Elevated body temperatures between 1 and 5 hours after recovery from anesthesia have been reported in cats given opioids.70,71 Hydromorphone at clinically recommended doses (0.05 to 0.1 mg/kg SC, IM, or IV) was associated with an increase in rectal temperature above 40° C (104° F) in 75% of cats in one study and a rectal temperature of 42.5° C (108.5° F) was recorded in one cat.⁷⁰ In another study, most cats undergoing elective surgery that received hydromorphone, diazepam, and ketamine followed by isoflurane had post anesthetic temperatures that exceeded those recorded before anesthesia, with a peak rectal temperature of 41.6° C (107.0° F) reported in one cat.⁷¹ In this study it was reported that the lower a cat’s temperature was during anesthesia and surgery, the more severe the rebound hyperthermia.⁷¹

In a laboratory study, hydromorphone at 0.1 mg/kg IV was associated with a significant increase in body temperature, whereas doses of 0.025 and 0.05 mg/kg were not. However, the lower doses were found to have minimal antinociceptive effects compared with the 0.1 mg/kg dose.⁷²

Transdermal fentanyl patches resulted in higher rectal temperatures compared with butorphanol in cats undergoing onychectomy, although no temperature exceeded 40° C (104° F).⁴² Alfentanil infusion during anesthesia was also associated with increased rectal temperature.⁷³

Laboratory studies in cats with previously implanted thermistors showed that IM administration of the opioids hydromorphone (0.05 to 0.2 mg/kg), morphine (0.5 mg/kg), buprenorphine (0.02 mg/kg), and butorphanol (0.2 mg/kg) alone or in combination with ketamine or isoflurane caused mild to moderate increases in body temperature (≤40.1° C [104.2° F]), which lasted several hours but was self-limiting.⁷⁴

After the end of anesthesia, body temperature is usually measured until the cat becomes normothermic, but as noted previously, it is prudent to monitor for 5 hours or longer after the end of anesthesia; this can be done after each pain assessment is performed. Using warm air or circulating water blankets can prevent intraoperative hypothermia, which may in turn limit severe rebound hyperthermia. If profound hyperthermia develops (>40.8° C [105.5° F], treatment is started by actively cooling the patient using fans and/or placing towels soaked in lukewarm (not ice-cold) water on the foot pads and fur. Removal of bedding from the kennel is also recommended. Rectal temperature should be monitored every 5 minutes and active cooling withdrawn when it reaches 40° C [104° F] to prevent rebound hypothermia. On the rare occasion that active cooling and time is ineffective, naloxone (0.01 mg/kg IM or SC) can be administered with the understanding this will reverse analgesia if an opioid is the only class of analgesic that has been given; an alternative analgesic drug such as a NSAID should be given prior to naloxone.

Some opioids, including morphine and hydromorphone, may cause retching, vomiting, and nausea characterized by salivation, drooling, and lip licking,^30,75 especially when used alone and in pain-free cats (e.g., as a premedication for an elective procedure). Vomiting and profuse salivation are common after SC administration of hydromorphone and appear to be distressing to cats.³⁰ Vomiting and retching should be prevented in cats with increased intraocular pressure, penetrating corneal foreign bodies, and elevated intracranial pressure. In many cases of foreign body ingestion (e.g., needles or linear objects), vomiting and retching can cause penetration of the GI tract.

In dogs, the administration of acepromazine reduces opioid-related vomiting⁷⁶ and is potentially effective in cats. Clinically, vomiting occurs less commonly when opioids are combined with acepromazine than when they are used alone in cats. Maropitant, a neurokinin-1 antagonist, is highly effective against the emetic effects of xylazine in cats.⁷⁷ Oral maropitant reduced, but did not eliminate vomiting in cats after IM administration of dexmedetomidine and morphine even when given up to 18 hours in advance of premedication.^78,79 This led the authors to suggest that owners administer maropitant the evening prior to a scheduled procedure to reduce motion sickness during travel to the clinic and vomiting associated with premedication.⁷⁸ If vomiting is contraindicated in a feline patient but an opioid is required to provide pain relief, appropriate choices would include the non-emetic opioids buprenorphine, methadone (IM or IV), or fentanyl as a CRI. It is also worth noting that while maropitant reduces the incidence of vomiting, clinical signs of nausea (salivation and lip licking) may be relatively unchanged.

In the cat, opioids induce marked mydriasis. Cats with dilated pupils often appear more agitated, perhaps because of reduced visual acuity, which causes them to bump into objects and become startled when approached. Dimming the lights and speaking softly to the cat as it is approached helps reduce these behaviors.

