MANAGEMENT OF PAIN 0195-5616/00 $15.00 + .OO

PERIOPERATIVE PAIN MANAGEMENT

Peter J. Pascoe, BVSc

For many years, there has been a litany in the human literature that postop- erative pain is undertreated; almost every article describing postoperative pain management refers to this "fact," and it is clearly a major issue in the manage- ment of cancer pain and pain in the emergency room. Articles with titles like "Are Emergency Physicians too Stingy with Analgesics?" continue to appear in the human 1iterat~r-e.~~ In veterinary medicine, we have been even more guilty of ignoring pain. One study from a teaching hospital on analgesic practices in companion animals also suggested woefully inadequate care of postoperative pain.19 A survey of practitioners in Vermont found that 56.5% of the respondents employed postsurgical analgesia if necessary.'* A study of Canadian practitioners showed that only about 50% were using analgesics routinely after surgery.13 Fewer than 50% of veterinary faculty, staff, house officers, and students at an American university were "very likely" to treat a cat after laparotomy to remove a linear foreign body.21 The most recent study from the United Kingdom showed a greater understanding and use of analgesics for major surgery, but routine procedures such as ovariohysterectomy were usually treated with analgesics by only 53% of the respondent^.^ This reluctance to deal with animal pain has been partly a result of our cultural heritage from Cartesian philosophy (animals are merely automata) and partly a result of the phenomenal ability of our patients to rapidly recover and mask the signs of pain. It is now abundantly clear that our patients do feel pain and that this merits our careful consideration. Some authors have proposed that analgesics should not be used, because the animal may feel too good and damage the surgical repair; unfortunately, this attitude is still pre~alent.~. 21 This is a fallacious argument, because most analgesics obtund the aching, and throbbing type of pain without interfering with the immediate

Portions of this article appear in Pascoe PJ: Problems of pain management. In Flecknell P, Waterman-Pearson A (eds): Pain Management in Animals. London, WB Saunders, 2000, pp 161-177.

From the Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, California

VETERINARY CLINICS OF NORTH AMERICA SMALL ANIMAL PRACTICE

VOLUME 30 - NUMBER 4 *JULY 2000 917

918 PASCOE

sharp pain. Treatment with these methods allows the animal to be comfortable, but it will still know that stimulation of the injured area hurts.

From the recent research concerning the mechanisms of nociception, it is clear that it is better to prevent pain than to treat This is a somewhat novel idea when applied to treating pain, but the idea of prevention is clearly entrenched in other medical disciplines. Many animals are vaccinated to prevent them from suffering the pain related to particular diseases even though the prevalence of many of these diseases is low. We know that every surgical procedure causes some pain to the patient and that some procedures are more painful than others. With the idea of prevention in mind, we must first do everything possible to reduce the factors that potentiate pain perception. To allay the patient's anxiety, we need to provide gentle care and handling of the animal. For the traumatized animal, it may mean that the animal is started on analgesics as soon as possible to reduce the nociceptive facilitation caused by the injury.

Experience in people and clinical experience with dogs and cats indicates that it is much harder to control pain once the patient has become conscious of that pain. Recent interest in pain management also suggests that patient morbid- ity may be reduced by pain therapy. In people, management of pediatric pain is still in its infancy (excuse the pun), because it was demonstrated in 1987 that the use of fentanyl during patent ductus arteriosus (PDA) ligation blunted the infant's stress response when compared with nitrous oxide and curare? Many babies had undergone open-heart procedures with inadequate intraoperative analgesia, and this was one of the first reports to document the increased stress and catabolic response associated with this practice. A further study in children revealed that the use of a local anesthetic technique at the time of circumcision reduced the baby's response to the pain of vaccination several months later.58, 59

Postoperative analgesics have also been shown to increase food and water intake in rats and to cause less depression of locomotor activity.I6 Another study in rats showed that metastases of a certain tumor in rats were reduced if the animals were treated with morphine after laparotomy. The treated rats in th s study also regained normal behavior and ate and drank more than the untreated controls.43

It is expected that animals experiencing surgical and some diagnostic proce- dures undergo some nociceptive stimulation. Most anesthetic agents in use today make the animal unconscious and therefore unable to feel pain, but they do not necessarily block the nociceptive input that occurs during surgery. This means that the sentient being is unaware of this activity but that there is still input into the central nervous system that may alter the processing of nociceptive and even some non-nociceptive signals. This can lead to altered perception of these stimuli when the animal regains consciousness. Given this premise, there is a need for analgesics to reduce the acute effect of this invasion on the patient and to prevent the development of the chronic pain syndromes discussed elsewhere in this issue. Anxiety, sleeplessness, and stress are all factors that can facilitate the animal's experience of pain; thus, approaches that minimize these things for the patient help in the management of pain. If it is feasible to bring the patient into the clinic on the day of the procedure rather than the night before, this is likely to prevent a great deal of anxiety (e.g., strange surroundings, strange smells) and sleeplessness (an animal placed in a novel environment is not likely to sleep well). These concerns are likely to be more of an issue in older patients, because aging tends to decrease the adaptability of the animal to novel situations. Further measures to decrease anxiety and discomfort of the patient contribute to the overall management of pain. Although this discussion focuses on pharmacologic management, it is important that all who come into contact with that animal do their best to provide a soothing voice, a gentle hand, and careful attention to the animal's needs.

