Current and Future Issues in the Development of Spinal Agents for the Management of Pain.

Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.

Effects of acetylcholinesterase inhibition on quality of recovery from isoflurane-induced anesthesia in horses.

OBJECTIVE: To compare effects of 2 acetylcholinesterase inhibitors on recovery quality of horses anesthetized with isoflurane. ANIMALS: 6 horses in phase 1, 7 horses in phase 2A, and 14 horses in phase 2B. PROCEDURES: The study comprised 3 phases (2 randomized, blinded crossover phases in horses undergoing orthopedic procedures and 1 prospective dose-determining phase). In phase 1, horses were anesthetized with isoflurane and received neostigmine or saline (0.9% NaCl) solution prior to anesthetic recovery. Phase 2A was a physostigmine dose-determining phase. In phase 2B, horses were anesthetized with isoflurane and received neostigmine or physostigmine prior to recovery. Objective recovery events were recorded and subjective visual analogue scale scores of recovery quality were assigned from video recordings. RESULTS: Recovery measures in phase 1 were not different between horses receiving neostigmine or saline solution. In phase 2A, 0.04 mg of physostigmine/kg was the highest cumulative dose that did not cause clinically relevant adverse behavioral or gastrointestinal effects. Horses receiving physostigmine had higher mean ± SD visual analogue scale recovery scores (70.8 ± 13.3 mm) than did horses receiving neostigmine (62.4 ± 12.8 mm) in phase 2B, with fewer attempts until sternal and standing recovery. Incidence of colic behavior did not differ among groups. CONCLUSIONS AND CLINICAL RELEVANCE: Inhibition with physostigmine improved anesthetic recovery quality in horses anesthetized with isoflurane, compared with recovery quality for horses receiving neostigmine. Inhibition of central muscarinic receptors by inhalation anesthetics may underlie emergence delirium in horses recovering from anesthesia.

Intrathecal substance P-saporin in the dog: distribution, safety, and spinal neurokinin-1 receptor ablation.

BACKGROUND: Neurokinin-1 receptors (NK1-rs) located on superficial dorsal horn neurons are essential for integration of nociceptive input. Intrathecal injection of substance P-saporin (SP-SAP) leads to local loss of spinal NK1-r (+) neurons suggesting its potential as a therapeutic agent for chronic pain. The authors determined, in a canine model, effects of lumbar intrathecal SP-SAP. METHODS: Distribution of SP-SAP and Saporin was determined in plasma, lumbar cerebrospinal fluid, and tissue. Safety of intrathecal SP-SAP was determined in four groups (six dogs each) administered 0 (0.9% saline), 1.5, 15, or 150 µg SP-SAP through lumbar intrathecal catheters. Behavioral, physiologic, and biochemical variables were assessed. Spinal tissues were collected at 7 and approximately 90 days, or earlier if significant morbidity developed, and analyzed for NK1-r (+) neuron loss and histopathology. RESULTS: SP-SAP and Saporin were detectable in lumbar cerebrospinal fluid for up to 4 and 24 h, respectively. Animals receiving intrathecal saline, 1.5, or 15 µg of SP-SAP showed no persistent neurologic deficits. Three animals receiving 150 µg of SP-SAP developed pelvic limb paraparesis and were euthanized prematurely. Immunohistochemistry and in situ hybridization cell counts confirmed a significant reduction in NK1-r (+) in superficial dorsal horn neurons from lumbar spinal cord after intrathecal administration of 15 and 150 µg of SP-SAP. A significant loss of NK1-r neurons in the lumbar ventral horn occurred only with 150-µg SP-SAP. CONCLUSION: Intrathecal 15-µg SP-SAP reduced dorsal, but not ventral, NK1-r (+) neurons at the spinal level of delivery with minimal side effects, whereas 150-µg SP-SAP resulted in motor neuron toxicity.

Cardiovascular and respiratory effects of incremental doses of dopamine and phenylephrine in the management of isoflurane-induced hypotension in cats with hypertrophic cardiomyopathy.

