Visceral Analgesia Research Articles

Effect of buprenorphine on the cardiovascular and respiratory response to visceral pain in conscious rabbits

ObjectiveTo evaluate the effect of buprenorphine administration on the cardiovascular and respiratory responses to noxious colorectal distension in conscious rabbits. Study designProspective experimental trial. AnimalsFifteen healthy, young adult New Zealand white rabbits (eight female). MethodsExperiments were performed on conscious rabbits that were instrumented with intraabdominal arterial and venous catheters, and diaphragmatic and abdominal electromyographic electrodes. Colorectal distension was achieved by inflation of an acutely placed colorectal balloon catheter until mean arterial pressure increased 10–15 mmHg. Buprenorphine (0.06 mg) or saline was administered intravenously prior to, or during colorectal distension. Arterial blood pressure, heart rate, respiratory rate, abdominal electromyographic activity, and intra-balloon pressure were monitored. ResultsIn the absence of colorectal distension, buprenorphine increased arterial blood pressure and decreased respiratory rate but did not change heart rate. Colorectal distension increased arterial blood pressure and heart rate, and decreased respiratory rate. The increase in arterial blood pressure associated with colorectal distension was attenuated following preemptive buprenorphine, but was not changed by buprenorphine administered during distension. Conclusions and clinical relevanceIf cardiovascular changes reflect the intensity of noxious stimulation, then these results support the preemptive administration of buprenorphine for visceral analgesia.

Pharmacokinetic‐Pharmacodynamic Modeling of Morphine and Oxycodone Concentrations and Analgesic Effect in a Multimodal Experimental Pain Model

Analgesia from most opioids is mediated by mu receptors located mainly in the central nervous system. Previous studies have shown a different pharmacological profile of oxycodone in respect to visceral analgesia. This study investigated if morphine and oxycodone have different pharmacokinetic/pharmacodynamic profiles, in particular with respect to delay between opioid blood concentration and analgesia. Twenty-four healthy subjects had oral morphine (30 mg), oxycodone (15 mg), or placebo. Mechanical, thermal, and electrical pain tests were performed in the skin and viscera. Blood samples and pain measurements were taken at baseline and after 15, 30, 60, 90, and 120 minutes. Pharmacokinetic/pharmacodynamic profiles were modeled using a 2-stage, nonlinear, mixed-effects approach with an effect compartment to represent the concentration-analgesia delay. Morphine kinetics was best described by a 2-compartment model, whereas oxycodone kinetics was best described with a 1-compartment model. Generally the analgesic effects of morphine were best related to plasma concentration by introducing a delay via an effect compartment. However, for oxycodone, this was only the case for analgesia in the somatic pain measures, whereas the plasma concentration correlated better to the course of the analgesia with no delay in the visceral pain measures. Oxycodone and morphine showed different pharmacodynamic/pharmacokinetic relationships for the visceral analgesia, whereas relationships were alike for somatic analgesia.

Effect of a New α2δ Ligand PD-217014 on Visceral Hypersensitivity Induced by 2,4,6-Trinitrobenzene Sulfonic Acid in Rats

PD-217014, a new GABA analog (1α,3α,5α-3-aminomethyl-bicyclo[3.2.0]heptane-3-acetic acid), inhibited [³H]-gabapentin binding to α₂δ subunit of voltage-gated calcium channels in a concentration-dependent manner (K_i = 18 nmol/l). Oral treatment with PD-217014 significantly inhibited the visceral hypersensitivity induced by an intra-colonic injection of trinitrobenzene sulfonic acid in rats. The anti-hyperalgesic effect of PD-217014 increased in a dose-dependent manner, and reached a plateau level at 60 mg/kg p.o. The visceral analgesia produced by PD-217014 at 30 and 60 mg/kg p.o. correlated with blood concentrations within 4 h after dosing, and maximal efficacy was obtained 2 h after dosing when the maximal blood concentration was achieved at either dose. These results indicate that PD-217014 is a potent α₂δ ligand and possesses visceral analgesic activity.

