Pain issues and management in veterinary dentistry and oral surgery: Part 2 (Proceedings)

Part II discusses some of the common agents used for managing pain associated with oral surgery in dogs and cats. There are six classes of agents discussed and they are the opiods (opiates), the cox-2 selective NSAID's, the 5-Lox selective NSAID's, the alpha-2 agonists, the NMDA receptor antagonists and the serotonin norepinephrine reuptake inhibitors.

Opiods

The most effective analgesia available for pre, peri and postoperative pain control in dogs and cats is provided by the opiod group. It is important to understand several characteristic of opiods to enable the clinician to make decisions on which agents would best be suited for use in a particular patient. Drugs in this class produce variable clinical effects based upon stimulation of a particular opiod receptor subtype. Selective effects of common opiods on different receptors vary as well. An individual opiate's ability to bind preferentially to a given receptor is termed receptor affinity. The characteristics of individual opiods determine their effect at a given receptor. (Table 1). These different classes of opiates are listed in decreasing order of receptor affinity: antagonist > partial agonist/mixed agonist antagonist > agonist.

Table 1: Definitions of Opiod Receptor Activity with Examples of Common Agents in Each Class

Pure Mu Agonist = Produces an optimal effect by binding to a given receptor.

Morphine, hydromorphone, fentanyl.

Partial Mu Agonist = Binds to the opiate receptor and produces a less profound effect than a pure agonist. Buprenorphine

Mu Antagonist = Causes no effect at the opiate receptor Naloxone, naltrexone, butorphanol

A full understanding of these concepts aids the clinician in choosing the correct opiate or combination of opiates based upon the species and the degree and duration of the anticipated pain. Opiate receptors are located throughout the body and are concentrated in the central and peripheral nervous system making the agents that bind to them invaluable analgesics.

It is widely understood that mu opiod receptor stimulation results in the most significant analgesic effect beyond that of any other receptor subtype. Research in this field has led to the ability to clone the mu, kappa and delta opiate receptors. Knockout mice that lack specific opiate receptor genes give researchers the ability to study the effects of different opiates on receptor subtypes.

The prototype agent in the opiod category is morphinea . It is the drug of choice for severe acute pain in dogs. Cats have been known to experience more of the undesirable effects at the sigma receptor (Table 1) with administration of morphinea 1 . Studies now suggest that it is likely that the dysphoric effects were due to unusually high doses used in research settings. Evidence now suggests that opiates actually convey euphoric effects in cats when used at lower doses.2.3 In the author's extensive experience with preoperative morphinea in cats, dysphoria and excitation appear to be an issue mostly postoperatively. In that respect consideration must be given to the combination of agents administered in the preoperative, induction and intraoperative periods combining to exacerbate the expected degree of recovery disillusionment.

Hyperthermia in cats with the use of opiates is predicatble and therefore monitoring is essential.4 Patients should be monitored during the anesthetic periodand up to five hours during post procedure. If hyperthermia becomes significant, reversal agents that are mu antagonists can be administered. Butorphanolb and nalbuphinec are kappa receptor agonists. That property provides some residual analgesia when they are used as mu antagonists to reverse morphine.a Naloxoned is an antagonist at the mu, kappa and gamma receptors so administration of this reversal agent provides no residual analgesia.

Morphinea , in particular will cause vomiting in a significant number of patients. A decrease in incidence occurs with intravenous administration. Histamine release is a problem with rapid administration so morphine given IV must be given slowly over a period of 30 seconds. An alternative to morphinec in cats is hydromorphonee which is an excellent analgesic in this species. Intravenous administration of hydromorphonee in cats provides quicker onset, increased intensity and longer duration with a decreased incidence of vomiting than IM or SQ administration.5 Again hyperthermia is a concern so monitoring temperature is essential.

Oral surgery patients may be painful and difficult to medicate postoperatively per os. Fentanylf transdermal patches are viable options for managing postoperative pain in dogs and cats undergoing oral surgical procedures. The onset of effect in dogs and cats is 18-24 hours and 6-12 hours respectively.6 If using fentanylf patches, the void between placement and onset of action should be adequately covered with additional analgesics.

