Pain Management: Anti-Inflammatories

• Highlights of Pain Management, focusing on Anti-inflammatories

Pain

• Pain is defined by the International Association for the Study of Pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage
• Pain sensation arises from nerve endings called nociceptors
• Nociceptors are activated through mechanical, thermal, and chemical stimulation
• Pain has varying degrees of severity and may be acute or chronic
• Chemical stimulation may be from exogenous or endogenous chemicals like prostaglandins
• Pain locations include superficial pain from subcutaneous tissue, deep pain associated with skeletal muscle/tendons/bone/joints, and visceral pain arising from hollow abdominal organs/peritoneum/heart/liver/lungs
• Assessment of pain in animals is very difficult, pain avoidance is a defense mechanism
• Vocalization is a poor indicator of pain
• Indicators of pain in animals, including, increased heart/respiratory rate, mydriasis, salivation, guarding, restlessness, withdrawal, and abnormal stance or rolling
• Pain-free patients are quiet, calm, and not guarded
• Pain should be controlled for humane reasons and to prevent delayed healing/return to homeostasis

Drugs for Pain Control

• Analgesics fall into two primary categories: nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids (narcotics)

Inflammation

• Inflammation is the body’s response to injury caused by physical, chemical, or biologic trauma
• The purpose of inflammation is to counteract injury by "walling off" the cause and to repair/replace damaged tissue
• Cardinal signs of inflammation include redness, heat, swelling, pain, and loss of use
• Damage to cells results in the release of chemicals like prostaglandins, leukotrienes, and cytokines to initiate or prolong the inflammatory response
• Chemical mediators include increased blood flow to the area via vessel dilation and increased permeability, phagocytic cell attraction, and histamine release
• Histamine release can cause bronchoconstriction, anaphylactic shock, and chronic inflammatory response (allergies)
• Fever may be initiated by chemicals released during the inflammatory response
• Pyrogens are foreign (exogenous) substances that cause fever
• Prostaglandins are endogenous pyrogens that reset the temperature control in the hypothalamus
• NSAIDs are the primary drugs used to control fever

Anatomy and Physiology

• Pain sensation arises by a process called transduction in nociceptors
• Pain impulses are carried to the CNS by type C unmyelinated fibers for dull, poorly localized pain and type A delta fibers for sharp, localized pain
• Information is perceived in the cortex of the brain, consciousness is required for pain perception to occur
• Reflex activity can occur without pain perception
• Hyperalgesia is a heightened perception of pain due to a lowered pain threshold in injured tissue
• Repeated stimulation of pain tracts in the spinal cord causes sensitization and discharge at a lowered threshold, resulting in painful perception of previously non-painful stimuli, known as "wind-up" pain
• Preventing wind-up is a primary reason pain should be treated preemptively

Non-steroidal Anti-inflammatory Drugs

• NSAIDs work by inhibiting cyclooxygenase (COX)
• COX-1 maintains physiologic functions, including modulation of renal blood flow and synthesis of gastric mucosal protection
• COX-2 promotes the formation of prostaglandins in the cell membrane and inflammation
• NSAIDs that selectively inhibit COX-2 are thought to block inflammation while protecting normal physiologic functions from COX-1
• Selective COX-2 inhibitors have less gastrointestinal side effects in theory
• Not all NSAIDs are alike, some have more pronounced analgesic effects, or have more pronounced analgesic effects on certain types of pain (visceral or musculoskeletal)
• Steroidal anti-inflammatories (glucocorticoids) block both COX-1 and COX-2
• Glucocorticoids block inflammation earlier in the inflammatory cascade by preventing arachidonic acid formation
• Glucocorticoids are more effective anti-inflammatories than NSAIDs, but with significantly more side effects
• Glucocorticoids typically have an -one suffix, for example Prednisone, dexamethasone, triamcinolone, betamethasone
• NSAIDs and glucocorticoids cannot be taken at the same time, can cause gastric perforation

NSAID Side Effects and Client Education

• NSAID side effects include gastrointestinal ulceration and bleeding, hepatotoxicity, nephrotoxicity, inhibition of cartilage metabolism, bone marrow suppression, and bleeding from reduced platelet aggregation
• NSAIDs are not completely benign, a complete physical examination and appropriate diagnostics and laboratory tests should be performed prior to treatment
• Pretreatment blood chemistry screening may be used to detect hepatic and renal changes that may direct choice of NSAID, dose, and duration of treatment
• Pets on long term NSAIDs should have their blood chemistry rechecked intermittently to detect problems, such as increased liver or renal values or decreased albumin or low red cell count (indicative of GI ulceration)
• Clients should be advised to watch for and call immediately if they see anorexia, vomiting, dark tarry or bloody stools, diarrhea, change in water consumption or urinary behavior, and lethargy
• NSAIDs should not be combined with glucocorticoids because of the risk of GI ulceration
• Changes between types of NSAIDs require a “wash-out” period to reduce the risk of toxicity, especially GI toxicity

Salicylates and Dipyrone

Salicylates

• Aspirin is acetylsalicylic acid, a non-specific COX inhibitor
• Aspirin functions as an analgesic, antipyretic (reduces fever), anti-inflammatory, and reduces platelet aggregation
• Aspirin has fallen out of favor as an analgesic because a single dose causes microscopic GI ulceration and bleeding in nearly 100% of patients
• The recommended “wash-out” period for a single dose of aspirin is a full week
• Aspirin retains its benefits for its antiplatelet aggregation effects for cats with cardiomyopathy, endotoxic shock, post adulticide treatment for heartworm disease, neurological "vascular accidents"/strokes, and equine recurrent uveitis.
• Aspirin is available in tablets, powder, and boluses
• Aspirin should be avoided in food animals
• If aspirin is used in small animals, it should be enteric coated to reduce GI irritation