Demonstration of Functional Neuronal β 3-Adrenoceptors Within the Enteric Nervous System

Although the beta(3)-adrenoceptor (AR) has been suggested to be involved in regulation of gut motility and visceral algesia, the precise mechanisms have been unknown. beta(3)-AR has been postulated to have a nonneuronal expression, being initially characterized in adipocytes and subsequently in the smooth muscle. We aimed to investigate the expression of beta(3)-AR in human enteric nervous system and its role in motility and visceral algesia. The expression of beta(3)-AR in human colon myenteric and submucosal plexus was investigated using immunohistochemistry. The effects of a beta(3)-AR agonist on nerve-evoked and carbachol-induced contractions as well as somatostatin release were investigated in strips of human colon. The effect of an agonist on diarrhea and visceral pain was investigated in vivo in rat models. beta(3)-AR is expressed in cholinergic neurons in the myenteric plexus and submucosal plexus of human colon. Activation of beta(3)-AR causes the release of somatostatin from human isolated colon. In a rat model of visceral pain, beta(3)-AR agonist elicits somatostatin-dependent visceral analgesia. beta(3)-AR agonists inhibit cholinergically mediated muscle contraction of the human colon, as well as chemically induced diarrhea in vivo in a rat model. This is the first demonstration of expression of beta(3)-AR in the enteric nervous system. Activation of these receptors results in inhibition of cholinergic contractions and enhanced release of somatostatin, which may lead to visceral analgesia and inhibition of diarrhea. Therefore, beta(3)-AR could be a novel therapeutic target for functional gastrointestinal disorders.

Noncardiac Chest Pain.

Noncardiac chest pain (NCCP) is a common condition with significant morbidity and economic implications. Psychological factors, gastroesophageal reflux disease (GERD), alteration in pain perception, and esophageal dysmotility play an important role in the pathogenesis of the disorder. Proton pump inhibitor (PPI) therapy is the most effective medical intervention for the treatment of GERD-related NCCP, as well as the most cost-effective diagnostic strategy for this condition. Pain modulators such as tricyclic antidepressants, trazodone, and selective serotonin reuptake inhibitors infer a visceral analgesic effect and consequently are the treatment of choice for patients with non-GERD-related NCCP. Furthermore, cognitive behavioral therapy has also been shown to be useful in the management of subset of patients with non-GERD-related NCCP. Newer therapeutic modalities and interventions such as lower esophageal sphincter injection of botulinum toxin in NCCP patients with spastic esophageal motility disorders, theophylline, and 5-HT4 receptor agonists may supplement or replace current treatment for non-GERD-related NCCP. Future compounds may include new visceral analgesics or medications that interfere with the development of peripheral or central sensitization.

Effect of 0.1, 0.2, 0.4, and 0.8 mg kg−1 of intravenous butorphanol on thermal antinociception in cats

Many cats do not receive analgesics for treatment of perioperative pain, but when they do, the opioid agonist–antagonist butorphanol (B) is widely used. B is reported to provide long-lasting visceral analgesia, but its somatic actions are not well documented. This study aimed to assess B by using a thermal threshold (TT) model. Six cats (four spayed females, two castrated males, 4.4–6.9 kg) participated in the study. The day before each study, the lateral thorax of each of the cats was shaved and a cephalic catheter was placed. TT was measured using a thermal threshold testing device specifically developed for cats. A heater element and temperature sensor housed in a small probe was held against the cat's thorax with an elastic band and pressure bladder to assure consistent contact. Skin temperature was recorded before each test, then the heater was activated. When the cat responded by flinching, turning, or jumping, the stimulus was terminated and the threshold temperature recorded. A cut-out temperature was set at 55.5 °C. Three baseline measurements were recorded before IV injections of 0.1, 0.2, 0.4, or 0.8 mg kg−1 of B. Each cat received all doses in a randomized order at least 1 week apart, and the investigator was blinded to the treatments. TT was measured at every 15 minutes for 6 hours. Data were analyzed using a three-factor anova, and the critical mean difference was calculated. Pre-treatment threshold was 40.8 ± 2.25 °C in all cats. There was a significant increase in threshold in all groups from 15 to 90 minutes, but no dose-related differences were observed. Peak threshold achieved was 48.35 °C, 60 minutes after 0.4 mg kg−1 of B was injected. Mydriasis was present in all cats after treatment, and many exhibited dysphoric behavior. In this model, B had a short duration of action and no dose–response relationship. Compared to other opioids tested under similar conditions, the intensity of the effect of B was small and of shorter duration.

Effect of low-dose ketamine on thermal thresholds in cats

The role of ketamine (K) in pain management is controversial. It is reported to provide visceral analgesia in cats. This study aimed to assess its somatic actions using a thermal threshold (TT) model.

