Safety and efficacy of a combination of pethidine and levallorphan for pain relief during labor: An observational study.

AIM: To evaluate the safety, effect on breastfeeding and efficacy of a combination of pethidine and levallorphan (Pethilorfan) for pain relief during labor. METHODS: We compared maternal or neonatal morbidities, suckling difficulties in newborns and breastfeeding rates between 177 women who received 50-200 mg (as pethidine) of Pethilorfan during labor (Pethilorfan group) and 354 women who delivered their infants without analgesic drugs immediately before or after each woman in the Pethilorfan group (control group) from January 1, 2005 to December 31, 2016. We performed univariate and multivariate analyses for comparison between the two groups. We also evaluated the efficacy of Pethilorfan retrospectively. RESULTS: The Pethilorfan group included more women with prolonged and/or operative deliveries than the control group. Nevertheless, no significant differences were seen between the two groups in the rates of Apgar scores less than 7 at 1 or 5 min, composite neonatal morbidities, hyperbilirubinemia or respiratory disturbances. The incidence of suckling difficulties lasting over 24 h and the breastfeeding rates at discharge or after 1 month were also similar. Maternal adverse effects of Pethilorfan were generally mild and transient. The efficacy ratio of Pethilorfan was 83.6%, although its analgesic effect was usually incomplete. CONCLUSION: Pethilorfan can be used safely for labor pain relief without increasing maternal or neonatal morbidities, or impeding breastfeeding, if it is administered at a prudent dosage. Parenteral opioids including Pethilorfan should remain as an option for treating women in labor pain, particularly when epidural analgesia is not readily available or contraindicated.

Analysis of 16,16-dimethylprostaglandin E2-induced diarrhea in cecectomized rats.

The 16,16-dimethylprostaglandin E2 (dmPGE2)-induced diarrhea was analyzed in cecectomized rats prepared by resecting the cecum and its vasculature without disturbing the ileocecal junction. dmPGE2 (0.1-1.0 mg/kg, p.o.) dose-dependently increased the number of defecation episodes and induced a soft and watery stool in cecectomized rats. At 0.3 mg/kg, the diarrhea-inducing effects of dmPGE2 were more pronounced in cecectomized than in control rats. When given i.p., dmPGE2 (0.3 mg/kg) induced a watery stool in cecectomized and control rats with the same efficacy, although these effects were short-lasting as compared to oral administration. Castor oil (4 ml/kg, p.o.) also induced diarrhea, but did not produce a watery stool in cecectomized rats. There were no differences between cecectomized and control rats in basal small intestinal transits or in dmPGE2 (0.3 mg/kg, p.o.)-induced enhancements. Moreover, the basal and dmPGE2-induced jejunal net fluid transfers were the same in cecectomized and in control rats. On the other hand, the enhanced secretion of colonic fluid by dmPGE2, given intraluminally, was only half of that in control rats, whereas the colonic transit-enhancing effect of dmPGE2 in cecectomized rats was more pronounced than in control rats at 15 but not at 30 min after its administration. The basal colonic fluid contents and transits were the same in cecectomized and in control rats. Loperamide and morphine (0.1 and 1.0 mg/kg, s.c.) inhibited the dmPGE2 (0.3 mg/kg, p.o.)-induced diarrhea in cecectomized rats. N-methyllevallorphan (5 mg/kg, s.c.) completely antagonized the inhibitory effect of loperamide and partly antagonized the effect of morphine. These results suggest that oral administration of dmPGE2 induces a more pronounced secretory diarrhea in cecectomized than in control rats, probably due to the lack of the reservoir function of the cecum in the operated animals. This secretory diarrhea model is suitable for evaluating the antidiarrheal activity of drugs.

Opioid antagonists: indirect antagonism of morphine analgesia by spinal dynorphin A.

Naloxone and norbinaltorphimine when given ICV to mice can antagonize IT morphine-induced analgesia indirectly by releasing spinal dynorphin A(1-17) (Dyn A). Dyn A produces an antianalgesic action against IT morphine. In the present study, drugs with varying amounts of opioid antagonist to agonist action (nalbuphine, levallorphan, naltrexone, and naltrindole) were given ICV to determine whether they antagonized IT morphine-induced inhibition of the tail-flick response as an indication of spinal Dyn A release. Additional pharmacological tests were used as criteria for Dyn A release: a) Small doses of the opioid antagonists naloxone and norbinaltorphimine administered IT inhibited the antagonistic action; b) dynorphin antiserum given IT blocked the action of Dyn A; c) desensitization to the effect of Dyn A was produced by 3-h pretreatment with morphine, 10 mg/kg SC, or by pretreatment with the agents themselves. When given ICV, nalbuphine, levallorphan, and naltrexone released Dyn A in the spinal cord to produce an antianalgesic effect. Naltrindole, a delta-receptor antagonist, did not release Dyn A. Dyn A release did not appear to involve delta-receptors. Thus, a number of opioid antagonists inhibit the analgesic action of opioid agonists indirectly through Dyn A release.

Opposite central and peripheral control by endogenous opioids of intestinal motility in fed rats.

