Pain management in veterinary medicine has long been a difficult subject, both from the aspect of knowing when to treat and also knowing how to treat. Multiple studies have tried to determine attitudes toward analgesia and also compliance in administration of anesthetic agents. Interestingly, a recent study found that 98% of owners thought that pain management post operatively was very important or somewhat important, indicating that pain management is crucial in maintaining good client relationships as well. Most research on pain management has examined pain post operatively, as these are somewhat more controlled situations than spontaneous disease; however, most of these studies have examined elective surgeries such as ovariohysterectomy or forelimb onychectomy. Few studies have examined the treatment of ocular pain, although it is clear that the eye, its adnexa, and orbit are richly innervated with sensory nerves, which implies a high potential for pain with ophthalmic disease and surgery.

Pain is defined as an "unpleasant sensory and emotional experience associated with actual or potential tissue damage." Multiple studies in both humans and animals show that successful pain management results in improvement of immune system function, the stress response associated with surgery, decreased hospital stays, decreased intensity of chronic pain, and decreased rate of cancer metastasis. Most veterinarians agree that animals need analgesics, however, some studies suggest that only around 50% to 60% of veterinarians in the United States, Canada and Britain actually administer pain medications after surgery. The challenge of evaluating pain in animals is one cause of this phenomenon of under-medicating veterinary patients. Physiologic outcome variables, including heart rate, respiratory rate, blood pressure, and pupillary mydriasis have been shown to correlate poorly, or not at all, with subjective pain measurements. To complicate matters further, these variables can be altered by analgesia. Therefore, the best way to evaluate pain in animals is through consistent, subjective observation and interpretation of pain-related behaviors.

Another common reason for analgesics to be withheld, or under dosed, is the fear of side effects. Opioids are generally safe and effective, however, many practitioners have concerns about cardiopulmonary depressions, and at times, the sedation may be frustrating to those in a busy private practice doing outpatient surgeries. In ophthalmology in particular, effective pain management through pre-emptive analgesia with opioids may be avoided due to fears of pupillary constriction. For procedures such as phacoemulsification, pre-emptive analgesia would helpful to prevent the establishment of central sensitization. Pre-emptive analgesia with NSAIDs is often used, however, many ophthalmology patients are geriatric, with multiple medical issues that may preclude treatment with NSAIDs. Therefore, to effectively treat ophthalmic pain, one should have a variety of drugs and delivery methods for the variety of procedures and the spectrum of patients treated. The purpose of this lecture is to provide a review of studies done specifically with ocular procedures in small animals.

Studies on Pain Management Post Enucleation

We have performed two studies on pain management post enucleation at University of Wisconsin. Both were randomized, masked prospective clinical trials in dogs.

In the first study, the efficacy of hydromorphone 0.2 mg/kg IM alone at extubation vs hydromorphone 0.2 mg/kg IM plus carprofen 4mg/kg IM at extubation with additional carprofen 2.2 mg/kg PO BID for 3 days post operatively. Twenty-two client-owned dogs were admitted for enucleation due to a painful ocular disease. No dogs had systemic analgesics or anti-inflammatory medications within 48 hours prior to surgery, and had no other painful conditions. Additionally, the dogs had no concurrent disorders for which study drugs would be contraindicated. All dogs had an identical anesthetic protocol (including pre-medication with 0.2 mg/kg hydromorphone), routine monitoring, and received a transpalpebral enucleation performed by a veterinary ophthalmologist or veterinary ophthalmology resident. A cumulative pain score above a minimum acceptable threshold of pain at any time point was considered treatment failure and warranted rescue hydromorphone. Again, the rescue point was determined by our assessment of what constituted mild pain versus moderate to severe pain that required treatment. To obtain additional follow-up on patient comfort and recovery, the owners of participants were contacted by telephone on days 3 and 7 postoperatively. The owner's impression of cumulative patient pain score was collected through an interview based on the scoring method. A single masked observer measured comfort/attitude, movement, appearance, unprovoked behavior, interactive behavior, vocalization, heart and respiratory rates at presentation, before and after pre-medication, at extubation (t = 0) and then at 30 minutes, 1, 2, 4, 6, 8, 12, 24, 36 and 48 hours. ANOVA was done between scores over time points within treatment groups and across treatment groups at corresponding time points.

