Assessment of pain is considered the fifth vital sign (after temperature, heart/pulse rate, respiratory rate, and blood pressure). Providing adequate analgesia to critically ill dogs and cats is a unique challenge, as potentially life-threatening derangements are commonly present, including:

 Bradycardia (concurrent vagal and sympathetic stimulation to induce a "hypodynamic" response)

 Hypoalbuminemia (negative acute phase reaction, primary disease process)

 Anemia (underlying disease process, Heinz body anemia)

 Hypoglycemia (sepsis, reduced intake, impaired gluconeogenesis, depleted glycogen stores)

 Liver dysfunction (primary disease process, sepsis-induced cholestasis)

 Coagulopathies (liver dysfunction)

 Pulmonary dysfunction (vascular leak, myocardial dysfunction, reduced COP)

Pain is a pro-inflammatory process and may lead to a wide variety of complications, particularly delayed wound healing, sepsis, and hospital-acquired infection(s). Analgesic medications should ideally be administered before pain develops (preemptive analgesia), but this approach is not always feasible in critically ill patients.

Systemic Analgesia

Opioids

Opioids interact with specific stereospecific pre- and post-synaptic receptors in the central (dorsal root ganglia, spinal pain tracts) and peripheral nervous systems. Clinically relevant receptors are detailed in the chart below.

Opioids induce analgesia by reducing pre-synaptic release of excitatory neurotransmitters and by inhibiting evoked activity post-synaptically, accomplished predominantly through hyperpolarization (increased conduction of potassium conduction) and calcium channel inactivation. Pure mu agonists: The ideal analgesic medication for critically ill patients is potent, easily titratable, and 100% reversible. Pure mu agonists satisfy these criteria, and duration of action is specific to each medication. Common examples of pure mu agonists are morphine, hydromorphone, fentanyl, oxymorphone and methadone. These medications typically induce analgesia within 1–5 minutes of intravenous injection and 5–10 minutes of intramuscular injection. Morphine is the prototypical pure mu opioid, but this drug is less effective in cats compared to dogs, as felines do not produce one of the intermediate metabolites responsible for some analgesia; nevertheless morphine may produce satisfactory analgesia in cats. Historically, this drug was falsely associated with hyperexcitability in cats ("morphine mania"), and this behavior is now attributed to administration of large doses to non-painful patients. Pure mu opioids are very useful medications for critically ill patients, as they may be delivered via different routes (parenterally, regionally, etc.). Administration of opioids may be associated with respiratory depression, bradycardia, hyperthermia, mydriasis and excitation in cats; vomiting, paralytic ileus, pruritus and urine retention have also been reported. Morphine-induced histamine release secondary to rapid intravenous injection has been documented, but is unlikely with slow administration.

Partial agonists: Buprenorphine is both a mu agonist and kappa antagonist; accordingly analgesia is not as profound as that provided by pure mu agonists. Onset of action is 10–30 minutes regardless of route of administration, but commonly lasts 6–8 hours. Buprenorphine is readily absorbed transmucosally in cats. Agonist-antagonists: Butorphanol is a kappa agonist and a mu antagonist. Accordingly this medication provides moderate analgesia (and sedation) for up to 90 minutes. The provided analgesia is not adequate for surgical pain. If selected, the author prefers to administer butorphanol as a constant rate infusion in the critical care unit.

Other: Tramadol is a synthetic opioid (an analogue of codeine) that binds weakly to all types of opioid receptors. This drug also activates descending inhibitory spinal monoaminergic pathways through inhibition of norepinephrine and serotonin reuptake at α2-adrenergic receptors and serotonin receptors, respectively. Tramadol effects are predominantly central, but some peripheral local anesthetic-like properties have been documented. Tramadol is metabolized in the liver to various metabolites, and major one involved in analgesia is O-desmethyl-tramadol (M1). The clinical response to tramadol differs between species, depending on the amount of M1 produced. The main side effect of this analgesic medication is sedation. Nausea has also been reported, and there is an increased risk of seizures in animals receiving other drugs that reduce the seizure threshold. There is an increased risk of gastrointestinal bleeding when tramadol is used concurrently with non- steroidal anti-inflammatory drugs. In cats this medication may cause profound dysphoria, has a horrid flavor and, if used, should always be a component of a multimodal protocol.

