|
|
Anesthesia, Analgesia, Sedation and EuthanasiaLast updated on June 28, 2002 Pharmacology of Anesthetics, Analgesics and Tranquilizers Take the quiz! Dosage recommendations by species Mice Rats Guinea pigs Hamsters Links to other pages: ACLAM has a Position Statement (in PDF format) entitled "Guidelines for the Assessment and Management of Pain in Rodents and Rabbits", which has information regarding diagnosis, management, and physiologic effects of pain, along with the effects of some analgesic classes and examples of efficacious analgesic strategies. Take the quiz! Take the quiz! Anesthesia of Dogs, Cats, and Ferrets Take the quiz! Anesthesia and Analgesia of Swine Take the quiz! Dealing with Pain and DistressDefinitionsAllodynia: pain due to a stimulus which does not normally provoke pain. Hyperalgesia: increased response to a stimulus which is normally painful Neurogenic pain: pain initiated or caused by a primary lesion, dysfunction, or transitory perturbation in the peripheral or central nervous system; this occurs in the absence of nociceptor stimulus and is a different sort of pain than nociceptive pain Neuropathic pain (a subset of neurogenic pain): pain initiated or caused by a primary lesion or dysfunction in the nervous system (I'm confused, too, but there doesn't seem to be much difference between the two terms)
Several elements must be present in order for a creature to perceive pain. First, there must be an injury which is sufficient to stimulate sensory nerves. Second, those nerve impulses must gain access to the central nervous system such that local muscle reflexes, autonomic reflexes affecting heart rate, blood pressure, respiration rate and endocrine responses occur. Third, afferent impulses must be sent to the thalamus and the cortex, where they must be translated into the sensation the animal knows as pain. This assessment by the mind includes comparison with past experience, present conditions, and the animal’s expectations for the future given the knowledge of the injury. When all these have taken place, behavioral events such as vocalization may occur.{3578} Experienced observers can assess
acute pain in animals, but chronic pain and distress are much harder to
diagnose because they tend to have more subtle signs. Acute pain is
characterized by:
Because it can be so difficult to
assess pain in animals, prevention is of paramount importance. The environment
can be used to advantage in controlling distress: white noise can be produced
to mask bothersome noise, ultrasound emissions can be controlled or limited,
human traffic can be limited to only that which is necessary, and animals
should always be conditioned prior to the commencement of experiments. When
performing experimental manipulations, investigators should always remove the
animal from the room, use chemical restraint wisely, consider using telemetry
where possible, and use the least painful technique to get the job done (i.e.
subcutaneous injections rather than IM or IP). Invasive experiments such as
antibody production and tumor induction must be limited to only those which
have been carefully evaluated by the IACUC.{3578}
Surgery and recovery are the most difficult areas to assess and control. Attention should be given to the use of fluids and electrolytes, analgesics, and maintenance of a warm comfortable environment.{3578} In rodents, testing methods for
analgesics include tail-flick and hot-plate tests. In the tail-flick test, a
commercially available apparatus (IITC Tail Flick Analgesy Meter, Life Science
Instruments) directs a beam onto the tail and measures the amount of time until
the rodent moves its tail. The beam intensity can be varied to control the
amount of latency time. In the hot-plate test (IITC Hot Plate Analgesy Meter),
the animal is placed on a plate heated to 53°C and the latency for the animal