OBJECTIVE: To determine cardiopulmonary effects of incremental doses of dopamine and phenylephrine during isoflurane-induced hypotension in cats with hypertrophic cardiomyopathy (HCM). ANIMALS: 6 adult cats with severe naturally occurring HCM. PROCEDURES: Each cat was anesthetized twice (once for dopamine treatment and once for phenylephrine treatment; treatment order was randomized). Hypotension was induced by increasing isoflurane concentration. Cardiopulmonary data, including measurement of plasma concentration of cardiac troponin I (cTnI), were obtained before anesthesia, 20 minutes after onset of hypotension, and 20 minutes after each incremental infusion of dopamine (2.5, 5, and 10 µg/kg/min) or phenylephrine (0.25, 0.5, and 1 µg/kg/min). RESULTS: Mean ± SD end-tidal isoflurane concentration for dopamine and phenylephrine was 2.44 ± 0.05% and 2.48 ± 0.04%, respectively. Cardiac index and tissue oxygen delivery were significantly increased after administration of dopamine, compared with results after administration of phenylephrine. Systemic vascular resistance index was significantly increased after administration of phenylephrine, compared with results after administration of dopamine. Oxygen consumption remained unchanged for both treatments. Systemic and pulmonary arterial blood pressures were increased after administration of both dopamine and phenylephrine. Acid-base status and blood lactate concentration did not change and were not different between treatments. The cTnI concentration increased during anesthesia and infusion of dopamine and phenylephrine but did not differ significantly between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Dopamine and phenylephrine induced dose-dependent increases in systemic and pulmonary blood pressure, but only dopamine resulted in increased cardiac output. Hypotension and infusions of dopamine and phenylephrine caused significant increases in cTnI concentrations.

Investigation of escalating and large bolus doses of a novel, nano-droplet, aqueous 1% propofol formulation in cats.

OBJECTIVE: Identify, describe, and quantitate effects of an escalating dose of a nano-droplet formulation of 1% w/v propofol in telemetered cats. STUDY DESIGN: Prospective two-period parallel design with one treatment procedure per period. ANIMALS: Four female intact, purpose-bred domestic short-hair cats. METHODS: Each animal served as its own control in each period. Telemetered cats were anesthetized on two separate occasions. In Phase I, cats received propofol (8 mg kg(-1)) over 90 seconds. Unless a severe adverse event (SAE) had occurred by this time, repeated doses of 4 mg kg(-1) intravenous (IV) propofol were administered every 3 minutes until the onset of an SAE. In Phase 2, the IV dose of propofol required to produce at least one SAE in Phase I was administered unless an SAE occurred before the dose was completed. Propofol infusion ceased after development of the first SAE. Heart rate, heart rhythm, respiratory rate, systolic, diastolic, and mean arterial blood pressure, SpO(2) and body temperature were continuously recorded before, during and after propofol administration. The incidence and time to onset of an SAE and dose of propofol required to produce an SAE were recorded. The response criteria included time to lateral recumbency, times to orotracheal intubation and extubation, time to sternal recumbency during recovery, time to and duration of first adverse event(s), and total dose of propofol administered. RESULTS: The dose of propofol required to produce an SAE in Phase I was 16.6 and 15.2 mg kg(-1) in Phase 2. Hypotension was the first and most frequently observed SAE. CONCLUSIONS: Larger doses of a novel, nano-droplet propofol formulation can produce SAEs similar to those reported for lipid emulsion formulations. CLINICAL RELEVANCE: Systemic arterial blood pressure should be monitored in cats administered IV propofol.

Anesthetic and cardiopulmonary effects of intramuscular morphine, medetomidine, ketamine injection in dogs.