Alpha-2 Agonists

Alpha-2 agonists are commonly prescribed for veterinary patients due to their potent sedation (mediated at the locus ceruleus), anesthesia-sparing effects (up to 27% reduction of minimum alveolar concentration/MAC) and analgesia. The analgesic effect of these agents is mediated by receptors in the dorsal horn of the spinal cord and brainstem. They exert effects pre-synaptically (negative feedback regulation of norepinephrine release) and post-synaptically. Common examples are dexmedetomidine and medetomidine. Use of alpha-2 agonists in critically ill patients must be considered carefully, weighing benefits against potential serious adverse effects. These drugs may cause mydriasis and may induce hypothermia through both reduced muscle activity and inhibition of the noradrenergic mechanism of body temperature regulation. Intravenous administration is associated with a biphasic cardiovascular response; initially systemic blood pressure increases secondary to rise in systemic vascular resistance from stimulation of vascular alpha-2 receptors, but subsequently decreases due to bradycardia (baroreceptor reflex and central sympatholysis) and subsequently reduced cardiac output (by ~50%). Various dysrhythmias (i.e., heart block, ventricular dysrhythmias) have been reported. Concurrent use of anticholinergic agents is not recommended due to the potential for inducing marked hypertension and adverse cardiac events. Respiratory effects are minimal when used as a single-agent, but these drugs may potentiate the respiratory depressant effects of other drugs (i.e., opioids).

Other less common effects that should be considered in critical patients include:

 Inhibition of insulin secretion/promotion of growth hormone secretion potential to induce hyperglycemia

 Inhibition of ACTH and cortisol secretion

 Promotion of diuresis/natriuresis through direct action at the pituitary gland and renal tubules (inhibit renin release, promote ANP secretion, increased GFR)

 Reduction of lower esophageal sphincter pressure

 Reduction of gastrointestinal motility

 Induction of vomiting

 Stimulation of platelet aggregation

If an alpha-2 agonist is selected, combination with an opioid is preferred to help minimize the cardiovascular effects and maximize analgesia. Constant rate infusion is very useful in critical patients, and the dosage is quite low (sometimes referred to as a "micro-micro" dose). Dexmedetomidine is seemingly the most commonly employed alpha-2 agonist in critically ill patients. Alpha-2 agonists may be completely reversed with an alpha-2 antagonist (i.e., yohimbine, atipamezole, and 4-aminopyridine).

Dissociatives

Ketamine antagonizes N-methyl-D-aspartic acid (NMDA) receptors in the dorsal horn of the spinal cord and brain, helping to minimize the development of central sensitization. Constant rate infusions are used most commonly in critically ill dogs and cats, but use of this medication should be restricted to those with adequate cardiac and renal function, no seizure history, and normal intraocular pressure (IOP) and intracranial pressure (ICP).

Gabapentin

While gabapentin is a structural analog of the inhibitory neurotransmitter gamma amino butyric acid (GABA), the analgesic effects are mediated via voltage-dependent calcium ion channels in the dorsal root ganglia. This medication induces minimal cardiopulmonary depression but increased somnolence has been reported.

Non-Steroidal Anti-Inflammatory Agents (NSAIDs)

Many patients hospitalized in a critical care unit have or at risk for gastrointestinal, hepatic and/or renal dysfunction. Given the potential of NSAIDs to cause gastrointestinal side effects (hypo/anorexia, vomiting, gastric ulceration, diarrhea), acute kidney injury (AKI) and fulminant hepatic necrosis, there use in critically ill patients, particularly those who are hemodynamically unstable, is quite questionable and often contraindicated.

Local Analgesics

Local analgesic medications completely block transmission of nociceptive impulses transmitted from the periphery to the central nervous system. They exert effect by binding to sodium channels to prevent sodium influx and subsequent depolarization of nerves. They also have the additional benefits of reducing production of inflammatory cytokines, free radicals, eicosanoids, thromboxane, leukotrienes, and histamine.

Common examples of the use of local analgesia in the critically ill include:

 Incisional splash blocks

 Intra-cavitary blocks

 Epidurals

 Intra-articular administration

 Topical/transdermal applications

 Wound infusion catheters

Local anesthetic medications may be fatal if administered via an inappropriate route or dosed incorrectly. Signs of toxicity are referable to the cardiovascular (myocardial depression, hypotension, bradycardia, CPA) and central nervous (excitation, twitching, seizures, coma) systems.

References

1.  Ko JC, Maxwell LK, Abbo LA, et al. Pharmacokinetics of lidocaine following application of 5% lidocaine to cats. J Vet Pharmacol Ther. 2008;31(4):359–367.

2.  Porters N, Bosmans T, Debille M, et al. Sedative and antinociceptive effects of dexmedetomidine and buprenorphine after oral transmucosal or intramuscular administration in cats. Vet Anaesth Analg. 2014;41(1):90–96.

3.  Ambros B, Duke T. Effect of low dose rate ketamine infusions on thermal and mechanical thresholds in conscious cats. Vet Anaesth Analg. 2013;40(6):e76–82.

4.  Steagall PV, Monteiro-Steagall BP. Multimodal analgesia for perioperative pain in three cats. J Feline Med Surg. 2013;15(8):737–743.

5.  Vettorato E, Corletto F. Gabapentin as part of multi-modal analgesia in two cats suffering multiple injuries. Vet Anaesth Analg. 2011;38(5):518–520.