Pain scores decreased from the initial score to 48 hours post enucleation in both groups. There was no significant difference between groups at any time point. Two dogs were rescued in the hydromorphone only group and one dog was rescued in the carprofen group. All dogs were rescued in the first 24 hours post operatively. There was no difference in owner assessed pain scores between groups, but owner assessed pain scores decreased significantly from initial presentation to postoperatively. This data suggests that enucleation is successful at alleviating pain independent of the post-operative analgesic regimen. Although not significantly different, the need for more rescue doses in the control group does suggest that adjunctive anesthesia may be useful in the postoperative period.

In a second study, a similar design was used to compare pre-medication with hydromorphone to pre-medication with hydromorphone and retrobulbar injection of bupivacaine. Twenty-two client-owned dogs were admitted for enucleation due to ocular disease. Dogs were excluded if they had any other condition that could be a source of pain. All dogs had similar anesthetic protocols, including pre-medication with 0.2 mg/kg hydromorphone, and routine monitoring.

In brief, retrobulbar injections were done with a 1.5 in spinal needle, inserted at the inferior orbital rim at the junction of its middle and temporal thirds. The needle is advanced until a slight popping sensation is detected, indicating piercing of the orbital fascia. The needle is then directed toward the apex of the orbit (slightly dorsally and nasally) 1–2 cm. The stylet is withdrawn, gentle aspiration performed to make sure the needle is not in a blood vessel, and the injection is made. This technique is contraindicated if orbital disease is present. See Accola PJ, JAVMA, 2005 for more information.

Patients were randomized to two groups, a control group which received hydromorphone as a pre-medication and a saline retrobulbar injection and a treatment group which received hydromorphone as a pre-medication and a retrobulbar injection of 0.5% bupivacaine dosed at 2mls for patients up to 15 kg, and 3 mL for patients > 15 kg (less than 2.0 mg/kg). Individuals administering the drug were masked to therapy. Patients were monitored at set time points postoperatively and pain scored by one of two trained, masked observers. Rescue analgesia, hydromorphone, (0.2 mg/kg IM q. 2–4hrs.) was administered as needed through 30 hours postoperatively as indicated (see above). Pain scores were assessed at initial presentation (12–24 hrs. preoperatively, at ophthalmic examination), before pre-medication, at extubation (t = 0), 15 and 30 minutes, and 1, 2, 4, 6, 8 and 24 hours postoperatively.

Breed, sex and age were similar across the two groups. Again, pain scores decreased over 24 hour following surgery. Only one dog in the retrobulbar bupivacaine group was painful enough to warrant rescue, while 8 dogs in the saline injection control group were rescued. Six of the eight rescued control dogs were painful enough at the 15 minute time point to warrant rescue, the seventh dog was rescued at 1 hour, and the eighth dog was rescued at 2 hours post extubation. Interestingly, no dogs in either group required rescuing after the 2 hour time points, even though monitoring continued through 24 hours postoperatively, and both hydromorphone and bupivacaine should have worn off 4–8 hours post operatively. This study suggests that retrobulbar injection of bupivacaine provides good analgesia throughout the postoperative period, and is a good alternative that avoids systemic side effects associated with many other analgesic agents.

Topical Nalbuphine versus Oral Tramadol for the Treatment Corneal Pain

We have just completed a study examining the use of topical nalbuphine for corneal pain. Previous studies have shown the efficacy of topical morphine for the treatment of corneal pain post keratectomy, but as a controlled dogs, many veterinarians sought a non-controlled substance. Nalbuphine is a non-controlled, mixed opioid agonist/antagonist, which may have some analgesic effects when use parentally, and was shown to decrease corneal sensitivity in normal canine eyes. Tramadol is a centrally acting analgesic whose efficacy is the result of complex interactions between opiate, adrenergic, and serotonin receptor systems.