OBJECTIVE: To determine the quality and duration of anesthesia and the cardiopulmonary effects of a morphine, medetomidine, ketamine (MMK) combination administered intramuscularly (IM) to dogs. STUDY DESIGN: Descriptive injectable anesthetic protocol evaluation. ANIMALS: Eight intact adult Beagle dogs: five males, three females. METHODS: The electrocardiogram, heart rate, direct arterial blood pressure, and core body temperature were monitored in eight chronically instrumented dogs. Each dog received 0.2 mg kg(-1) morphine sulfate, 20 microg kg(-1) medetomidine hydrochloride, and 5 mg kg(-1) ketamine hydrochloride IM. Anesthetic and analgesic effects (clamping the tail and metatarsus) were categorized, and the times to lateral recumbency, orotracheal intubation, extubation, and sternal recumbency were recorded. Respiratory, cardiovascular, temperature, and acid-base variables were recorded 5 minutes before, and 3, 10, 20, 30, 45, 50, and 60 minutes after MMK. Atipamezole, 100 microg kg(-1) IM, was administered 60 minutes after MMK administration and data recorded 10 minutes later. RESULTS: The onset of anesthesia was uneventful and rapid. Time to lateral recumbency was 7.1 +/- 4.1 minutes. The tracheas of four dogs were orally intubated in 5.1 +/- 0.8 minutes. After MMK administration most dogs were unresponsive to noxious stimulation from 20 to 60 minutes and heart rate, cardiac index and venous blood pH were significantly decreased from baseline values. Arterial blood pressure increased initially and then returned to baseline values. Times to extubation (four dogs) and return to sternal recumbency after atipamezole administration were 2.8 +/- 1.8 and 4.3 +/- 4.4 minutes, respectively. CONCLUSION: The IM administration of MMK produced anesthesia and analgesia in Beagle dogs. Hemodynamic data were within accepted normal values. Atipamezole administration produced rapid return to consciousness in all dogs. CLINICAL RELEVANCE: Morphine/medetomidine/ketamine may be used for minor medical and surgical procedures requiring short-term anesthesia and analgesia but it is not recommended for medical procedures that are painful.

Effects of perzinfotel on the minimum alveolar concentration of isoflurane in dogs.

OBJECTIVE: To determine the effect of IV administration of perzinfotel on the minimum alveolar concentration (MAC) of isoflurane in dogs. Animals-6 healthy sexually intact male Beagles. PROCEDURES: Dogs were instrumented with a telemetry device that permitted continuous monitoring of heart rate, arterial blood pressure, and body temperature. Dogs were anesthetized with propofol (4 to 6 mg/kg, IV) and isoflurane for 30 minutes before determination of MAC of isoflurane. Isoflurane MAC values were determined 4 times, separated by a minimum of 7 days, before and after IV administration of perzinfotel (0 [control], 5, 10, and 20 mg/kg). Bispectral index and percentage hemoglobin saturation with oxygen (SpO(2)) were monitored throughout anesthesia. RESULTS: Isoflurane MAC was 1.32 +/- 0.14%. Intravenous administration of perzinfotel at 0, 5, 10, and 20 mg/kg decreased isoflurane MAC by 0%, 24%, 30%, and 47%, respectively. Perzinfotel significantly decreased isoflurane MAC values, compared with baseline and control values. The bispectral index typically increased with higher doses of perzinfotel and lower isoflurane concentrations, but not significantly. Heart rate, body temperature, and SpO(2) did not change, but systolic, mean, and diastolic arterial blood pressures significantly increased with decreases in isoflurane MAC after administration of perzinfotel at 10 and 20 mg/kg, compared with 0 and 5 mg/kg. CONCLUSIONS AND CLINICAL RELEVANCE: IV administration of perzinfotel decreased isoflurane MAC values. Improved hemodynamics were associated with decreases in isoflurane concentration.

Anaesthetic and cardiopulmonary effects of intramuscular morphine, medetomidine and ketamine administered to telemetered cats.

The quality and duration of anaesthesia, cardiorespiratory effects and recovery characteristics of a morphine, medetomidine, ketamine (MMK) drug combination were determined in cats. Six healthy, adult female cats were administered 0.2 mg/kg morphine sulphate, 60 microg/kg medetomidine hydrochloride, and 5 mg/kg ketamine hydrochloride intramuscularly. Atipamezole was administered intramuscularly at 120 min after MMK administration. Time to lateral recumbency, intubation, extubation and sternal recumbency were recorded. Cardiorespiratory variables and response to a noxious stimulus were recorded before and at 3 min and 10 min increments after drug administration until sternal recumbency. The time to lateral recumbency and intubation were 1.9+/-1.2 and 4.3+/-1.2 min, respectively. Body temperature and haemoglobin saturation with oxygen remained unchanged compared to baseline values throughout anaesthesia. Respiratory rate, tidal volume, minute volume, heart rate, and blood pressure were significantly decreased during anaesthesia compared to baseline values. One cat met criteria for hypotension (systolic blood pressure <90 mmHg). End tidal carbon dioxide increased during anaesthesia compared to baseline values. All but one cat remained non-responsive to noxious stimuli from 3 to 120 min. Time to extubation and sternal recumbency following atipamezole were 2.9+/-1.1 and 4.7+/-1.0 min, respectively. MMK drug combination produced excellent short-term anaesthesia and analgesia with minimal cardiopulmonary depression. Anaesthesia lasted for at least 120 min in all but one cat and was effectively reversed by atipamezole.

