Pain Management: Constant-Rate Infusion
Alonso Guedes, DVM, MS, PhD, DACVAA, University of Minnesota
Profile
Definitions
Pain categories
Adaptive pain is physiologically important and essential for an animal’s survival by preventing tissue damage or promoting healing once damage has occurred. This type of pain should be managed to the point of being tolerable while healing occurs.
Maladaptive pain reflects malfunction of the nervous system and serves no true purpose.
Types of pain
Nociceptive pain is typically transient in response to noxious stimuli (ie, mechanical, chemical, thermal).
Inflammatory pain results from inflammatory mediators produced following tissue injury to activate or modify the stimulus response properties of nociceptor afferents, setting up changes in the responsiveness of neurons in the CNS.
Neuropathic pain is associated with damage to or dysfunction of central or peripheral neurons.
Functional pain is not well understood. It is most likely associated with distorted pain generation/processing without evidence of tissue damage.
Pathophysiology
Pain involves four physiologic processes amenable to pharmacologic intervention (Figure 1, above):
Transduction is the translation of a given noxious stimulus into an electric signal at the peripheral nociceptor.
Transmission is the propagation of action potentials in the axon of neurons.
Modulation is the modification of nociceptive transmission via the endogenous descending analgesic systems (ie, opioid, serotonergic, GABAergic, noradrenergic).
Perception is the conscious subjective and emotional experience of pain that results from successful transduction, transmission, modulation, and integration of thalamocortical, reticular, and limbic functions.
Uncontrolled or poorly controlled adaptive pain can become maladaptive. Pain perception is shifted and results in hyperalgesia—excessive pain in response to a noxious stimulus—and allodynia—pain in response to innocuous stimuli (Figure 2, below).
Constant-rate infusion (CRI) of analgesics may prevent/revert such changes by maintaining more stable plasma concentrations of administered analgesics than with intermittent treatment. Homeostasis is better preserved, optimizing conditions for return to normal function (Figure 3, below).
Figure 2. (View larger image)
Figure 3. (View larger image)
Diagnosis
Guidelines for pain recognition and treatment in dogs and cats have been published.1
Hyperalgesia or allodynia should be suspected if a patient responds excessively to a mildly painful procedure or a procedure that is not considered painful.
Any procedure considered painful in humans should be considered painful in animals. Analgesics should be administered and effectiveness assessed accordingly.
Treatment
Analgesic selection should be individualized and the underlying mechanisms of pain, side effects, and potential beneficial or deleterious effects on comorbidities considered.
Preemptive and multimodal analgesics are generally more beneficial than analgesics that are provided after pain develops or are of single modality.
Analgesic Drugs
Morphine
Pharmacology
Prototype opioid agonist that acts at mu- and kappa-opioid receptors.
Inhibits ascending nociceptive neurotransmission via inhibition of presynaptic neurotransmitter release and by hyperpolarizing projecting neurons in the spinal cord dorsal horn.
Activates descending inhibitory pathways by activating the monoaminergic system.
Dose
Dogs: 0.12–0.3 mg/kg/hr is clinically useful. Lower doses may be helpful for analgesia in conscious dogs and higher doses for use in anesthetized dogs as part of balanced anesthesia.2,3
To avoid histamine release with loading dose, it can be omitted or administered IM, as this route does not induce histamine release.
Cats: No studies have evaluated morphine via CRI in cats.
Precautions
May cause dose-dependent vasodilation, bradycardia, respiratory depression, and histamine release2-5 associated with the loading dose or CRI.
During anesthesia, control ventilation to avoid hypercapnia.
Syringe or fluid pumps are preferred when administering morphine CRI, as inadvertent increases in the rate may result in overdose and induce significant histamine release.
Avoid or use with caution in patients predisposed to cardiac arrhythmias or at increased risk for bleeding.
Histamine can predispose to cardiac arrhythmias directly and indirectly via stimulation of epinephrine secretion.
Release of heparin, stored in mast cell granules, may impair coagulation.
Hypotension resulting from histamine release can be treated with H1- and H2-receptor antagonists (ie, diphenhydramine, cimetidine), fluid administration, vasopressors, bronchodilators, and respiratory support.
Inhalant anesthetics should be given to effect to maintain adequate surgical anesthesia without anesthetic overdose.
Hydromorphone
Pharmacology
Morphine derivative with similar pharmacokinetics.
5–10 times more potent than morphine.6
Minimal to no risk for histamine release.7
Dose
Pharmacokinetic data in dogs available6 but no CRI studies have been published.
