Dr. Dave Thompson

2-05

The sedative-hypnotic effects of alpha-2s are a result of inhibition of norepinephrine release from noradrenergic receptors (autoreceptors) in the locus ceruleus section of the brainstem. Analgesic effects are principally due to spinal anti-nociception via binding to non-noradrenergic receptors (heteroreceptors) located on the dorsal horn neurons of the spinal cord. These heteroreceptors are found presynaptically, where they inhibit the release of neurotransmitters and neuropeptides, and postsynaptically, where they decrease ascending spinal nociceptive transmission. There is some evidence of supraspinal analgesic mechanisms as well; suppression of norepinephrine release in the locus ceruleus leads, via disinhibition of certain catecholaminergic nuclei in the pons, to increased release of norepinephrine from dorsal horn terminals, which then activates presynaptic and postsynaptic heteroreceptors.

At low doses, both the sedative and analgesic effects of alpha-2 agonists are dose-dependent. As the dose is increased, there is a ceiling on the degree of analgesia, and further dosing only acts to lengthen the duration of sedation and increase the risk of adverse effects. For this reason, it’s best to administer an alpha-2 in conjunction with other agents (opioids, dissociatives) as part of a balanced regimen. Opioids work particularly well with alpha-2's, as receptors for both compounds occupy similar sites in the brain and on some neurons and produce similar actions (membrane associated G protein activation leading to neuronal hyperpolarization and a reduced response to excitatory input). This results in a synergistic effect, leading to improved quality and duration of analgesia.

Side effects occur frequently with alpha-2 agonists. The most common effect noted is an initial hypertension (due to peripheral postsynaptic adrenoreceptors causing vasoconstriction), which results in a baroreceptor-mediated reflex bradycardia. As the peripheral effects diminish, central alpha-2 actions predominate, leading to decreased blood pressure and cardiac output. Anticholinergics have been advocated to reduce the bradycardic effects, but their use is controversial (elevating heart rate in the presence of high systemic vascular resistance can result in increased cardiac workload and myocardial oxygen consumption). If used, it's probably best to give the anticholinergic before or with the alpha-2 (to minimize the risk of reflex tachycardia occurring at the time of peak hypertension); severe bradycardia occurring after the alpha-2 has been administered should be treated with a reversal agent.

Other side effects can include short term A-V block (most often first or second degree), sinus arrhythmia, sinoatrial block, decreased respiratory rate, peripheral venous desaturation (resulting in a cyanotic appearance to the mucous membranes), vomiting, increased urine output, transient hyperglycemia (due to inhibition of insulin secretion) and increased myometrial tone and intrauterine pressure. Additionally, xylazine has been associated with the development of aerophagia, gastric dilatation, gastric reflux and cholinergic bradycardia..

Traditionally, the use of alpha-2 agonists has been limited to healthy adult dogs and cats with adequate cardiovascular reserve capacity and no evidence of heart disease, liver or kidney failure, shock or severe debilitation. More recently, work from the University of Illinois[1] using butorphanol (0.22 mg/kg) with medetomidine (0.0085 mg/kg in dogs averaging 8.9 years of age, 0.0165 mg/kg in cats averaging 10.8 years of age) to create heavy sedation during radiation therapy for cancer patients suggests a broader application of medetomidine. The dogs averaged 12 sedative events, the cats 15. There were 8191 total events over the eight-year period. No fatalities occurred.

There is consideration for medetomidine use in feline hypertrophic cardiomyopathy patients with concurrent left ventricular outflow obstruction as 20 ug/kg (0.020 mg/kg) has been shown to improve the hemodynamics of these patients.[2]

Alpha-2 agonists should be avoided in pediatric patients less than 12 weeks of age (cardiac output is heart rate dependent, limited ability to increase contractility) and used with caution in advanced geriatric animals (where cardiovascular reserve may be diminished).