Helicobacter pylori and cholesterol gallstone formation in C57L/J mice: a prospective study.

Recently, we demonstrated that cholesterol gallstone-prone C57L/J mice rarely develop gallstones unless they are infected with certain cholelithogenic enterohepatic Helicobacter species. Because the common gastric pathogen H. pylori has been identified in the hepatobiliary tree of cholesterol gallstone patients, we wanted to ascertain if H. pylori is cholelithogenic, by prospectively studying C57L infected mice fed a lithogenic diet. Weanling, Helicobacter spp.-free male C57L mice were either infected with H. pylori SS1 or sham dosed. Mice were then fed a lithogenic diet (1.0% cholesterol, 0.5% cholic acid, and 15% dairy triglycerides) for 8 wk. At 16 wk of age, mice were euthanatized, the biliary phenotype was analyzed microscopically, and tissues were analyzed histopathologically. H. pylori infection did not promote cholesterol monohydrate crystal formation (20% vs. 10%), sandy stone formation (0% for both), or true gallstone formation (20%) compared with uninfected mice fed the lithogenic diet (10%). Additionally, H. pylori failed to stimulate mucin gel accumulation in the gallbladder or alter gallbladder size compared with uninfected animals. H. pylori-infected C57L mice developed moderate to severe gastritis by 12 wk, and the lithogenic diet itself produced lesions in the forestomach, which were exacerbated by the infection. We conclude that H. pylori infection does not play any role in murine cholesterol gallstone formation. Nonetheless, the C57L mouse develops severe lesions of both the glandular and nonglandular stomach in response to H. pylori infection and the lithogenic diet, respectively.

Characteristics of pain and response to analgesic treatment in dogs and cats examined at a veterinary teaching hospital emergency service.

OBJECTIVE: To estimate the prevalence and characteristics of pain in dogs and cats examined by an emergency service at a veterinary teaching hospital and evaluate the response of dogs and cats with signs of pain to analgesic treatment. DESIGN: Cross-sectional study. ANIMALS: 317 dogs and 112 cats. PROCEDURE: A questionnaire was used to categorize the characteristics of pain. The location, cause, and signs of pain were determined by obtaining a thorough history and conducting a physical examination. Pain was categorized by type (superficial somatic, deep somatic, or visceral), mechanism (inflammatory, neuropathic, or both), severity (mild, moderate, or severe), and duration. Evidence for primary or secondary hypersensitivity and hyposensitivity to manipulation was determined. The response to single or multiple analgesic drug administration was assessed. RESULTS: 179 (56%) dogs and 60 (54%) cats had signs of pain. In most of these dogs and cats, pain was classified as acute (< 24 hours' duration) and of moderate severity and was associated with primary hypersensitivity. Most dogs had deep somatic pain; most cats had visceral pain. Inflammation was the most common mechanism. One hundred nineteen (66%) dogs and 41 (68%) cats were treated with analgesic drugs. Analgesic treatment was considered effective in 73 (61%) dogs and 31 (76%) cats. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that moderate to severe acute somatic pain caused by inflammation is common in dogs and cats examined by an emergency service and that a combination of multiple analgesic drugs is more effective than any single analgesic drug in the treatment of pain in these dogs and cats.

Comparison of lactated Ringer's solution and a physiologically balanced 6% hetastarch plasma expander for the treatment of hypotension induced via blood withdrawal in isoflurane-anesthetized dogs.