to jump, lick its hind paw or vocalize is measured.{4138} Neonatal PainMice and rats (and perhaps humans) show exaggerated non-specific basal pain behaviors, and have lower nociceptive thresholds, but there is insufficient information to make assessment of the degree to which a neonate (i.e. first week of life) feels pain. For example, in a toe-clipping experiment in mice at either 3 or 7 days of age, about half the pups showed no pain response at all, a further 30-40% showed sporadic paw withdrawal when the hind toe was clipped, and a very small minority withdrew a front, or both, paws. P7 pups displayed a bit more withdrawal response than did P3 pups. The pups clipped or just handled at P3 had longer hotplate latency times (about 2 seconds) when tested at 12 weeks of age. Serum corticosterone levels of P7 pups were increased with handling, but not further increased with toe clipping. There is a "stress hypo-responsive" period from birth until P12 in mice and rats during which basal corticosterone levels are low and do not respond to stress.{4739}
Anesthetics{4161}Hypnotics (chloral hydrate, a-chloralose, urethane, propofol, metomidate/etomidate, tribromoethanol) a2-agonists (xylazine, medetomidine, detomidine) Sedatives and tranquilizers (phenothiazines, butyrophenones, benzodiazepines) BarbituratesDescription: sedative-hypnotic; all derived from barbituric acid, which is itself non-depressant but has side-chain substitutions that result in short-acting (pentobarbital) or ultra-short-acting (thiamylal, methohexital, thiopental) drugs. Ethyl-(1-methylpropyl)malonylthiourea, also known as EMTU and thiobutabarbital (trade name Inactin®) have been popular in rat renal studies because it induces long stable states; however it is ineffective and toxic in rabbits (although {4156} says that it can be combined with xylazine to provide safe and consistent anesthesia). The old veterinary preparation made by Abbott was dissolved in 10% ethanol. The human formulation, Nembutal (Abbott), is dissolved in 40% propylene glycol, 10% ethanol, and sterile water. When given to rabbits, significant intravascular hemolysis may result. This is apparently due mostly to the propylene glycol, although sterile water and 40% ethanol can also cause it. Rabbit RBCs are said to be osmotically fragile. {4122} Biodisposition: Ultra-short-acting barbiturates are more lipid-soluble, resulting in rapid crossing of the blood-brain barrier. Barbiturates are redistributed from the CNS to other tissues, causing short durations of action unless the animal is infused or re-dosed. Prolonged recovery results from this redistribution. Pentobarbital and thiopental are metabolized in the liver by cytochrome P450-dependent microsomal enzymes. Rats excrete it in the bile, but sheep excrete it in the urine. Tolerance to barbiturate effects occurs when there is hepatic enzyme induction, causing a reduced response to the same dose on subsequent exposures. Drugs that depress hepatic microsomal enzyme function, such as chloramphenicol, prolong sleep times{4177}. Other drugs (sulfonamides, salicylates, doxycycline, phenylbutazone) displace barbiturates from serum protein-binding sites with the same effect. Administration of glucose, fructose, lactate, pyruvate or glutamate during recovery can cause the animal to be re-anesthetized; this is called the "glucose effect." Mechanism of Action: Enhanced GABA-mediated inhibition of synaptic transmission. Thiobarbiturates act preferentially in the reticular activating system, depressing higher brain centers. Pharmacologic Effects:
Back to anesthetics/analgesics HypnoticsChloral hydrateDescription: Originally used in horses as a pre-medication, and extended to lab animals because of a wide margin of safety. Biodisposition: Reduced to the active metabolite (trichloroethanol), and then hepatic conjugation with glucuronic acid and excreted in the urine. Pharmacologic Effects: Acts in the cerebrum; motor and sensory nerves are not affected and it causes minimal analgesia. Cerebral depression is so slow that if used for euthanasia there is much gasping and muscle spasm. Although hypnotic doses have little cardiovascular or respiratory depression, anesthetic doses are severely depressive. Sensitizes the heart to sudden vagal arrest or arrhythmia (dog). Irritates stomach mucosa and causes severe inflammation and necrosis if given perivascularly. Concentrated solutions cause hemolysis and hematuria. Causes adynamic ileus with morbidity and death in rats and hamsters when given ip. Back to anesthetics/analgesics a-chloraloseDescription: a water-soluble reaction product of glucose and anhydrous chloral; the b-isomer causes convulsions but the a-isomer is hypnotic. Is solubilized for administration