Single-drug analgesia protocols can be effective in common surgeries, but a combination of analgesics can be more effective with a multimodal approach that targets multiple sites in the pain pathway.^1,2 There are many multimodal drug combinations designed to prevent and treat operative and postoperative pain, including opioids, NSAIDs, ketamine, alpha-2 agonists (eg, dexmedetomidine), local anesthetic agents, and oral agents not in previously mentioned drug classes. 

Following are the author’s 5 most frequently used and effective combinations of analgesics for common surgeries based on current trends and availability.

Use of an injectable opioid and injectable NSAID is common for perioperative analgesia and pain management.³ Pure mu-opioid receptor agonists (eg, morphine, hydromorphone, methadone, fentanyl) act on mu receptors at the spinal and supraspinal level and are highly effective analgesics. Pure mu agonists can manage moderate to severe pain and provide a moderate level of sedation.⁴ Butorphanol (a mixed agonist/antagonist) and buprenorphine (a partial agonist) also act at spinal and supraspinal levels; however, they are generally preferred for mildly painful procedures.¹ Butorphanol is also used for its reasonable sedative effects, commonly in conjunction with dexmedetomidine or acepromazine.

NSAIDs (eg, carprofen, meloxicam, robenacoxib) are also commonly used and effectively contribute to analgesia in acute painful situations (eg, surgery).^5-7 The primary mechanism of action is inhibition of COX enzyme activity and subsequent reduction in prostaglandin synthesis that reduces inflammation. Other non-COX–mediated anti-inflammatory and analgesic activities (eg, activity at the 5-lipoxygenase pathway, activities impacting other proinflammatory enzyme pathways) have been proposed to contribute to the overall effectiveness of NSAID pain management.⁶

Opioids and NSAIDs are effective analgesics when used alone but generally provide better pain management when coadministered. A recent study demonstrated inadequate early postoperative analgesia when dogs received only opioid premedication prior to surgery.⁸

Protocols that use a pure mu agonist (eg, methadone) can be applied to other soft tissue surgeries, basic orthopedic procedures, and longer procedures. Top-up doses of opioids can be administered midsurgery when the procedure is longer than the duration of the premedication agent. For example, premedication with hydromorphone (0.1 mg/kg IM or IV) can be supplemented intraoperatively with another dose (0.05 mg/kg IV) if the procedure lasts >2 hours. NSAID administration can be preoperative or intraoperative, but waiting until the patient has returned to normal physiologic status postoperatively can help avoid potential negative impacts on renal function during anesthesia-induced hypotension.

Dogs and cats undergoing ovariohysterectomy can benefit from opioid and NSAID protocols. Dogs can be given preoperative hydromorphone (0.05-0.1 mg/kg IM or IV) or methadone (0.1-0.25 mg/kg IM or IV), postoperative meloxicam (0.2 mg/kg SC), and at-home meloxicam (0.1 mg/kg PO every 24 hours) after the initial SC dose.

Cats can be given preoperative butorphanol (0.3-0.4 mg/kg IM, ideally followed by buprenorphine, 0.01-0.02 mg/kg IV, during or after surgery due to the mild impact of butorphanol on pain) or methadone (0.1-0.25 mg/kg IM or IV). Postoperatively, they can receive robenacoxib (2 mg/kg SC) and at-home robenacoxib (1 mg/kg PO every 24 hours for 3 days) after the initial SC dose.

Local anesthetic agents (eg, lidocaine, bupivacaine, ropivacaine) are particularly effective at providing pre-emptive analgesia because they block conduction of sensory nerve impulses via inhibition of voltage-gated sodium channels in neurons, causing complete blockade of nociceptive input from the surgical site. Local anesthesia can effectively reduce general anesthetic requirements during surgery.¹ 

Combination of a local or regional block with injectable analgesics (eg, opioids, NSAIDs) can provide a complete perianesthetic pain management plan (see When to Use Local Anesthesia). 

When using local anesthetics, it is important to calculate the total dose to avoid exceeding maximum recommended doses and to prevent toxicosis. In cats and dogs, the maximum dose of bupivacaine 0.5% is 2 mg/kg, and the maximum dose of lidocaine 2% is 8 mg/kg. Although the reported toxic dose of topical lidocaine 2% is up to 10 mg/kg in cats, there is some variability in the literature; the maximum dose ranges from 6 to 8 mg/kg. 

Dogs can be given preoperative hydromorphone (0.05-0.1 mg/kg IM or IV) or methadone (0.1-0.25 mg/kg IM or IV), as well as a preoperative incisional infiltration (ie, line block; lidocaine 2%, 4-8 mg/kg, or bupivacaine 0.5%, 1-2 mg/kg). After the procedure, meloxicam (0.2 mg/kg SC) can be administered.