PERIOPERATIVE PAIN MANAGEMENT 919

PREMEDICATION

Premedication should be used to decrease anxiety and provide analgesia before the noxious event occurs. In young healthy patients, a neuroleptanalgesic technique is ideal, and this is best achieved with a combination of a tranquillizer (e.g., acepromazine) and an opioid. In older patients, the sedation achieved with opioids alone tends to be more profound, thus it is less necessary to use a tranquilizer like acepromazine. Alpha-2 agonists could also be regarded as neuroleptanalgesics, and their use for premedication would achieve the same goals. There is a significant difference in the degree of cardiovascular depression associated with these drugs compared with the acepromazine-opioid combina- tionssp 47; therefore, their use should be restricted to young healthy patients. It should be noted that there is a profound cardiovascular effect with medetomi- dine in dogs even with doses as low as 1 to 2 ~ g J k g . 4 ~

Until recently, there has been great reluctance to pretreat surgical small animal patients with nonsteroidal anti-inflammatory drugs (NSAIDs) because of the risks of gastric ulceration, renal injury, and increased hemorrhage related to the platelet dysfunction associated with these drugs. With the advent of specific drugs that seem to have weak activity as prostaglandin irhbitors (e.g., carpro- fen, meloxicam) and drugs that have most of their effect on the inducible cyclooxygenase 2 (COX-2) enzyme (e.g., celecoxib, rofecoxib, valdecoxib), fewer of these side effects are likely to occur. Some caution should be expressed on the use of these drugs, however, as there is recent evidence that even COX-2 inhibitors may affect angiogenesis and hence the healing of ulcers.zs As well as having central analgesic actions, these drugs may reduce the peripheral inflammatory response associated with surgery (and hence reduce swelling). Injectable preparations of these drugs make them most likely to be used in the preoperative setting (an injectable form of carprofen is available in Europe, and injectable meloxicam is available in Canada and Europe), although oral or rectal administration may be used. This author expects that within the next few years, it may be normal to use an NSAID as part of routine premedication and that these drugs may provide sufficient analgesia for mild to moderate and, in some instances, even severe pain. There may be less need for opioids, as their use may be reserved for cases requiring immediate analgesia, where the NSAIDs are contraindicated, or where more severe pain is experienced and an NSAID-opioid combination is required. In these cases, the combination is most beneficial, because there is some synergistic action between these drugs with such different mechanisms of action.

Premedication with ketamine or tiletamine may be beneficial from an anal- gesic perspective. These drugs are N-methyl-D-aspartate (NMDA) antagonists and have analgesic actions via central inhibitory pathways in their own right. Thus, the use of these drugs provides preoperative analgesia and also helps to prevent the facilitation associated with surgical intervention. Studies in human patients have shown that the use of preoperative and intraoperative ketamine decreased wound hyperalgesia for up to 7 days postoperatively. The use of ketamine did little to change the overall intensity of pain at rest or in association with movement.56,57, 6o The amount of opioid used during the early postoperative period (< 6 hours) was less in the ketamine group compared with the placebo group, possibly because of a residual effect from the ketamine. Studies that have combined ketamine with opioids suggest a reduced requirement for opioids in the management of postoperative pain. Anesthesia with ketaminemedeto- midine in cats provided better analgesia in the postoperative period after an ovariohysterectomy than anesthesia with acepromazine-thiopental-halothane.52

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The data from people and laboratory animals support the use of NMDA antago- nists as part of the clinical management of pain.

INDUCTION

Consistent with the approach suggested here, induction should proceed with a minimal amount of stress on the patient. This means that the animal should tolerate the placement of intravenous access or a mask with little concern. Some dogs that resist restraint can be distracted by gentle talk and head patting and stroking, although others may need more chemical restraint. In the latter case, the clinician should recognize that most tranquilizers have a ceiling effect with regard to sedation and that giving more of the same drug may only prolong the duration of action without improving restraint. Increasing doses of opioids in dogs may improve sedation particularly in elderly patients. If the animal has already received a high dose of a tranquilizer and opioid, it may be necessary to consider the use of a dissociative drug. To this end, tiletamine-zolazepam has a rapid onset of action and can give excellent chemical restraint in dogs at doses of 4 to 5 mg/kg. In cats, increasing doses of opioids are contraindicated. Tiletamine-zolazepam at 2 to 3 mg/kg works well to calm the fractious cat. With the provisos noted previously, alpha-2 agonists can provide excellent chemical restraint, but it would be best to start with low doses (5-10 pg/kg of medetomi- dine, 0.1-0.2 mg/kg of xylazine) if the animal has received other premedication.