either by heating or by combining with 25% urethane. It produces 8-10 hours of hypnosis without affecting reflexes. Analgesia is poor. As an anesthetic there is much species variation. It is generally not recommended for survival procedures because of rough induction, prolonged recovery and seizures in some species. Biodisposition: Metabolized to chloral and then to trichloroethanol, and should therefore be like chloral hydrate. Pharmacologic Effects: Used for restraint with minimal cardiac and respiratory depression. Spinal reflexes may be increased. Is commonly considered to preserve autonomic reflexes such as baroreceptors and chemoreceptors. IP administration in guinea pigs, rats, pigs, and calves causes severe inflammation depending on concentration. Back to anesthetics/analgesics Urethane (ethyl carbamate)Description: Readily soluble ester of carbamic acid, is volatile at room temperature. Has more analgesic property than chloralose, allowing surgery to be performed in small rodents. In combination with alpha chloralose, deeper surgical anesthesia can be obtained. The urethane component suppresses muscle activity and reflexes and the CNS, while maintaining stable respiratory patterns. Has minor effects on neurotransmission which should be noted by those researchers.Has a wide margin of safety, causes 8-10 hours of narcosis with minimal respiratory or cardiovascular depression while maintaining spinal reflexes. Biodisposition: Is carcinogenic and mutagenic. Metabolized to CO2 (blown off by lungs), ammonia, and ethanol (which may account for its anxiolytic, sedative/hypnotic action). Following IP injection, urethane distributes evenly to all tissues. Transient narcosis occurs even with skin exposure in mice. It is also well absorbed when given SQ or orally. Pharmacologic Effects: At anesthetic doses (1-1.2mg/gm) in rats, it causes minimal changes in blood pressure, aortic blood flow and blood gas values. Plasma ß-endorphin-like immunoreactivity is increased. Respiratory effects include changes in blood gases in rabbits and rats; hypercapnia and hypoxia in hamsters, whereas one report claimed that rats hyperventilated. A/J mice breathe slower, deeper, and with more variability than C57BL/6 mice. They respond differently to brief periods of 8% oxygen, which may be of interest in sleep apnea research. Whereas isoflurane decreases response to hypoxia and hypercapnia, urethane does not appear to do so; respiratory rate increases in both mouse strains (from roughly 140 to 200/min) when anesthetized with urethane.{4733} Cardio-respiratory effects are minimized when the drug is NOT given ip and when doses are kept to a minimum. In rats, urethane is toxic to mesenteric vessels, resulting in peritoneal effusion and hypovolemia. The kidneys stop responding to NaCl and water load, and the body becomes hyperosmolar. Renin and aldosterone increase and the pressor response to aldosterone is reduced. In rabbits (IV or IP) there is hemolysis, hyperkalemia and prolonged clotting time. Urethane is immunosuppressive and partly anti-neoplastic; it was originally discovered during the search for herbicides and was used briefly to treat human cancer before it was discovered that it arrests chromosomal division at metaphase. Now it is known to be a carcinogen. It is highly mutagenic to fruit flies, and at the usual anesthetic dose (1gm/kg=1mg/gm), it's cytotoxic to dividing cells. Mouse strains that normally develop pulmonary tumors will do so at higher incidence and earlier in life after a single anesthetic dose. Although there are no studies of the carcinogenic potential in humans, it is assumed, as is the potential for immunosuppression. For safety, urethane should be mixed only in a fume hood, and open containers are never permitted.