Butorphanolb is a mu antagonist allowing for only minimal control of somatic pain. It is expensive and frequent dosing is required due to its short half life. Consequently it is a poor choice for managing pain associated with oral surgery.

Buprenorphineg has partial agonist activity at the mu receptor and consequently less profound analgesic properties than would a pure agonist. However it is a safe and effective analgesic and is a great option for use in cats sublingually and transdermally. It is a good choice when anticipating mild to moderate postoperative pain.

Cox-2 Selective NSAIDs

The breakdown of arachidonic acid by cyclooxygenase (Cox) enzymes produces prostaglandins. These proinflammatory compounds are released from various cell types at the site of tissue injury. Other compounds including cytokines and growth factors aid in stimulating the production of additional prostaglandins. Prostaglandins sensitize afferent neurons to noxious chemical, thermal and mechanical stimuli7, 8 and play a major role in the process of maintaining inflammation. Prostaglandins are involved at the site of inflammation and play at significant role at the spinal level.9 Peripheral inflammation upregulates cyclooxygenase enzyme expression in the spinal cord .10 Therefore drugs that can prevent the prostaglandin production can be used to decrease this phenomenon. This may be particularly effective when given preoperatively prior to surgical stimulation.

The non-steroidal anti-inflammatory drugs (NSAIDs) inhibit Cox enzymes. Their use allows for effective treatment of pain and hyperalgesia associated with inflammation.11 Cyclooxygenase-2 (Cox-2) selective NSAIDs have been widely utilized in veterinary medicine as analgesics. Adverse effects consistently experienced with earlier NSAID's are nowhere near as significant with these newer agents. Adverse effects are still possible however. NSAIDs as sole agents for analgesia can be effective12 however using multiple agents in a multimodal approach offers safety and efficacy beyond that of single agents. An NSAID in combination with an opiate in humans has demonstrated opiod sparing effects in the range of 20-30%.13 At the date of publication no Cox-2 selective NSAID approved for use in veterinary medicine has been show to demonstrate significant advantages over another.

5-Lox Selective NSAIDs

Arachidonic acid breakdown by 5-lipoxygenase (5-Lox) produces leucotrienes that, like prostaglandins, significantly affect the inflammatory process. Both classes work together synergistically potentiating the inflammatory cascade. The combination of Cox-2 and 5-Lox pathway inhibition could theoretically enhance the anti-inflammatory effect on tissue.14 The NSAID tepoxalinh , approved for use in dogs, demonstrates Cox-1, Cox-2 and 5-Lox inhibition. This agent has not been shown to demonstrate significant advantages over Cox-2 inhibition alone and bleeding may be an issue due to its Cox-1 effect.

Alpha2 Agonists

Alpha2 agonists involve mechanisms associated with the activation of guanine nucleotide binding proteins (G proteins) which modulate intracellular second messenger systems. G protein activation of these second messenger systems produces a complex cascade of events that results in both beneficial and detrimental physiologic effects. These include sedation, analgesia, increased systemic vascular resistance, bradycardia, respiratory depression and vomition.15 Zylazinei is the prototypical drug in this class and carries the reputation for negative side effects. With the introduction of the alpha2 agonist medetomidinej many of these side effects have been minimized. This agent is currently being utilized in combination with opiates in doses of 5-20 micrograms per kg to provide effective sedation and analgesia. However due to the negative physiologic effects of this agent it should only be used if blood pressure, end tidal CO2, SPO2 and EKG can be monitored. Doses above 20 micrograms per kg contribute considerably to medotomidine'sj adverse effects. Atipamezolek is an alpha2 agonist reversal agent and is used to reverse the action of medotomidinej .

Controvery exists surrounding the practice of administration of an anticholinergic in conjunction with medetomidinej to offset bradycaria. It is believed that the initial reflex tachycardia seen with atropinel combined with the increased cardiac afterload associated with increased systemic vascular resistance may result in cardiac compromise. A full review of medetomidinel is beyond the purpose of this discussion. Additional references should be consulted prior to its use.