Dipyrone

• Dipyrone is an atypical nonsteroidal anti-inflammatory in the pyrazolone family
• Dipyrone is labeled for the control of pyrexia in horses only, given IV up to every 12 hours for no longer than 3 days
• Use dipyrone with precaution in horses prone to gastric ulcers or at risk for coagulopathy
• Adverse effects include gastric ulcers, colic, and diarrhea
• Avoid self-injection as dipyrone has been associated with agranulocytosis in humans
• An example of a the Brand name is Zimeta®

Phenylbutazone, Flunixin Meglumine, Propiononic Acid Derivatives, & Carprofen

Phenylbutazone

• Phenylbutazone, also known as bute or butazolodin, is a pyrazolone derivative
• Phenylbutazone functions as an analgesic, antipyretic, and anti-inflammatory
• Phenylbutazone is used for musculoskeletal pain in horses (formerly used in dogs, now rare)
• Phenylbutazone is used extensively in horses for lameness, but is thought to be less effective as a visceral pain reliever
• Phenylbutazone is also used for pain control in ruminants with caution regarding meat and milk withdrawal time and a long withdrawal
• Phenylbutazone is available as an injectable, tablets, oral paste, and powder
• Injectable phenylbutazone must be given carefully IV, as perivascular administration can cause extensive tissue necrosis and sloughing
• It is labeled as 4gm per day/1,000#, though more recent studies prove an analgesic effect is just as effective at 2gm per day, with less potential for toxicity

Bute toxicity

• Bute can cause decreased mucus and blood flow
• Gastric ulceration is a side effect, and may be diagnosed with endoscopy
• Renal papillary necrosis and acute renal failure may also result
• Monitor/observe for right dorsal colitis, chronic intermittent colic, and hypoproteinemia

Flunixin meglumine

• Flunixin meglumine, is labeled for horses and cattle under the brand name Banamine®
• Flunixin meglumine functions as an analgesic (visceral pain), antipyretic, anti-inflammatory, and "antiendotoxic" (reduces vasculitis from endotoxemia)
• Flunixin is very good, frequently used in the treatment of equine colic, though some believe its use may hide the surgical pain
• It is often used at low doses for its protective effects during endotoxemia, and is available as an injectable, paste and granules
• Labeled for IM and IV use, IM use may predispose horses to Clostridial myositis by causing muscle irritation and an anaerobic environment for bacterial growth
• Small animals should be protected from gastric ulceration and well-hydrated with IV fluids to protect their kidneys

Propiononic acid derivatives

• Ex Carprofen
• Ketoprofen
• Naproxen
• Ibuprofen

Carprofen

• Carprofen is sold under the brand names Rimadyl® (oral and injectable), Vetprofen®, and Novox ®(oral)
• Is a NSAID labeled for management of surgical and osteoarthritic pain in dogs
• Functions as an antipyretic, and is thought to target COX 2 resulting in decreased GI side effects
• It’s rare idiopathic liver toxicity, with Labrador retrievers overrepresented
• If severe jaundice (hyperbilirubinemia) occurs and is not treated aggressively, it may result in death.
• Monitor patients with pretreatment blood work and 2 weeks of post-treatment blood work, especially those to be treated long term
• Carprofen may cause Gastrointestinal upset and bleeding, which are less common

Ketoprofen, Naproxen, Ibuprofen & Coxib Class

Ketoprofen

• Ketoprofen is a NSAID labeled for horses for musculoskeletal pain and inflammation
• Functions as an antipyretic, anti-inflammatory, and analgesic
• Though less ulcerogenic than phenylbutazone
• Before Rimadyl®, it was used for post-operative pain management in cats and dogs, though it is no longer used because of the availability of labeled products for these species
• Is injectable only and given IV only

Naproxen

• Naproxen is an NSAID labeled for the relief of pain, inflammation, and lameness associated with myositis and other soft tissue disease in the musculoskeletal system of horses
• Known as Equiproxen®, for ‘muscle and soft tissue pain’
• Uncommon side effects in horses, is not widely used in the US, and is Contraindicated in dogs because of the risk of gastric ulceration

Ibuprofen

• Sold as Advil and Ibuprofen
• Ibuprofen is dose dependent
• Ibuprofen is to be avoided in veterinary species, because it causes a frequent cause of gastric perforation in dogs

Coxib Class NSAIDS

Deracoxib

• Also known as Deramaxx®
• Deracoxib is a Coxib class analgesic NSAID
• It is a selective COX 2 inhibition, very limited COX 1 inhibition
• Labeled for post orthopedic surgical pain in dogs >4# and for pain and inflammation from osteoarthritis in >14#, and given once daily, tablets only
• Giving after a meal increases bioavailability
• Deracoxib has Typical NSAID side effects - gastric perforation

Firocoxib

• Firocoxib is marketed under the brand names Previcox® and Equioxx®
• A NSAID in the coxib class with Selective COX 2 inhibition
• Labeled for use in dogs and horses for pain and inflammation from osteoarthritis