New and old approaches to treating acute peri-operative pain (Proceedings)

Opioid drugs

Because the entire CNS is heavily invested with opioid receptors that mediate central and spinal analgesia, the most effective class of analgesics is the pure agonist opioids, i.e. drugs such as morphine, hydromorphone, oxymorphone, etc. Exogenous administration of these drugs results in binding to endogenous receptors, thus mimicing the analgesic effects of the endogenous opiate system. Analgesia occurs from receptor activation in both the dorsal horn of the spinal cord and in the brain. A spectrum of opioid receptors have been identified within the CNS. The clinically important receptors are the mu, kappa, and delta opioid receptors. The mu receptor mediates central and spinal analgesia, as well as CNS sedation, bradycardia, respiratory depression, increased locomotor activity and euphoria or excitement. The kappa receptor mediates spinal analgesia and mild CNS sedation and respiratory depression. The delta receptor mediates excitement, mania, and dysphoric behavior.

The prototype opioid to which all others are compared with respect to receptor affinity is morphine. In addition to analgesia, all pure agonist opioids, such as morphine, can cause CNS sedation, respiratory depression, bradycardia, nausea and vomiting (although this is less common when the drugs are given to treat existing pain), GI ileus, and urinary retention. The extent of these side effects varies with species and with the individual. In certain species, such as cats and horses, excitement and increased locomotor activity are common, although this occurs less frequently or less dramatically when the drugs are given to treat preexisting pain. With all the opioid agonists, the degree of analgesia achieved, as well as the attendant side effects, are dose-related. Ideally, lower doses should be administered "pre-emptively" to provide intra- and post-operative analgesia and minimize side-effects. An important concept when using opioids in the perioperative period is that agonist opioids will decrease anesthetic requirement 40-50%. This means that a healthy dog or cat that has received an agonist opioid for premedication may only need the vaporizer set at ~ 1.0 – 1.5% (isoflurane) or 1.7 – 2.0% (sevoflurane).

Morphine

Morphine can cause histamine release, particularly when higher doses are given intravenously as a bolus. Clinical signs of histamine release are vasodilation, flushing, facial swelling, hypotension, and urticaria. Very slow IV administration, if necessary, will minimize histamine release, but preferably this drug should be given intramuscularly or subcutaneously. It has been shown in humans that metabolites of morphine, specifically morphine-3-glucuronide and morphine-6-glucuronide, are responsible for much of the analgesic effect of this drug. Cats are unable to synthesize glucuronide metabolites. Clinical studies have verified that morphine is not a very useful analgesic in cats, likely due to the lack of glucuronide metabolite production. In dogs, morphine is a useful premedication (0.5 – 1.0 mg/kg), both by virture of its sedative effects and because it provides effective preemptive analgesia prior to surgery. The duration of action is approximately 6 hours, therefore a premedication dose of morphine may last long enough to cover analgesic needs into the post-operative period. For post-operative analgesia, morphine can be given IM 15 minutes before anticipated recovery. The animal thus recovers in a calm and pain-free fashion. There is some art to the administration of morphine prior to extubation. If a full dose is given IM while the animal is still anesthetized, then recovery will be slow. In my experience, if ¼ to ½ the normal dose of morphine is given (i.e. 0.25 –0.5 mg/kg) to a warm (i.e. rectal temperature must be ≥ 99° F) patient then recovery is not unduly prolonged and the animal is calm and comfortable at extubation.

