Pain assessment and management strategies (Proceedings)

Physiology of Pain

Pain is defined as an aversive sensory and emotional experience.1 Nociception is the neural response to the application of a noxious stimulus. It is observable and recordable, but does not necessarily equate to pain. Pain in animals can only be characterized by the observation of behavioral changes in response to a noxious stimulus which may be painful.

Nociception receptors are free nerve endings located in most tissues of the body. These receptors are sensitive to mechanical, thermal, or chemical stimulation. The primary afferents of the nociceptor pathways include the A-delta fibers and the C fibers. A-delta afferent pathways are responsible for the first, acute, fast, sharp pain associated with an injury; the conduction velocity of these pathways are very fast. The receptive area of these afferents is very discrete, enabling the animal to localize exactly the site of the stimulus. C afferent pathways are responsible for the second, dull, aching, burning, throbbing, chronic pain of an injury. The receptive area is relatively large and localization of the site of the stimulus is limited to general areas of the body. A-beta fibers are associated with the sensations of vibration, tickling, prickling, or tingling. These afferent fibers have a major role in ascending anti-nociception mechanisms of the spinal gate control mechanism (transcutaneous electrical nerve stimulation, acupuncture/acupressure, massage, and mechanical manipulation of the painful area). A-beta fibers exhibit lower stimulation thresholds than do A-delta and C fibers and therefore can be selectively stimulated.

The gate theory of pain control was introduced in 1965.2 Afferents of A-delta, C, and A-beta fibers synapse with neurons in the dorsal horns which send long axons upward to the brain.3,4 Prior to synapsing with these "central transmission cells", the nociceptor fibers give off branches which synapse with interneurons in laminae I and II (the substantia gelatinosa) of the dorsal horn. The substantia gelatinosa cells, in turn, presynaptically inhibit the release of neurotransmitter by the primary nociceptor fibers at the synapse to the central transmission cells. The A-delta and C fibers inhibit the substantia gelatinosa cells thereby facilitating the A-delta and C fiber stimulation of the central transmission cell and the secondary afferents to the brain. This positive feedback mechanism of A-delta and C fibers serve to enhance the magnitude of the nociceptive input from a given painful stimulus. The A-beta fibers activate the substantia gelatinosa cells and thereby inhibit neurotransmitter release and stimulation of the central transmission cell. This negative feedback system serves to minimize the nociceptive input to the central nervous system from a given painful stimulus. Several modes of pain therapy are based upon this ascending pain modulation mechanism since A-beta fibers can be stimulated at sub-pain thresholds.

Assessment and Recognition of Pain

Pain is herein defined as an aversive (perceptual) physical nociceptive stimulus, which threatens to, or does, cause tissue damage, and which would evoke protective motor actions and avoidance. Nociception is the neural response to a noxious stimulus and does not, per se, equate to pain. Discomfort encompasses a broad range of aversive sensory and emotional experiences, of which pain is only one form. When discomfort is great enough or prolonged enough so as to alter normal behavior or activity, the recipient is said to be suffering. The existence of pain in an animal and the need for analgesic therapy is dependent upon the observation of behavioral changes or abnormalities in the animal which can reasonably attributed to pain. It might be helpful to divide pain into levels of magnitude: severe, moderate, and mild. Severe pain might be defined as that which is intolerable; the kind of pain where the animal throws itself about its cage in a mindless frenzy because the pain is so severe that the animal simply cannot deal with it in any other way. Unprovoked vocalizing (crying, whimpering) in an animal that does not have CNS disease and is not recovering from anesthesia, and does have a disease which might be painful, is also taken as evidence of severe pain. Mild pain might be equated with that amount which is a nuisance; the animal is well able to tolerate it and to go about its daily activity since it does not interfere with behavior in any fashion.