Cats can be given preoperative butorphanol (0.3-0.4 mg/kg IM; ideally followed by buprenorphine, 0.01-0.02 mg/kg IV, during or after surgery due to the mild impact of butorphanol on pain) or methadone (0.1-0.25 mg/kg IM or IV). A preoperative incisional infiltration (ie, line block; lidocaine 2%, 2-4 mg/kg, or bupivacaine 0.5%, 1-2 mg/kg) can also be administered. Postoperatively, patients can be given robenacoxib (2 mg/kg SC).

Before surgery, dogs can be given hydromorphone (0.05-0.1 mg/kg IM or IV) or methadone (0.1-0.25 mg/kg IM or IV). Perioperatively, an intraperitoneal splash block on the ovarian pedicle and uterine stump (lidocaine 2%, 6-8 mg/kg, or bupivacaine 0.5%, 2 mg/kg; doses divided among sites) can be administered.¹³ Postoperatively, meloxicam (0.2 mg/kg SC) can be administered.

Cats can be given preoperative butorphanol (0.3-0.4 mg/kg IM; ideally followed by buprenorphine, 0.01-0.02 mg/kg IV, during or after surgery due to the mild impact of butorphanol on pain) or methadone (0.1-0.25 mg/kg IM or IV), followed by a perioperative intraperitoneal splash block on the ovarian pedicle and uterine stump (lidocaine 2%, 2-4 mg/kg, or bupivacaine 0.5%, 1-2 mg/kg; doses divided among sites).¹³ Robenacoxib (2 mg/kg SC) can be administered postoperatively.

For an intraperitoneal splash block, lidocaine 2% (2-4 mg/kg) or bupivacaine 0.5% (1-2 mg/kg) should be diluted to a total volume of 0.4 to 0.6 mL/kg. Addition of an incisional line block can improve the pre-emptive quality of analgesia. Total lidocaine 2% should not exceed 6 to 8 mg/kg, and total bupivacaine 0.5% should not exceed 2 mg/kg.

Dogs can be given preoperative butorphanol (0.2-0.4 mg/kg IM or IV), dexmedetomidine (1-3 μg/kg IV or 3-10 μg/kg IM), local anesthetic (lidocaine 2% or bupivacaine 0.5%, 0.25-0.5 mL) injected into the center of the testicle with the tip of the needle pointed at the spermatic cord,^14,15 and a line block (lidocaine 2%, 2-4 mg/kg, or bupivacaine 0.5%, 1 mg/kg) along the incision site.

Before the procedure, cats can be given butorphanol (0.3-0.4 mg/kg IM; ideally followed by buprenorphine, 0.01-0.02 mg/kg IV, during or after surgery due to the mild impact of butorphanol on pain) or methadone (0.1-0.25 mg/kg IM or IV), as well as local anesthetic (lidocaine 2% or bupivacaine 0.5%, 0.25 mL) injected into the center of the testicle with the tip of the needle pointed at the spermatic cord.^14,15

Administration of an opioid with an alpha-2 agonist for analgesia and sedation is common in short procedures and patients in which heavier sedation is indicated. Alpha-2 agonists (eg, medetomidine, dexmedetomidine) are commonly used to produce profound sedation; they also provide effective analgesia, presumably via modulation of nociceptive signals at the level of the spinal cord. Alpha-2 agonists have high dosage requirements and adverse effects that prevent their use as sole analgesic agents; however, their analgesic effectiveness is enhanced when combined with an opioid.⁹

Dexmedetomidine as part of an analgesia plan can range from 0.5 to 10 μg/kg IM or IV based on the level of sedation needed and patient status. Lower doses (0.5-5 μg/kg) are administered IV, and higher doses (5-10 μg/kg) are administered IM. The optimal approach is generally to maximize the opioid dose and adjust the alpha-2 agonist dose to fit the patient and level of sedation needed due to the lesser impact of opioids on cardiopulmonary function. Although alpha-2 agonists provide analgesia when used alone, they are not sufficient for most procedures, and an opioid should be included to maximize analgesic benefits.

It is important to note that alpha-2 agonist doses are in μg/kg, not mg/kg.

Preoperatively, local anesthetic (lidocaine 2%, 0.25-0.5 mL) can be injected into the center of the testicle with the tip of the needle pointed at the spermatic cord,^14,15 a line block (lidocaine 2%, 2-4 mg/kg, or bupivacaine 0.5%, 1-2 mg/kg) can be administered along the incision site, and butorphanol (0.2-0.4 mg/kg IM or IV) and dexmedetomidine (1-3 μg/kg IV or 3-10 μg/kg IM) can be administered. After the procedure, meloxicam (0.2 mg/kg SC) can be given.