It is important to note that in most instances, combining an alpha-2 with an opioid will enable lower doses to be used while enhancing sedation/analgesia. The following are some suggested applications and dosages for medetomidine (Domitor) in dogs and cats:

Sedation/restraint -- for radiographs, bandage changes, wound care, minor lacerations, control of fractious animals, etc.

Dogs: 5-20 ug/kg (0.005-0.020 mg/kg) IM or IV with an opioid (butorphanol 0.2 mg/kg, morphine 0.5 mg/kg , hydromorphone 0.1 mg/kg).

·        Extremely fractious/fearful dogs may require 30-40 ug/kg of medetomidine.

·        Effective sedation/analgesia should be present within 10-20 minutes (less if given IV), and can persist for 1-4 hours (depending on the doses, type of opioid and route of administration).

Cats: 10-20 ug/kg (0.010-0.020 mg/kg) IM or IV with an opioid (butorphanol 0.2 mg/kg, hydromorphone 0.1 mg/kg).

·        As in dogs, higher doses (30-40 ug/kg) of medetomidine can be used if fractious/fearful.

·        Also, ketamine (2-5 mg/kg) can be added for much more profound sedation if needed.

o       A simple and useful formula for an average sized adult cat is to combine 0.1 cc (100 ug) medetomidine, 0.1 cc (1 mg) butorphanol and 0.1 cc (10 mg) ketamine in an insulin syringe and give IM-- this will provide profound sedation/restraint for the majority of cats within 10-15 minutes, and will be effective for 45-60 minutes.

Several important factors should be kept in mind when using medetomidine/opioid sedation:

1) Extreme stress may cause some patients to resist the sedative influence of the alpha-2 agnists. Providing some quiet time in a darkened room may facilitate the drug’s effect.

2) Arousal and the potential for biting can occur, even with seemingly heavy sedation. Always exercise appropriate precautions, especially with fractious animals.

3) Sedation is not necessarily "safer" than general anesthesia. Attention to proper patient monitoring is important with any sedative protocol.

4) Reversal of the effects of medetomidine can be achieved with atipamezole (Antisedan) if necessary or desired. In dogs, a volume of atipamezole equivalent to the medetomidine dose is given IM or IV(if more than 1 hour since sedated, half the volume may be used). In cats, some advocate giving atipamezole at 1/2 the medetomidine volume routinely, though this author has used the full volume without adverse effect. If ketamine was used, wait at least 30 - 45 minutes before reversing to reduce the risk of a rough recovery. NOTE: Yohimbine can also be used as a reversal agent, but its lack of receptor specificity (40:1 alpha-2/alpha-1 ratio vs. 8500:1 for atipamezole), its effects on dopaminergic, serotonergic and GABAergic receptors, and its potential to induce hypotension and tachycardia make it a less attractive option.

5) Intramuscular administration is best achieved by injection into the lumbar epaxial muscles (to avoid delayed or reduced effectiveness if inadvertently injected intrafascially in other muscle groups).

6) Intravenous injection provides more immediate sedation/analgesia, but may, depending on dose, produce more significant adverse hemodynamic effects. In most instances, intramuscular injection is preferred.

Pre-anesthetic -- in combination with an opioid (and anti-cholinergic depending on user preference and/or patient/procedure) as part of a balanced anesthetic approach. The following are the most common dose ranges for dogs and cats:

Dogs: 5-10 ug/kg (0.005-0.010 mg/kg) IM with an opioid

Cats: 10-15 ug/kg (0.010-0.030 mg/kg) IM with an opioid +/- ketamine.

Important factors to remember when using medetomine as a pre-anesthetic include:

1) Medetomidine will markedly reduce the amount of induction and maintenance drugs required for anesthesia. Generally, half or less of the standard induction drug dose should be used, and inhalant levels should be carefully monitored, with close attention paid to blood pressure intraoperatively.