Pain may be described as moderate when it starts to interfere with normal behavior, appetite, or the normal activity in an animal that has a disease or that has undergone a surgical procedure which is reported to be painful in humans. Appetite may be decreased or absent and the animal may lose weight, energy, or productivity. The animal may exhibit an anxious expression and may not rest comfortably and may be unable to sleep; rather the animal seems to be lying there "stiffly", with its eyes open for long periods of time, and sleeping infrequently or not at all. The attitude may become one that is less concerned with its environment; the animal more often "stares off into space" and is not mentally "there" for the moment. The attitude may also change to that of an animal that is less tolerant to being handled than normal (because it hurts every time it is handled). The attitude may become more fearful or more aggressive. These changes in attitudes must be differentiated from an "intensive care psychosis" where the animal is disoriented by its disease process or drug therapy, discouraged by loneliness and the discomfort associated with the underlying disease, and exhausted by lack of sleep. The psychological well-being of the animal must receive as much attention as the physiological disease process. Secondary physiologic changes may result from pain, as well as the underlying disease process: tachycardia, tachypnea, hypertension, arrhythmias, dilated pupils, salivation, and/or hyperglycemia. The animal's activity may become increased (if the animal is trying to find a position wherein the pain is diminished) and the animal may assume abnormal positions. The animal's activity may become decreased (if the animal is trying to minimize pain associated with movement). The animal may move, but infrequently, and stiffly, as if to guard and protect the painful area. The pain may be classified as moderate if the animal develops an anxious expression or tenses when the area in question is about to be touched, or if it cries out or responds aggressively when the area is touched; when these represent an inappropriate response for this particular individual/species to an otherwise innocuous stimulus.

None of the "pain signs" are specific to pain and there are many non-painful situations in which they might appear. When it is not clear whether an animal is experiencing undue pain and when it is not clear whether analgesics should be administered, it is appropriate to administer a test dose of an analgesic.

Agonist Opioids

Agonist opioids, including oxymorphone, morphine, meperidine, methadone, and codeine, have been the drugs primarily used for analgesia therapy over the years. These agents, while being very effective analgesics, cause a dose-dependent CNS depression (dogs, primates, rats, and rabbits), or CNS excitation (cats, horses, ruminants, and swine). This difference in effect may be due to differences in the distributions of the various opioid receptors within the central nervous systems of the various species. Opioids, in those species in which they induce CNS depression, are associated with euphoria and psychological and well a physical dependency. For this reason, these drugs are regulated by the Federal Bureau of Narcotics and Dangerous Drugs and very careful records of their utilization must be kept. Tolerance to their effects does develop over time. Innovar has been associated with an aggressive personality change in the dog (or a change to a personality that is less tolerant of its environment); the change is probably due to the droperidol and is virtually always limited to the duration of action of the drug.

Opioid agonists cause a dose-dependent respiratory depression, except when they cause CNS excitation. Panting is not uncommonly seen in the dog after administration of some opioids (fentanyl/droperidol, oxymorphone); a response that is attributed to the narcotic's effects on the thermoregulatory center. These animals generally are neither hypoventilating nor hyperventilating, but the breathing pattern makes delicate procedures difficult and may be associated with an elevation in body temperature. The breathing pattern usually normalizes after about 20 minutes, but can go on much longer, especially if the animal becomes hyperthermic. Opioid agonists generally have little adverse cardiovascular effect although larger doses can induce a centrally-mediated, atropine-responsive, increase in vagal tone and bradycardia. Hypotension may occur due to bradycardia, venous pooling (morphine), histamine release (morphine, meperidine), myocardial depression (meperidine, fentanyl), and/or a central sympatholytic effect.

Emesis and/or defecation commonly occurs following opioid administration in the dog, and occasionally the cat, due to stimulation of the chemoreceptor trigger zone. Opioids (morphine) increase resting smooth muscle tone (peristalsis is decreased; bladder, biliary, pancreatic sphincter tone is increased). Constipation, tolerance and physical dependence may be a problem with prolonged small-dose administration.