Of the induction drugs used, only the dissociatives and opioids provide any analgesia in their own right. The other drugs-propofol, thiopental, etomidate, benzodiazepines, and inhalants-do not have significant analgesic properties; thus, their contribution to the management of perioperative pain is simply to provide unconsciousness. Although it has not been shown that induction with an opioid or dissociative in the absence of an analgesic premedication drug provides pre-emptive analgesia, it is logical to expect that this would be the case. This may be of benefit when there has been little or no time for premedication or when the animal is sufficiently compromised such that premedication has been excluded.

MAINTENANCE

The maintenance of anesthesia can be carried out with injectables (e.g., propofol) or volatile inhalants. Neither of these options is likely to provide any significant analgesia; thus, it may be helpful to add an analgesic technique if the procedure is likely to be highly invasive or extensive in nature. Although the intraoperative addition of analgesics has not been shown to improve the pre- emptive effect of drugs given preoperatively, it makes sense that such treatment would add to a pre-emptive effect by exerting an influence on nociceptive input during surgery. Most of the analgesic techniques that might be used intraoperatively provide an additional benefit in that they reduce the amount of other anesthetic needed to keep the patient anesthetized. This is beneficial, because the inhalants cause significant cardiovascular depression, and the ability to minimize the dose of inhalant may improve tissue perfusion throughout the anesthetic period. It is also beneficial because it may decrease the stress response associated with the surgery. Inhalant anesthetics do little to blunt the stress response, and the application of more "balanced techniques designed to mini- mize this activity speeds the overall rate of recovery of the animal from the

PERIOPERATIVE PAIN MANAGEMENT 921

procedure. The most effective way of reducing the nociceptive input is by the use of local anesthetics to abolish the neural traffic from the surgical site. In most instances, the local anesthetic can be given before surgery, and many of the blocks that can be used for this purpose are described elsewhere in this issue and in other articles.* When injecting local anesthetics into an anesthetized patient, it is important to remember that there is no reaction if the needle penetrates the nerve or if the drug is injected directly into the nerve. Because prolonged or permanent nerve injury could result from such damage, it is essential that nerve blocks be carried out with due care and attention using appropriate equipment. Thought must also be given to the duration of action of the local anesthetic in relation to the duration of the procedure. An animal that wakes up with no sensation at the surgical site may unwittingly do something to the area that could compromise the surgical procedure, This is especially true when a motor block is involved, because the animal may apply abnormal forces to the surgical repair. Use of local anesthetics epidurally and spinally may be accompanied by hypotension if sufficient drug is given to cause a lumbar or thoracic sympathetic block. Care must be taken to monitor the animal’s blood pressure when such epidural or spinal injections are used. Intra-articular local anesthetics provide good postoperative analgesia with little risk to the patient.5O Because the drug is only deposited in the joint, it does not affect motor nerves and is less likely to induce superficial changes in sensation, reducing the likeli- hood of any adverse response from the animal (e.g., chewing or licking at the joint). This author typically uses 0.5% bupivacaine at a volume appropriate for the joint concerned (0.2-0.25 mL/kg for the elbow and 0.2-0.4 mL/kg for the shoulder and stifle). The total dose of bupivacaine is usually restricted to 2 mg/kg, and this needs to be taken into account when multiple joints are being injected.

Nitrous oxide is an excellent analgesic and provides benefits similar to those of other intraoperative additives. It has recently been reported that nitrous oxide may induce part or all of its effect via the release of opioids or cat echo la mine^.'^ T h s may mean that there is less benefit with nitrous oxide in the presence of opioids or alpha-2 agonists. Nitrous oxide is blown off quickly after it is turned off; thus, this approach is unlikely to provide significant analgesia into the recovery period.

Opioids given as intermittent boluses or as a continuous infusion provide excellent analgesia intraoperatively, and this analgesia lasts into the postopera- tive period according to the duration of action of the chosen drug. These drugs induce significant respiratory depression, and it is usually necessary to ventilate any dog that has been treated in this way. Opioid infusions can be used in cats, although the inhalant-sparing effect is not as profound as that seen in dogs,=, and the doses needed are lower. Opioids with relatively short half-lives should be used so that their effects disappear early in the recovery period; otherwise, the cat may become excited. Fentanyl and alfentanil have been used as infusions during feline anesthesia without causing significant excitation during the recov- ery period.

Epidural administration of opioids is best carried out before the start of surgery. In this context, epidural procedures are typically performed in the anesthetized patient after the animal has been clipped and before it is scrubbed for surgery. Ideally, the opioid chosen should reach its peak effect before the start of surgery, but one of the main reasons for using epidural opioids is to provide analgesia into the postoperative period; this is of more concern than having an immediate onset in most cases. Morphine, oxymorphone, and bupre- norphine have the longest duration of action and are likely to give the greatest

922 PASCOE

benefit during the subsequent 12 to 24 hours. Descriptions of techniques and drugs are found in the article on epidural analgesia in this issue.