Analgesia

Critical to reducing patient morbidity as well as heightened ethical awareness, alleviation of pain in animals has become integral to medical case management and surgical procedures. Pharmacotherapy is directed at peripheral nociceptors, primary and secondary spinal neurons, and pain-processing areas in the CNS. Accordingly, three primary pharmacologic strategies have evolved: drugs that bind to and activate opioid receptors, drugs that bind to and activate alpha 2 receptors, and drugs that reduce de novo prostaglandin synthesis. In horses, the two predominant types of pain encountered are musculoskeletal and visceral pain. Several factors must be considered when devising a therapeutic strategy, including the etiology of the painful event, desired duration of therapy (acute vs chronic), desire for sedation, and potential side effects and toxicity. Opioids and alpha 2 agonists are particularly effective for visceral pain associated with colic. Butorphanol remains the only commercially available opioid and provides superior visceral analgesia compared with pentazocine or flunixin meglumine but not compared with the alpha 2 agonists. The behavioral changes such the sedative effects of alpha 2 agonists and the increased locomotion and CNS excitability seen with some opioids are important considerations when these agents are used as analgesics. NSAIDs may be considered for visceral pain therapy also, especially pain associated with an inflammatory component or endotoxemia. In particular, flunixin meglumine and ketoprofen provide prolonged analgesia and suppress the effects of endotoxin. Long-term therapy of musculoskeletal diseases usually necessitates chronic NSAID use. Although many NSAIDs are now available in approved equine formulations, there remain some important differences among NSAIDs for the practitioner to consider when choosing an analgesic. NSAIDs differ in their ability to ameliorate pyrexia, affect platelet function, alleviate pain, and reduce inflammation. For ease of administration, those available for oral use include phenylbutazone, meclofenamic acid, flunixin meglumine, and naproxen. All are potentially ulcerogenic, and poor tolerance to one may necessitate switching to another with a better toleration profile or to drug from a different analgesic class.

Visceral analgesic tolerance to intrathecal butorphanol in rats.

Recent experimental data suggest that intrathecal (it) kappa-opioid agonists produce profound visceral analgesia. This study investigated the development of visceral analgesic tolerance to it butorphanol, a potent kappa-agonist that has fewer side effects than commonly used it opioids. Understanding of this tolerance could make it butorphanol more effective in treating chronic visceral pain. This was a randomized, controlled animal study involving 80 Sprague-Dawley rats. Rats implanted with lumbar it catheters were infused either with it saline or butorphanol (52 nmol.hr-1) for 96 hr. Six hours afterwards, each rat was challenged once with one of the differing it butorphanol doses to construct dose-response curves. Visceral analgesia was evaluated by the abdominal writhing responses to the acetic acid injected intraperitoneally. The time of the first writhe and the total number of writhes were recorded. For both the saline- and butorphanol-infused groups, a higher challenge dose of it butorphanol produced longer time for the first writhe to occur (P < 0.01, one-way ANOVA), and fewer writhes occurring within 30 min (P < 0.01, one-way ANOVA). However, the dose response curves of the butorphanol-infused groups were shifted rightward (P < 0.001, partial F test). The challenge doses of it butorphanol produced dose-dependent visceral analgesia in both the saline- and butorphanol-infused groups, confirming its efficacy. The butorphanol-infused groups showed dose-response shifts, demonstrating the development of tolerance to this visceral analgesia.

Antagonism of peripheral 5-HT 4 receptors reduces visceral and cutaneous pain in mice, and induces visceral analgesia after simultaneous inactivation of 5-HT 3 receptors

