Analgesia Beyond Opioids: Reevaluating Pain Management in a Changing Landscape

Human and veterinary medicine currently use a pain management model that focuses on opioids as the primary treatment for most painful conditions. In the human medical setting, opioid therapy has opened the door to potential abuse, addiction, overdose, and death, and the current public health crisis surrounding opioids has brought opioid-centered pain management into the worldwide spotlight. In 2017, the U.S. Drug Enforcement Administration began working to mitigate this crisis by implementing annual decreases in opioid production.¹ These decreases primarily target full µ-agonist opioids, such as morphine, fentanyl, and hydromorphone. As of 2020, the production of some drugs, such as hydrocodone and oxycodone, had been reduced by 65% to 75%.²

Realistically, many veterinary anesthesia, surgery, and pain management cases will still require some form of opioid analgesic therapy, but veterinary medicine is moving analgesia beyond just opioids. The future of analgesia involves embracing multimodal approaches that include nonopioid drugs like N-methyl-D-aspartate (NMDA) antagonists, locoregional analgesic drugs, and nonsteroidal anti-inflammatory drugs (NSAIDs), as well as pain scoring systems to evaluate true analgesic need and effectiveness.

The Pain Pathway

To create a multimodal analgesia plan, it is necessary to understand the pain process and the tools to best target it. Pain is complex and multifactorial, and poorly managed pain has many sequelae: impaired healing, infection, hyperalgesia, and changes to the central nervous system (CNS).³ A pain score should be part of every temperature, pulse, and respiration assessment (see Pain Scoring sidebar).

The “pain pathway” is a figurative representation of the course noxious stimuli take from the moment of inception to the point of comprehension. It is divided into 4 parts: transduction, transmission, modulation, and perception (BOX 1).

Analgesics work to modify, downregulate, or eliminate painful stimuli felt and transmitted throughout the pain pathway. Different analgesic drugs work on different parts of the pathway. Individual drugs may work on multiple parts, but no single drug covers the entire pathway (TABLE 1). Multimodal analgesia uses multiple drugs at lower doses to cover all parts of the pain pathway.⁶

Opioids: The “Old” Gold Standard

Opioids are considered the gold standard in pain management because they interact with 3 of the 4 areas of the pain pathway: transduction, modulation, and perception. Many nonopioid analgesics also work in 2 or 3 of those areas; therefore, opioids do not have to be the only analgesic tool. The addition of nonopioid analgesics to a pain management protocol can reduce or eliminate the need for opioids in some situations.

Opioids are described based on their effects on µ receptors and κ receptors (TABLE 2). The µ receptors are located throughout the CNS and gastrointestinal (GI) tract. These receptors are responsible for central interpretation of pain. Pure opioid agonists (often referred to as “µ opioids” because they activate the µ receptors most strongly) provide moderate to heavy analgesia and are appropriate for many situations. While they do cause dose-dependent respiratory depression, true respiratory depression associated with µ opioids typically only occurs with very high doses. The κ receptors are located throughout the brain, spinal cord, and peripheral sensory neurons. Agonist–antagonist opioids or partial agonist opioids (sometimes referred to as “κ opioids”) provide mild to moderate analgesia. Unlike pure opioid agonists, agonist–antagonist opioids tend to cause minimal respiratory depression, minimal physical dependence, and only some dysphoric effects.

Opioids are commonly administered as a systemic injection for preoperative, postoperative, or chronic pain states. They can be delivered as part of a locoregional block or constant-rate infusion (CRI). These applications allow for titration and decrease in overall usage. Opioids are associated with side effects (BOX 2); however, these effects serve as a reason to use opioids with caution and are not a contraindication to using opioid analgesic therapy as warranted.⁷

Multimodal Analgesia

Multimodal analgesia is the concept of combining lower doses of analgesic drugs to better cover more parts of the pain pathway. Lower dosing often results in fewer side effects, and drug combinations offer more comprehensive analgesia.

A combination of NSAIDs; anticonvulsants (specifically gabapentin); locoregional anesthetic blocks; and CRIs including NMDA antagonists, α₂ agonists, and sodium-channel blockers can provide effective multimodal analgesia.

Regardless of the drugs being used, it is important to be familiar with their benefits and drawbacks. When working with a less familiar drug or protocol, consider cautious dosing and extra vigilance.

NSAIDs

NSAIDs include carprofen, etodolac, meloxicam, ketoprofen, deracoxib, robenacoxib, tepoxalin, and acetylsalicylic acid (aspirin). The appropriateness of each agent depends on the species being treated. Cats, in particular, are limited to robenacoxib and meloxicam, while a wider variety of agents can be used in dogs.

NSAIDs act to mediate inflammation and work well as part of a multimodal plan addressing mild to severe pain. They can be a beneficial addition to many analgesic plans in patients without GI or renal insufficiency. NSAIDs are long acting, inexpensive, and readily available. Studies in human medicine have demonstrated that the addition of NSAIDs to analgesic protocols led to quicker inpatient discharge.⁸ There is also evidence of a decrease in postoperative nausea and vomiting with NSAID use, likely a result of decreased opioid administration.⁸

NMDA Receptor Antagonists

Ketamine, gabapentin, and amantadine work at NMDA receptor sites and have applications in treating neuropathic pain. Ketamine can be added to many parts of an anesthetic plan: premedication, induction, and intraoperative CRI. Ketamine has been shown to be useful in mediating wind-up pain, hyperalgesia, and chronic pain.

Gabapentin is an anticonvulsant used in veterinary medicine to treat chronic and neuropathic pain. Use of gabapentin has expanded to include treatment of pain and anxiety, though studies show mixed results in various species.⁹ The mechanism of action is not well understood, but it is thought to inhibit or decrease the release of certain neurotransmitters. Gabapentin is readily available and generally considered safe but may cause sedation. It is currently not a controlled drug federally, although this status may change.