OBJECTIVE: To compare the effects of lactated Ringer's solution (LRS) with those of a physiologically balanced 6% hetastarch plasma expander administered to isoflurane-anesthetized dogs with hypotension induced by blood withdrawal. ANIMALS: 12 healthy Beagles. PROCEDURE: Blood was withdrawn from isoflurane-anesthetized dogs (volume withdrawn measured) to a systolic arterial blood pressure (SAP) of 80 mm Hg. Six dogs each received either LRS or hetastarch solution (90 mL/kg/h, i.v.). Hemodynamic variables, pH, blood gas concentrations, PCV, serum electrolyte and total protein concentrations, and colloid osmotic pressure (COP) were determined at baseline, while SAP was 80 mm Hg, and after fluid treatment. The volume of fluid administered and rate of return of SAP to within 10% of baseline values were recorded. RESULTS: Mean +/- SD volume of blood withdrawn to decrease SAP to 80 mm Hg was 173 +/- 38 mL. Hemodynamic variables decreased after blood withdrawal but returned to baseline values more rapidly after infusion of a smaller volume of hetastarch solution, compared with the response to LRS infusion. Whereas PCV and serum total protein concentration decreased after administration of either solution, COP decreased only after administration of LRS. The total volume of hetastarch solution and LRS required to restore and maintain SAP to within 10% of baseline values was 1.1 +/- 0.9 and 4.4 +/- 1.7 times greater than the volume of blood removed, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with LRS infusion, smaller volumes of hetastarch solution normalized and maintained SAP without lowering COP in isoflurane-anesthetized dogs after blood withdrawal.

Prevalence and characteristics of pain in dogs and cats examined as outpatients at a veterinary teaching hospital.

OBJECTIVE: To determine prevalence of pain among dogs and cats examined as outpatients at a veterinary teaching hospital and characteristics of pain in dogs and cats with evidence of pain. DESIGN: Cross-sectional study. ANIMALS: 1,153 dogs and 652 cats examined as outpatients at The Ohio State University during 2002. PROCEDURE: A questionnaire was administered to owners of all dogs and cats. For dogs and cats with evidence of pain, the cause, signs, anatomic location, type (superficial somatic, deep somatic, or visceral), duration, and severity of the pain and the principle mechanism (inflammatory, neuropathic, both, or unknown) responsible for the pain were determined on the basis of questionnaire responses and results of physical examination. The presence of primary hyperalgesia, secondary hyperalgesia, allodynia, and hyposensitivity was recorded. RESULTS: 231 (20%) dogs and 92 (14%) cats had evidence of pain. Dogs with evidence of pain were significantly older and heavier than dogs without. Cats with evidence of pain were significantly older than cats without. In most dogs and cats with evidence of pain, the pain was determined to be of short duration (< 7 days), of mild or moderate severity, somatic, associated with primary hyperalgesia, and inflammatory. Analgesic drugs were frequently administered to dogs with chronic pain, but were not always considered effective. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that mild or moderate pain associated with inflammation may be seen in dogs and cats examined as outpatients. Older, heavier dogs and older cats were more likely to have evidence of pain.

Effects of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane.

OBJECTIVE: To determine the effects of constant rate infusion of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine (MLK) combination on end-tidal isoflurane concentration (ET-Iso) and minimum alveolar concentration (MAC) in dogs anesthetized with isoflurane and monitor depth of anesthesia by use of the bispectral index (BIS). ANIMALS: 6 adult dogs. PROCEDURE: Each dog was anesthetized with isoflurane on 5 occasions, separated by a minimum of 7 to 10 days. Individual isoflurane MAC values were determined for each dog. Reduction in isoflurane MAC, induced by administration of morphine (3.3 microg/kg/min), lidocaine (50 microg/kg/min), ketamine (10 microg/kg/min), and MLK, was determined. Heart rate, mean arterial blood pressure, oxygen saturation as measured by pulse oximetry (Spo2), core body temperature, and BIS were monitored. RESULTS: Mean +/- SD isoflurane MAC was 1.38 +/- 0.08%. Morphine, lidocaine, ketamine, and MLK significantly lowered isoflurane MAC by 48, 29, 25, and 45%, respectively. The percentage reductions in isoflurane MAC for morphine and MLK were not significantly different but were significantly greater than for lidocaine and ketamine. The Spo2, mean arterial pressure, and core body temperature were not different among groups. Heart rate was significantly decreased at isoflurane MAC during infusion of morphine and MLK. The BIS was inversely related to the ET-Iso and was significantly increased at isoflurane MAC during infusions of morphine and ketamine, compared with isoflurane alone. CONCLUSIONS AND CLINICAL RELEVANCE: Low infusion doses of morphine, lidocaine, ketamine, and MLK decreased isoflurane MAC in dogs and were not associated with adverse hemodynamic effects. The BIS can be used to monitor depth of anesthesia.