Managing acute pain (Proceedings)

It is important to remember that pain is an experience, not a neurologic process. The experience of pain varies with many factors such as genetic make-up, sex, species and breed, hormonal influences, time of day, and age. Overall, there is about a 5-fold variation in the need for analgesics among normal individuals with similar injuries. In general, males require more analgesics than females, anxious individuals need more analgesics than calm individuals, and immature nervous system function is more deranged (and for longer periods) after injury than mature nervous system function.

Although acute pain has important survival benefit for untreated animals and man it has little benefit for hospitalized patients. When sufficiently intense, acute pain actually increases morbidity and mortality, primarily by excess amplification of the neuroendocrine response to injury. In hospitalized patients its value is greatly diminished; in fact, current ideology in human medicine holds that acute pain has no value at all in hospitalized patients, and every effort should be made to minimize it. This form of pain generally peaks in intensity within 24-72 hours of injury, and wanes progressively thereafter. In the absence of ongoing inflammation or repeated injury it is unusual for background pain (not necessary movement-associated) to be distressingly intense beyond 1-3 weeks. In fact, if debilitating pain remains beyond this time it usually indicates ongoing tissue pathology or a transition to chronic pain due to pathology within the nervous system.

This 3-week duration for acute pain overlaps with the same window of early opportunity for physical rehabilitation. Although movement-associated pain teaches the patient and caregivers what limits should be placed on physical therapy to avoid injury, left untreated it often interferes with reasonable goals for mobility and recovery of function. In some it is sufficiently intense to prevent adequate recovery altogether, setting the stage for abnormal neuromuscular function and chronic pain syndromes. Therefore, it is important to employ patient management strategies that maximize early recovery of function, particularly following orthopaedic procedures. Effective strategies often incorporate elements of both pharmacologic and physical therapy to achieve greater benefit than may be had by either alone.

The efficacy of acute pain control depends on how effectively you can interfere with its genesis at each step of nociception. From a drug therapy standpoint this interference should ideally be directed against nociception at the level of the first-order neuron to prevent any stimulation of higher-order nociception. The sensitivity of these neurons is enhanced by inflammation and can be modified with drugs such as nonsteroidal anti-inflammatory drugs. Signal transmission to the spinal cord can be completely blocked with local anesthetics. Physical maneuvers to modify inflammation (heat, cold, massage) will influence the response of the peripheral nervous system at this level. Nonsteroidal anti-inflammatory drugs, opioids, alpha-2 agonists, and NMDA receptor antagonists act in part by influencing processing and transmission at the level of the spinal cord. Physical therapy also affects spinal processing by modifying both nociceptive and somatosensory input. Stimulation of non-nociceptive input will not only interfere with acute pain (think of the effect of rubbing a painful elbow) but over time may interfere with the phenomenon of central sensitization.

In the worst stages of acute pain (for example the immediate postoperative period), drugs that alter consciousness and anxiety may modify pain without modifying nociceptive processing at the first two levels. For example, tranquilizers used at doses sufficient to relieve anxiety can promote restful REM sleep in the hours after exhausting surgery, limiting fatigue and its detrimental effects on pain and recovery. In man, patient education and incentive training are key elements to providing patients the psychological resources to master their pain, recover function, and minimize the risk of chronic pain or function loss. Although we are just beginning to understand the role of this in veterinary medicine there is abundant evidence attesting to the value of incentive, forced exercise, and placebo.

Another key concept in acute pain is that of postinjury facilitation. Everyone is familiar with the wood splinter that doesn't hurt much when you are first jabbed but that becomes exquisitely painful hours to days later. Persistent nociception and inflammation characteristically intensify perception of pain in an affected area. Consequently, normally mildly painful stimuli become more intensely painful (hypersensitivity) and normally non-painful stimuli become painful (allodynia). For the first week or two following the onset of pain this phenomenon is due largely to events occurring at both the first and second levels of transmission. The local inflammatory response following tissue injury lowers the first-order neuron response threshold, recruits quiescent ('sleeping') nociceptors, and intensely stimulates non-nociceptive neurons (for example, those associated with touch). When their output is sufficiently intense, information from the non-nociceptive neurons may be coded as nociception by second-order neurons. Consequently, the size of area of stimulation enlarges and the signal intensity presented to the second order neurons is increased. Similar changes occur at the second order neurons within the spinal cord, in a process commonly referred to as central sensitization, or wind-up. The second order neurons also become more sensitive, meaning that they depolarize in response to progressively less stimulation, and become more likely to code information from those recruited non-nociceptive neurons (e.g., those associated with touch or pressure) as nociception. These changes give rise to the 'tenderness' following injuries, and explain why just touching the skin next to an injured area can result in pain.