Oxymorphone and hydromorphone

Oxymorphone and hydromorphone are acceptable opioids for use as premedication or for post-operative pain. Both are effective in dogs as well as cats. Their duration of effect is approximately 2-3 hours. Both drugs are less likely to induce vomition than morphine and both drugs can safely be given IV due to their lack of histamine-releasing properties. Panting is more common with oxymorphone and hydromorphone than with morphine. Because these 2 drugs can be safely given IV, they are well-suited to intra-operative "top off" for analgesic management. This may be useful when the premedication dose is beginning to wear off. For example, if the patient has spikes of increased blood pressure or appears to have periods where anesthetic depth is too light (i.e. "roller coaster anesthesia), a small top-off dose of oxymorphone or hydromorphone will stabilize the situation. Keep in mind, however, that opioids decrease inhalant requirement by 40-50%, so the vaporizer should be adjusted accordingly. When given close to recovery, these drugs may delay extubation, as they will greatly obtund laryngeal reflexes. Thus, for post-operative analgesia, it is recommended that these drugs be given upon extubation, and hopefully before the animal has become completely aware of its surroundings and painful. Hydromorphone, but not oxymorphone, has been documented to cause dramatic post-operative hyperthermia in cats (temperatures reaching 107° F). This is most often a problem when the cat has become cold during surgery and then homeostatic mechanisms to rewarm seem to overshoot normothermia.

Fentanyl and remifentanyl

These 2 opioid agonists have a very short duration of effect and thus are not very useful as premedicant drugs. Both drugs are extremely useful as an IV constant rate infusion (CRI), for administration both during and after surgery. The use of fentanyl or remifentanyl intra-operatively greatly reduces inhalant requirements, thus leading to greater hemodynamic stability. For patients with significant systemic or organ disease, the use of fentanyl infusions during surgery will help to preserve blood pressure and cardiac output because of the much reduced inhalant. Typically when animals are receiving fentanyl as a CRI during surgery, the vaporizor setting can be reduced by > 50-75%. Post-operatively, the fentanyl CRI can be continued if the animal is to recover in an intensive care setting. As analgesic needs wane, the fentanyl CRI can be gradually turned down until the animal is ready to be discharged from intensive care and alternative analgesic drugs can be administered PO or transdermally. Typical intra-operative doses of fentanyl range from 3-10 mcg/kg/hour and post-operatively are usually between 3-5 mcg/kg/hour. The use of remifentanyl is very much like fentanyl, but the onset and offset time is almost immediate, as this drug is metabolized by plasma esterases. Therefore, remifentanyl is useful for patients with hepatic insufficiency, but care should be exercised in bolusing the drug or turning it off, as the resultant effects (sudden increased depth or sudden absence of analgesia, respectively) can be dramatic. Typical intra-operative doses for remifentanyl are 6-20 mcg/kg/hour and post-operative are 3-8 mcg/kg/hour.

Butorphanol and buprenorphine

Butorphanol is a mixed agonist-antagonist opioid, with agonist activity at kappa receptors and antagonist activity at mu and delta receptors. This drug is not as effective an analgesic as the pure agonist opioids, but it is associated with fewer side effects. Butorphanol is less likely to cause CNS excitement, respiratory depression, or sedation. Clinical impression, however, is that butorphanol is only moderately effective in treating major pain, and should be reserved for simple procedures involving minimal tissue trauma. Butorphanol's duration of action is only 45-60 minutes after an IM dose. Dose ranges for dogs and cats are 0.1 – 0.4 mg/kg. Butorphanol CRI's can be useful for treatment of refractory nausea at doses of 0.1 – 0.2 mg/kg/hour. Because of butorphanol's antagonist activity at the mu receptor, it will also reverse the clinical effects of agonist opioids, including analgesia. Because it is a scheduled drug (like other opioids), requiring DEA licensure and record keeping, and because it is not very useful for analgesia except for the most minor procedure, I personally use butorphanol rarely for acute pain and prefer to reach for the agonist opioids and their superior analgesia.

Buprenorphine is a "partial agonist" opioid with high affinity for the mu receptor but moderate intrinsic activity. Thus, buprenorphine has moderate analgesic potency and a long duration of action (8 – 12 hours). It is only mildly sedative in dogs and cats but appears to provide acceptable post-operative analgesia for low-grade pain. In cats and ferrets, but not in dogs, buprenorphine is absorbed transmucosally as well. This is because the pKa of buprenorphine is close to the pH of saliva in the mouth of a cat and ferret and the non-ionized portion of drug is well absorbed across mucosal membranes. This route will not be effective in dogs. Dose ranges for buprenorphine in the dog and cat range from 10 – 40 mcg/kg.