All of these unfavorable effects would be expected to be minimal in the dosages normally recommended for analgesia, but could be a problem if these agents were administered in large dosages, as intravenous boluses, or in animals already debilitated by systemic disease.

Oxymorphone, fentanyl, morphine, methadone, sufentanil have all been used for analgesia and all work well. Meperidine may be used but often is not very effective. It is a potent liberator of histamine and may be hypotensive if administered intravenously. Morphine is also a liberator of histamine. The administration of an adjunctive tranquilizer, such as diazepam or acepromazine, often enhances the apparent effect of these drugs (the animal acts as if it where more comfortable because of the tranquilization) even though these drugs actually diminished the analgesia provided by analgesic drugs.

Agonist opioids, in generally, can be administered subcutaneously, intramuscularly, or intravenously as an intermittent or continuous infusion. Fentanyl is available in a patch for transdermal absorption. Some opioid agents are commercially available as oral preparations.

Dosages for opioid agonists and fentanyl patch

The effects of agonist opioids can be reversed by any agonist-antagonist or naloxone. Naloxone reverses all effects: the CNS depression, the respiratory depression, and the analgesia. It is difficult to titrate to the desired endpoint of less CNS/respiratory depression while maintaining some of the analgesia. The agonist-antagonist agents may be more efficacious in this regard.

Dosages for opioid antgonists

Agonist-Antagonist Opioids

At least six classes of opioid receptors have been identified: Mu1, Mu2, Kappa, Sigma, Delta, and Epsilon. Mu2 receptors mediate CNS depression, supraspinal analgesia, bradycardia, miosis, respiratory depression, hypothermia, constipation, indifference, euphoria and physical dependency. Kappa receptors mediate primarily spinal analgesia, some CNS and respiratory depression, and miosis. Sigma receptors mediate primarily CNS excitation, anxiety, tachypnea, tachycardia, delirium, dysphoria, and mydriasis. The clinical implication of multiple opioid receptors is that perhaps specific drugs, yet to be identified, could provide effective analgesia without any of the disadvantageous effects of the diffusely-acting agonist opioids. Additionally, if tolerance develops to the analgesic drug at one receptor type, a different drug could then be administered which would affect analgesia at a different receptor.

In contrast to the agonist opioids, for which the dose-response curve is fairly linear, the agonist-antagonist drugs exhibit a plateau, or ceiling, effect, after which further increases in dosage do not produce further increases in effect. This ceiling effect cuts across advantageous and disadvantageous characteristics. The CNS/respiratory depression ceiling means that this group of drugs are fairly safe, even in the event of an inadvertent over-dose. The analgesic ceiling means that this group of drugs may not be very effective for more severe categories of pain.

Most agonist-antagonists exhibit a duration of activity of 1 to 4 hours, buprenorphine may last as long as 10 to 14 hours. The effects of agonist-antagonist opioids can be reversed by naloxone.

Dosages for agonist-antgonist opioids

Antiprostaglandins

Antiprostaglandin drugs are effective analgesics for mild to moderate, but not severe, pain of an inflammatory nature in most species and for acute colic pain in horses. The disadvantages of these drugs is that they inhibit mucous secretion and may therefore be associated with gastrointestinal ulceration and hemorrhage (and perforation). Naproxen, tolmetin, indomethacin, and flurbiprofen are so prone to do this that their use is not recommended in the dog. Antiprostaglandins may also be associated with afferent arteriolar vasoconstriction. (PGE2) is a primary competitor to angiotensin II and norepinephrine-induced renal vasoconstriction in times of stress) and a prerenal or vasogenic renal failure in animals with pre-existing renal disease or co-existing renal insults. Antiprostaglandins also impair platelet adhesion due to the impaired production of thromboxane.