{4733} Back to anesthetics/analgesics Metomidate and EtomidateDescription: Carboxylated imidazole with GABA-mimetic effects in the CNS. Used when combined (fentanyl) for long-term anesthesia because of good preservation of cardiovascular function. Etomidate is used in humans; metomidate is used in large animals and rodents. Have no analgesic properties. Cause muscle tremors. Biodisposition: Ester hydrolysis in liver, excreted in urine. Pharmacologic Effects: Anticonvulsant. Side effects in humans are pain on injection, vomiting, myoclonic twitching. Back to anesthetics/analgesics Propofol (2,6-diisopropylphenol)Description: Alkylphenol, unique drug. Is put either in Cremophor EL (polyoxyethylated castor oil), in which case it causes histamine release in the dog and anaphylactoid reactions in rats and pigs, or in an emulsion of soybean oil, glycerol and egg phosphatide, which has slightly greater potency in mice and male rats. In most cases it acts in a similar way to thiopental without the cumulative effects. Biodisposition: Has a biphasic or triphasic redistribution, with metabolic clearance by the liver. Utilization rate is fastest in mice. Rabbits seem to metabolize propofol differently than other species; plasma concentration at which they awake is higher (7µg vs 1-4µg in pig, rat and cat) and they awaken during the drug distribution phase. Mechanism of action: Positive modulator of central GABAergic transmission, enhancing function of GABA-activated chloride channel. It appears to act at a unique site compared with other anesthetics. Pharmacologic effects: Poor analgesic. Apnea occurs in mice, rabbits, cats and pigs, but rarely in rhesus macaques; apnea was cited as the major side-effect in cats and dogs{1477}{4159}. Dose-dependent decrease in minute volume in rabbits, possibly leading to respiratory arrest at high doses. Causes hypotension; heart rate is increased in rats and rabbits. Decreases myocardial contractility in swine. Depresses the heart rate-baroreceptor reflex in the rat, but less so than Saffan, thiopentone or ketamine. In dogs with poor cardiovascular function, propofol combined with an opioid or a2 agonist is a good choice, as myocardial contractility and heart rate are minimally affected.{4159} In sub-anesthetic doses (2-3mg/kg), propofol acts as a short term (15 minutes) appetite stimulant in the dog{4259}. Back to anesthetics/analgesics Tribromoethanol (formerly Avertin®)Description: Causes general CNS depression with respiratory and cardiovascular depression Biodisposition: Metabolized in the liver with glucuronic acid and excreted in urine as tribromoethanol Pharmacologic Effects: Rapid induction of short-term anesthesia in mice, used in transgenic facilities because it's always been done that way. High death losses were associated with fluid distension of the gut, suggesting ileus, in mice and gerbils. Adverse side effects are blamed on the breakdown products, hydrobromic acid and dibromoacetaldehyde, but Flecknell reported high death losses after a second injection of fresh solution. Dissociative Anesthetics (Cyclohexamines)Description: These are congeners of phencyclidine, including ketamine and tiletamine. The pH of 10% ketamine is 3.5, and it may cause muscle necrosis and pain on injection. Marked species differences in response account for the lesser use of tiletamine/zolazepam. Biodisposition: Has high lipid solubility (therefore rapid induction and recovery), and is rapidly redistributed to tissues besides the CNS. Ketamine is metabolized by the liver in most species by the cytochrome P450 system, and excreted by the kidney. Ketamine readily crosses the placenta of dogs, monkeys and humans. In rats >2 weeks of age, females sleep longer, and all neonatal rats sleep longer. Hepatic microsomal enzymes are induced with repeated doses, and tolerance occurs in humans and rats. Mechanism of action: Largely unknown. Ketamine is a potent analgesic, especially in the musculoskeletal system but less so in the abdomen. No effect on GABA. Inhibits excitatory poly-synaptic pathways mediated by N-methyl-d-aspartate (NMDA) in the brain, and acetylcholine and L-glutamate in the spinal cord. The NMDA receptor is involved in synaptic plasticity (which may be part of the learning process) and memory. In large doses in rats it causes vacuolation and permanent lesions, particularly in the posterior cingulate cortex and the retrosplenial cortex, called Olney's lesions after the man who discovered them. NMDA receptor antagonists can cause anesthesia, hallucinations, and dissociation (the blockage of signals from one part of the brain to another). Ketamine has a keto group and an amine group, and resembles the NMDA molecule. It was first given to soldiers in Vietnam, and is still used widely on the battlefield, to treat bronchospasm in asthmatics, for anesthetic