In humans, decreased intestinal motility is a common, unpleasant, and problematic adverse effect of opioid administration especially with chronic use.⁸⁰ In the authors’ experience, it is uncommon to see constipation in cats being treated for acute pain when opioids are only used for a few days. If opioid use is anticipated to last more than 4 to 5 days, it is important to maintain hydration and it may be advisable to use a stool softener to prevent constipation. An excellent evidence-based review of the practical use of opioids in cats is available.⁸¹

With the increasing use of psychoactive drugs (selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors and serotonin agonists; see Chapter 17: Behavioral Therapeutics) in veterinary medicine as part of a treatment regimen for behavior problems, there is a growing concern for the possibility of adverse drug interactions.⁸² Serotonin toxicity which can range from mild signs such as salivation and diarrhea to severe signs such as myoclonus and hyperthermia resulting in death can occur when drugs that increase serotonin levels are overdosed alone or co-administered with drugs that can increase serotonin levels.^82,83 Meperidine (pethidine), fentanyl, remifentanil, pentazocine, and tramadol impair the reuptake of serotonin. The addition of these analgesic agents to an established psychoactive drug protocol in humans has triggered serotonin toxicity.⁸⁴ A case report on a cat experiencing serotonin syndrome following an accidental overdose of tramadol suggests that we need to be cautious when prescribing certain analgesic drugs.^74,83 Before an analgesic plan is created for a cat, it is essential to establish a list of all current medications. This includes any supplements or herbs the owner is administering; St. John’s wort (Hypericum perforatum), for instance, alters serotonin reuptake.

Current nomenclature of opioid receptors is defined by the Nomenclature Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR). Current NC-IUPHAR-approved nomenclature refers to opioids as delta (δ or DOP), kappa (κ or KOP), and mu (µ or MOP), respectively.85 Opioid drugs are traditionally classified into agonists, partial agonists, agonist–antagonists, and antagonists based on their actions at opioid receptors. Suggested doses of commonly used drugs are given in Table 6.1.

Butorphanol is one of the few analgesic drugs to have market authorization for use specifically in the cat in some countries, including the United States and the United Kingdom. It is an agonist at the kappa receptor, an antagonist at the mu receptor, and exhibits a ceiling effect. This is clinically relevant because increasing the dose does not produce additional analgesia.⁸⁶ In one research model using a somatic thermal stimulus, the duration of action was approximately 90 minutes, regardless of dose,⁸⁷ whereas a similar study showed large intercat variability, with antinociception lasting up to 8 hours in some cats.⁸⁸ The response to butorphanol may vary depending on the source of pain. Visceral antinociception was demonstrated with 0.1 mg/kg of butorphanol, whereas somatic antinociception was unaffected in the same cats.⁸⁹

A large multicenter study comparing the clinical usefulness of butorphanol with that of buprenorphine in more than 150 cats undergoing primarily, but not solely, ovariohysterectomy or castration found that buprenorphine resulted in lower pain scores for a greater duration than did butorphanol.⁹⁰ Current data suggest that butorphanol is a sensible choice for acute, visceral pain (e.g., cystitis) but considering its relatively short duration of action, it must be given often or administered as a CRI. Its ceiling effect makes it a poor choice for moderate to severe somatic or visceral pain that is more than transient in nature, such as would occur with invasive surgery.⁶⁷

Nalbuphine, like butorphanol, is an opioid agonist–antagonist. Little has been published regarding the use of nalbuphine in cats. One study demonstrated visceral analgesia, with IV doses of 0.75, 1.5, and 3 mg/kg producing similar effects that lasted between 156 and 200 minutes.⁸⁹ None of these doses resulted in somatic analgesia.

Pentazocine, another agonist–antagonist, only provided visceral analgesia when 3 mg/kg IV was administered.⁸⁹ No somatic antinociception was noted with this dose, and undesirable side effects such as ataxia and apprehension were described, which suggests that this drug has little utility in cats.

Buprenorphine is a mu opioid agonist, with what Steagall and colleagues aptly describe as a “complex pharmacologic profile,” owing largely in part to the diverse ways that buprenorphine’s actions at opioid receptors have been described in research studies.³³ It is available in four formulations with geographical differences in availability of each. What is referred to as “standard” buprenorphine is a human product and is also available with a veterinary label in some counties. The human product is 0.3 mg/mL with no preservative and the veterinary product (Vetergesic multidose [MD]; licensed for cats, dogs, and horses) is distributed in a 10-mL bottle and can be used for 28 days after it is breached; this product is available in Canada and the United Kingdom. High-concentration buprenorphine (Simbadol, 1.8 mg/mL) is FDA-approved for use in cats in the United States. An SR formulation (Zoopharm, 3 mg/mL) is also available for SC injection but does not have market authorization for use in cats at the time of this writing. The newest formulation of buprenorphine is a transdermal solution (Zorbium).