2 The lower heart rates commonly encountered when using medetomidine take some getting used to. As a general rule, if blood pressure is normal mild bradycardia is not a cause for concern. If severe bradycardia or hypotension occurs, the medetomidine can be reversed with atipamezole; this will often necessitate increasing other analgesic/anesthetic drugs to maintain the patient. Maintaining induction agents with the patient at all times provides a more attractive option than high level inhalant agent, should the patient become unexpectedly responsive.

3) Wait at least 15-20 minutes after giving medetomidine before inducing the patient; this allows maximal effect to occur, and reduces the risk of inadvertent overdose of induction drugs.

4) Doses as low as 0.2 to 2.0 ug/kg (0.0002 to 0.002 mg/kg) may be clinically useful when combined with an opioid.

5) Doses as high as 30 ug/kg (0.030 mg/kg) may be necessary when managing more aggressive patients.

IM only anesthetic protocol -- for routine feline elective procedures, some practitioners favor what has come to be known as "DKT"(Domitor/Ketamine/Torbugesic). This consists of medetomidine 25-30 ug/kg, butorphanol 0.2 mg/kg and ketamine 5 mg/kg given IM. Many short surgical procedures (including OHE, castration, declawing, etc) can be completed without the need for additional induction agents or inhalant agents, although all cats should be intubated and on oxygen support, placed on IV fluids and administered appropriate analgesics postoperatively. Note that these patients are usually ready for intubation within 3 to 5 minutes of the IM injection.

Constant rate infusion -- of medetomidine can be used in severely painful or anxious patients to provide sedation and analgesia. The alpha-2s dexmedetomidine and clonidine are currently being used for human patient management in the ICU setting where it has been shown that controlling the neuroendocrine stress response reduces patient morbidity and shortens the clinical course for many trauma and surgical patients. Alpha-2s agonists have also been shown to influence hormonal patterns to counter protein catabolism and nitrogen losses. Medetomidine can be added to a preexisting analgesic infusion (ketamine, ketamine/morphine, ketamine/morphine/lidocaine -- see the section on "Constant Rate Infusions" for more information). A simple formula involves adding 0.5 cc (500 ug or 0.5 mg) of medetomidine to a 1 liter bag; when delivered at 2 ml/kg/hour, this will provide 1 ug/kg/hour; this rate can be doubled if needed. At these low dose rates (0.001 to 0.002 mg/kg/hr), there are rarely any significant cardiovascular effects[3] but, because medetomidine CRI's have the potential to cause severe bradycardia/hypotension, these patients should be monitored very closely. A loading dose of at least 1 ug/kg (0.001 mg/kg) IV should precede the initiation of the medetomidine CRI.

Epidural use -- of medetomidine can enhance the analgesic effects of other agents given epidurally. Besides the aforementioned action at heterotropic spinal receptors, medetomidine also produces analgesia by stimulation of cholinergic interneurons when given epidurally. It acts synergistically with opioids, improving the quality and duration of analgesia, and there is some evidence that it prolongs the effects of local anesthetics. This author routinely uses medetomidine 5 ug/kg (0.005 mg/kg) in an epidural cocktail containing an opioid and local anesthetics. It should be noted that, being highly lipophilic, medetomidine is rapidly absorbed from the epidural space, anatomically limiting the site of action and leading to systemic levels of the drug.

Intra-articular use -- of medetomidine is very effective. Both opioid and alpha-2 adrenoreceptors are distributed throughout the peripheral nervous system (on the terminal ends of primary afferent nociceptive fibers). By inhibiting the release of norepinephrine locally, they reduce noxious input and minimize the development of peripheral sensitization. The combination of medetomidine 2-5 ug/kg (0.002-0.005 mg/kg), morphine 0.1 mg/kg and bupivicaine 0.5-1.0 mg/kg can provide long-lasting analgesia when given in the joint after closure of the arthrotomy. 

  General references

Handbook of Veterinary Pain Management. Gaynor JS, Muir WW: 199-220

Manual of Small Animal Anesthesia. 2nd Edition. Paddleford RR: 19-24