Local anesthetic drugs

Local anesthetic drugs can be used to treat pain by virtue of their blockade of sodium channels within sensory neurons, thus preventing nerve depolarization and action potential propagation. There is a large body of evidence suggesting that local anesthetics are useful as analgesics in dogs when given systemically as a CRI. Intravenous lidocaine can be safely used as an analgesic adjunct intra-operatively and the intra-operative use of lidocaine CRI may reduce post-operative analgesic requirements. The dose for a lidocaine CRI is a 1 – 2 mg/kg bolus IV, followed by a CRI dose of 25 – 50 mcg/kg/minute. I do not recommend this technique in cats because of increased risk of toxicity with lidocaine. The intra-operative use of lidocaine has been shown to reduce anesthetic requirement ~ 20%.

NMDA antagonist drugs

The N-methyl-D-aspartate (NMDA) receptor is found within the spinal cord dorsal horn and is thought to participate in the amplification or "wind up" phenomenon associated with major pain. Both amantadine and ketamine act as antagonists at the NMDA receptor, but for peri-operative pain management, ketamine is the more useful. Recent evidence has suggested that intra-operative administration of subanesthetic doses of ketamine as a CRI may reduce post-operative analgesic needs and may reduce intra-operative analgesic and inhalant requirements. Use of ketamine as a CRI has not been scientifically investigated in cats, but I have used ketamine CRI's in cats for intra-operative adjunctive analgesia with some success. The dose for a ketamine CRI is a 0.5 mg/kg bolus (unless the animal was induced with ketamine), followed by a CRI rate of 2 – 10 mcg/kg/minute. The use of ketamine as an analgesic may be contraindicated in animals with pre-existing seizure disorders, hyperthyroid disease, hypertension under anesthesia, or elevations in intracranial or intraocular pressure.

MLK and FLK

MLK (morphine-lidocaine-ketamine) and FLK (fentanyl-lidocaine-ketamine) are useful "balanced analgesia CRI's for major surgical and post-operative pain. These CRI's appear to be equally effective to epidural analgesia in orthopedic procedures and are my CRI of choice for painful soft tissue cases as well. MLK can be mixed up into a 1L bag of isotonic crystalloids and administered at a surgical rate of 10 ml/kg/hour during surgery and reduced to maintenance rates (2 – 3 ml/kg/hour) post-operatively. To a 1 L bag of fluids add: 20 mg morphine, 300 mg lidocaine, 60 mg ketamine. Some clinicians advocate bolusing a loading dose of these 3 drugs prior to starting the CRI. My practice is to bolus an agonist opioid (e.g. hydromorphone) only if the animal was not premedicated with an agonist opioid, and to bolus lidocaine at 1 – 2 mg/kg IV and ketamine at 0.5 mg/kg IV (unless ketamine was used for induction). The rationale behind the loading dose is to increase serum drug levels to therapeutic ranges quickly so that the CRI maintains those levels and you maximize analgesic effectiveness. MLK will substantially delay recovery and the animal may appear sedated for several hours after extubation. Because of this, I now recommend that the MLK rate be slowed to 5 ml/kg/hour during the last hour of surgery.

FLK is the same principle, but I run the fentanyl separately in a syringe pump at 5 – 10 mcg/kg/hour and add the lidocaine and ketamine to the fluids at 10 ml/kg/hour as described above for MLK. I choose FLK when I have a patient where anesthetic stability may be a concern and where I want to be able to fine-tune or titrate the fentanyl dose independently of fluids or lidocaine and ketamine administration.

Nonsteroidal antiinflammatory drugs

The nonsteroidal antiinflammatory drugs (NSAIDs) are analgesic by virtue of their inhibitory effects on cyclooxygenase, thus blocking the peripheral and central production of prostaglandins during and after tissue injury. Because they block only one chemical mediator in the nociceptive pathway, their use should be reserved for chronic, low-grade pain, or post-operative pain, particularly musculoskeletal, a few days into recovery. They are not very effective as the sole analgesic agent in the management of perioperative, acute pain. Several studies have suggested that either carprofen or ketoprofen may be more effective in providing post-operative analgesia when used preemptively prior to surgery, rather than when they are administered post-operatively. One disadvantage of administering NSAIDs prior to surgery is that anesthetic induced hypotension will exacerbate potential renal injury. Thus, I reserve preemptive NSAID administration to healthy patients where I do not predict hypotension and I monitor blood pressure routinely in every case, managing anesthetic depth, fluids, etc to maintain mean arterial pressure > 65 mm of Hg.