The role of 5-HT 4 receptors on cutaneous and visceral pain remains largely unexplored. The objective of this study was to establish the activity profile of SDZ 205-557, a 5-HT 4 antagonist, on cutaneous (hotplate) and visceral (writhing) models of pain, after peripheral administration. Since SDZ 205-557 possesses some affinity for 5-HT 3 receptors at high doses, nociceptive effects of a 1:1 combination of SDZ 205-557 and MDL 72222, a 5-HT 3 antagonist, were also evaluated. Drugs were injected 30 min before tests (0, 0.001, 0.01, 0.1 or 1 mg/kg IP). A hypoalgesic effect of SDZ 205-557 on cutaneous pain was found at 0.1 and 1 mg/kg doses, as revealed through an enhanced nociceptive threshold in rats placed on the hotplate. This effect was likely mediated through inactivation of peripheral 5-HT 4 receptors. After the 1:1 combination, the hypoalgesic effect disappeared, which indicates that simultaneous inactivation of 5-HT 3 and 5-HT 4 receptors antagonized peripherally 5-HT 4-mediated hypoalgesia by an unknown mechanism. SDZ 205-557 also induced hypoalgesia in the writhing test over the entire dose range tested, and visceral hypoalgesia turned out to be analgesia after 1:1 combination. In summary, findings of the present study imply that: i) antagonism of 5-HT 4 receptors mediates antinociception in enteric viscera and, to a lesser extent, in cutaneous terminals, and ii) dual inactivation of both 5-HT 4 and 5-HT 3 receptors induces visceral analgesia, a fact which might have clinical importance.

Assessment of xylazine hydrochloride epidural analgesia for open castration of rams

Epidural xylazine injected at the sacrococcygeal site 40 to 150 min prior to surgery (at a dose of 0.05 to 0.10 mg/kg) provided good analgesia during scrotal skin incision in all 20 experimental rams but in only 10 rams (50%) at incision and separation of tunica vaginalis, and 6 rams (30%) during ligation of the spermatic cord. There was a significant correlation between the decrease in heart rate and the dosage of epidural xylazine. Heart rate increased significantly during incision of the tunics and spermatic cord ligation but was not significantly correlated to the clinical assessment of analgesia. There was no significant correlation between the presence of surgical analgesia and the dosage of epidural xylazine: Pelvic limb ataxia was still evident in 12 rams (60%) at 8 h after epidural xylazine injection. Epidural xylazine provided good somatic analgesia during open castration of 20 rams but visceral analgesia was unpredictable. Factors in addition to the dosage of sacrococcygeal epidural xylazine affects the degree of surgical analgesia obtained for open castration of rams.

Dose response to butorphanol administered subcutaneously to increase visceral nociceptive threshold in dogs

SUMMARY Butorphanol (0.025, 0.05, 0.1, 0.2, 0.4, and 0.8 mg/kg of body weight, and placebo) was given sc to 8 healthy unmedicated dogs to determine its efficacy for visceral analgesia, using a colonic balloon for minimal threshold nociceptor stimulation. Degree of sedation; systolic, diastolic, and mean arterial pressure; and pulse rate were recorded. The highest 3 dosages, 0.2, 0.4, and 0.8 mg/kg, were found to be most effective, with 0.8 mg/kg the only dosage that was significantly different from control responses at the 45-minute interval. Duration of analgesia ranged from 23 to 53 minutes for all 6 dosages and dosing durations were not significantly different from one another. Blood pressures did not change, but pulse rate was significantly decreased by 0.8 mg of butorphanol/kg. We concluded that butorphanol is an effective visceral analgesic of relatively short duration in the dog.

Selected aspects of the clinical pharmacology of visceral analgesics and gut motility modifying drugs in the horse.

Comparison of the visceral analgesic effects of xylazine, morphine, butorphanol, pentazocine, meperidine, dipyrone, and flunixin in a cecal distention model of colic pain indicated that xylazine produces the most relief from abdominal discomfort. Repeated administration of xylazine may reduce visceral pain so effectively that the seriousness of abdominal disease is obscured. Xylazine decreased propulsive motility in the jejunum and pelvic flexure of healthy ponies. Morphine and butorphanol also gave relief from visceral pain in the cecal distention model. Morphine may inhibit colonic, and butophanol jejunal, motility. Whether xylazine or opiate mediated decreases in gut motility cause clinically important slowing of ingesta transit is controversial and requires further investigation. The development of behavioral changes (i.e., apprehension and pawing) in horses given opiate therapy may limit the use of these drugs. Combinations of xylazine and morphine or butorphanol produce excellent, safe, visceral analgesia and sedation without untoward behavioral effects. Although flunixin fails to demonstrate good visceral analgesic effects in the cecal distention model, this drug produces analgesia in some cases of colic by blocking prostaglandin mediated induction of pain. Improvement of propulsive gut motility in patients with ileus may follow administration of neostigmine (which is particularly effective when the large bowel is hypomotile), naloxone (which experimentally stimulates propulsive colonic motility), and metoclopramide (which stimulates stomach and proximal small intestinal motility).