1. The effects of the inhibitors of endopeptidase EC 24.11, thiorphan and phosphoramidon administered i.c.v. (40 micrograms kg-1) i.p. (400 micrograms kg-1), or orally (400 micrograms kg-1), on intestinal motor activity in fed rats was compared to the effects of similar doses of the angiotensin converting enzyme inhibitor, captopril and the synthetic enkephalin analogue [D-Ala2 Met5] enkephalinamide (Dalamide). Drugs were administered alone or after pretreatment with naloxone or N-methyl levallorphan (300 micrograms kg-1, i.p.) given 10 min prior to gavage with a standard meal. 2. In control conditions, in the duodenum, the disruption of the migrating myoelectric complex (MMC) by gavage with a standard meal lasted between 105.6 and 119.1 min. This duration was significantly decreased by thiorphan (60.3 +/- 15.0 min), phosphoramidon (67.9 +/- 7.3 min), captopril (26.3 +/- 10.2 min) and Dalamide (42.4 +/- 9.6 min), administered i.c.v. 3. In contrast, after the i.p. administration of thiorphan, phosphoramidon and Dalamide the delay in the return of the MMC pattern was increased. Such an effect was also seen after the oral administration of phosphoramidon or Dalamide. Neither i.p. nor oral captopril administration altered the duration of postprandial pattern. 4. A prior treatment with naloxone i.p. (300 micrograms kg-1) that had no effect per se, antagonized the effect produced by i.c.v. administration of thiorphan, phosphoramidon or Dalamide, but failed to reverse the effect of captopril. In contrast, i.p. administration of N-methyl levallorphan (300pgkg-1) did not affect the response induced by central administration of thiorphan, phosphoramidon, captopril or Dalamide, but was able to prevent that of thiorphan, phosphoramidon or Dalamide when they were administered i.p. or orally. 5. These data strongly support the hypothesis of a dual control by endogenous opioids of intestinal motility in the rat: a central component that favours, and a peripheral control that delays the occurrence of the MMC profile in fed rats.

Central and peripheral injection of quaternary antagonist, SR58002C, reduces drinking.

Earlier research has demonstrated that opioid involvement in drinking is primarily mediated centrally [8,10]. Drinking is attenuated by the centrally and peripherally active opioid antagonists naloxone and naltrexone in doses as low as 1.0 mg/kg, but not by the quaternary forms of these antagonists [4]. Peripherally administered quaternary forms of these antagonists fail to suppress drinking in doses as high as 10 mg/kg. We generated dose-response curves for centrally and peripherally administered SR58002C, a "newer" quaternary opioid antagonist purported to have high peripheral selectivity, on drinking in 23.5 hr water deprived rats. SR58002C was administered both intracerebroventricularly (ICV, 0, 10, 40 and 80 micrograms/rat) and intraperitoneally (IP, 0, 10, 40 and 80 mg/kg). Doses of SR58002C above 10 mg/kg IP or 10 micrograms ICV significantly reduced drinking in comparison to controls. However, SR58002C appears to be less potent than quaternary naltrexone in suppressing drinking after ICV administration.

Mode of antagonistic action of levallorphan in morphine-dependent rats and assessment of physical dependence liability.

The antagonistic mode of levallorphan in rats dependent on morphine or codeine was studied from the viewpoints of the doses of morphine and the lengths of administration and also from the standpoint of timing of the challenge. In morphine-dependent rats on morphine-admixed food (60--100 mg/kg/day) for 1, 3 and 6 weeks, the rate of maximum weight loss on application of levallorphan (2 mg/kg, s.c.) did not correlate with the length of morphine treatment. The rate of weight loss on single application of levallorphan 0, 6, 12 or 24 hours after withdrawal or morphine was lower with the passage of time after the withdrawal. Rats which were given levallorphan 3 times in succession, i.e., at 0, 5 and 10 hours after morphine withdrawal showed such a pattern of weight loss that the first application of levallorphan resulted in 7% loss, while with the second and third applications there was little weight loss. Despite the continued withdrawal, the animals began to gain body weight as early as 14 hour, and body weight was totally recovered before the withdrawal in 24 hour. In conclusion, it is advisable to challenge with levallorphan at 0 hour of withdrawal to obtain qualitative and reproducible results. In addition, the application of levallorphan to morphine-dependent rats at adequate intervals provides for the early recovery of abstinence signs.

The absence of Levallorphan-induced post-depressant hyperactivity following stress-reduction

Following the administration of levallorphan(100 mg/kg) rats' well-established avoidance behaviour is severly depressed for 30 minutes. During this period, animals are almost incessantly shocked. During saline trials, rats receive relatively few shocks. It is postulated that the rate enhancement observed after the drug-induced depressant period is probably due to the excessive stress which animals undergo during the depressive phase. Following drug treatment, rats were kept out of operant during the depressive phase. No rate enhancement was observed throughout the 120-minute experimental period. Response rate enhancement seems to depend on the level of stress during the depressant phase of the drug (AU)

Supplementation of general anaesthesia with narcotic analgesics.

Four analgesic drugs--fentanyl, phenoperidine, morphine and pethidine--were compared in a double-blind trial involving 113 patients paralysed and ventilated with nitrous oxide and oxygen. The differences between the drugs were relatively small. There were only slight differences in "duration of action", a term which is questioned in this context. Pethidine appeared to have a slightly longer duration of action than the other drugs. The problems inherent in studying analgesics in this manner are discussed.

Sites of action of morphine involved in the development of physical dependence in rats. I. Comparison of precipitated morphine withdrawal after intraperitoneal and intraventricular injection of morphine antagonists.

In rats made dependent on morphine by implantation of morphine pellets, withdrawal, as precipitated by intraventricular injection of morphine antagonists, was compared to withdrawal as precipitated by systemic antagonist application. The results, most clearly those obtained with a hydrophilic compound, diallyl-nor-morphinium-bromide, point to periventricularly located sites of action for the release of most withdrawal signs by antagonists. Jumping, reaching only low levels after i.ventr. injection of levallorphan and nalorphine, was very pronounced when the benzomorphane derivative SH 254, was used. In the case of writhing and diarrhea, the situation is more complicated. Possibly, central as well as peripheral mechanisms are involved in the expression of these signs.