Transoperative pain management: A framework

Pain can be protective, but through the stress response it also may make significant contributions to patient morbidity and even mortality. A recent study in humans, for example, revealed that in people undergoing routine ambulatory surgery, persistent pain will be experienced by 10 percent to 50 percent of patients, and the chronic pain will be severe in 2 percent to 10 percent of these individuals.1

Thus, the priority clinicians should place on pain management in the acute and perioperative setting is not just to minimize discomfort but to prevent, insofar as possible, the potential for any chronic pain syndrome.

Mark E. Epstein, DVM, Dipl. ABVP, AAPM, CVPP

A foundation of effective pain management is the use of multiple modalities, which allows for intervention at several different places along the nociceptive pathway. This can not only improve patient comfort but minimize the need for high or protracted doses of any one particular drug.

For example, it is well-established in human medicine, that using adjunct medications will minimize the use of patient-controlled analgesia (opioids), resulting in a decreased incidence of adverse effects such as nausea and constipation and an earlier exit from the hospital.2-5 And the U.S. military concluded in a recent landmark analysis, "Multimodal therapy encompasses a wide range of procedures and medications, including regional analgesia with continuous epidural or peripheral nerve block infusions, judicious opioids, ... anti-inflammatory agents, anticonvulsants, ketamine, [alpha-2 agonists], ... antidepressants, and anxiolytics as options to treat or modulate pain at various sites of action."6 So, with a more aggressive, acute pain management strategy, the military decreased acute and chronic pain conditions, which may have application in the civilian sector, too.

The need for a framework

The good news is that veterinary clinicians have a vast array of possible pharmacologic interventions. The bad news: Clinicians are faced with a vast array of possible pharmacologic interventions. That is, of all the possibilities, what should any one patient receive? At what dose, or in what combination? How often and for how long? And many clinicians remain uncertain or uncomfortable with polypharmacy, concerned with matters such as possible drug interactions, adverse effects, cost and managing scheduled drugs.7

Proposed here is a framework of transoperative pain management—preceding the incision, through the surgical period itself and into the recovery period. By definition, it cannot be a one-size-fits-all strategy, because there's no such thing. Rather, it's a scaffold upon which clinicians can structure the pain management needs of most every patient.

While there is no metric to evaluate the quality of pain management across veterinary practices, previous studies have demonstrated a tendency toward the underuse of strong opioids and locoregional anesthesia.8 Also, while use of nonsteroidal anti-inflammatory drugs (NSAIDs) remains widespread and fairly ubiquitous, over-reliance on this class of drugs alone likely would not only undermanage some (perhaps many) patients for their pain, but could increase the possibility of NSAID-induced adverse effects. In contradistinction, using a combination of antianxiety medications, strong opioids and locoregional anesthesia in addition to NSAIDs would elevate a practice's pain management strategies to the top tier.

Anxiolytics

Anxiety appears to contribute directly to the hyperalgesic state through a cholecystokinin-mediated "nocebo" effect.9 That is, pain is to be expected after surgery, but in humans, anxiety and anticipation of pain enhance pain sensitivity. And in many animal studies, hyperalgesia has been shown to be induced by restraint, novelty, rotation and social defeat10 —all of which occur during a pet's stay in the hospital for surgery. This highlights the important role anxiolytics can play to mitigate the postoperative pain experience.

From a pharmacological perspective, this refers to phenothiazines such as acepromazine, benzodiazepines such as midazolam and alpha-2 agonists such as dexmedetomidine. Nonpharmacologically, this can refer to the patient's entire experience, from the admissions process, to restraint for lab samples and catheter placement, to the environment in which the animal is held. So the first step in the transoperative pain management process occurs during or shortly after admission: handling the patient in the most calming manner and place possible and administering anxiolytics as early as feasible during the preoperative timeframe.

