[Dyspnea in the last period of one's life]. / Atemnot in der letzten Lebensphase.

Therapy and the handling of dyspnea in the last period of one's life is described and discussed from a case report. A patient with lung cancer and a distinct chronic obstructive pulmonary disease is presented. His coping with increasing dyspnea and the therapeutic strategies are described. Problems with the side effects of therapy and coping strategies are dealt with, too.

[Symptom control and ethics in final stages of COPD]. / Symptomkontrolle und ethische Aspekte im terminalen Verlauf einer COPD.

On the basis of a case study, the complex problems of the final stages of a COPD will be demonstrated and discussed. Dyspnea and anxiousness are the primary symptoms. If they can be adequately brought under control by opiates and benzodiazepines, a palliative sedation is then not necessary. The communicative and ethical demands on the team responsible are high. It is important to be aware of the specific needs of the patient and of his/her family members, and to competently accompany the patient throughout the decision-making process--such as the decision to end respiratory therapy, for example. Clarifying the situation with the patient and finding out his/her wishes, accompanied by the corresponding documentation, is advisable.

N-cubylmethyl substituted morphinoids as novel narcotic antagonists.

N-Cubylmethylnormorphine (1) and N-cubylmethylnoroxymorphone (2) have been synthesized and found to be more potent ligands at the mu and kappa opioid receptors than morphine and oxymorphone respectively. In the guinea-pig ileum preparation, compounds 1 and 2 were characterized as opioid mu antagonists (Ke = 68 and 16 nM, respectively). Compound 2 also showed effective kappa-antagonism (Ke = 22 nM). The narcotic antagonism activity of 1 has been confirmed by in vivo assays.

Modulation by peripheral opioids of basal and distension-stimulated gastric acid secretion in the rat.

1. The influence of opioids in modulating gastric acid secretory responses has been investigated in the continuously perfused stomach of the anaesthetized rat. 2. Intravenous administration of morphine (0.75-3 mg kg-1) or the peripherally acting enkephalin analogue, BW443C (0.75-3 mg kg-1), substantially augmented acid secretion in basal conditions. These effects were significantly inhibited by the opioid antagonists naloxone (1 mg kg-1) and the peripherally acting N-methylnalorphine (2 mg kg-1). When administered alone, neither opioid antagonist influenced basal acid output. 3. Acid secretory responses to different levels of gastric distension (5-20 cmH2O) were significantly and dose-dependently reduced in rats pretreated with morphine (3 mg kg-1) or BW443C (1.5 mg kg-1). Previous administration of either naloxone or N-methyl nalorphine reversed the inhibitory effects of opioids on gastric acid secretion stimulated by distension. Likewise, blockade of opioid receptors with naloxone or N-methylnalorphine significantly increased acid output induced by distension. 4. Levels of serum gastrin in control animals were not increased after intragastric distension (20 cmH2O). Pretreatment with BW443C (1.5 mg kg-1) did not modify the levels of gastrin present during basal or distension stimulated conditions. 5. Pretreatment with morphine or BW443C did not influence the acid responses to i.v. injection of pentagastrin (100 micrograms kg-1), histamine (5 mg kg-1) or carbachol (4 micrograms kg-1). Acid secretion induced by i.v. administration of 2-deoxy-D-glucose (150 mg kg-1) was reduced in rats pretreated with morphine but not with BW443C. Gastric secretory responses to insulin (0.3 i.u. kg-1) were not modified by i.v. morphine.6. These observations support a role for peripherally acting opioids in the regulation of gastric acid secretion during basal and distension-stimulated conditions.

Possible participation of endogenous opioid peptides on the mechanism involved in analgesia induced by vouacapan.

The involvement of opioid peptides in the mechanism of action of vouacapan, a new experimental compound extracted from seeds of Pterodon poligalaeflorus Benth, was investigated both in mice utilizing acetic acid writhing response and in rats utilizing inflammatory hyperalgesia induced by carrageenan and modified Randall-Selitto method. Vouacapan, in both models, caused a dose-dependent analgesia when injected p.o., s.c. and i.p. The analgesic effect was partially blocked by naloxone, nalorphine and n-methyl-nalorphine. Significant tolerance to analgesic effect was observed following repeated administration of vouacapan or morphine. On the last day of treatment, cross administration revealed symmetrical and asymmetrical cross-tolerance between vouacapan and morphine, in rats and mice, respectively. We conclude that a release of endorphins could be involved in the analgesic mechanism of vouacapan in both models tudied.