Loading dose of 0.05–0.1 mg/kg followed by CRI of 0.03–0.06 mg/kg/hr may produce clinically useful analgesia.
Precautions
Similar to morphine; in compromised patients, administer loading dose slowly to minimize risk for small but clinically significant (ie, sufficient to cause hypotension) histamine release.7
Fentanyl
Pharmacology
Synthetic mu-opioid receptor agonist.
50–100 times more potent than morphine, with similar adverse effects but no risk for histamine release.
Preferred opioid for patients with hemodynamic instability or that react unfavorably to morphine.
Dose
Dogs: Loading dose of 2–10 µg/kg and CRI of 1–40 µg/kg/hr are clinically useful. Lower doses may be helpful for analgesia in conscious dogs and higher doses as part of balanced anesthesia.
Cats: Loading dose of 1–5 µg/kg and CRI of 1–20 µg/kg/hr may be used.8 Infusion can be discontinued 30 minutes before end of anesthetic event to minimize potential for dysphoric recovery.
Dogs and cats: For dysphoria, consider reducing dose, administering tranquilizer/ sedative (ie, acepromazine, dexmedetomidine), or discontinuing fentanyl.
Precautions
Similar to morphine, except for histamine release; high doses are more likely to result in bradycardia (responsive to anticholinergic) and respiratory depression (managed with controlled ventilation).
May have significant anesthetic-sparing effect. Titrate inhalant anesthetic to effect to avoid excessive anesthetic depth.
Ketamine
Pharmacology
Injectable anesthetic with analgesic properties (NMDA-receptor antagonist).
Prevents or reverses CNS hypersensitization and hyperalgesia.
For neuropathic and chronic pain, may provide analgesia and/or improve response to opioids.9,10
Minimal to no respiratory and hemodynamic effects at subanesthetic doses.
In dogs, undergoes mainly hepatic metabolism. In cats, excreted by kidneys, mostly unchanged.
Dose
Dogs: CRI of 10 µg/kg/min reduces isoflurane minimum alveolar concentration (MAC) by 29%.3
Cats: CRI of 23 µg/kg/min reduces isoflurane MAC by 45% but can prolong recovery from anesthesia.11
Dogs and cats: Loading dose of 0.25–0.5 mg/kg may be used.
Precautions
Indirect cardiovascular stimulating effects increase central sympathetic output.
Myocardial-depressant effects may predominate in critically ill patients with protracted catecholamine stores.
Avoid or use cautiously in cats with impaired renal function.
Lidocaine
Pharmacology
Local anesthetic that can be administered IV as adjunct to decrease inhalant anesthetic requirement in dogs.3
Antioxidant and inflammatory modulator; potentially valuable against ischemiareperfusion injury.12
May be beneficial for neuropathic pain.10
Dose
Loading dose of 0.5–1.0 mg/kg may be given, followed by CRI of 1.5–3.0 mg/kg/hr (dogs only)
Precautions
Excessive doses may cause adverse CNS effects (eg, depression, ataxia, muscle tremors, seizures, nausea, vomiting) and cardiac effects (eg, prolonged PR and QRS interval, shortened QT interval).
Patients with atrial fibrillation may experience increases in ventricular rate. Hypotension may occur if IV bolus given rapidly.12
In cats, not recommended for reducing isoflurane requirements.13 Systemic doses adequate to produce analgesia are unknown.
Drug Combinations
Ketamine significantly potentiates opioid analgesia,14 allowing a decrease in the opioid dose and dose-related adverse effects.
A combination of ketamine, lidocaine, and morphine can significantly decrease isoflurane requirement in dogs.3 Morphine may be substituted for fentanyl in compromised patients.
Ketamine and fentanyl administered postoperatively can produce better analgesia and comfort compared with fentanyl alone in dogs undergoing forelimb amputation. The beneficial effects are still apparent 3 days following surgery.9
Studies evaluating these combinations have not been conducted in cats.
In General
Relative Cost
The overall cost of using CRI analgesics to manage pain (eg, drugs, placement and maintenance of IV catheter, patient monitoring, equipment) is typically higher than that for intermittent analgesics.
When considering drugs alone, CRI of analgesics is less costly and more efficacious than intermittent administration; in addition, patients are more closely monitored.
Depending on length of hospitalization and equipment used: $–$$$
Hourly drug cost for 20-kg patient:
Future Considerations
The benefits of pain management are increasingly recognized. Multimodal analgesic techniques, including CRI analgesics, can produce the best possible pain control while optimizing homeostasis and return to function.
General Guidelines: Analgesic Constant-Rate Infusions