A preoperative incisional infiltration (ie, line block; lidocaine 2%, 2-4 mg/kg, or bupivacaine 0.5%, 1-2 mg/kg) or perioperative intraperitoneal splash block on the ovarian pedicle and uterine stump¹³ (lidocaine 2%, 2-4 mg/kg, or bupivacaine 0.5%, 1-2 mg/kg) can be administered, along with preoperative methadone (0.25 mg/kg IM or IV) and dexmedetomidine (3-5 μg/kg IV or 5-10 μg/kg IM). Postoperatively, robenacoxib (2 mg/kg SC) can be administered.

For dogs and cats, a preoperative local infiltration of lidocaine 2% can be administered; it may be divided among multiple sites but should not exceed a total of 6 to 8 mg/kg in dogs and 6 mg/kg in cats. Preoperative butorphanol (0.4 mg/kg IV or IM for dogs or cats) and dexmedetomidine (3-5 μg/kg IV or 5-10 μg/kg IM for dogs or cats) can also be administered.

Intraoperative infusion of opioids or nonopioid analgesics as a single bolus or CRI can be a useful adjunct for common surgical procedures. For example, a patient responding excessively to traction on the ovarian pedicle during ovariohysterectomy will not have a rapid response to increased inhalant anesthetic gas. Although the simplest choice may appear to be administration of an additional dose of the premedication opioid, a small dose of ketamine (0.5-1 mg/kg IV) can provide additional analgesia and slightly deepen anesthesia without negatively impacting blood pressure or ventilation. 

Ketamine is an N-methyl-D-aspartate receptor antagonist that is mildly analgesic at subanesthetic doses and can work synergistically with opioids to improve analgesia during acute pain scenarios (eg, surgery). Ketamine can also be administered as a perioperative infusion alone or in combination with an opioid infusion (eg, fentanyl CRI). Lidocaine IV also has analgesic properties and can reduce inhalant requirements in dogs during surgery but is not recommended in cats.¹⁰ Most common surgical procedures are often not long enough to warrant CRI of these drugs.

When traction is placed on the ovarian pedicle or uterus during ovariohysterectomy, a single bolus of ketamine (0.5-1 mg/kg IV) can be administered and repeated every 20 to 30 minutes if a CRI cannot be performed.

If a patient is responding to surgical stimulation and increasing the inhalant is contraindicated due to hypotension, a single bolus of half the premedication dose of a pure mu agonist (eg, methadone, hydromorphone) can be administered.

To reduce inhalant requirements in fragile patients (ie, those sensitive to the negative cardiovascular effects of inhaled anesthetic agents) during longer procedures (eg, orthopedic), fentanyl (2-5 μg/kg IV) and/or ketamine (1-2 mg/kg IV) can be used preoperatively. Fentanyl (5-20 μg/kg/hour CRI) or ketamine (0.5-1 mg/kg/hour CRI) can be administered for maintenance.

Oral analgesia combinations are generally part of a postoperative analgesia plan, but they can also be used preoperatively in patients with painful pre-existing conditions. Potential interactions with perianesthetic analgesics should be considered. For example, buprenorphine oral transmucosal (OTM) likely reduces the initial effectiveness of pure mu agonists that are unable to bind to the receptor occupied by buprenorphine during the 6 hours following buprenorphine administration.

NSAIDs are anti-inflammatory and analgesic, but they are best used as part of multimodal analgesia with other classes of agents (eg, opioids) or other approaches (eg, local and regional anesthesia). NSAIDs are thus not optimal to manage most surgical pain alone. 

Buprenorphine (cats, 0.01-0.04 mg/kg OTM; typically started at 0.02 mg/kg) is particularly useful in cats as an adjunct analgesic that can improve postoperative pain management. This drug is also effective in dogs, but the analgesic dose (up to 0.12 mg/kg OTM) can be cost prohibitive in large dogs.¹¹ One cost-effective option is extra-label use of more concentrated buprenorphine (1.8 mg/mL); this article refers to the buprenorphine 0.3 mg/mL product.

Gabapentin (5-20 mg/kg PO every 8 hours) is an adjunct perioperative oral analgesic agent that can also be used as outpatient treatment in dogs and cats. The mechanism of analgesic action is not well understood but is thought to be via binding voltage-gated calcium channels.¹² Several studies have examined perioperative use of gabapentin for analgesia in dogs and cats, but none have demonstrated evidence of significant analgesia.¹² There is some evidence that gabapentin may improve analgesia when used as an adjunct with NSAIDs or opioids in small animals.¹²

The analgesic combinations described in this article are not mutually exclusive. Procedure type, invasiveness, and duration; pre-existing conditions; anticipated perianesthetic complications; and best practices for anesthesia management should be considered. Opioids, NSAIDs, alpha-2 agonists, other analgesic infusions, and other oral drug combinations should be selected to achieve optimal perianesthetic pain management, and local anesthesia should be part of multimodal analgesia when possible.