Remember that sick patients may be too obtunded by surgery or illness to show visible behavioral signs of pain yet may require the most aggressive analgesic therapy possible. In addition, consider that animals with systemic inflammation ('SIRS') have some sensitization of all peripheral neurons, and may be in considerable distress from injuries that would otherwise be well tolerated (remember how you ached the last time you had a fever?). There are few instances where monotherapy is completely effective. Combining 2 or more analgesics from different classes (e.g., a nonsteroidal anti-inflammatory and an opioid) and combining pharmacological therapy with physical therapy, distraction, and behavioural modification is much more effective than any one modality alone. Many analgesic drugs act synergistically and multi-modal therapy allows use of lower doses that markedly reduce side effects.

Options for therapy of acute pain

Well-established and effective options for acute pain include the non-steroidal anti-inflammatory drugs, the opioids, and local anesthetic agents. Drugs in routine use but with less well documented efficacy for clinical pain include intravenous lidocaine and low-dose ketamine. The alpha-2 agonist drugs xylazine and dexmedetomidine are useful analgesics when sedation is desired.

Analgesics drugs used as fluid additives for continuous rate infusion

For animals being treated with intravenous fluids that also require analgesic therapy, continuous infusion of analgesic drugs is convenient and often more effective than intermittent administration in response to patient signs. "Cookbook" formulations can be used for intraoperative fluid therapy and have the advantage of being made the same way and given at the same rate for every patient. Drug therapy can also be tailored to meet individual needs for postoperative or postinjury patients, or animals with other painful conditions such as pancreatitis, burns, severe dermatitis, etc.

Useful drugs include

1. Opioids

a. Morphine: Dog: 0.05 – 0.2 mg/kg/hour Cat: 0.025 – 0.1 mg/kg/hour

b. Hydromorphone: Dog: 0.0125- 0.05 mg/kg/hour Cat: 0.0125 – 0.025 mg/kg/hour

c. Buprenorphine: Dog: 2-4 mcg/kg/hour Cat: 1-3 mcg/kg/hour

d. Butorphanol: Dog: 0.2 – 0.8 mg/kg/hour Cat 0.2 – 0.4 mg/kg/hour

e. Fentanyl: Dog: 2-6 mcg/kg/hour Cat: 2-4 mcg/kg/hour

2. Lidocaine: Dog: 2-3 mg/kg/hour

3. Ketamine: Dog or cat: 0.1 – 2 mg/kg/hour

4. Dexmedetomidine: Dog or cat: 1 – 3 mcg/kg/hour

Based on information from the Handbook on Injectable Drugs(1), all of these agents are probably stable for several days in combination and in any commonly used intravenous fluid. There is no need to protect the solution from light. When used in combination, the dosages for these drugs can be at the low end of the suggested range.

Examples of "cookbook" preparations

A very useful technique in practices that routinely administer intravenous fluids during general anesthesia is to add the same amount of analgesic drugs to the fluid bags and to administer the fluids at the same rate to every patient. In this system, everyone involved – doctors and staff – knows to make the fluid the same way. When controlled drugs are used, staff is trained to account for usage by calculating the amount administered to each patient.

Example: M-L-K for dogs:

To a 1 liter bag of fluid, add:

• Morphine 20 mg

• Lidocaine: 240 mg

• Ketamine: 200 mg

Administer at 10 ml/kg/hour to achieve the following dosages:

• Morphine: 0.2 mg/kg/hour

• Lidocaine: 2.4 mg/kg/hour

• Ketamine: 2 mg/kg/hour

Example: F-K for cats

To a 500 ml bag of fluid, add:

• Fentanyl 250 mcg

• Ketamine 100 mg

• Administer at 10 ml/kg/hour to achieve the following dosages:

• Fentanyl: 5 mcg/kg/hour

• Ketamine: 2 mg/kg/hour

One method to implement this approach is to formulate a fluid bag with no more than ½ of the recommended dosage of opioid and ketamine (use the full dose of lidocaine in the MLK mix) and try it on a few patients to get a sense for how it affects your patients. Use your preferred preanesthetic protocol and begin the fluid therapy as soon as anesthesia has been induced. Discontinue it as soon as you remove the patient from the surgery room, or, if significant postoperative pain is anticipated, slow the administration rate down and continue it postoperatively. When it is time for a new bag, increase the concentration of the additives a bit and compare your results. Experiment with different ratios – for example, try relatively more opioid or less ketamine, and find a ratio and concentration that works best for you. The optimal dose should result in lower gas anesthesia requirements and slower, smoother recovery of consciousness.