NSAIDs

The primary mode of action of NSAIDs is to inhibit cyclooxygenase-2 (COX-2), the enzyme that's expressed at the site of inflammation and results in the production of proinflammatory and vasoactive prostaglandins. Since tissue damage from surgery invariably leads to inflammatory pain, NSAIDs are clearly indicated. But also, through poorly understood mechanisms (likely by modulating multiple gene-expression pathways11 ), they appear to inhibit central perception of pain.

Several superior products are now labeled for use in dogs (and some in cats, including the new product robenacoxib), making them among the most popular pain management medications in veterinary medicine. All seem to be effective, though not all will be equally effective for every patient.

The main limitation of all NSAIDs revolves around the potential for adverse effects, because both COX-1 and COX-2 enzymes may be constitutive, that is, consistently present and crucial to the production of cytoprotective prostaglandins (COX-1 in the gastrointestinal (GI) tract and renal tubules, especially; COX-2 in the renal tubules). Thus, the primary adverse effects of nonselective NSAIDs may include GI erosion/ulceration and nephrotoxicosis. COX-1–sparing NSAIDs should have a dramatically diminished GI toxicity profile but will maintain their risk for nephrotoxicosis, especially in low-flow states (COX-2 upregulates in the renal tubules with local hypotension). Rarely and on an idiosyncratic basis, hepatotoxicosis may occur.

The GI and renal adverse effects can be expected to occur most commonly in higher risk patients, such as those with hypovolemia, hypotension (including anesthetic procedures, especially those unsupported by intravenous fluids) or preexisting GI or renal disease; overusage or an inappropriate combination with other NSAIDs or corticosteroids. Notable in this last category is client administration of aspirin to their pets, which may be unbeknownst to the clinician unless specifically queried in a thorough history. Unique to aspirin, this NSAID produces a cytoprotective lipoxin through the COX pathway,12 so when COX is inhibited through the use of another concurrently given NSAID, the potential for GI toxicosis is increased considerably.

The relative roles and molecular dynamics of COX-1, COX-2 and a possible new variant COX-1b, are still being elucidated. The final word on the optimal COX-selective or COX-sparing effect to maximize effectiveness and limit toxicity is yet to be heard. With any use of NSAIDs, the potential for adverse effects needs to be made clear to pet owners (including to withhold the drug in the event of vomiting or inappetence, usually the first signs of gastropathy), and the avoidance of concurrent NSAIDs or corticosteroids before and after surgery needs to be a prime point of client education.

Whether to administer NSAIDs preoperatively or postoperatively remains a clinical choice. Evidence of superior efficacy can be ascribed to dogs when given preoperatively,13 but some clinicians choose to administer in the postoperative period only, out of an abundance of caution to further minimize the potential for adverse effects. In either event, transoperative intravenous fluids are considered a customary precaution to take in every anesthetic event.

Opioids

Opioid receptors are distributed ubiquitously throughout the body and can be found in most central and peripheral tissues. Several opioid receptor types and subtypes have been isolated, each with a variant effect; activation of an opioid receptor inhibits presynaptic release and postsynaptic response to excitatory neurotransmitters. The resulting effect is greatly impeded nociceptive transmission.14

Several opioid drugs are available that vary in their relative potency and receptor affinity. Of the pure mu agonists, morphine remains the prototype in widest use; it has no ceiling effect on analgesia or respiratory depression, elicits histamine release and causes vomiting at low doses. (Higher doses, intravenous administration and chronic use don't elicit vomiting, presumably by interaction with mu receptors in the antiemetic center.15 )

Cats lack glucuronate metabolism, resulting in minimal production of the analgesic M6G metabolite16 ; therefore, morphine may not be the ideal opioid for use in this species. Oxymorphone and hydromorphone cause minimal histamine release (and, therefore, may be wiser choices in cases of hypovolemia, such as trauma or dehydration), and nausea may be less pronounced. But they have a shorter duration of action than morphine. Also, hydromorphone in particular is implicated in episodes of hyperthermia in cats.17