Amantadine is an antiviral drug originally used to treat dyskinesia associated with Parkinson’s disease. It is an NMDA antagonist and dopamine agonist, working as an adjunctive medication. Often synergistic with opioids, NSAIDs, and gabapentin, this medication tends to be an “add-on” for well-managed pain or pain that is increasing despite an analgesic regimen. Amantadine is often used in oncology patients or those with unmanageable orthopedic pain.⁹

Local and Regional Analgesia

Locoregional anesthesia comes in many forms: epidurals, brachial plexus blocks, paravertebral blocks, incisional blocks, ring blocks, and line blocks, to name a few. Local anesthetics are a remarkable class of drugs that completely inhibit the transmission of the pain signal, thus preventing perception of the stimulus. Through this mechanism, local anesthetics can provide intense analgesia.⁴

In human medicine, locoregional analgesic techniques are used in many surgical procedures. The addition of these techniques has been shown to decrease persistent postoperative pain compared with cases not using locoregional blocks.¹⁰ This effect has also been demonstrated in veterinary medicine: A study reviewing pain scores of 26 dogs randomly assigned to 2 groups undergoing thoracotomy (one receiving only buprenorphine, the other receiving a bupivacaine intercostal block) found pain scores were demonstrably lower in those receiving local nerve blocks.⁴

Primary concerns with local anesthetics are related to toxicity. This situation arises most commonly with incorrect drug calculations or rapid IV boluses of the drug. It is essential to carefully calculate the local anesthetic dose, taking into account any other doses that may have been given. This specifically highlights the need for good communication between services. If the anesthesia service is doing an epidural with a local agent and the surgical team uses a local anesthetic for closure, it will be necessary to determine total drug doses to prevent accidental overdose. To prevent accidental intravenous administration, best practice dictates aspirating the syringe to confirm absence of blood in the needle.

Local anesthetic duration can be 2 to 72 hours, depending on the chosen agent (TABLE 3).⁵ Once the local anesthetic wears off, rebound pain can be significant; therefore, these drugs should be part of a multimodal approach. It is also good practice to score pain during the postoperative phase to establish a baseline and catch potential rebound effect immediately.

Local blocks are highly versatile and can be used in many situations and across species. Some examples are illustrated in FIGURES 1 THROUGH 4.

Figure 1. Marmoset in dystocia receiving a bupivacaine–morphine epidural. The patient was exceptionally critical; the locoregional block allowed use of lower inhalant levels and decreased doses of systemic drugs.

Figure 2A. Nasal biopsy in a cat, post–ropivacaine block. The patient received bilateral infraorbital blocks using ropivacaine. Using the local blocks allowed for easier sample collection and increased patient stability.

Figure 2B. The monitoring display for the same patient shows vital parameters demonstrating absence of pain midbiopsy.

Figure 3. Lidocaine incisional block of a mammary tumor in a guinea pig. Guinea pigs are hindgut fermenters and can be sensitive to the gastrointestinal effects of both opioids and pain. Utilizing a lidocaine incisional block allowed for decreased inhalant levels and opioid usage.

Figure 4. Lidocaine testicular block for an equine castration. Like guinea pigs, horses are hindgut fermenters and may be sensitive to ileus from opioids. Additionally, due to their size, horses may recover poorly when waking up in pain; a local block may decrease required inhalant and opioid usage and lead to a smoother recovery period.

Constant-Rate Infusions

CRIs are both inhalant and opioid sparing. Lidocaine, ketamine, and dexmedetomidine are used as CRIs perioperatively and into the postoperative period (TABLE 4). Each provides adjunctive analgesia, working synergistically within the multimodal plan.

Lidocaine works in part by blocking sodium ion channels. It can reduce the amount of opioids and inhalant needed for anesthesia. Lidocaine is inexpensive and has antiarrhythmic and anti-inflammatory properties. It may be useful in cases involving visceral pain or GI motility (FIGURE 5). However, cats have increased myocardial sensitivity to local anesthetics; therefore, it is not recommended to use lidocaine infusions in cats.

Figure 5. Rabbit receiving a lidocaine constant-rate infusion after laparotomy to manage gastrointestinal pain and encourage gastric motility.

Ketamine works by antagonizing the NMDA receptors responsible for central sensitization, hypersensitization, and wind-up pain. Ketamine may not provide complete analgesia on its own, but when used as part of a multimodal approach, it can lower anesthetic and opioid requirements (FIGURE 6).

Figure 6A. Cat prepared for perineal urethrostomy procedure. The patient was extremely painful and received a morphine–bupivacaine epidural and a ketamine constant-rate infusion.

Figure 6B. Image of monitor for same patient showing vital parameters indicating comfort with the multimodal plan.

Dexmedetomidine has analgesic, anxiolytic, and sedative properties. It works by simulating α₂ receptors in the CNS. Dexmedetomidine CRIs are commonly used intraoperatively to reduce minimum alveolar concentration of inhalant agents. Dexmedetomidine can be added as a postoperative CRI or used in microdoses to decrease stress and anxiety in recovering patients.¹¹

Postoperative Care

Postoperative nursing care is often minimized in discussions of pain management, but its importance cannot be overemphasized. Patients that are kept clean and comfortable appear to need less opioid-assisted pain control. Nursing care includes timely medication administration, bladder management, bandage care, eye lubrication, position rotation, and patient interaction.¹² Other considerations include easy access to food and water, as well as managing nutritional considerations. While more difficult to quantify, basic compassionate care such as grooming, stroking, and individual interaction can go a long way toward improving patient morale.