induction in pediatric patients, and as a component of topical anesthetic mixtures (i.e. 10% ketoprofen, 5% lidocaine and 10% ketamine). Pharmacologic effects: Causes seizures in dogs and cats, but raises the seizure threshold in rats and mice. Go figure. Tiletamine causes excitation in rats and mice at low doses. Has minor respiratory effects except when low doses are used in rabbits. Unlike most other anesthetics, ketamine increases hemodynamic variables in dogs and cats; increases heart rate and mean arterial pressure in rats and rabbits; and in NHPs it has no effect on heart rate, mean arterial pressure and rectal temperature. In rats it causes hypothermia, unlike in rhesus macaques. Humans and NHPs have resting myopia due to central parasympathetic tone. A single injection of high doses of tiletamine in rabbits causes significant elevations in BUN and creatinine with mild nephrosis. At very low doses in humans (0.1mg/kg) it is used topically for neurogenic pain. When combined with opioids it is effective in treating chronic pain, such as in cancer patients. A bolus dose of ketamine IV (50mg) given to adult male rhesus macaques, when measured 5 minutes later, caused decreased heart rate (significant, but only from 158 to 149bpm) and left ventricular diastolic compliance.{4606} Antagonists: Although several agents have been theorized, most don't work. Those that might include metaphit, naloxone, norepinephrine, serotonin receptor blockers, and anticholinesterases (physostigmine, 4-aminopyridine). Back to anesthetics/analgesics Steroids (alphaxalone/alphadolone, Saffan®, Althesin®)Description: This drug is not available in the US, only in the UK where it is licensed for cats and NHPs. It causes rapid induction of short-term anesthesia with a wide margin of safety. Problems have arisen with the Cremophor emulsion in dogs, with histamine release and hypotension. Alphaxalone is the major drug, but alphadolone was added to increase the solubility of alphaxalone. Biodisposition: Excretion in feces and urine. In rats the metabolite is a glucuronide. Mechanism of Action: Positive modulation of GABAergic transmission at different binding site than the barbiturates. Pharmacologic Effects: Similar to barbiturates. Decreases (or doesn't alter) blood pressure and decreases cardiac output in rats. Back to anesthetics/analgesics a2-agonists (xylazine, detomidine, medetomidine)These drugs are sedative-analgesics and skeletal muscle relaxants; they NOT tranquilizers nor are they anesthetics by themselves (in most species). The mechanism is thought to be inhibition of presynaptic calcium influx and neurotransmitter release (dopamine, norepinephrine) in the brain and spinal cord. In the periphery, they cause vasoconstriction, decreased insulin release, diuresis, decreased GI motility and thrombasthenia. In humans, a2-agonists are used to treat migraine headaches, hypertension and relief of heroin withdrawal. XylazineDescription: Thiazole drug, approved in the US for use in cats, dogs and horses. Biodisposition: Rapidly absorbed, rapidly metabolized (about 20 different metabolic products), excreted in urine Pharmacologic effects:
Antagonists: Yohimbine, tolazoline, idazoxan, and now atipamezole MedetomidineDescription: Highly selective a2-agonist developed for animal use in Finland as a sedative-analgesic. Biodisposition: As for xylazine, rapidly absorbed; metabolized by hepatic mono-oxygenases, then oxidized or conjugated with glucuronic acid and eliminated in the urine. Pharmacologic effects:
Antagonists: Atipamezole is highly selective a2-antagonist. DetomidineDescription: Imidazole derivative developed in Finland for horses and cattle. Sedative and potent analgesic in rats and mice that does not affect the righting reflex. Biodisposition: As for medetomidine. Pharmacologic effects:
Antagonists: Yohimbine blocks effect in SHR rats Sedatives and TranquilizersCharacteristics of tranquilizers (also called ataractics, neuroleptics and psychotropic agents) include calming, decreased response to stimulation and muscular relaxation. Tranquilizers do NOT produce sleep, anesthesia or analgesia, and their effects can be reversed with enough stimulation. Although there has been much work on their effects in domestic species there is little information on their use alone in laboratory species. Phenothiazines (acepromazine, chlorpromazine, promazine)