Antiprostaglandins inhibit cyclo-oxygenase enxymes and postaglandin production from arachidonic acid. There are many isoforms of cyclo-oxygenase enxymes. The COX-1 are the constitutively expressed isoforms which are responsible for baseline prostaglandin synthesis important to many normal physiologic functions. The COX-2 are the induced isoforms which are involved in pathologic inflammatory processes, including pain. PGE2 is the major mediator of pain. Antiprostaglandins may inhibit both COX-1 and COX-2 or may be COX-2 selective. The theoretical advantage of selective COX-2 inhibitors is that they can inhibit pathologic pain without inhibiting the normal biologic function of the constitutive prostaglandins. In practice, COX-2 selective does not exclude some COX-1 inhibition, COX-1 and COX-2 enzymes have overlapping functions, and the COX-2 selective antiprostaglandins are not immune to GI side effects. COX-2 selective drugs have less effect on thromboxane activity.

Dosages for antiprostaglandins

Acetaminophen, an aniline-derived analgesic, is a potent cyclo-oxygenase inhibitor. It exhibits good central analgesic and antipyretic activity (compared to the other antiprostaglandin drugs), but exhibits minimal anti-inflammatory effects and therefore may not be as good an analgesic in peripheral tissue damage/inflammation-mediated pain. Acetaminophen does not inhibit platelet aggregation or cause gastrointestinal ulceration. Metabolism is normally associated with the production of a small amount of a reactive metabolite that is normally scavenged by glutathione. There is a finite supply of glutathione and hepatotoxicosis may occur if it is overwhelmed with an overdosage. The reactive metabolite oxidizes: 1) cellular protein causing cytolysis, 2) sulfur groups causing further glutathione depletion, and 3) hemoglobin iron causing methemoglobinemia. The cat is deficient in glucuronyl transferase (for glucuronide conjugation), greater amounts of this reactive metabolite will be produced. The cat is particularly prone to this hepatotoxic effect and toxicosis can develop after a single dose of acetaminophen. Compounds which contain this agent or phenacetin (which is converted to acetaminophen) are contraindicated in cats. Cats with acetaminophen intoxication can be treated with activated charcoal, N-acetylcysteine, cimetidine, and urine alkalinization.5

Anxiolytics

Anxiolytics do not provide any analgesia, per se, but decrease the animal's concern about its environment. The clinical signs of anxiety are similar to those of pain and it is difficult to determine which might be the cause of the animal's restlessness. When, after the administration of a suitable dose of an analgesic, the "pain" signs persist, it would be appropriate to administer an anxiolytic. Phenobarbital, pentobarbital, thiamylal, and thiopental, when used in small dosages as hypnotic/sedatives, are also anxiolytic.

These agents may, however, decrease the magnitude and duration of the analgesic properties of other drugs while at the same time increasing their apparent effectiveness. These agents are well tolerated by normal patients, however unpredictable vasodilation and hypotension may occur in debilitated patients. Phenothiazines may decrease an animal's tolerance to being handled and it is important to approach tranquilized animals with care.

The benzodiazepine tranquilizers (diazepam, midazolam) are effective tranquilizers, amnesics, central muscle relaxants, and anticonvulsants in most species. Diazepam and midazolam, however, are not effective tranquilizers in dogs and cats which do not have some disease-induced or drug-induced CNS depression beforehand. The initial response in normal dogs and cats is often excitation, occasionally extending to mania.

Epidural Analgesia

Local anesthetics may be injected locally as a field or regional block for analgesia purposes. Local anesthetics may be deposited into the epidural space, either as a single administration or repeatedly via a preplaced catheter. Lidocaine and bupivacaine can be used but bupivacaine exhibits much longer durations of action (3 to 4 hours vs 1). The duration of action of the local anesthetics can be prolonged by admixing epinephrine (1 to 100,000 or 200,000 dilution).