Fentanyl is a short-acting intravenous opioid commonly administered as a constant-rate infusion. A fentanyl transdermal patch remains useful in veterinary medicine, though studies have demonstrated wide kinetic variability in veterinary patients due to such factors as species, body condition score, body temperature, surgical procedure and where and how well the patch is placed.18,19

Buprenorphine is a partial agonist on the mu receptor, though it has greater affinity for it than morphine (and will displace it if given together). A great benefit of the drug in veterinary medicine is that its pKa (8.4) closely matches the pH of the feline oral mucosa (9.0). This allows for nearly complete absorption when given buccally in that species,20 with kinetics nearly identical to intravenous and intramuscular administration,21 and eliciting very little sedation.

Butorphanol is a partial mu antagonist and a kappa agonist; its short duration of action in dogs (30 to 40 minutes22 ) and minimal analgesia23 make it a poor choice for an analgesic in this species, though when used parenterally, it has utility as an adjunct with other medications such as alpha-2 agonists.

For all their effectiveness, opioids may create clinical challenges. In the acute setting, opioid-induced dysphoria, hyperalgesia and respiratory depression (though this appears to be a much greater hazard in people than in dogs and cats) may be encountered. Recognizing and having strategies for counteracting these effects will minimize the complications they present.24 However, the most effective way to avoid opioid-induced adverse effects is to develop opioid-sparing strategies. This is precisely the goal of a multimodal approach: using several modalities so the use of any one can be minimized. Opioids customarily are administered preoperatively in combination with anxiolytics as described earlier. They can be followed postoperatively with subsequent doses or constant-rate intravenous infusions, if indicated.

Locoregional anesthesia

Local anesthetics were once a mainstay of pain management in veterinary medicine and may now be one of the most underused modalities. The effect of properly administered local anesthetics can be complete anesthesia to a site rather than mere analgesia or hypoesthesia. Further, local anesthetics have also been shown to have anti-inflammatory25 and antimicrobial26 activity.

Local anesthetics have variable onsets and durations of action, and they may be combined for a rapid and extended effect. The locality of administration often is limited only by a clinician's ability to learn various utilities and anatomic landmarks; few are outside the scope of any clinician to master. Consider some of the following types of locoregional anesthesia:

• Local line, paraincisional27 and subcutaneous infiltrative blocks

• Carpal radial, ulnar, median (RUM or Ring) nerve block28

• Dental (orofacial) nerve blocks

• Intracavitary (abdominal, thoracic) infusions

• Intercostal nerve blocks29

• Testicular blocks30

• Intra-articular blocks31

• Retrobulbar blocks32

• Brachial plexus blocks33

• Epidurals

• Intravenous regional anesthesia (Bier blocks)34

Use of subcutaneous diffusion catheters is a locoregional technique now well-established in people to reduce both static and dynamic postoperative pain, and it is opioid- and hospitalization-sparing.35 This technique is finding increasing traction in veterinary medicine; commercial diffusion catheters are available (recathco.com, milaint.com) or can be fashioned out of 5-F red rubber catheters.

Best of the rest

Many, if not most, practices use one or more of the above modalities for surgical patients. But a practice that uses all four of these modalities for each surgical procedure is providing superior pain management to patients. These four modalities form the foundation of any transoperative protocol. Building on this foundation, various additional tools can further enhance patient comfort, reduce hyperalgesia and perhaps minimize the likelihood of chronic pain states. The following are among the easiest to adopt.