The standard formulation has been extensively studied in cats, both in laboratory and clinical settings. Laboratory studies report varying times to onset of effect and duration of action, which appear partly related to dose and route of administration. For example, when antinociception is evaluated using a thermal threshold model, a dose of 0.02 mg/kg IV showed a significant effect at 30 minutes, a peak effect at 90 minutes, and a duration of 6 hours.⁵⁶ Intravenous administration of buprenorphine at doses ranging from 0.01 mg/kg to 0.04 mg/kg showed dose-related thermal antinociception, but based on mechanical threshold testing, 0.02 and 0.04 mg/kg produced greater and longer lasting antinociception than 0.01 mg/kg.⁹¹ Higher doses (0.04 mg/kg) do not have the ceiling effect which was once the subject of much speculation, and hence may be more appropriate for some patients.³³

High concentration formulations of buprenorphine (1.8 mg/mL) administered SC were effective over a 24-hour period in a thermal threshold model.³⁵

The studies used laboratory models of antinociception; however, clinical reports of analgesia achieved with buprenorphine are more variable. Buprenorphine (standard formulation) had clear advantages over butorphanol for providing better and longer lasting analgesia in a multicenter, prospective study carried out in 2010.⁹⁰ Since that time, additional studies report that buprenorphine alone or given once is not sufficient for some procedures including ovariohysterectomy.^92–94 There are a multitude of reasons for this including timing of drug administration. For example, Warne and others found that if they administered buprenorphine as a premedication and at wound closure, there was sufficient analgesia for ovariohysterectomy. In contrast, one dose given prior to surgery did not provide sufficient postoperative analgesia.⁹³

Combining other drugs such as NSAIDs and alpha₂-adrenergic agonists with buprenorphine may improve analgesia. Effective analgesia was demonstrated when an NSAID was co-administered.⁹⁴ Likewise, studies combining alpha₂-adrenergic agonists with buprenorphine demonstrated favorable analgesia.⁵³

The degree of tissue trauma and resultant inflammation is correlated with pain after surgery and it is presumed that experienced surgeons cause less tissue damage, which may influence whether buprenorphine is an effective analgesic after surgery.⁹⁵ A link between postoperative pain and surgical experience has been reported previously.⁹⁶

Another reason for the differences among studies is significant intercat variability, a reminder that pain and the efficacy of drugs used to relieve it are unique to each individual and that individual assessment is the key to success in each patient.⁸⁸

Similar to the reported effects of SC hydromorphone, this route also seems less effective when a single dose of standard buprenorphine is used.^97,98 In a laboratory setting, there was no difference in onset or duration of thermal antinociception (30 minutes and 6 hours, respectively) between OTM and IV administration of buprenorphine at 0.02 mg/kg.⁵⁶ In a clinical trial in cats undergoing ovariohysterectomy, IV and IM administration of buprenorphine were more effective than the OTM route, but the dose used was lower (0.01 mg/kg).⁹⁸ Additional information gained from these studies is the time of peak effect, which consistently occurs between 60 and 90 minutes after administration. Pain is often most intense in the immediate postoperative period; therefore, the timing of preoperative buprenorphine administration should be planned to meet these needs.

In several clinical studies, the analgesia produced by buprenorphine (usually given IM) in cats undergoing a variety of invasive procedures was greater in magnitude and longer lasting than that produced by several other opioids, including butorphanol, levomethadone, morphine, oxymorphone, and pethidine.^90,99–102 However, it should be noted that equianalgesic doses of opioids were not necessarily used, and the methods of pain assessment were not standardized. This is likely the reason why later studies found methadone, for example, at least as effective as buprenorphine.^95,103

The SR preparation of buprenorphine has been evaluated in cats undergoing ovariohysterectomy. A single SR (SC) dose of 120 µg/kg was as effective as 20 µg/kg buprenorphine given by the OTM route every 12 hours until 60 hours after surgery.³¹ Additional studies also report effective analgesia for up to 72 hours when using the SR product.³² The SR formulation is convenient to use, and for trap-neuter-return programs for community cats, which are difficult to handle safely after anesthesia, this formulation is a viable option.

Buprenorphine is available for use in humans as a matrix patch. In cats, the plasma concentrations were quite variable after application of a 35 µg/h patch, and no antinociception was evident during a 4-day period in the only published study.³⁸ Until further studies are performed with different sizes of patches and perhaps using a loading dose of buprenorphine, this method of administration cannot be recommended.

A buprenorphine/naloxone combination produced enhanced analgesia in humans and rats and has been tested in cats. No effect on mechanical nociception was noted and naloxone did not enhance the thermal antinociceptive effect of buprenorphine. In agreement with previous work, naloxone antagonized the clinical analgesia of buprenorphine, and this combination cannot be recommended for feline patients.¹⁰⁴

The following conclusions are drawn from the extensive published data on buprenorphine (standard injectable formulation) in cats. Doses for clinical use should be 0.02 mg/kg to 0.04 mg/kg; IV, IM, and OTM routes of administration are effective, but the SC route is not; and individual variation is well-documented.