Butyrophenones (droperidol, azaperone, fluanisone)
Benzodiazepines (diazepam, midazolam, zolazepam)
When midazolam at 0.5mg/kg was used to sedate micropigs while blood pressure was being measured, blood pressure (systolic, diastolic and mean arterial) and heart rate decreased significantly (but was it clinically significant?).{4593} Local or Regional Anesthesia
Spinal or Epidural AnesthesiaSpinal anesthesia was investigated as an alternative to general anesthesia for hindlimb orthopedic procedures in sheep. Regimes compared were: repetitive boluses of xylazine IV (0.5mkg/kg); single dose of xylazine (1)/ketamine (1) mg/kg IM; or continuous infusion of xylazine (0.75)/ketamine (0.75)/propofol (2)mg/kg/h. Spinal anesthesia was induced (location not specified, "at the superior border of the bony pelvis") with 1.4-1.8ml bupivacaine 0.5%. Location was confirmed by the free flow of CSF. One animal in the repetitive bolus group died of bradyarrhythmia and AV block, despite resuscitation efforts. The arrhythmia and AV block occurred to differing degrees in all groups. Heart rate and mean arterial pressure decreased over 15 minutes and remained low for at least 75 minutes, particularly in the continuous infusion group. The continuous infusion group also had the highest PaO2 and PaCO2 levels; the PaCO2 was significantly higher at all time points. Recovery was in 180-200 minutes in all sheep. They concluded that (1) xylazine causes reduced HR and MAP, and caused death in one sheep receiving repeated IV boluses; (2) propofol added to a xylazine/ketamine IM cocktail results in hypoventilation due to CO2 retention in spontaneously-breathing sheep; (3) spinal anesthesia was possible with all three regimes.{4604} Anesthetic combinationsNeuroleptanalgesia (opioid + tranquilizer)Fentanyl-droperidol (Innovar-vet®)
Fentanyl-fluanisone (Hypnorm®)
Telazol®
Analgesics
NSAIDs
Opioids
Agonist-antagonists
Strong opioids:
morphine and morphine-like agonists
Fentanyl (N-phenyl-N-(1-2-phenylethyl-4-piperidyl) propanamide) is a schedule II narcotic. It is 75-100 times more potent than morphine and is considered a "strong opioid". It interacts with opioid µ receptors in the brain, spinal cord, and other tissues. Fentanyl will accumulate in muscle and fat, for which it has high affinity. Repeated doses will accumulate in fat and be released after administration is discontinued.{4502} Dermal patches (Duragesic Transdermal Therapeutic System, Janssen Pharmaceutica) containing fentanyl are available in 25, 50, 75, or 100µg/hr release formulations. Advantages of transdermal delivery include (1) continuous, controlled delivery for up to 72 hours; (2) minimal peaks and troughs; (3) less discomfort and inconvenience; (4) reduction of first-pass hepatic clearance; (5) decreased effort to maintain IV administration; (6) decreased stress. However, there is much debate in medicine over whether transdermal fentanyl has a place in postop analgesia, and the manufacturer insists it does not. Humans suffer from hypoventilation and respiratory depression, perhaps because of the morphine that is often used as a "rescue" analgesic while waiting for the patch to kick in. Fentanyl has a high affinity for fat, so that as the patch dose is increased the half-life gets longer (zero-order kinetics). Fentanyl patches have been studied in cats in which it works well; the drug is not a CNS depressant in that species. It has been used in several dog studies, but the major problem is that the effective analgesic levels are unknown. In Yucatan minipigs, highly variable plasma levels were obtained (0.38-0.99ng/ml), but there were no signs of respiratory depression. In humans it is assumed that plasma levels of 0.5-3.0ng/ml may be suitable.{4502} In rabbits, 25µg/hr patches produce levels of 0.27-6.7 ng/ml at 12-24 hours, well within the range considered analgesic in humans. The drug levels depend on the presence of hair regrowth. If the fur is depilated prior to patch application, fentanyl levels are the highest; in fact, two rabbits showed signs of undue sedation. Clipped fur resulted in somewhat lower levels. In rabbits that get patched during anagen, hair regrowth at 24 hours is significant and drug levels are undetectable.{4586} Partial agonist