The presence of peripheral opioid receptors has only been demonstrated recently, but they are activated during the inflammatory response and thus are active in most cases where joint surgery is indicated. One factor that was identified as contributing to the efficacy of this technique was the use of a tourniquet above the joint into which the opioid is injected.26 In dogs and cats, t h s means that it would be difficult to apply this technique effectively in the shoulder and stifle, because it is virtually impossible to place a tourniquet above these joints. In a clinical trial in dogs, the addition of intra-articular morphine did nothing to improve postoperative pain scores over those attained with intra-articular bupi~aca ine .~~ In another study, intra-articular morphine was as effective as epidural morphine at controlling postoperative pain after stifle arthrotomy? We have been using this techruque for elbow surgery and usually place a catheter in the joint during closure of the surgical wound. After the surgery is finished, we place a tourniquet above the elbow and inflate it to 300 mm Hg. Morphine (1 mg in 5 mL of saline) is injected into the joint, and the tourniquet is left on for 10 minutes. At this time, the tourniquet is released and the catheter is pulled from the joint. The most beneficial effects probably result from the combination of opioids and bupivacaine. Interest is also developing in the use of NSAIDs given intra-articularly, but this has not yet been used in dogs and cats.49

Ketamine may also be used as an intravenous infusion intraoperatively; however, the doses required to provide good analgesia but not to prolong recovery have not yet been established in dogs and cats.

RECOVERY

Towards the end of the procedure, an analgesic should be given such that it has time to reach its peak effect before the animal wakes up. This is important because long-term pain control is better if the animal does not experience a great deal of pain in the early postoperative period. This was well illustrated in a study in which buprenorphine was given for postoperative analgesia. When the drug was given immediately before the animals woke up, no analgesia was apparent. Buprenorphine takes 20 to 30 minutes to reach peak effect because of its slow association with the mu receptors, and when the drug was given 30 minutes before the end of the procedure, analgesia was apparent.62 The analgesic may be given by any appropriate route as long as enough time is allowed for peak effect. Drugs that have a strong sedative effect are likely to prolong recovery to some extent. This is particularly true for some opioids; sedation is produced, and their antitussive effect may make the animal tolerate the endotra- cheal tube for a longer period of time than usual. A moderately slow recovery may be the best thing for the animal, however, because it will be less distressed and anxious if it returns to consciousness without getting excited or experiencing severe pain. During recovery, the animal should be assessed continuously to see whether the chosen dose of analgesic is effective. This is an essential part of the management of postoperative pain, because the response of individual animals to these drugs is greatly variable. In one relatively small study in adult people (15 patients), the amount of morphine given over the first 24 hours after craniot- omy ranged from 2 to 79 mg.55 Assuming that the surgical insult to these patients was relatively similar, t h s is a huge variation in the dose required to obviate pain. It must also be recognized that a human patient may choose to tolerate

PERIOPERATIW PAIN MANAGEMENT 923

the pain because of some fear associated with the treatment. As we are not currently able to give our patients that kind of choice, it is incumbent on us to give appropriate doses at appropriate times.

It is not uncommon for dogs recovering from surgery to go through a period of excitement or delirium. This is often a short-lived phenomenon and may just require some physical restraint and soothing for the animal to calm down. One contributing factor to this excitement may be pain, and it is some- times difficult to determine whether pain is present or not. If the analgesic has been given as described previously, there is less chance that pain is present; however, for any given animal, a routine dose may not be enough. If it is thought that the analgesic is not working for a particular patient, an additional dose can be given intravenously. An opioid with a rapid onset of action is chosen for this approach so that it can be rapidly titrated to the desired effect; typically, drugs like alfentanil or fentanyl would be used. If the dog continues to be excited and has received what is thought to be adequate analgesic therapy, it is then appropriate to use a tranquilizer. This should be given intravenously at a low dose (e.g., acepromazine at 0.01 mg/kg). More can be given if necessary, but this is usually sufficient to calm the animal. Once the animal is calm, it is advisable to assess the surgical site if possible and see if the animal is still sensitive to manipulation; this may suggest that further analgesic therapy is warranted. Some animals do not calm down even with this approach, and it may be that they are getting agitated from the effects of the opioid. There are two ways of approaching this. One is to give a further dose of short-acting opioid (alfentanil or fentanyl) to see if the agitation gets worse; this is generally done if there is some concern that the animal's behavior is still motivated by pain. If the behavior dissipates, the animal can be treated with a longer acting analgesic, but if the behavior remains or intensifies, it is necessary to give an opioid antagonist. Ideally, a mixed agonist-antagonist is used for this purpose as it reverses the effect of the mu agonist but leaves the animal with some analgesia from the kappa agonist. Nalbuphine (0.03-0.1 mg/kg) is an excellent choice for this purpose because it provides adequate reversal, good analgesia, and minimal sedation. If a pure antagonist is used, it should be one of the shorter acting drugs such as naloxone. It should be given slowly and titrated until the animal calms down. A dose of 1 pg/kg is a good starting point with naloxone. In people, administration of naloxone has been associated with pulmonary edema, but t h s has usually been the result of giving a high dose rapidly. This problem has not been reported in dogs.

