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Spinal co-administration of peptide substance P antagonist increases antinociceptive effect of the opioid peptide biphalin.

Intrathecal injection of 0.25 micrograms of undecapeptide substance P antagonist (SPA) produced transient antinociception with a peak effect at 5 min. Increasing the SPA dose resulted in neurotoxicity. Intrathecal injection of the opioid peptide biphalin (BIP) produced antinociception for over 3 hrs without neurotoxicity. Co-administration of SPA (at subtoxic doses) increased BIP's antinociceptive effect. Naltrexone reversed analgesia due to BIP alone as well as after BIP+SPA.

Analgesics↗

Complications of lumbar puncture with injection of hydrosoluble material.

We report two cases of severe disorders after spinal puncture with injection of hydrosoluble material. The first case concerned a 36-year-old woman with intrathecal injection of 125 ml of hydrocortisone acetate. An intracranial occipital hematoma developed. The second case concerned a 26-year-old man with intrathecal injection of contrast media and hydrocortisone. A chemical meningitis occurred. In both cases the natural course was favorable. Both complications are well known but rare. A review of the literature is made with description of the mechanisms. Preventive therapeutic measures are reported.

Adult↗

Spinal nociception induced by intramuscular injection of oxytetracycline preparations in rats and pigs.

Some drug formulations for intramuscular use may cause damage, which potentially can be associated with pain. In animals, spinal nociception can be assessed by stereological quantification of number of regional dorsal horn neurones containing intranuclear Fos-protein as a consequence of expression of the c-fos gene. The aim of the present study was to use c-fos gene expression as a measure of nociceptive input after intramuscular injection of different oxytetracycline formulations. Rats were given a 0.3 ml intramuscular injection in the thigh of one of two 100 mg/ml oxytetracycline preparations (Maxicyklin Vet., Boehringer-Ingelheim or Engemycin Vet., Intervet; n=6 for both), 0.9% saline (n=4) or 4% formalin (n=2). In addition, five pigs were given an intramuscular injection of Aquacykline Vet. (Rosco) in a dose of 1.0 ml/10 kg. After three hours the animals were anaesthetised and perfusion fixed and their spinal cords were taken out. Cryostate sections of the spinal cords were stained immunohistochemically for Fos-protein in dorsal horn neurones and then subjected to stereological quantification of Fos-positive neurones. Rats receiving a saline injection had 905+/-586 (mean+/-S.D.) Fos-positive neurones, whereas formalin injection increased this number to 11,091+/-4,825. Rats receiving an injection of Engemycin had 1,932+/-893 Fos-positive neurones, which was not significantly different from the saline group. In contrast, injection with Maxicyklin increased the number of Fos-positive neurones to 5,488+/-3,116, which was higher than after injection of saline (P<0.05). In pigs receiving an Aquacyklin injection, the number of Fos-positive neurones was 3,493+/-2,027, which was not significantly higher than the previously determined basal level. The increased neuronal activation after intramuscular injection of Maxicyklin Vet. may suggest that injection of this drug may be more painful than injection with saline. In contrast, no significant difference in neuronal activation caused by saline and Engemycin Vet. was found.

Animals↗

A selective and extremely potent antagonist of the neurokinin-1 receptor.

Sendide [Tyr6,D-Phe7,D-His9]-substance P(6-11) has been examined by measurements of ligand binding to crude membrane fractions and by functional tests on the spinally mediated behavioral response. Sendide potently displaced [3H]-labeled substance P (SP) binding to mouse spinal cord membranes in a competitive manner. In vivo, sendide, intrathecally co-injected with SP, competitively antagonized SP-induced scratching, biting and licking. The behaviors elicited by physalaemin, septide and [Sar9, Met(O2)11]-SP were also reduced by co-administration of sendide. Large doses of sendide were needed to reduce the action of neurokinin A, D-septide, neurokinin B and eledoisin. The in vitro and in vivo pharmacological profile of sendide demonstrated that it is a selective and extremely potent antagonist of the neurokinin-1 receptor.

Amino Acid Sequence↗

Spinal muscarinic and nicotinic subtypes activated by clonidine in postincisional pain.