Because of their effect on prostaglandin synthesis, all NSAIDs have the potential to cause gastric irritation and ulceration, diarrhea, and melena. They can also cause liver function impairment and renal tubular necrosis when moderate to high doses are used for long periods of time or when renal perfusion is compromised, as with dehydration or hypotension during surgery. Finally, they block platelet adhesion, so will increase clotting time. This effect is not clinically relevant in a healthy patient, but NSAIDs are contraindicated in patients with coagulopthy or thrombocytopenia. Because cats have low levels of glutathione-dependent enzyme pathways, hepatic metabolism of many NSAIDs will be impaired, and toxic blood levels can accumulate. Aspirin, carprofen (one time dose only), and meloxicam are the only NSAIDs considered safe in cats, and should be used with extreme caution in geriatric cats or those with hepatic or renal disease. In general, NSAIDs should be used with caution in any animal with hepatic or renal disease, coagulopathies, thrombocytopenia, inappetance or gastrointestinal disease, and in the neonatal or geriatric patient.

Alpha-2 agonist drugs

The predominant alpha-2 agonist drug in small animal medicine today is dexmedetomidine, although xylazine and medetomidine may still be used in some practices. Dexmedetomidine is the R enantiomer of medetomidine, the R enantiomer being the pharmacologically active form. Therefore, doses of dexmedetomidine are ½ those for medetomidine, and range from 1 – 10 mcg/kg in dogs and cats. This class of drugs are all potent CNS depressants, causing marked dose-dependent sedation in small animals. They are considered analgesic by virtue of their sedative properties, and because there are alpha-2 receptors in the interneurons of the spinal cord dorsal horn which are thought to mediate analgesia by similar mechanisms to opioids. Alpha-2 agonist drugs, particularly dexmedetomidine, are useful as analgesic adjuncts when administered either prior to surgery as a preemptive analgesic, or post-operatively. This class of drugs provides effective analgesia for acute pain. A major disadvantage, however, is the profound sedation associated with alpha-2 agonist administration. In my experience, animals that are sedated from an alpha-2 agonist drug may not exhibit behavioral signs of pain due to sedative effects.

Dexmedetomidine can be used as a premedication and analgesia in healthy patients without significant cardiovascular, respiratory or CNS disease, but I usually combine it with an opioid for major surgical pain. Dexmedetomidine is very useful in the post-operative period at very low doses for treatment of emergence delirium or dysphoria (0.5 – 1 mcg/kg IV). Dexmedetomidine can also be given as a CRI for post-operative sedation (1 – 2 mcg/kg/hour). In cats, dexmedetomidine absorbed transmucosally, so this offers another potential route of administration when this drug is used as a premedication.

Side effects of the alpha–2 agonist drugs can be significant and include bradycardia, clinically important decreases in cardiac output, hypertension followed by hypotension, peripheral vasoconstriction, respiratory depression, hypoxemia when breathing room air, hypercapnia and elevated intracranial pressure, ileus, hyperglycemia, and increased urine output. Due to the hemodynamic effects of these agents, their use should be reserved for healthy young to middle-aged animals. The magnitude and duration of these side effects are dose-dependent, and can be reversed with specific reversal agents such as atipamezole. When used, atipamezole should be given IM in equal volume to the dose of dexmedetomidine that was used and, if reversal is performed under anesthesia, be prepared for sudden changes (reduction) in anesthetic depth! Bradycardia from dexmedetomidine should not be treated with the anticholinergic drugs atropine or glycopyrrolate. Doing so will greatly increase myocardial work because of increased heart rate in the face of peripheral vasoconstriction and increased afterload caused by the dexmedetomidine.