Although many of the same comments apply to cats, opioid excitation is more predictable in this species if hgh doses of opioids are used. Nevertheless, there are individual cats that become excited with relatively low doses, and these animals need to be handled in the manner described previously. In some cats, particularly after an extremely invasive procedure, opioid analgesics do not seem to be enough, and the cat throws itself around the cage in a self-destructive fashion. These cats do not respond well to acepromazine, and the only method that has worked for this author is to use either pentobarbital or medetomidine. The latter is my preference in cats that have normal or nearly normal cardiovas- cular function. Medetomidine is an analgesic and provides profound sedation; a dose of 2 to 5 pg/kg administered intravenously is often enough to sedate the animal long enough for it to recover smoothly. Higher doses or repeated doses are needed in some cases. One big advantage with medetomidine is that if the animal becomes too sedated or some other problem is noticed, the effect of the drug can be antagonized with atipamezole. Pentobarbital, although not an analgesic, gives profound sedation at doses from 2 to 10 mg/ kg intravenously,

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and recovery after this treatment is usually much smoother. Pentobarbital is not reversible, and the animal needs physiologic support if the dose given causes excessive sedation.

THE FIRST 24 HOURS

Beyond the immediate recovery from anesthesia, it is important to monitor the animal for signs of pain and to provide treatment accordingly. Most animals undergoing major surgery need some analgesic therapy for at least this period. NSAIDs are useful because they generally have a long duration of action and have been shown to be effective analgesics in the 4- to 24-hour period after surgery.” 27, 30, 33, 39* 46 In a recent study in cats, ketoprofen (2 mg/ kg) provided the most effective analgesia (compared with meperidine and buprenorphine) over the whole 18-hour assessment period after ovariohy~terectomy.~~ Giving these drugs postoperatively (rather than preoperatively) reduces the likelihood of decreased platelet function causing a problem. The risks of renal damage are also decreased, because there is little inhalant left in the animal that might interact with the NSAID. Gastric ulceration is still possible and depends on the dose and type of NSAID, volume status of the patient, and postoperative activity of the gastric circulation and gastric mucosa and potential for stress ulceration. For example, it would not be appropriate to use an NSAID for postoperative analgesia after gastric dilation-volvulus in which there was evidence of marginal gastric blood supply. Given these caveats, it is clear that most of our patients benefit from the use of NSAIDs. The addition of opioids enhances the analgesic effect of the NSAID, confers a smoother recovery, and provides analgesia during the first hour after recovery, as the NSAIDs require this period of time for optimum effect. In giving opioids, a method should be chosen that provides as much of a constant effect as possible. The most effective method is to use the drug as a constant infusion. The infusion rate can be tailored to the needs of the patient, and once an adequate degree of analgesia has been reached, the animal is afforded comfort with little noxious stimulation. Using such an approach requires close supervision of the animal to prevent it from chewing off infusion lines or suffering any adverse effects from the opioids. This may preclude the use of infusions in many cases, although novel delivery methods such as the fentanyl patch can achieve these goals without requiring intravenous access or a constant-rate infusion pump. If it is not feasible to provide a constant infusion, the analgesic of choice should be given at fixed intervals based on the pharmaco- kinetics of the drug and the response of the individual patient. This approach should at least provide relatively constant concentrations and control most of the animal’s pain. If breakthrough pain occurs at some time between the fixed doses, a further dose should be given at that time. This may be an indication to increase the dose or decrease the intervals between administration. The least reliable approach to providing adequate pain relief is to wait until the animal shows signs of being in pain and treat at that time. Such a technique means that the animal has to be in pain before someone can recognize this pain, and it is always harder to control pain once it has occurred, with higher doses of drug resulting in a narrower safety margin. The other factor in this approach is that, to date, the recognition of pain in dogs and cats is poorly defined without prolonged observation; thus, the animal may have to manifest more overt signs before it is treated.

In human medicine, there has been increasing interest in evidence-based medicine, and the management of acute postoperative analgesia has come under