The HC formulation labeled for SC administration may provide analgesia for 24 hours. It is not recommended for IV or OTM administration and should not be dispensed as a “go home” medication. For readers interested in learning more about buprenorphine, extensive reviews on this drug are available for download at no cost.³³

Fentanyl is a potent opioid used in cats as an IV bolus, a CRI, and a transdermal patch. Intravenous fentanyl (10 µg/kg) reaches peak effect in less than 5 minutes and provides significant antinociception for almost 2 hours (in a laboratory model) with minimal to no adverse effects.43 The pharmacokinetic profile of fentanyl makes it a suitable agent for use as a CRI. The plasma levels and therefore the degree of analgesia can be rapidly altered, and fentanyl is frequently used in this manner to provide analgesia in trauma cases both during and after surgery. A research model suggests that the effective plasma concentration in cats is >1.07 ng/mL.⁴³ Using thermal and mechanical threshold testing, Ambros and others demonstrated antinociception following a loading dose of 5 μg/kg followed by 5 μg/kg per hour. Plasma fentanyl concentrations were measured and correlated with antinociception.¹⁰⁵ In agreement with Robertson et al.,⁴³ plasma levels <1.33 ± 0.30 ng/mL were not associated with antinociception.¹⁰⁵ However, it is likely that that in a clinical setting, requirements will vary depending on the individual and the severity of injury or extent of surgery. These authors have used infusion rates from 0.08 to 0.8 µg/kg per minute (5 to 50 µg/kg per hour) during surgery and from 0.03 to 0.16 µg/kg per minute (2 to 10 µg/kg per hour) postoperatively and in trauma patients. It is important to recognize the role premedication may play in the effect of fentanyl for reducing noxious stimuli. Pretreatment with an avid binder of mu receptors, such as buprenorphine, will at least partially inhibit fentanyl’s antinociceptive actions.¹⁰⁶

After application of a transdermal (most commonly a 25 µg per hour) patch, the plasma concentration of fentanyl is highly variable and undetectable in some cats. Many factors may account for this variability, including body weight (which dictates the dose per kg from the patch), amount of subcutaneous fat, body temperature, peripheral vasoconstriction or vasodilation, and location and method of patch placement. Serum levels of fentanyl are higher in normothermic (38° C [100.4° F]) than in hypothermic cats (35° C [95° F]).¹⁰⁷ Cats weighing less than 4 kg have higher plasma concentrations when the full adhesive layer of a 25 µg per hour patch is exposed to the skin, as opposed to half.¹⁰⁸ A steady state can be achieved within 6 to 12 hours and maintained for up to 72 hours after patch placement in some cats.³⁹ Feline skin may act as a drug depot because, unlike dogs, the serum concentrations can take up to 20 hours to decline after the patch is removed.³⁹ Clinical reports suggest that the transdermal fentanyl patch has clinical utility in cats undergoing onychectomy and ovariohysterectomy,^40–42 but clinicians should be aware that just because the patch has been applied does not mean it is providing adequate analgesia in every case.

There is a case report of a dog that became extremely sedate after it punctured and presumably ingested or licked the contents of a transdermal fentanyl patch applied to its flank,¹⁰⁹ and it is highly plausible that this could also occur in a cat. The clinician should consider all consequences carefully before sending a cat home with a patch; this has caused some serious liability issues in human medicine, including diversion, abuse, and accidental ingestion by a child.^110,111

Remifentanil is rapidly metabolized and does not accumulate. It is used as a CRI in several species, including humans, because of the ability to change plasma concentrations very quickly. Currently, remifentanil is predominantly used to provide analgesia during anesthesia at rates of 1 to 2 µg/kg per minute (60 to 120 µg/kg per hour), which would cause dysphoric and sometimes frantic behavior in conscious cats;¹¹² dose finding studies suggest that 0.4 µg/kg per minute (24 µg/kg per hour) is likely the most suitable rate.¹¹³ If infusion rates are kept below 1 µg/kg per minute (<60 µg/kg per hour), these adverse effects can be avoided and antinociception can still be demonstrated,¹¹² making it suitable for postoperative use. Intraoperatively, remifentanil must be combined with drugs such as ketamine to demonstrate a reduction in inhalant anesthetic requirements.¹¹⁴

Hydromorphone is widely used in veterinary medicine with one reason being its low cost.¹¹⁵ Hydromorphone (0.1 mg/kg) and oxymorphone (0.05 mg/kg) provide clinically equivalent analgesia in cats undergoing a variety of surgical procedures.¹¹⁵ In a research model, hydromorphone at 0.05 mg/kg IV provided moderate antinociception for 80 minutes, whereas 0.1 mg/kg provided profound effects for 200 minutes in one study and for up to 7 hours in another.^72,116 Two independent studies reported that nausea and vomiting are associated with the use of hydromorphone in cats.^30,115 The concerns related to hydromorphone-related hyperthermia were discussed previously, and combined with the side effects of nausea and vomiting, compel the authors to use other mu agonist opioids (such as methadone), whenever possible.

