level of the dosage form, use of a pure polymer coating around the drug/polymer matrix, and the surface area/unit volume of the dosage form.     

Symptoms of neonatal abstinence syndrome. Case report

A case of the neonatal narcotic abuse syndrome is presented. A newborn baby additionally suffered from the congenital infection. Marked symptoms of narcotic withdrawal required an administration of the opiates and tranquillizers for three weeks.     

A METHOD FOR MEASURING THE NARCOTIC ACTION OF CHEMICALS USING THE GRAIN WEEVIL, CALANDRA GRANARIA

A method of measuring narcotic potency is described. Grain weevils ( Calandra granaria ) are exposed to the narcotic vapour in 2l. round-bottomed flasks illuminated from the bottom, and narcotic potency measured as number of grain weevils so affected as to be unable to climb the glass walls. Some common anaesthetics have been examined as an illustration of this method. Results are fitted by the probit plane
Y= A + b ₁ log α+ b ₂ log t ,
where Y = a function of the number of insects affected (probit); α= the thermodynamic concentration of the narcotic vapour; t = time of exposure of insects to the narcotic vapour. The values of the coefficients b ₁ and b₂ are discussed in relation to the biological action of the narcotic vapours.