The technique of introducing a needle or catheter (for repeated administrations) into the epidural space is easy to learn and generally well-tolerated by the animal. Place the animal in sternal recumbency with the hind legs tucked up underneath. Placing the abdomen on a sandbag may also help open the lumbosacral joint. Palpate the dorsal-most prominences of the iliac crests. Draw an imaginary line between the two; this line is close to the L7-S1 interspace. Palpate slightly cephalad the dorsal process of L7; sometimes this is difficult to feel, especially in obese dogs, because it is slightly smaller than the dorsal process of L6. Clip the hair over this area and surgically prepare the skin with antiseptic solutions. Put on sterile gloves. Palpate with the middle finger and thumb of one hand, the iliac crests while simultaneously palpating the lumbosacral junction with the index finger. Block the skin and underlying tissues with lidocaine. Introduce the spinal needle (22 ga) at approximately a perpendicular angle to the skin (or may be tilt the hub slightly toward the tail). Needle introduction should be slow and steady (not jerky). You want to feel the sudden decrease in resistance when the needle passes through the intervertebral ligament. Stop! Remove the stylet; inject some air with a glass syringe - there should be no resistance (if there is, you are not in the epidural space). If the needle is properly placed, slowly (30 seconds) inject the analgesic solution.

If the purpose of the procedure was to insert a catheter, a special needle and epidural catheter kit is used. Once the needle is properly placed, the catheter is inserted. It should go easy and without resistance. These are, however, very soft, flexible catheters and will usually insert easily, even if they are being fed into a "catheter ball" at the end of the needle. Always radiograph the area to verify that the catheter is properly placed. Tape the catheter and then suture the catheter to the skin. Keep this area scrupulously clean; an epidural infection is not a pretty thing.

Problems with the epidural administration of a local anesthetic include: 1) sympathetic paralysis which causes peripheral vasodilation and hypotension; 2) motor paralysis to the hind limbs (for dogs and cats this is a minimal problem although paresthesias during the wearing off of the block may incite the animal to chew at the appendage; in large animals, posterior paralysis and the associated panic and thrashing is a major disaster); and 3) if the block gravitates too far anteriorly in the epidural space, intercostal paralysis and ventilatory impairment may occur.

Other agents: agonist opioids, agonist-antagonist opioids, alpha-2 agonists, have also been deposited in the epidural space for the provision of analgesia. The proposed advantage is analgesia without the adverse effects noted above for the local anesthetics, and, hopefully, without the adverse systemic effects of the agent. Reports of xylazine administered into the epidural space suggest that it is an effective analgesic but that posterior paresis may still be a problem, although the safety margin is greater than it is with local anesthetics. Reports of morphine administered into the epidural space suggest that analgesia may last 24 to 48 hours.

Dosages of drugs for epidural analgesia

Body Cavity Analgesia

Bupivacaine has been used to provide body cavity analgesia by placing it into the chest or abdominal drain. Dilute 2 mg/kg in sterile saline (1 part bupivacaine: 4 parts saline: 1/10 part sodium bicarbonate). The sodium bicarbonate is necessary to adjust the pH of the solution so that it will not be irritating to the tissues and painful upon instillation. Moving the animal to different positions to facilitate the distribution of the solution throughout the cavity would be a good idea. Clamp the drainage tube for 20 minutes. The procedure may need to be repeated every 4 to 8 hours.

References

1.Kitchel RL, Problems in defining pain and peripheral mechanisms of pain, JAVMA, 1987;191:1195-1199.

2.Melzack R, Wall PD, Pain mechanisms: A new theory, Science, 1965;150:971-978.

3.Nolan MF, Anatomic and physiologic organization of neural structures involvd in pain transmission, modulation and perception, in Echternach JL (ed), Pain, Churchill Livingstone, New York, 1987. P. 1-37.

4.Wall PD, Introduction, in Wall PD, Melzack R, (eds), Textbook of Pain, Churchill Livingstone, New York, 1989. P. 1-20.

5.Oehme FW, Aspirin and acetaminophen, In Kirk RW, (ed), Curr Vet Ther IX, WB Saunders Co., Philadelphia, 1986. P. 188-190.