Oxymorphone has been used in clinical settings and there are published studies on this drug in cats, but this drug has become more difficult to source in recent years. There was no antinociceptive effect demonstrated using a thermal threshold model when using oxymorphone at 0.1 mg/kg IV or 0.25 mg/kg OTM, suggesting that at least in a laboratory setting, these doses and routes of administration are ineffective.¹¹⁷ Oxymorphone has minimal bioavailability via the OTM route, making it less versatile than buprenorphine for pain management.¹¹⁸ In a small number of cats, oxymorphone at 0.05 mg/kg IV appeared as effective as hydromorphone at the same dose in a clinical setting.¹¹⁵ In another study, oxymorphone was not as effective an analgesic as buprenorphine for cats undergoing onychectomy with or without castration.⁹⁹ Although the published information suggests few adverse effects from oxymorphone, current work does not support its use in the feline patient when other suitable opioids are readily available.

Meperidine (Demerol), also known as pethidine, can cause excitement when administered via the IV route; therefore, only SC or IM administration is recommended. Both clinical and laboratory studies suggest that it is short acting,^69,119,120 and clinicians should expect it to be effective for only 1 to 2 hours. Because meperidine can result in sedation, it can be used for this purpose when a traditional sedative or tranquillizer is contraindicated, such as in a hemodynamically unstable patient.

Methadone usage is increasing in veterinary medicine and has market authorization for use in cats in some countries. In addition to its opioid actions, methadone has other desirable properties, including action at the N-methyl D-aspartate (NMDA) receptor,¹²¹ which is involved in the development of central sensitization. Methadone is available as an isomer (levomethadone) and a racemic mixture. The racemic mixture, at the relatively low dose of 0.2 mg/kg SC, increased thermal thresholds between 1 and 3 hours but had little effect on mechanical thresholds.⁹⁷ In a clinical setting, both racemic methadone (0.6 mg/kg IM) and levomethadone (0.3 mg/kg IM) given before ovariectomy provide effective postoperative analgesia, as assessed by palpation and behavior, with no adverse effects.¹²² However, when compared with buprenorphine or carprofen, levomethadone (0.3 mg/kg SC every 8 hours for 5 days) was not as effective for orthopedic surgery and was associated with excitement in some cats.¹⁰⁰ The racemic mixture appears to provide suitable antinociceptive effects in laboratory settings, when administered IV, IM, and OTM.^123,124 Analgesia has been demonstrated in clinical studies with methadone administered via a variety of routes.^95,124,125 Methadone is superior to butorphanol for cats undergoing ovariohysterectomies.¹²⁶

Morphine has a long history of use in humans and animals and is often considered the gold standard opioid to which others are compared. Because of the limited ability of cats to glucuronidate drugs, morphine may have less overall efficacy than in other species, insofar as glucuronidation is necessary to produce morphine-6-glucuronide (M-6-G), a potent and active metabolite.¹²⁷ This metabolite was not detected after IM administration of morphine in cats and was detected in only three of six cats receiving IV morphine.¹²⁸ Because of the belief that morphine caused excitement in cats (which has been disproved at clinically relevant doses¹²⁹), low doses (0.1 to 0.2 mg/kg) have historically been recommended and may have led to the clinical impression that morphine is not an effective analgesic in cats. However, 0.2 mg/kg SC produced short-term thermal antinociception.⁹⁷ Owing to the lack of M-6-G production, it is possible that higher doses of the parent compound are necessary to produce analgesia in the cat equivalent to that in species able to produce this metabolite.

Intravenous morphine has been associated with histamine release in dogs in a dose-related manner, although no similar study has been performed in cats.¹³⁰ If morphine is used via the IV route, slow administration is advised.

Epidural morphine is discussed in greater detail in this chapter under “Epidural Administration of Opioids”.

Coadministration of opioids is proposed as a means of utilizing the positive benefits of each drug; for example, combining a fast onset drug with a long-acting one. Although coadministration of opioids has been reported, the results are variable, ranging from a decrease in intensity of antinociception but prolongation of effect,86 to no measurable effect.⁸⁸ Studies with hydromorphone and butorphanol suggest butorphanol decreases the efficacy of hydromorphone but extends its duration of action when these drugs are administered together.⁸⁶ Because of this unpredictability, simultaneous administration of different opioids is not recommended. As previously discussed, combining low-dose naloxone with buprenorphine in cats failed to show any benefits over buprenorphine alone,¹⁰⁴ which suggests that direct extrapolation of data among species is unwise without careful evaluation in the target species.