In this study, we created 5mm corneal erosions in the right eye of 14 male laboratory Beagle dogs, after performing complete ophthalmic examinations, including slit lamp biomicroscopy, indirect ophthalmoscopy, Schirmer tear testing, fluorescein staining and applanation tonometry. Dogs were randomized to one of three groups: topical saline TID (control, n = 4), topical 1.2% nalbuphine TID (n = 5), and oral tramadol TID (n = 5, ~ 4 mg/kg). Additionally, all dogs were treated with gentamicin TID, the tramadol group was treated with topical saline TID, and the nalbuphine and saline groups received an oral placebo. Dogs were sedated with dexmedetomidine and then reversed with atipamezole. Dogs received medications as soon as they were able to swallow, and this time was recorded as time 0. Dogs were pain scored at 1, 2, 4, 6, and then q6 hours until healed. If pain score were above what we considered minimally painful, they were rescued with IM morphine (1 mg/kg IM). All dogs healed by 72 hours post wounding, and no differences between time to healing was noted.

Four of the five nalbuphine dogs were painful enough to warrant rescue within the first 12 hours (2 rescued at 6 hours, 2 rescued at 12 hours, one dog rescued a second time at 18 hours). Two of four saline dogs were rescued within 12 hours (1 rescued at 2 hours and again at 18 hours, 1 at 12 hours). One of the five dogs receiving tramadol was rescued once at 2 hours. This data suggests that nalbuphine is may be contraindicated in male intact dogs, and tramadol is a reasonable choice for analgesia in corneal pain.

The increased number of painful dogs on nalbuphine is an intriguing finding. Previous work has demonstrated that men receiving low dose nalbuphine orally actually experienced greater pain than men receiving a placebo, although a higher dose produced analgesia. This antianalgesic effect was not noted in women in the same study. A separate study determined that rats do not have this sex differentiated response to nalbuphine. Since our study utilized male dogs, it is possible that in fact, dogs do demonstrate a gender specific response to nalbuphine. A second possibility is nalbuphine may have an antianalgesic effect when used topically in the dog. Either possibility suggests that nalbuphine may not be a good first choice for corneal analgesia treatment.

Conclusions

Taken together, several conclusions can be drawn from the studies above. First, it appears that aggressive treatment of ocular pain in the first 24 hours after surgery, and potentially injury, may be very effective at controlling ocular pain in dogs, based on most dogs only needing rescue medications in the first 12 to 24 hours postoperatively. Second, since some placebo dogs never appeared to be particularly painful, ocular pain may not be quite as severe as we imagine. Given that dogs have a corneal sensitivity that is approximately half that of humans, this conclusion is a possibility, but must be made very carefully. Additionally, placebo controlled spay/neuter studies have also shown that some animals do not seem to be particularly painful. Given how well animals mask pain, however, it is important to assume that all patients are feeling some degree of pain with surgery and most diseases. Another factor that likely plays a role in the enucleation studies is that most dogs have eyes removed due to painful ocular diseases, often with inflammatory components. Recent research has focused on the presence of endogenous analgesic systems, often involving leukocytes and opioids and their receptors. Once the painful eye has been removed, these endogenous systems likely blunt the pain response due to surgical trauma, leading the rapid recovery noted in most dogs post enucleation.

Evidence based medicine should be a starting point for the management of individual clinical patients. However, each individual patient will respond to pain differently, and therefore, each pain management plan should be designed for that individual patient. Oral and topical opioids and opioid derivatives are logical places to start, and are usually considered the 'gold' standard for pain relief. Local anesthesia is likely underutilized in veterinary ophthalmology, and can provide safe and effective analgesia. NSAIDs also play an important role, particularly as safer forms are developed. Discussing pain management with the client and encouraging them to play a role in both formulating and changing the plan is likely to be equally important as which drug you choose initially. Prescribing a drug for pain relief is only the first step-following the patient to ensure that drugs are actually helping is the second and more important step.