Central opioid receptor involvement in gastrointestinal motility

The recent development of selective opioid agonists has permitted a better understanding of the importance of the central opioid system in the modulation of propulsion of gastrointestinal contents. It is now apparent that the types of cerebral opioid receptors involved in gut motility are also associated with other opioid effects (e.g. thermal and visceral analgesia). Other types of cerebral opioid receptors are associated with analgesia, but not with gastrointestinal effects. Furthermore, the opioid receptor subtypes in the spinal cord that are involved in these centrally initiated gut effects are not necessarily the same as those at the cerebral level; compounds affecting the gut at spinal cord sites do not always produce similar effects when given into the brain. Spinally-administered opioids do not require communication with supraspinal sites in order to affect the gut. In contrast, bombesin, a nonopioid neuropeptide that normally inhibits transit after intracerebroventricular or intrathecal administration, fails to alter gut motility on intrathecal administration if communication between the brain and the spinal cord has been disrupted. Frank Porreca, James J. Galligan and Thomas F. Burks discuss these developments which indicate that distinct chemosensitive sites within the CNS can be activated to alter gut motility and which offer exciting possibilities for future therapeutic application.

Is lumbar epidural analgesia an alternative in patients who have incomplete colonoscopy with standard premedication?

Total colonoscopy is unsuccessful in about 10% of attempts. In three fourths of the cases, failure is due to the patient's inability to tolerate the procedure and difficulty in negotiating the sigmoid colon. Lumbar epidural analgesia has been used in a series of 29 patients referred for total colonoscopy which had been unsuccessful using intravenous analgesia. The cecum was reached in 27 of 29 examinations. Mean time required to perform total colonoscopy was 10 min and took less than 5 min in one third of the cases. Complete visceral analgesia was responsible for one case of perforation.

Neonatal capsaicin does not affect unmyelinated efferent fibers of the autonomic nervous system: functional evidence

Visceral nociceptive thresholds, viscero-visceral reflexes and the effects of efferent stimulation of autonomic nerves have been studied in adult rats treated at birth with capsaicin. These animals showed visceral analgesia and depressed visceral reflexes. However, stimulation of unmyelinated efferent fibers in autonomic nerves produced normal effects. It is concluded that neonatal treatment with capsaicin destroys selectively unmyelinated afferent fibers.

Kidney Transplantation: Patient Selection and Management

To describe a quadratus lumborum (QL) block technique in canine cadavers and the spread of injectate.Prospective, randomized, descriptive, experimental anatomic study.A group of 12 adult canine cadavers.Gross and ultrasound anatomy of the sublumbar musculature and the relationship with the spinal nerves was studied in two cadavers. Bilateral ultrasound-guided injections were performed in eight cadavers in the fascial plane between the QL and psoas muscle using a dye–lidocaine solution [low volume (LV) 0.15 mL kg–1 or high volume (HV) 0.3 mL kg–1]. The ultrasound transducer was positioned caudal and parallel to the proximal aspect of the last rib, and an insulated needle was introduced in-plane using a ventrolateral to dorsomedial approach. Dissections were performed to determine the number of spinal nerves successfully stained (>1 cm) and the presence of injectate in the epidural space or abdominal cavity. Additionally, two cadavers were transversally cryosectioned after QL injection.Ventral branches of the last thoracic and first three lumbar spinal nerves ran between the bundles of the QL muscle and between the QL and psoas muscles. The target fascial plane was ultrasonographically identified and filled with the dye solution following all injections. Ventral branches of the thirteenth thoracic and first, second and third lumbar nerves were stained by 0.0%, 71.4%, 100%, 100%, and 25%, 100%, 100%, 100% using LV and HV, respectively. Multisegmental spread stained the lumbar sympathetic trunk on 0 (0–3) and 3 (0–4) vertebral levels with LV and HV, respectively. No abdominal or epidural spread was identified.Although no significant differences were found, HV resulted in a higher percentage of stain on spinal nerves and sympathetic trunk than LV. Further studies are warranted to determine if the QL block provides somatic and visceral abdominal analgesia in dogs.

Excitatory and Inhibitory Mechanisms in Visceral Pain and Analgesia

Excitatory and Inhibitory Mechanisms in Visceral Pain and Analgesia