When evaluated using a thermal threshold model, epidural buprenorphine (12.5 µg/kg) and morphine (0.1 mg/kg) provided analgesia, but morphine provided analgesia of greater intensity and longer duration (16 hours as opposed to 10 hours).131 Meperidine, methadone, tramadol, fentanyl, and buprenorphine have all been evaluated after epidural injection.^132–135 These drugs are more lipophilic than morphine, resulting in systemic diffusion and actions that mimic those of the drug when given by the IV or IM route. Buprenorphine is rapidly dispersed from the epidural space.¹³⁵ In contrast, hydrophilic drugs, such as morphine, do not readily diffuse, remaining in the epidural space and providing a long duration of action and minimal systemic effects.¹³¹ Epidural morphine does not produce motor dysfunction and is an excellent choice of technique for perianal and hind limb surgery, including amputation, and is available for use in a preservative-free formulation. The rate of complications associated with epidural morphine is low, although urinary retention was noted in 2 of 23 (8%) cats in one study.⁶³ A single case report discussed a cat with both urinary and bowel dysfunction and suggested it was related to an epidural injection containing morphine.¹³⁶ However, with appropriate nursing care (e.g., observing for urination, expressing the bladder after the procedure, placing a urinary catheter), urinary complications can be minimized. The reported bowel dysfunction was unusual and unless further similar reports surface, morphine should not be condemned due to this isolated report. There are reports of hypotension (one cat) and pruritus (three cats) secondary to an epidural containing morphine, which reminds us that not all complications are urinary in nature.^137,138 Appropriate patient selection and careful observation are necessary when morphine is given epidurally.

Although not classified as a true opioid, tramadol is included here because much of its analgesia results from its opioid effects. Tramadol produced mild euphoria,139 but this was not deemed an undesirable attribute of the drug during short-term use. Tramadol exerts its action at multiple sites, including opioid, serotonin, and adrenergic receptors.¹⁴⁰ It is available in injectable and oral formulations. It has oral bioavailability in cats, and its active metabolite O-desmethyl-tramadol (M1) was found after both systemic and oral administration.^47,141 The disposition of tramadol in cats makes dosing intervals practical.⁴⁷ In a research model, a SC dose of 1 mg/kg did not increase thermal threshold.¹¹⁹ The combination of the NSAID vedaprofen and tramadol at 2 mg/kg provided superior postoperative analgesia than either drug given alone.¹⁴² In a study done by the same authors, no adverse effects on platelet aggregation, vomiting, GI function, or biochemical values were found.¹⁴² However, a single case report does exist of possible serotonin syndrome in a cat related to an accidental overdose⁸³ (see “Potential Drug Interactions” previously in this chapter for more information).

Tapentadol, like tramadol, is a centrally acting opioid analgesic that is a μ opioid receptor agonist and norepinephrine reuptake inhibitor. In humans, the opioid analgesia can be profound. Although pharmacokinetic information has been available for some time,¹⁴³ this drug has only recently been examined for its analgesic effects in cats. Antinociceptive actions have been demonstrated after oral administration in laboratory settings;¹⁴⁴ however, the formulation was considered highly unpalatable which is a significant concern for inclusion of this drug into a “go home” regime. We are likely to see more clinically relevant information on this drug once the palatability issue has been addressed.

Cyclooxygenase (COX) enzymes are traditionally thought to exist in two major isoforms, COX-1 and COX-2, although COX-3 and other subclasses are also reported. Initially, COX-1 was considered the constitutive “housekeeping” enzyme responsible for multiple essential physiologic functions, and COX-2 was considered an inducible enzyme that resulted from inflammation. Therefore, preferential blockade of the COX-2 enzyme was thought to increase the safety of NSAIDs. It is now understood that COX enzymes are multifaceted, there is overlap in their functions, and it is unlikely that COX-2 is inhibited without some impact on the COX-1 enzymes.145 Cyclooxygenase-2 is also constitutive and required for normal function in many tissues; for example, in the kidney of dogs, rats, monkeys, and humans.^146,147

Nonsteroidal anti-inflammatory drugs have been used less in cats than other species because of documented adverse effects which many believe to be higher than in other species. Some studies report the incidence of adverse events to be as high as 11.7%.¹⁴⁸ However many veterinary studies are not well designed to assess the clinical safety of NSAIDs. While many adverse effects of this class of drugs has been reported in dogs, in a systemic review, unwanted side effects were no different between treated and control dogs.¹⁴⁹ Articles which outline the challenges of using NSAIDs in cats conclude that with proper precautions and choice of patient, these drugs can be part of successful acute pain management.^150,151 Many NSAIDs are heavily dependent on glucuronidation for metabolism, and for this reason some NSAIDs have long half-lives in cats. Although aspirin is the classic example of one such drug, carprofen also has a relatively long half-life in the cat compared with the dog.^152,153 Conversely, NSAIDs that are oxidized (e.g., meloxicam and robenacoxib) often have a shorter and more predictable half-life.^150,154