BACKGROUND: A recent model of acute incisional pain has been characterized that strongly parallels the postoperative period in patients experiencing evoked pain. In that setting, abundant literature has revealed antihypersensitive effects produced by intrathecally administered alpha2-adrenergic receptor agonists, such as clonidine, in both animals and humans. Recent reports have suggested an obligatory role of spinal acetylcholine receptors in the analgesic action of intrathecal clonidine. The authors sought to determine the involvement of spinal muscarinic and nicotinic receptor subpopulations in the antihypersensitivity effect of intrathecal clonidine in a rodent model for human postoperative pain. METHODS: After intrathecal catheterization, rats underwent superficial plantar incision. Clonidine or a combination of clonidine and muscarinic receptor subtype antagonists (M1, M2, M3, and M4) or nicotinic receptor subtype antagonists (alpha4beta2 and alpha7) were intrathecally administered, and withdrawal thresholds to mechanical stimuli were examined. RESULTS: Spinal clonidine maximally reduced hypersensitivity adjacent to the wound 30 min after its injection. When animals were intrathecally pretreated with the M1 muscarinic antagonist toxin MT-7, the M3 muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine, and the M4 muscarinic antagonist toxin MT-3, clonidine lost its antihypersensitive action. When animals were intrathecally pretreated with the alpha4beta2 nicotinic receptor antagonist dihydro-beta-erythroidine, but not with the alpha7 nicotinic receptor antagonist methyllycaconitine, the antihypersensitivity action of clonidine was abolished. CONCLUSIONS: These data indicate for the first time that the clonidine-induced increase in punctuate mechanical threshold is mediated via the activation of all but M2 muscarinic receptor subtypes, and via the activation of alpha4beta2 but not alpha7 nicotinic receptor subtypes in a rodent model for human postoperative pain.

Aconitine↗

Administration of narcotics in cancer pain.

Cancer pain can be successfully managed with oral or parenteral narcotics in 80% of patients, if those factors that magnify pain perception are also controlled. Pain from any source can be made worse and pain tolerance impaired by depression, regression, intolerance to stress, and/or recurrent withdrawal, all of which require attention and management. Those patients whose cancer pain is still intractable may benefit from a procedure to interrupt pain pathways. Such procedures have become far less common since the introduction of chronic administration of intraspinal narcotics. The subarachnoid route is preferable to the epidural route because it is less likely to result in catheter failure and because much smaller doses can be used, with less systemic effect. In addition, tolerance can be managed more readily by readjustment of dose with the subarachnoid route, and there is no greater incidence of complications. Intraventricular narcotics can be considered in patients whose spinal canal does not allow catheter placement, at approximately 1/10th the spinal dose requirement.

Administration, Oral↗

[Pharmacokinetics of lidocaine used for total spinal anesthesia--a comparison between cervical and lumbar injection].

We studied the effects of site of injection on the serum concentration of lidocaine following total spinal block. Six mg.kg-1 of lidocaine was given into the cervical (n = 11) or lumbar (n = 7) subarachnoid space in 10 patients. The mean maximum serum concentration of lidocaine in the cervical group was found to be significantly greater than that in the lumbar group. Lidocaine given into the cervical subarachnoid space seems to be infiltrated easily into the intracranial space and consequently into the systemic circulation.

Adult↗

Intrathecal fentanyl prolongs sensory bupivacaine spinal block.

The purpose of investigation was to study the effect of intrathecal fentanyl on the onset and duration of hyperbaric bupivacaine-induced spinal block in adult male patients. Forty-three patients undergoing lower extremity or genitourinary surgery were enrolled to receive either 13.5 mg hyperbaric bupivacaine 0.75% + 0.5 ml CSF it, (Group I) or 13.5 mg hyperbaric bupivacaine 0.75% + 25 micrograms fentanyl it, (Group II) according to a randomized assessor-blind protocol. The onset and duration of sensory block were assessed by pinching the skin with forceps in the midclavicular line bilaterally every two minutes for first twenty minutes and then every five to ten minutes. Similarly, the onset and duration of motor block were assessed and graded at the same time intervals using the criteria described by Bromage. The time required for two sensory segment regression and sensory regression to L1 dermatome was 74 +/- 18 and 110 +/- 33 min vs 93 +/- 22 and 141 +/- 37 min in Groups I and II, respectively (P < 0.05). Intrathecal fentanyl did not enhance the onset of sensory or motor block, or prolong the duration of bupivacaine-induced motor spinal block. Fewer patients demanded pain relief in the fentanyl-treated group than in the control group in the early postoperative period (19% vs 59%; P < 0.05). Episodes of hypotension were more frequent in the fentanyl-treated group than in the control group (43% vs 14%; P < 0.05). We conclude that fentanyl, 25 micrograms it, prolonged the duration of bupivacaine-induced sensory block (sensory regression to L1 dermatone) by 28% and reduced the analgesic requirement in the early postoperative period following bupivacaine spinal block.

Adjuvants, Anesthesia↗

Intrathecal and epidural analgesia.

Centroneuraxis analgesia has a place in the management of critically ill patients. With the safety of the intrathecally placed microcatheter now in question, epidural blockade is more suitable in the intensive care unit setting. The different mechanisms of action and the resultant synergy of local anesthetic agents and opioids, as well as their different side effects, are outlined. The contraindications to neuraxial blockade are discussed, and the role of epidural analgesia in the management of flail chest syndrome is addressed in detail.

Analgesia, Epidural↗