N-methly-D-aspartate (NMDA) Receptor Antagoinsts

The pathophysiology of central sensitization was discussed in part 1 of this series. Specific agents must be utilized to minimize pain involved with this process. Attenuation or inhibition of central sensitization may be achieved with the use of NMDA receptor antagonists.16 Agents in this class act by competitively binding to the NMDA receptor and preventing central sensitization. Central sensitization occurs with activation of the glutamate and aspartate recptors resulting in accentuation in pain perception. Ketaminem antagonizes the NMDA receptor in microdoses in conjunction with a constant rate infusion. Further discussion follows in the section on constant rate infusions.

Dextromethorphan,n an antitussive and amantidine,o an antiviral agent are both orally administered NMDA receptor antagonists. They are currently used in dogs and cats for the treatment of chronic pain and to minimize central sensitization.17 They may have particular applications to decreasing central sensitization in chronic pain states prior to surgical manipulation. Neither is a particularly good analgesic when used alone, however combining them with an opiate and/or an NSAID seems to provide safe and effective analgesia when indicated. Amantidineo is available in 100 mg capsules and a 10 mg/ml liquid. It can be administered once daily at a dose of 3-5 mg/kg for dogs and cats.17 Dextromethorphann is an active ingredient in Vick's Forumla 44 cough syrup and Robitussin DM capsules. At 2.0 mg/kg it has been determined safe for treatment of dogs with allergic dermatitis.18 In cats lower doses have been used however it appears to be poorly accepted making amantidineo better choice in this species.

Serotonin/Norepinephrine Reuptake Inhibitors

Tramadolp acts to alleviate pain centrally by inhibiting the reuptake of two inhibitory neurotransmitters; serotonin and norepinephrine allowing them to remain in the synapse to exert their positive effects. Tramadolp is not an opiod but has been shown to possess weak mu agonist activity. It is available in 50 mg tablets and dosed at 2.5–10 mg/kg SID-TID in dogs and cats.17 Preemptive administration of Tramadolp with Morphinea has been proven to be safe at a dose of 2.0 mg/kg.19 It is currently used for chronic and postoperative pain management in a multimodal approach with opiods and NSAIDs. Tricyclic antidepressants, selective serotonin reuptake inhibitors and monoamine oxidase inihibitors should not be used concurrently with Tramadolp due to the risk of serotonin syndrome.

A variety of analgesics are available for use in dogs and cats undergoing oral surgical procedures. Multimodal pain management utilizes these agents in combination to target specific anatomic regions and proalgesic mechanisms to customize and fine tune their analgesic effects. Familiarization with these and other agents allows the practitioner to maximize pre and postoperative comfort.

Products

a. Morphine sulfate 15mg/ml, Baxter Animal Health Care Corp, Deerfield, IL

b. Torbugesic, Fort Dodge Animal Health, Fort Dodge, IA

c. Nalbuphine, Hospira, Lake Forest, IL

d. Naloxone, Abbott Laboratories, Abbott Park, IL

e. Hydromorphone, Baxter, Deerfield, IL

f. Duragesic, ALZA Corp, Mountain View, CA

g. Buprenex, Reckitt & Colman, Wayne, NJ

h. Zubrin, Schering-Plough, Kenilworth, NJ

i. Xylazine HCI injection, Fermenta Animal Health Co., Kansas City, MO

j. Domitor, Orion Corp, Espoo, Finland

k. Anteseden Orion Corp, Espoo, Finland

l. Atropine sulfate, Phoenix Parmaceuticals, Inc., Belmont, CA

m. Ketaset, Fort Dodge Animal Health, Fort Dodge, IA

n. Vick's Forumula 44D Hygiene and Helathcare Limited , Maharashta, India

o. Amantidine, Alliance Pharmaceuticals, Wilshire, UK

p. Tramadol hydrochloride, Caraco Pharmaceutical, Detroit MI

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