Nonsteroidal anti-inflammatory drugs should not be used concurrently with corticosteroids or in cats with GI compromise. Neither meloxicam or robenacoxib alter glomerular filtration rate (GFR) in healthy, euvolemic, conscious cats,^155,156 but in the face of hypotension, renal autoregulation is dependent on prostaglandins; therefore, decreased circulatory volume and/or function, as may be seen after acute trauma, is considered a contraindication for NSAID use. Hypotension (a mean arterial blood pressure <60 mm Hg or systolic blood pressure <90 mm Hg) is documented in between 10% and 33% of cats under anesthesia.^157,158 For this reason many veterinarians reserve NSAIDs for use in the immediate postoperative period, provided the cat is hemodynamically stable at that point.

Nonsteroidal anti-inflammatory drugs can alter hemostasis because of their effect on platelets and vascular endothelium. There is no evidence that the newer NSAIDs with market authorization for use in cats have a significant effect on surgical bleeding.¹⁵⁰

When compared with one another, ketoprofen, carprofen, meloxicam, and tolfenamic acid were equally effective in cats undergoing routine soft tissue surgery,¹⁵⁹ and therefore the clinician may select the NSAID based on personal preference, ease of administration (oral ­versus injection), and market authorization for each drug in different countries.

Although aspirin (acetylsalicylic acid) is readily available over the counter, its side effects (e.g., GI ulceration, platelet inactivation, and decreased protective renal prostaglandins160,161), in combination with a half-life of up to 45 hours,¹⁶² make aspirin an unsuitable perioperative analgesic for cats. Only the most widely used NSAIDs are discussed here; for complete information on these and other less commonly used agents, the reader is referred to the review by Lascelles and colleagues.¹⁵⁰ The individual NSAIDs discussed in this chapter have market authorization for use in cats in some but not all countries, and their labeled indication may also vary. Therefore, it is strongly recommended that clinicians verify this data in each country before use.

Carprofen is a COX-1–sparing NSAID, although this selectivity appears to decrease as dosage increases in in vitro models.¹⁶³ Because the half-life in the cat is variable among individuals and ranges anywhere from 9 to 49 hours,¹⁵³ repeat dosing is not advised. In countries where it has market authorization for use in cats, it is for one-time use only. When a single dose of each drug was given in a clinical setting, carprofen provided better postoperative analgesia than meperidine, buprenorphine, and levomethadone;^100,164,165 this is likely due to the difference in duration of action of the two classes of drugs. In cats that underwent ovariohysterectomy, doses ranging from 1 to 4 mg/kg were more effective than meperidine (pethidine) from 2 to 20 hours after surgery.¹⁶⁵ An IV or SC dose of 1 to 2 mg/kg is most commonly recommended.¹⁵⁰

Ketoprofen is not a selective COX inhibitor and has the potential to produce similar adverse effects as described for aspirin. However, obvious effects on hemostasis are not reported.¹⁵⁰ Gastrointestinal effects are more likely in adult cats than in younger cats, making the latter a more “tolerant” population.¹⁶⁶ It is effective in alleviating the pain associated with soft tissue surgery and injury.^49,99,159 In cats with musculoskeletal pain, it has been administered at 1 mg/kg PO for 5 days with beneficial effects.¹⁶⁷

Meloxicam is a COX-1–sparing NSAID and decreasing the dosage of the drug may decrease the incidence of COX-1-inhibition–mediated effects.¹⁵⁰ Meloxicam (at the label dose of 0.3 mg/kg SC, given once only) is one of only two NSAIDs approved for postoperative control of pain in cats in the United States; the other is robenacoxib. Based on multiple behavioral assessments, cats receiving meloxicam were more comfortable after onychectomy compared with those receiving butorphanol.¹⁶⁸ Meloxicam is as effective as ketoprofen in alleviating pain in cats with musculoskeletal disease, but an advantage of meloxicam is its palatability, which may increase compliance.^49,167 In healthy, euvolemic, conscious cats there was no measurable effect on GFR when meloxicam was administered once at 0.2 mg/kg followed by 0.1 mg/kg once daily PO for 4 additional days.¹⁵⁵ Although off-label in the United States, 3 to 5 days of treatment for postoperative or musculoskeletal pain using a combination of injectable and oral formulations is approved in Canada and other countries; see Table 6.1 for details. Lower doses of meloxicam are still associated with clinical efficacy; 0.05 mg/kg PO daily was effective at reducing pain in a synovitis model of osteoarthritis.¹⁶⁹ Results from clinical studies suggest that long-term administration of meloxicam at 0.02 mg/kg PO to cats with degenerative joint disease and stable chronic kidney disease provides pain relief with no deterioration of their renal disease.^170–172 Cats with reduced renal mass resulting in azotemia and categorized as International Renal Interest Society chronic kidney disease stage 2 and 3 were given meloxicam (0.2 mg/kg SC on day 1 and 0.1 mg/kg SC from day 2 to 7).¹⁷³ The cats were euvolemic and based on indicators of GFR, the authors hypothesize that, under these conditions, GFR is not dependent on COX function.¹⁷³ This provides veterinarians with an option for long-term pain management in cats. In addition, there is minimal effect on platelet aggregation.¹⁷⁴ This and other considerations of long-term NSAID use are more thoroughly addressed in the AAFP and ISFM consensus guidelines for long-term NSAID use in cats, as well as the review article on management of long-term osteoarthritis by Bennett and colleagues, to which the reader is referred for more extensive information on this topic.^151,175 Please also see the “Chronic Pain” section of this chapter for more information.