Buprenorphine is a mixed partial opioid mu-agonist and kappa-antagonist drug used for analgesia. A skin-twitch analgesiometric test was used to determine the level of analgesia produced by several dosages of buprenorphine given IV to Yorkshire-Landrace pigs. Doses of 0.01mg/kg were found to provide 6 hours of effect; doubling the dose to 0.02mg/kg extended the analgesia to more than 10 hours. A dose of 0.005mg/kg did not provide analgesia above baseline in any time period.{4503} A medical records review indicated that swine with pain related to inflammatory processes did not respond as well to buprenorphine, but that NSAIDs worked better. Buprenorphine worked well for pain related to surgical incisions, dental, ophthalmic and orthopedic procedures. It did not work well for swine with organ failure or systemic diseases.{4503} In another study, buprenorphine (0.5mg/kg) was used for analgesia every 12 hours in a mouse model of warm ischemia to induce renal failure. Mice were housed at 30° C rather than 23-25°C, as these low temperatures induced "some degree of cold stress." Two groups of mice were followed in a telemetry box to measure temperature and activity postop. The treated mice showed improved body weight and activity postop, without any changes in renal failure parameters (creatinine, histologic changes). Two doses, at the time of surgery and one 12 hours later, were sufficient.{4538} Guinea pigs are used in an evaluation of keratoconjunctivitis model of Shigella infection called the Sereny test. It is used to measure bacterial virulence and the efficacy of Shigella vaccines by the Army. Buprenorphine given at 0.05mg/kg subcutaneously every 12 hours did not affect the Sereny test or the immune response to vaccination. However, treated animals had less weight gain during the treatment period, thought to be due to narcosis leading to inactivity, decreased grooming and reduced food intake.{4587}
Anesthetics and Analgesics by SpeciesCats Gerbils Cats: Carprofen given at 4mg/kg SQ preoperatively provided as good a level of analgesia as pethidine at 3.3mg/kg IM postop, but of longer duration, i.e. 24 hours. Carprofen may be a good pre-emptive analgesic in cats.{3542} RatsAnestheticsInhalants
Injectables
AnalgesicsIn
rats, food restriction (i.e. maintenance at 80% of normal body weight) may be
stressful, as evidenced by increased activity in an open field and increased
levels of corticosterone. However, water restriction (15 minutes' access to
water daily) was not stressful as measured by the same parameters{4022}. Buprenorphine may induce pica behavior in rats (at doses of 0.05 or 0.3mg/kg). Pica is indicative of gastric distress; in rats it may be a response analogous to vomiting in other species. Buprenorphine also causes nausea in man.{3825} Buprenorphine produces analgesia that is weaker than that of morphine, but lasts longer. The analgesia curve is somewhat phasic, perhaps corresponding to degree of receptor binding. At doses of 0.5 mg/kg [yes, this dose is correct], it should be re-dosed approximately every 6-8 hours, although some investigators believe its effects can last longer.{4138} A common method of administration of buprenorphine is to mix it with gelatin for oral consumption. The commonly-recommended dose is 0.5mg/kg po. However, Martin found that at this dose, there was no increase in latency to flick the tail out of a hot water bath. Doses of 5-10mg/kg were required to achieve an increase in latency; however, the rats would not consume buprenorphine at high concentrations necessary to get the full dose. Gavage was needed to achieve this high dosage.{4597} Other investigators believe that oxymorphone is a superior analgesic for postoperative relief following bowel resection. In studies of short bowel syndrome, the authors noted significant postop pain in male Sprague-Dawley rats that was not alleviated by buprenorphine. They conducted a study comparing oxymorphone with buprenorphine, finding that oxymorphone was better. Buprenorphine was given at 0.5mg/kg q 6h; oxymorphone was given at 0.03mg/kg/hr by continuous IV infusion along with TPN fluids. Pain was assessed with a semi-quantitative scheme evaluating posture, physical condition and behavior. They also evaluated three different methods of administering oxymorphone: Alzet minipump (0.03mg/kg/hr), continuous IV infusion, and periodic IV boluses (0.18mg/kg q6h). There was no difference in pain score with any method of oxymorphone administration. They noted that buprenorphine at the doses given seems to cause agitation (chewing on cages, tails and paws), even in unoperated rats. There was also reduced urinary output in buprenorphine-treated rats (28ml/48hr vs. 60ml/48hr in oxymorphone) despite the same amount of fluid administration (62ml/48hr).{4491} Morphine is the most potent analgesic