PERIOPERATIVE PAIN MANAGEMENT 925

such scr~tiny.3~ To obtain the data required for such determinations, it is essential to have randomized controlled clinical trials with well-defined outcome mea- sures and of sufficient size to have the power to determine differences of treatment versus placebo. Although many trials in human medicine have sample sizes of 40 to 50 patients per group, current estimates suggest that it may be necessary to have up to 500 patients per group in analgesia trials to be sure of the result.35 This carries serious implications for trials in veterinary medicine, where group sizes are often less than 20 animals. Through reviews of multiple randomized controlled clinical trials, McQuay and have assembled a league table of analgesic efficacy based on a statistic known as number needed to treat (NNT). This approach defines the number of patients that one would need to treat to get at least 50% relief of pain. If a treatment were available that always abolished pain, although the control group demonstrated absolutely no relief of pain, the NNT would be 1. Ths is rarely the case, because even in animals, there are placebo effects and physiologic changes during a noxious event that give positive results in the control group?8, 34 In the human data, an NNT of 2 is thought to represent about the best result possible with the analge- sics and methods of assessment currently available. This has led to the develop- ment of the league table comparing various treatments (http: / / www.jr2.0~. ac.uk/Bandolier/ painres/painpag/Acutrev/ Analgesics/lfcol.gif). It is notewor- thy that the top three analgesics in t h s table are NSAIDs (ibuprofen, ketorolac, and diclofenac) with NNTs of 2 or less, while morphine (10 mg intramuscularly) has an NNT of 2.9 and is rated about 24th. Although these data are of great importance and represent research that should take years to match in veterinary medicine, they cannot be translated directly for use in dogs and cats (especially in the latter species, where acetaminophen is toxic). Nevertheless, they do suggest that for many routine procedures, NSAIDs provide significant pain relief. With the advent of new safer NSAIDs, we can look forward to increasing use of these drugs for perioperative analgesia in small animals (Tables 1 and 2).

PERIOPERATIVE PAIN MANAGEMENT

Pediatric Patients

Although the nervous system of the neonate is immature, there is no doubt that nociceptive pathways are present and that pain is perceived by the neonate subjected to noxious stimuli. In some tests, the nociceptive threshold in neonates is much lower than in adults. This may be the result of a lack of some of the descending inhibitory mechanisms found in older animals. The coordination of motor responses to noxious stimuli are not well developed, and the animal may have much wider receptive fields to noxious Neurotransmitters may not have reached full function as evidenced by the lack of effect of NMDA antagonists in some nociceptive tests in ne0nates.I Mu and kappa opioid receptors are active, but delta receptor activation may be tied to weaning of the animal.61 These differences suggest that drugs effective in adults may not be as effective in neonates (e.g., ketamine). Procedures carried out on neonates with insufficient pain control produce greater stress responses than those in which analgesia has been provided.63, 64 It is therefore important to recognize potentially painful procedures and to treat accordingly (Table 3). The pharmacokinetics of the opioid analgesics are different in the neonate versus the adult. Recent studies examining the effects of fentanyl and morphine in puppies have shown that

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Table 1. OPlOlD AND NONSTEROIDAL ANTI-INFLAMMATORY DRUG DOSES FOR PERIOPERATIVE PAIN

Duration Drug Dose Species Route of Action

Morphine

Merperidine Methadone Oxymorphone

Hydromorphone

Fentanyl

Butorphanol Pentazocine Nalbuphine Buprenorphine Carprofen*

Ketorolac*

Ketoprofen" Meloxicam*

0.5-1.0 mg/kg 0.5 S mg/kg loading

dose followed by 0.1-1.0 mg/kg/h

preservative-free morphine

0.05-0.1 mg/kg 1-5 mgin5-10 mL 3-5 mg / kg 0.1-0.5 mg/kg 0.054.1 mg/kg 0.03-0.05 mg/kg 0.14.2 mg/kg

5 pg/kg + 3-6

0.1 mg/kg

pgIkg/h

kg/h 2-3 pg/ kg + 2-3

0 .142 mg/kg 1-3 mg/ kg 0.03-0.1 mg/kg 5-20 pg/kg 2 4 mg/kg 2 4 mg / kg 0.3-0.5 mg/kg 0.25-0.3 mg/kg 2 mg/kg 0.2 mg/kg

Canine Canine

Canine Feline

Feline Canine Canine/ feline Canine/ feline Canine Feline Canine Feline Canine

Feline

Canine/feline Canine/ feline Canine/feline Canine/feline Canine Feline Canine Feline Canine / feline Canine/feline

IM, SC IM, slow Iv

IV Epidural

IM, SC Intra-articular IM, SC IM, sc IM, IV, SC IM, SC IM, IV, SC IM, SC IV

IV

IM, IV, SC IM, IV, SC IM, IV, SC IM, IV, SC Oral Oral IM, Iv sc IM, IV, SC IV, sc

3 4 hours Duration of

CRI

12-24 hours

3 4 hours

1-2 hours 2 4 hours 3 4 hours 3 4 hours 2 4 hours

Duration of CRI

3 4 hours 2 4 hours 2 4 hours 8-12 hours &24 hours Once 8-12 hours 8-12 hours 12-24 hours 24 hours

*Initial dosing only. Refer to the article on nonsteroidal anti-inflammatory analgesics for specific

LM = intramuscular; SC = subcutaneous; IV = intravenous; CRI = constant-rate infusion. dosing instructions and contraindications.

lower doses of these drugs are required for analgesia at 1 day of age compared with 34 days (threefold-fourfold difference^).^^ It has also been shown that puppies are more sensitive to the respiratory depressant effects of morphine, and this work suggests that there would be a greater safety margin with the use of fentanyl as an analgesic in canine neonates." 32 Local anesthetics can be used and are quite effective. When using these drugs, the dose requirements are lower because of the immaturity of the nerves,*O but the neonate does not seem to be at any greater risk of toxic side effe~ts.3~ There is little clinical information