Taste aversion involving central opioid antagonism is potentiated in morphine-dependent rats.

A sensitive taste conditioning test was used to measure the aversive effect of a single intraventricular (i.c.v.) or subcutaneous (s.c) injection of an opioid antagonist that readily crosses the blood brain barrier (naltrexone), and one of two that do not (methylnaltrexone and diallylnormorphinium). This was done in drug-naive rats and in rats implanted 5 days earlier with a pellet containing 75 mg morphine. It was found that the morphine exposure had no significant effect on the dose-response curve of the taste aversion produced by s.c. methylnaltrexone and s.c. diallynormorphinium but reduced the lowest effective dose for the other antagonist treatments from three to more than 100 times. Consideration of the data, together with the pharmacokinetic properties of the drugs and the routes of administration used, supported a conclusion that only those aversions involving central antagonist activity show the potentiation effect of chronic morphine treatment. The findings were also discussed with regard to the location of receptors important for aversions produced by opioid antagonists in naive rats.

Effects of codeine, morphine and a novel opioid pentapeptide BW443C, on cough, nociception and ventilation in the unanaesthetized guinea-pig.

1. Antitussive, antinociceptive and respiratory depressant effects of codeine, morphine and H.Tyr.D-Arg.Gly.Phe(4-NO2) Pro.NH2 (compound BW443C) were investigated in unanaesthetized guinea-pigs. Antagonism of the antitussive and antinociceptive effects was investigated by the use of nalorphine and N-methylnalorphine. Naloxone was used to antagonize respiratory depression. 2. Antitussive ED50s (with 95% confidence limits) for inhibition of cough induced by citric acid vapour were for codeine, morphine and BW443C respectively, 9.1(5.8-15), 1.3(0.7-2.4) and 1.2(0.6-2.6) mg kg-1 s.c. and 8.7(4.2-12), 1.6(1.2-1.9) and 0.67(0.002-3.3) mg kg-1, i.v. The antitussive effects of subcutaneous codeine (25 mg kg-1) morphine (8.1 mg kg-1) and BW443C (2.5 mg kg-1) were significantly antagonized by subcutaneous nalorphine (3.0 mg kg-1) and N-methylnalorphine (3.0 mg kg-1). 3. In the multiple toe-pinch test, the antinociceptive ED50s (with 95% confidence limits) of codeine and morphine were 18(16-22) and 2.3(0.4-4.3) mg kg-1, s.c., respectively. Compound BW443C was ineffective in doses of 2.5 and 10 mg kg-1 s.c., a result consistent with its lacking penetration into the CNS. Subcutaneous nalorphine (3.0 mg kg-1) antagonized the antinociceptive action of codeine (25 mg kg-1) and morphine (8.1 mg kg-1). In contrast, N-methylnalorphine (3.0 mg kg-1) had no significant effect on the antinociceptive action of codeine and morphine, suggesting lack of penetration of the CNS by N-methylnalorphine. 4. At doses near to the i.v. ED50 values for the antitussive activity, morphine (1.5mg kg- ', i.v.) and codeine (10mg kg-', i.v.) caused small but significant depressions of ventilation (7.0 +/- 2.3% and 16.5 +/- 8.4% respectively). Higher doses of morphine (10, 30 and 60mg kg- ', i.v.) caused further doserelated depression of ventilation (9.6 +/- 5.3%, 22.4 +/- 6.2% and 36.2 +/- 9.6% respectively) whereas codeine (30 and 60mg kg-' i.v.) caused stimulation of ventilation which was marked (191.3 +/- 43.9%) at 60 mg kg-'. 5. Compound BW443C in doses of 1 or 10mgkg-',i.v. (approximately equal to, and 10 times the EDo for antitussive activity) did not cause significant depression of ventilation. Only at higher doses of 30 and 60mg kg-', i.v. was there a significant decrease in minute volume (13.1 +/- 6.8% and 15.9 +/- 1.89% respectively). The depression of ventilation caused by either BW443C (60mg kg-', i.v.) or morphine (60mg kg-', i.v.) was prevented by pretreatment with naloxone (3mg kg-', i.v.) administered 15 min before morphine or BW443C. 6. These results in the guinea-pig support the hypothesis that the antitussive action of the opiates codeine and morphine and the opioid pentapeptide BW443C do not require penetration of these drugs into the CNS.