available for rats; at doses of 10 mg/kg it should be re-dosed every 2-3 hours
and used for severe pain. Butorphanol isn't a very good or long-lasting
analgesic; if used at a dose of 2 mg/kg it should be re-dosed in 1-2 hours.{4138} For neonatal rats, one study concluded that methoxyflurane or hypothermia are good choices for short- or long-term anesthesia of rats 1-3 days old, and that use of a protective Latex sleeve appears to reduce distress associated with induction of profound hypothermia{3599}. MiceAnestheticsInhalants
InjectablesIn general, intramuscular injections are discouraged in small rodents. In neonatal mice, an unusual route of injection has been suggested, to avoid having leakage of the injected material through the skin. The needle is passed "ventrally through the clavicle, subcutaneously past the ribs, and through the diaphragm into the peritoneal cavity."{4154}
AnalgesicsAs with any species, there are strain differences, and there are also likely to be gender and age differences as well. CBA and C57BL mice have been reported to be less sensitive to morphine than DBA and BALB. Mice that are selectively bred for morphine sensitivity have a different receptor profile; if the opioid receptors are lacking, there will be no response to opioids at all. Both sensitivity and tolerance to morphine are genotype-dependent, with dominance or partial dominance. One variable to be considered, however, is the behavioral difference in when and how mice respond to the pain stimulus.{4138} In male ICR mice, morphine produces the highest levels of analgesia, when measured with either the hot-plate test or the tail-flick test. However, it needs to be re-dosed every 2-3 hours. The high dose for morphine in mice is 10 mg/kg. Buprenorphine produces longer-lasting (3-5 hours) but less potent analgesia when given at high doses of 2 mg/kg. Butorphanol is a weak analgesic; at doses of 5 mg/kg it must be re-dosed every 1-2 hours. All of these opioids take effect in about 10 minutes after subcutaneous administration.{4138} For blood collection from the
retro-orbital sinus, an approach combining sedative doses of analgesics and
anesthetics combined with topical proparacaine was deemed a success in 129/SvSj
mice of both sexes and all ages. Ketamine at 76 mg/kg combined with medetomidine at 1 mg/kg worked
well, as did half-doses when proparacaine was used. The medetomidine was
reversed with atipamezole for quick righting response.{4175} Guinea pigsAnestheticsInhalants
Injectables
AnalgesicsGuinea pigs were infected with Pseudomonas
aeruginosa as a model of sepsis, and temporary neutropenia was induced by
six days of cyclophosphamide. Good predictors of imminent death were the
inability to ambulate and inability to rise from a supine position.{3872} HamstersFor some things, one can use hypothermia in neonates 48-72 hours old; chill for 9-11 minutes{3988}. Anesthetics
Analgesics
|
 | Ether should not be used due to too rapid induction and death{4154} |
| Pentobarbital causes the usual respiratory depression and unexpected mortality.{4154} |
| Ketamine/xylazine and ketamine/diazepam produce only sedation and immobilization, with frequent swimming or "athetoid" movements.{4154} |
| Telazol must be used in high doses (60mg/kg) to produce surgical anesthesia, at which point recovery will take 4-6 hours and there may be a rebound following initial recovery.{4154} |
| Tribromoethanol must be used carefully in gerbils. Use only the more dilute concentration (1.25%), give IP only, and do not give supplemental doses. Adhesions and death are the consequences of higher concentrations.{4154} |
|
©1999, Janet Becker Rodgers, DVM, MS, DipACLAM, MRCVS All rights reserved. Comments? Send an email to janet.rodgers@vet.ox.ac.uk |
