Pharmacology of Pain Management

Therapeutics for the musculoskeletal system

• This presentation outlines various therapeutic approaches for musculoskeletal conditions in veterinary medicine.
• Learning outcomes include identifying functional issues from musculoskeletal diseases, understanding drugs modifying neuromuscular function (peripherally vs centrally), and recognizing uses for these in common animal diseases.
• The presentation delves into drugs used to alter neuromuscular function (e.g., benzodiazepines, neuromuscular blocking agents [NMBAs]).
• Benzodiazepines like diazepam and midazolam are pre-anesthetics/sedatives, relaxing muscles for balanced anesthesia, via central action on GABA receptors.
• Neuromuscular blocking agents (NMBAs) are used for inducing paralysis (non-depolarizing, e.g., atracurium, vecuronium; depolarizing, e.g., suxamethonium).
• These agents affect acetylcholine (ACh) receptors and can be reversed (non-depolarizing) or not (depolarizing).

Drugs to alter neuromuscular function

• Benzodiazepines (e.g., diazepam) are used as pre-anesthetics/sedatives to relax muscles (during balanced anesthesia).
• These also have sedative and anxiolytic effects and reduce muscle tone by centrally acting on GABA-A receptors in the spinal cord.
• Muscle relaxation is weak and without noticeable coordination loss.
• Neuromuscular blocking agents (NMBAs) are used to induce paralysis (e.g., atracurium, vecuronium, suxamethonium).
• Non-depolarizing NMBAs (eg., atracurium/vecuronium) are ACh antagonists. These can be reversed with acetylcholinesterase agents (e.g., neostigmine).
• Depolarizing NMBAs (e.g. suxamethonium) are ACh receptor agonists and cannot be reversed.
• Ryanodine receptor (RYR1) antagonists (e.g., dantrolene) are used to treat recurrent exertional rhabdomyolysis in horses and in the past, malignant hyperthermia where there is runaway muscle contraction.
• This is often due to complications of older volatile anesthetics.

Peripherally and centrally acting drugs to treat neuromuscular disorders

• Glucocorticoids, such as methylprednisolone and triamcinolone, are intra-articular glucocorticoids used to treat inflammatory musculoskeletal conditions.
• Non-steroidal anti-inflammatory drugs (NSAIDs) like meloxicam, carprofen, and firocoxib are commonly used, as they inhibit cyclooxygenase enzymes, reducing inflammation, pain, and fever.
• Certain NSAIDs (e.g., aspirin) affect renal blood flow, so usage is not recommended in dehydrated or renal impaired individuals.
• Paracetamol may also be used as an NSAID with analgesic and antipyretic properties, but with weak anti-inflammatory action.
• Caution is advised with its use and it's not recommended for use in cats.

Pain and inflammation

• Tissue injury triggers a series of events involving inflammatory mediators.
• Drugs like glucocorticoids or NSAIDs are used to treat inflammatory responses.
• Anti-NGF monoclonal antibodies effectively target NGF function.
• Various treatments for pain include local anesthetics (e.g., bupivacaine, lidocaine, mepivacaine).
• Other options include opioids (e.g., tramadol), GABA agonists (e.g., gabapentin), and NMDA receptor antagonists (e.g., ketamine, amantadine).
• These drugs modulate pain signals at different stages.

Intra-articular glucocorticoids

• Intra-articular glucocorticoids (e.g., methylprednisolone, triamcinolone) are used to treat inflammatory musculoskeletal conditions, especially in horses, via aseptic techniques.
• Single doses are well-tolerated, but chronic use can lead to side effects like Cushingoid signs and may exacerbate laminitis.

Arachidonic Acid Cascade and Inflammation

• The arachidonic acid cascade is involved in inflammation, prostaglandin production, and inflammatory mediators
• Glucocorticoids and NSAIDs interfere with prostaglandin synthesis in this cascade.

Cyclo-oxygenase COX1 and COX2

• Cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) are enzymes and play roles in inflammation and homeostasis.
• COX-2 is generally responsible for inflammation in the body.