Table 2. APPROACHES FOR THE MANAGEMENT OF PAIN IN HEALTHY YOUNG OR OLD DOGS AND CATS

Mild to Moderate Pain Severe Pain

NSAID (carprofen, meloxicam) Butorphanol, buprenorphine

NSAID S mu opioid agonist Epidural opioid 2 local anesthetic Local anesthetic blocks

PEFUOPERATIVE PAIN MANAGEMENT 927

Table 3. ANALGESIC DOSES (GIVEN BY SUBCUTANEOUS INJECTION) FOR PUPPIES AND KllTENS LESS THAN 4 WEEKS OF AGE

Mild to Moderate Pain Severe Pain

Dogs Oxymorphone, 0.02-0.05 mg/ kg Oxymorphone, 0.05-0.1 mg/kg Morphine, 0.24.5 mg/ kg Methadone, 0 2 4 . 5 mg/kg Buprenorphine, 5-10 Fg/kg

Oxymorphone, 0.02-0.05 mg/kg Morphine, 0.05-0.1 mg/kg Buprenorphine, 5-10 pg / kg

Morphine, 0.5-1.0 mg/kg Methadone, 0.51.0 mg/kg Fentanyl, 5-10 pg/kg

Oxymorphone, 0.024.1 mg/kg Morphine, 0.14.3 mg/kg

Cats Butorphanol, 0 . 1 4 2 mg/ kg Butorphanol, 0.14.8 mg/ kg

available on local anesthetic techniques for young cats and dogs. Analgesia and anesthesia for tail docking and dewclaw removal in neonatal puppies have been the subjects of debate for a long time. Carrying out such procedures in the absence of any analgesic method is contrary to the oath that veterinarians take with regard to the prevention of suffering. Application of local anesthetic techniques is difficult in small wiggling animals, and great care must be taken not to overdose the animal. The injection of a local anesthetic is invasive; thus, it carries some risk and requires further handling of the animals with a time delay while the anesthetic takes effect. These factors make it hard to recommend the use of injectable local anesthetics. A topical application of eutectic mixture of local anesthetics (EMLA) cream has been shown to provide analgesia for circumcision in baby boys, but for this to work, it requires adequate time for penetration into the skin (about 30 minutes), and the hair coat of the puppy would tend to resist the uptake of the drug. Systemic analgesics may be useful, but the doses of opioids and NSAIDs to use in these young patients have not been defined; as noted previously, ketamine may not be effective, because the NMDA receptors have not yet developed. It is clear that more work needs to be done in this area to gain a better understanding of neonatal canine physiology and pharmacology. Because the American Veterinary Medical Association has recently endorsed some opposition to tail docking and dewclaw removal, it might be better to invest the energy in convincing the breeders and their breed societies that these are unnecessary procedures.

Geriatric Patients

Although there do seem to be significant changes in the pharmacodynamics of drugs in humans with aging, little is known about this in veterinary medicine. Elderly people seem to need lower doses of opioids, and the same is certainly this author's clinical impression with the use of these drugs in older dogs. Elderly people are at greater risk for gastric ulceration after the use of NSAIDs, but even though there are no data available for dogs and cats, a similar concern exists. Other major considerations in elderly animals are the risks of drug interactions; many of these patients are on other drugs, and the practitioner must be aware of potential problems with these combinations. An animal that is receiving a corticosteroid would have an increased risk of gastric ulceration if it were given an NSAID concurrently. Recently, selegiline, a noncompetitive lnhibitor of monoamine oxidase-B, has been prescribed for aging dogs and for pituitary-dependent hyperadrenocorticism in dogs. This drug has been associ- ated with severe reactions when people receiving chronic treatment have been

928 PASCOE

given some opioids. The responses seen include hyperpyrexia, coma, severe hypertension, seizures, and and some of these cpes have had a fatal outcome.J6 The opioids most commonly associated with this reaction are meperidine and pentazocine, with individual patients given some of the more potent mu agonists41 (e.g., fentanyP) being unaffected. There have been severe reactions associated with other monoamine oxidase inhibitors and fentanyl, however.24, 38 Until more data become available on the likely interactions between selegiline and opioids, the clinician should avoid their use if possible in these animals. If opioids need to be used, morphine and fentanyl seem to be the drugs of choice, but the doses should be titrated carefully and discontinued if any untoward effects are seen. Pain management may be achieved more safely by the use of local anesthetics and NSAIDs if these can be used appropriately.

Older animals are also more likely to have arthritic changes and spon- dylosis, which may be quite painful for the animal when lying in certain positions. This pain is typically manifested by an unusually high heart rate or blood pressure during anesthesia that is inappropriate for the concurrent level of stimulus. These signs often occur in response to a change in body position. The clinician should try to support the limbs and back in such a way as to minimize the noxious input from these bony changes and should consider giving analgesics to these patients even when they have been anesthetized for a noninvasive procedure.