Pharmacological effects of nalorphine and nalorphine-7,8-oxide (nalorphine-epoxide): interaction of the intrinsic activity, affinity and pharmacological responses.

We examined the relationship between the pharmacological effects and the interactions of the receptors of nalorphine and its epoxide. The abilities of nalorphine-epoxide to displace [3H]-dihydromorphine (mu-site) and [3H]-ethylketocyclazocine (kappa-site) were practically equal to those of the parent compound, nalorphine, using binding assay to the rat brain membrane preparations. Furthermore, the affinities of mu- and kappa-receptors are virtually uninfluenced by epoxidation of the 7,8-double bond of nalorphine using electrically stimulated mouse and rabbit vasa deferentia. The intrinsic activity of nalorphine, however, is considerably decreased by epoxidation. Moreover, the antagonistic effect of nalorphine to the morphine-induced antinociception (via mu-receptors) was little influenced by epoxidation, but the antinociceptive effect of nalorphine using the acetic acid writhing test was considerably reduced by epoxidation. These results suggest the presence of a higher receptor capacity for the antinociception mediated through kappa-receptors and that the differences between the pharmacological responses of nalorphine and its epoxide are due to the differences of their intrinsic activities.

Methylnalorphinium fails to reverse naloxone-sensitive stress-induced analgesia in mice.

Exposure of mice to cold-restraint stress markedly decreased the number of abdominal constrictions induced by IP acetic acid. Naloxone pretreatment significantly attenuated the antinociceptive effect of cold-restraint stress, suggesting a partial mediation by opioid mechanisms. Pretreatment with the quaternary opioid antagonist methylnalorphinium did not reverse analgesia in stressed mice. Also, nociception in both stressed and non-stressed mice was not modified by pretreatment with the selective alpha 2-adrenoceptor blocker yohimbine. The results suggest that cold-restraint stress promotes analgesia in mice which is mediated in part by opioid but not alpha 2-adrenoceptor mechanisms. Furthermore, the results do not substantiate a peripheral analgesic role for circulating opioids in this model of stress.

Intrinsic activity and effects of guanyl-5'-yl imidodiphosphate, Gpp(NH)p and sodium ion on the affinity of dynorphin 1-13, nalorphine and nalorphine-7,8-oxide to kappa-opioid receptor.

Nalorphine and nalorphine-7,8-oxide (nalorphine epoxide) behaved as partial agonists on the kappa-receptor in the electrically stimulated mouse vas deferens. The effects of a GTP-analogue, GppNHp and Na+ on the inhibition of [3H]ethylketocyclazocine binding by dynorphin 1-13, nalorphine, its epoxide and naloxone (antagonist) were studied with a synaptosomal fraction of guinea pig brain (except a cerebellum) and compared with the intrinsic activity of the test drugs, which was estimated in the electrically stimulated mouse vas deferens. The effects of GppNHp and Na+ on the affinity of the drugs to the kappa-receptor correlated with their intrinsic activities.

Antinociceptive models displaying peripheral opioid activity.

A writhing syndrome was induced in mice by intraperitoneal administration of carbacyclin (1-100 micrograms/kg), a potent stable analogue of prostacyclin. A quaternary opiate agonist and antagonist, N-methyl morphine and N-methyl nalorphine respectively, exhibited potent antinociceptive properties on subcutaneous administration in this model. Naloxone and naltrexone also displayed weak antinociceptive activity in carbacyclin-induced writhing. Given subcutaneously, N-methyl morphine, but not N-methyl nalorphine or naloxone, inhibited carrageenan-induced hyperalgesia in the rat paw. Thus, demonstration of the peripheral antinociceptive effects of quaternary morphine or nalorphine depends upon the experimental model used, in which small variations may affect the ability to exhibit such effects.

Is methylnalorphinium the prototype of an ideal peripheral analgesic?