• Topical prilocaine-lidocaine: Commercial transdermal products are useful in facilitating catheter placement and for minor procedures involving the dermis and epidermis. And 5% lidocaine patches (Lidoderm [Endo Pharmaceuticals], manufactured and labeled for post-herpetic neuralgia such as shingles) can provide postoperative wound paraincisional analgesia.36

• Tramadol: This is a synthetic, nonscheduled (for now) opioid whose active M1 metabolite in humans has 1/100th of the affinity for the mu receptor as morphine but a much better analgesic effect than this would predict.37 This is likely due to the combined effect of serotonin and norepinephrine (NE) (both inhibitory neurotransmitters) agonism. However, recent work demonstrates that dogs make little of the M1 metabolite,38 so in dogs the primary pain-modifying potential may be found in the serotoninergic and noradrenergic effect. Furthermore, it appears to have a short half-life (1.7 hours) in dogs,39 so for 24-hour effectiveness, it might need to be given as often as every six hours. Only in the past year have studies appeared to confirm an antinociceptive and analgesic effect in dogs.40,41 Tramadol should not be used with other serotoninergic medications such as tricyclic antidepressants.

• Alpha-2 agonist: Medetomidine and dexmedetomidine bind opioid-like receptors on C- and A-delta fibers, especially in the central nervous system. When binding presynaptically, NE production is reduced and sedation occurs; binding postsynaptically, analgesia is produced and is profoundly synergistic with opioids. It also blocks NE receptors on blood vessels, resulting in vasoconstriction. The resulting hypertension parasympathetically induces bradycardia, which is extended by a subsequent direct decrease in sympathetic tone. However, central perfusion is maintained, and I have found a wide use for these alpha-2 agonists in acute and perioperative settings, though only in combination with opioids and at doses much lower than those suggested by the manufacturer. Anecdotally, one particularly novel and user-friendly utility is intravenous microdoses (0.25 to 1 µg/kg) given intraoperatively and postoperatively. This may result in intravenous volumes of only 0.01 to 0.03 ml in even the largest of dogs and approximates a "bolus" dose of the constant-infusion rate reported for dogs.42

• Ketamine: This is a dissociative anesthetic, and the evidence is strong for its pain-preventive effects when given at subanesthetic doses in an intravenous constant-rate infusion. Ketamine binds to a phencyclidine receptor inside the NMDA receptor (note, the calcium channel would have to already be open and active for ketamine to exert its effect). But once bound, it decreases the channel's opening time and frequency, thus reducing calcium ion influx and dampening secondary intracellular signaling cascades. Hence, it's unlikely (and has not been shown) to be truly analgesic in nature. Rather, it appears to be protective against hyperalgesia and central hypersensitization postoperatively,43 including in dogs.44

• Gabapentin: Labeled for use as an anticonvulsant drug, gabapentin is widely used in people for its analgesic properties. Its primary pain-modifying effect appears to be through its interaction with the alpha-2-delta subunit of the voltage-gated calcium channel.45 Although in veterinary medicine it's most often considered to treat chronic pain, the human literature is replete with data regarding its utility in the perioperative setting (often just a single dose before and after surgery). In a study of women undergoing hysterectomy, only the patients receiving both an NSAID and gabapentin were completely satisfied with their postoperative pain management when compared with women receiving either an NSAID or gabapentin alone.46 And in a meta-analysis of 896 patients undergoing various surgical procedures, gabapentin significantly reduced pain both four and 24 hours postoperatively when compared with placebo.47 The preoperative and postoperative oral administration of gabapentin has begun to gain traction among some veterinarians. However, a study of gabapentin in dogs failed to demonstrate a positive postoperative pain-modifying effect,48 although the design may have prevented detecting such an effect. Pharmacokinetic studies in dogs show a half-life of three to four hours,49 suggesting a two- or three-times-daily administration schedule if dispensed postoperatively. The primary adverse effect in dogs appears to be somnolence (as in people).

Conclusion

The construction of a comprehensive, multimodal approach to surgical patients is within the reach of any clinical practice. The fundamental elements generally include, insofar as possible, anxiolytics, opioids, local blocks and NSAIDs, with additional modalities used at the clinican's discretion. Pain management systems so constructed would likely find themselves in the top tier of veterinary practices.

Dr. Epstein is president of the International Veterinary Academy of Pain Management and medical director at the Total Bond Animal Hospital in Gastonia, N.C.

References

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