Pregnant and Lactating Patients

The use of analgesics in these patients needs to be considered carefully, because the two main classes of drugs that are used, NSAIDs and opioids, can have significant effects on the dam and fetus or neonate. In people, it is well established that mothers who are taking opioids during ancy have an

deficits and an increased mortality. Such findings have been repeatable in labora- tory animals, and there has been some work to suggest that some behavioral problems may result from a decreased nervous system plasticity incurred by opioid action on the development of normal synaptic connections and neuw transmitter production and metabolism.11 These changes seem to be the result of chronic administration of opioids and are not found with short-term opioid administration. Opioids are also involved in aspects of postnatal reproductive control. In other species, administration of morphine has been associated with a suppression of luteinizing hormone and prolactin secretion.1° The effect on luteinizing hormone did not appear in the first 48 hours of lactation and became more pronounced out to 10 days after parturition. These effects have not been researched in dogs and cats, but it is unlikely that such an effect would be of significance in seasonal breeding animals such as these. Along with the effect on prolactin, morphine may also decrease the secretion of oxytocin in the lactating animal, which could interfere with milk letdown. In a human trial, there did not seem to be any clinical effect on milk production or infant feeding, despite measurable decreases in ~xy toc in .~~ Many of the drugs given to the mother are excreted in the milk; thus, concerns have been raised about the use of opioids in the dam because of transfer to the puppies or kittens. There are no data for these species, but some limited data in people indicate that transfer of drug in the milk does occur but that, in general, the quantity excreted via the milk is significantly less than 1% of the maternal dose.5, 14, 15, 64

The appearance of the drug and its metabolites in the milk are governed to

re increased incidence of babies with a low birth weight w hpB" o ave behavioral

PERIOPERATIVE PAIN MANAGEMENT 929

a large extent by the lipid solubility of the drug. This makes the choice of a hydrophilic drug like morphine better than a more lipid-soluble agent such as meperidine. In a human study in which mothers were treated with morphine or meperidine for up to 3 days after cesarean section, the babies of the mothers receiving meperidine were less responsive on the third day compared with the babies of the group on morphine.64 In this report, it was also suggested that neonatal ability to metabolize the opioid or its metabolites would play a signifi- cant role in the overall effect on the infant. Opioids may also be involved in the regulation of some aspects of maternal behavior. In mice, it has been shown that morphine may affect the retrieval of pups taken from the nest, delay the onset and vigor of aggression towards a threatening animal (trend but not signifi- cant),'* and decrease the activation of gene expression in areas of the brain associated with maternal behavior.54 These effects seem to be most significant during the first week after birth. None of these changes have been demonstrated in the cat or dog but should be considered in situations where an animal has a history of poor maternal behavior or cannibalism. Opioids have been used perioperatively in thousands of dogs and cats for cesarean sections and pain control in many lactating animals without notable side effects in the dam or offspring, but it is clear that we know little about the subtleties of opioidergic activity during late pregnancy and lactation in these species.

NSAIDs may also have significant effects if given chronically throughout pregnancy. With high doses of potent drugs such as aspirin, there has been increased fetal mortality and an increased incidence of fetal malformations in animals and people when the drug is used during early gestation." 51 Babies born to mothers who had taken aspirin within the last few days of pregnancy may have increased bleeding tendencies. NSAIDs are used clinically in women to delay the onset of labor and may do this if given during the last few days of pregnancy in animals as well. In the premature neonate, the closure of the ductus arteriosus is affected by circulating prostaglandins, and the administration of NSAIDs to the dam has resulted in premature closure of the ductus in utero. These drugs also cross the placenta and have effects on the fetus similar to those seen in the adult, leading to reports of gastric or duodenal ulceration and oliguric renal failure in newborn infants. NSAIDs are excreted in the milk, but the level of fetal exposure is again likely to be low.l5 The advent of newer NSAIDs with increased potency for COX-2 should decrease the likelihood of most of these side effects, but these drugs have not been in use for long enough to know what other changes may be seen during pregnancy or lactation. If an NSAID is needed for analgesia during this time, the drug chosen should have few side effects in normal animals, it should be used at the minimum effective dose, and it should be administered for as short a time as possible until greater knowledge of these issues has been gained.

SUMMARY

The management of perioperative pain starts with the use of approaches to minimize anxiety and distress before the procedure. The administration of anal- gesics or local anesthetics before the start of surgery reduces the nociceptive input occurring during the procedure and reduces the need for postoperative analgesics. As the animal recovers from anesthesia, it is important to administer analgesics to minimize the patient's experience of pain and to continue this therapy through at least the first 12 to 24 hours. Techniques that provide a

930 PASCOE

continuous level of analgesia are more effective than those that allow the pain to return.

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Address reprint requests to Peter J. Pascoe, BVSc

University of California School of Veterinary Medicine Department of Surgical and Radiological Sciences

School of Veterinary Medicine Davis, CA 95616

e-mail: pjpascoe@ucdavis.edu