Robenacoxib (Onsior), a COX-2–selective NSAID is the most recent NSAID and first coxib class NSAID approved for use in cats.¹⁷⁶ It is available in both injectable and tablet formulations and is marketed for the alleviation of acute pain and inflammation associated with musculoskeletal disorders and soft tissue surgery. The injection is approved for preoperative use, and the tablets for up to 6 days in some countries. When prescribing the tablet for use as a “go home” medication, instructing owners to give it with a small amount or no food will result in optimum bioavailability of the drug.¹⁷⁷ At a dose of 2 mg/kg, robenacoxib was effective at reducing pain and swelling in an inflammatory feline paw model.¹⁷⁸ The drug appears to have a favorable safety profile, with its high safety index related to both its high COX-2 selectivity and short residence time in the central compartment and therefore short-term exposure of well perfused organs (<4 hours) compared to its long residence time in inflamed tissue.¹⁷⁹ There is minimal effect of robenacoxib on GFR, and in some cats, GFR increased.¹⁵⁶ Robenacoxib was considered clinically safe in one study where it was administered for 1 month in cats with osteoarthritis, some of which had chronic kidney disease.¹⁸⁰ When compared to meloxicam for efficacy in acute, perioperative settings, robenacoxib had superior efficacy to meloxicam for soft tissue procedures and was as efficacious as meloxicam for orthopedic surgery.^181,182

There is limited pharmacokinetic information on tolfenamic acid, and its status as a COX-1–sparing agent is controversial.¹⁸³ Although not licensed in the United States, tolfenamic acid is licensed and popular in many other countries.¹⁵⁰ At 4 mg/kg SC, it appears to be as effective as meloxicam (0.3 mg/kg SC) in the cat for control of postoperative pain and there appears to be minimal effects on renal values related to its administration.^183,184

Grapiprant belongs to a class of drugs called piprants. It is a new-to-market analgesic that selectively blocks the prostaglandin E2 EP4 receptor and is licensed for use in dogs in the United States. There is less information on grapiprant in cats, but its pharmacokinetics have been described and a safety study conducted over 28 days using a wide range of doses that evaluated body weight changes, food consumption, clinicopathologic variables, and gross or histologic necropsy findings supported daily oral use.^185,186 Efficacy in cats remains to be established.

The aim of this procedure is to block the ventral branches of cervical nerves 6, 7, and 8 and thoracic nerve 1; this technique reduces the intraoperative inhalant anesthetic requirement, and early postoperative pain in the cat.195 This is a useful technique for procedures that are located at or distal to the elbow. The block can be performed in three ways: with ultrasound guidance to visualize the nerves, with use of a nerve stimulator to confirm proximity to the nerves (Fig. 6.4), or based on anatomic landmarks. Ultrasound-guided brachial plexus nerve blocks are the subject of multiple studies.^196–198 Because the appropriate equipment for the first two techniques is not yet widely available in general practice, the technique described here is based on anatomic landmarks,⁶¹ with the reader referred to the references listed for other techniques should they have that equipment available. The point of the shoulder (scapulohumeral joint), first rib, and cervical vertebrae are the anatomic landmarks that will assist with correctly performing this block. Once the hair coat has been clipped and the insertion site prepared using sterile technique, the patient’s head and neck are placed in a neutral position (i.e., with minimal flexion or extension). The cervical transverse processes form a line that typically traverses the proximal brachial plexus at the first rib.⁶¹ The first rib is followed dorsal as far as possible, and a 1.5-inch, 22-gauge sterile needle is inserted and advanced toward and caudal to this rib, below the scapula. A syringe containing lidocaine (4 mg/kg) or bupivacaine (2 mg/kg) is attached to the needle. The ideal volume for this appears to be no less than 5 mL, but this would exceed the toxic dose of bupivacaine in most cats, meaning that blocks may or may not be effective due to lack of volume alone.¹⁹⁹ Dilution of local anesthetic to this volume has not been evaluated. Bupivacaine is available in several strengths (0.25%, 0.5 %, and 0.75 %); therefore, if volume is needed, the best choice is the 0.25% solution.

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