Oral methylnalorphine ( methylnalorphinium ) caused a dose-dependent selective inhibition of inflammatory hyperalgesia (measured in the rat by a modified version of the Randall- Selitto test) without affecting the oedema. When subcutaneously injected, repeated doses of morphine for 5 days caused progressive analgesic tolerance. Tolerance was not observed after similar treatment with methylnalorphinium or methylmorphinium . Animals displaying analgesic tolerance to systemic morphine did not exhibit tolerance to the local ( intraplantar ) injection of morphine, methylnalorphinium or methylmorphinium . In contrast with nalorphine and other opiates, methylnalorphinium did not reduce intestinal transit in mice. Methylnalorphinium , a mixed opiate agonist-antagonist devoid of central effects, might be considered the prototype of an ideal peripheral analgesic since it was orally active, did not affect intestinal transit and did not cause analgesic tolerance.

Ventral tegmental site of opiate reward: antagonism by a hydrophilic opiate receptor blocker.

The ventral tegmental area has been suggested as a possible site of action for the rewarding effect of opiates on the basis of the fact that local morphine injections in this but not other regions are rewarding. That this is a necessary and not just a sufficient site of opiate rewarding action was suggested by the fact that diallyl-normorphinium bromide, a hydrophilic opiate blocker, caused compensatory increases in intravenous heroin self-administration when injected into the ventral tegmental area but not other brain regions.

Peripheral antinociceptive effects of N-methyl morphine.

Morphine and N-methyl morphine were compared in two antinociceptive tests in mice, the hotplate and acetic acid-induced writhing. Whereas morphine was active in both models, N-methyl morphine was only active in the writhing model. In this model, the antinociceptive effects of N-methyl morphine were antagonized by both naloxone and N-methyl nalorphine. In separate experiments the two quaternary analogues were both [14C]-labelled and shown not to penetrate the blood brain barrier. These results indicate a peripheral site of action for the opioid antinociceptive effects of N-methyl morphine in the writhing model.

Subcutaneous morphine reduces intestinal propulsion in rats partly by a central action.

Rats were given intracerebroventricular or intravenous injections of the quarternary opioid receptor antagonist N,N-diallyl-normorphinium (DANM. 100 microgram). Ten min later morphine (7.5 mg/kg) or loperamide (10 mg/kg) was injected subcutaneously. Intestinal propulsion was assessed by measuring the progress of radioactive chromium (Na51(2) CrO4, 0.5 microCi) along the small intestine. The radioactive chromium was instilled into the proximal duodenum 20 min after injection of morphine or loperamide, and the animals sacrificed 35 min after giving radioactive chromium. Morphine and loperamide both inhibit intestinal propulsion. DANM (100 microgram i.c.v.) reduces the effect of morphine but not loperamide. Intravenous injection of DANM does not reduce anti-propulsive action of morphine. By itself DANM neither increases nor decreases intestinal propulsion. These experiments indicate that morphine, when administered by a peripheral route, reduces small intestinal propulsion in the rat partly through an action on brain opioid receptors.

Morphine antagonists and consummatory behaviors.

Opiate antagonists were tested for their effects upon either drinking or eating in eight experiments. Naloxone, nalorphine, and the active isomer of WIN 44,441 all reduce drinking. Neither an analog of nalorphine that does not cross the blood-brain barrier, nor the inactive isomer of WIN 44,441 is effective in reducing water intake. These data provide support for the conclusion that these antagonists ahve stereospecific effects within the central nervous system. Naloxone suppresses drinking following procedures inducing osmotic, volemic, or hormonal thirst. Naloxone suppresses eating following procedures inducing glucoprivation but does not alter eating elicited by tail-pressure. Collectively, these data lead to the conclusion that endorphins play a role in the organization of ingestive behavior following challenges to homeostasis.

Morphine no longer blocks gastrointestinal transit but retains antinociceptive action in diallylnormorphine-pretreated rats.

Diallylnormorphine (DANM) the quaternary N-allyl derivative of nalorphine, administered to rats, 8 mg/kg i.p., 20 min before i.v. injection of the potent opiate buprenorphine (1 microgram/kg, tritrium-labeled), reduced in vivo binding of the latter (63% of controls at 30 min) in small intestine longitudinal muscle including myenteric plexus, but not in cerebrum. Naloxone, 1 mg/kg s.c., had the same effect of buprenorphine binding in the two sites (52 and 54% of controls respectively). The marked slowing in the transit of a forced charcoal meal through the small intestine of rats given 10 mg/kg morphine, i.v. was prevented to comparable extents by DANM and naloxone; the latter also abolished the delay in hot plate reaction induced in these animals by morphine which, however, retained considerable antinociceptive effect in DANM-pretreated rats.