Examples of "tailored" therapy for hospitalized patients

A commonly employed treatment for painful patients who need sleep in our intensive care unit is to combine an opioid with lidocaine, ketamine, and dexmedetomidine (dogs) or ketamine (cats). This approach is particularly useful for vigorous postoperative patients that require sleep the night after surgery. When the drugs are going to be administered for many hours, some considerations include:

1. Morphine (and to a lesser extent hydromorphone) will tend to have a increased effects on sedation and side effects when used at a dosage > 0.1 mg/kg/hour for more than 12 hours; therefore plan on reducing the dosage if starting out at a higher administration rate than this.

2. Ketamine will provide some protection against central hypersensitivity at dosages too low to produce obvious clinical signs of ketamine treatment. If you do not need the sedative properties of this drug use no more than 0.1- 0.2 mg/kg/hour.

3. A reliable sign in cats of borderline overdosage with an opioid is mydriasis; if this is accompanied by behavioral signs of agitation interrupt the infusion for 1-6 hours and restart at a lower rate. If the cat appears comfortable, dim the lights and keep it in a cage that does not have reflective sides!

4. If begun as an infusion with no loading dose, dexmedetomidine causes relatively mild cardiorespiratory effects and will take 1-2 hours to reach its peak effect. If a loading dose is desired (for example to treat emergence delirium), draw up .05-1 mcg/kg and dilute into 10 ml of saline; administer 1 ml of this at a time and titrate to effect.

5. Sedation and respiratory depression from the opioids and dexmedetomidine are much more likely if the animal is hypothermic. Verify satisfactory recovery of consciousness and normothermia after surgery.

6. If sedation is excessive, interrupt the infusion for a few hours and restart at a lower rate or lower drug concentration.

7. For cats and small dogs, use 250 ml bags, or install an in-line burette to meter the fluid and put all additives into that container instead of a large bag.

8. If additional fluids are needed, 'piggy back' a separate bag and administration set onto the primary IV set at an injection port and administer as needed; do not change the rate of the medicated fluid.

9. When first learning how to use this on your patients, start with lower dosages and work your way up as you gain confidence and experience. For the first few times, treat only patients whose infusion can begin before noon. Generally, by the time 4-6 hours have passed drug effects and clinical signs will reach a plateau. After you gain some confidence on the use of this technique, you can begin the technique on patients who receive fluids unattended overnight – ASSUMING you have a fluid pump a burette and can confidently predict the rate of administration.

10. Be sure to consider combination therapy with an injectable or oral NSAID. As the patient recovers the ability to drink, the IV fluid rate can be slowed if less drug is needed.

For this technique, plan on adding the drugs to a bag of fluids whose administration rate will not change. This usually means to pick a fluid and administration rate calculated to provide maintenance needs for water. For example, let's calculate the drug plan for a 20 kg dog that we wish to administer morphine, lidocaine, ketamine, and dexmedetomidine for the first 8-24 hours postoperatively. Drug doses to consider might include:

• Morphine: 0.1 mg/kg/hour x 20 kg = 2 mg/hour

• Lidocaine: 2.5 mg/kg/hour x 20 kg = 50 mg/hour

• Ketamine: 0.1 mg/kg/hour x 20 kg = 2 mg/hour

• Dexmedetomidine 2.0 mcg/kg/hour x 20 kg = 40 mcg/hour

The maintenance fluid administration rate for a dog this size lying quietly in a cage is roughly 800 ml/day or 33 ml/hour. Therefore, a 1 liter bag contains 1000/33 or 30 hour's worth of treatment and to a 1 liter bag we must add:

• Morphine: 2 mg/hour x 30 hours = 60 mg = 4 cc

• Lidocaine: 50 mg/hour x 30 hours = 1500 mg = 75 cc

• Ketamine: 2 mg/hour x 30 hours = 60 mg = 0.6 cc

• Dexmedetomidine: 40 mcg/hour x 30 hours = 1200 mcg = 1.2 cc

If the drugs are added to a 1 liter bag of fluid, the final volume is greater than a liter – in this case 1081 ml. Therefore, 81 ml should be removed from the bag prior to addition of the medications.

Reference List

Trissel LA. Handbook on Injectable Drugs. 11 ed. Bethesda, MD: American Society of Health-System Pharmacists, Inc.; 2001.