COX-2 vs COX-1 selectivity

• COX-2 selective NSAIDs are favored due to lesser GI side effects compared to non-selective ones
• Older NSAIDS are non-selective while newer NSAIDs are usually COX-2 selective.

NSAIDs

• NSAIDs (e.g., aspirin, phenylbutazone) have actions as anti-inflammatory, analgesic, and antipyretic agents
• Possible adverse effects of NSAIDs include GI issues, reversible renal insufficiency, and cardiac failure in predisposed animals.
• NSAID 'failure' can occur in a smaller percentage of dogs and alternative NSAIDs should be considered if needed.

Grapiprant

• Grapiprant is a non-steroidal, non-cyclooxygenase inhibiting anti-inflammatory drug
• Grapiprant specifically blocks the EP4 receptor, an important mediator of prostaglandin E2-induced inflammation and pain.
• Minor GI problems (soft faeces/diarrhoea, or vomiting) tend to be temporary.

Pentosan polysulfate Sodium

• Pentosan polysulfate sodium (NaPPS) is used to treat lameness and pain from degenerative joint disease (OA) in dogs via a course of weekly subcutaneous injections
• Response can be variable and some dogs might need multiple courses.
• Concurrent use with steroids and NSAIDs is avoided due to bleeding risk.

Nutraceuticals

• Nutraceuticals such as chondroitin sulfate, glucosamine, antioxidants, and EFAs, are nutritional supplements used in arthritis treatment.
• Evidence for their effectiveness is variable and often incomplete.

Bedinvetmab / frunevetmab

• Nerve growth factor (NGF) increases inflammatory mediators and stimulates nociceptors.
• Bedinvetmab and frunevetmab are anti-NGF monoclonal antibodies to manage OA pain (but not acute pain), targeting long-term management.
• Usage should be avoided in young or pregnant animals to avoid possible teratogenic effects.

Paracetamol

• Paracetamol is a first-line pharmaceutical treatment for OA in humans.
• The mechanism is not fully understood but it affects CNS COX3 and reduces ion conduction in pain sensory neurons.
• Paracetamol is used in dogs, but specific veterinary products are not licensed, and it should not be used in cats.

Tramadol

• Tramadol is a centrally acting analgesic, acting on opioid, norepinephrine, and serotonin receptors. In contrast to morphine, tramadol has less effect on respiration and GI motility.
• It's helpful for mild-to-moderate acute pain and as adjunct for chronic pain.
• Potential effects include sedation at high doses and other potential dysphoria issues especially in cats.

Gabapentin

• Gabapentin is an analogue of GABA, often used as an antiepileptic but also for neuropathic pain.
• The mechanism for analgesia is uncertain, low starting doses are needed and slow increased dosages. It can sometimes cause mild sedation and ataxia.
• Withdrawal has potential for rebound pain, so it needs tapering off gradually.

Amantadine

• Amantadine is an NMDA receptor antagonist, acting similarly to ketamine but blocking excitatory signals in the CNS.
• It's used for treating moderate-severe OA and osteosarcomas pain in animals.
• Potential side effects include potential anxiety, confusion, depression, hallucinations, headaches, altered mood, movement issues, sleep disorder, and problems with vision.
• Its use may increase the risk of seizures when used along with tramadol.

Multimodal management of osteoarthritis

• Managing osteoarthritis (OA) often uses multimodal approaches involving physical therapy, hydrotherapy, and joint repair surgery.
• Medical management typically includes NSAIDs, and protection/supplementation of cartilage with nutraceuticals like Cosequin.
• Further care should include appropriate exercises, weight control and Omega-3 fatty acid rich diets.

Key Points - summary

• LO - Identify drugs for modifying neuromuscular function: various drugs, including benzodiazepines (e.g., diazepam) and neuromuscular blocking agents (NMBAs) are used to modify neuromuscular function.
• LO - Identify peripherally vs centrally active drugs: glucocorticoids, NSAIDs, and various other analgesics have varying action in managing inflammatory conditions and pain.