Get off my back you pain in the neck: Managing pain in neurologic patients (Proceedings)

The inability of our veterinary patients to speak to us can make determining the presence of pain a challenging process. Vocalization is often a clear sign that an animal is painful. However, even this can be misleading at times, as animals with brain disorders may vocalize without being painful. Tremors and muscles spasms may indicate pain. However, dogs with neuromuscular, cerebellar or diffuse CNS disorders may tremor as well. Thus identifying the presence of pain in the neurologic patient can be difficult. Ruling out other causes for vocalization and tremors with a thorough neurological examination is essential. Changes in body posture such as decreased head carriage, kyphosis and lordosis may indicate cervical or back pain. Changes such as tachycardia, tachypnea, decreased grooming, decreased appetite, lethargy and a change in elimination habits can also be general indicators of pain. Several pain scoring systems are available each with benefits and short comings. Pain scoring is helpful in raising hospital staff awareness and recognition of pain. Serial pain scoring enables us to evaluate the efficacy of pain therapy and optimize pain management. The variable pain responses patients manifest make definitive criteria challenging. One patient may vocalize when painful while another is less vocal and reclusive. Inter user interpretation and variation may affect accuracy of pain scoring.

Cervical pain often manifests with decreased head and neck carriage. Muscle spasms at times may be present. Palpating the cervical spine may indicate cervical pain. However, some dogs may resent palpation in general and may exhibit a behavioral response/reluctance to be handled in the head and neck region. Vocalization or reluctance to allow cervical flexion either laterally, ventrally or dorsally is often the best indicator or cervical pain. Voluntarily turning the whole body instead of the neck may also indicate cervical pain.

Kyphosis is a common finding in patients with thoraco-lumbar pain. Other signs may include reluctance to walk, a tense abdomen or apparent pain on paraspinal palpation. Further diagnostic evaluation of the abdomen via serum chemistry, particularly pancreatic enzyme evaluation and abdominal ultrasound can be helpful in distinguishing abdominal diseases vs thoracolumbar pain.

Cauda equina syndrome is a common cause of pain and discomfort in aging large breed dogs. Dogs often present with a history of decreased tail carriage, difficulty rising, jumping and decreased frequency or ability in walking up and down stairs. A stiff pelvic limb gait or lameness may be apparent on examination. Conscious proprioception deficits may be present in the pelvic limbs. In the most severe cases fecal and urinary incontinence, the loss of a perineal reflex and diminished anal tone may be present. On examination palpation of the lumbosacral region and more commonly dorsoflexion of the tail yields an apparent pain response. Stiff gaits may also be caused by degenerative joint disease, polyarthritis and neuromuscular diseases such as polymyopathies and polyneuropathies. Creatine kinase evaluation is extremely important and may be the only other clue that a polymyopathy is present as signs can overlap.

Several diagnostic tools may be utilized to assess the localized area of pain. Plain radiographs may indicate: narrowed disc spaces suggestive of IVDD, endplate lysis consistent with discospondylitis and vertebral lesions (lysis or production) consistent with either neoplasia or infection. MR imaging has become increasingly favored. Advantages of MR imaging include minimal invasiveness, evaluation of contrast enhancement, multiplanar imaging and the ability to detect lesions both within and outside the spinal cord. MR imaging can detect lesions such as discospondylitis and neoplasia before radiographic abnormalities may be present. Myelography in combination with CT scan is also very good at detecting extra-axial spinal cord lesions such as IVDD. In very small/toy breed dogs myelography combined with CT scan may be superior to MR imaging for the diagnosis of IVDD as thinner slice thickness is possible with CT scan compared to MR imaging. The increasing strength of magnets, MRI coil quality and software upgrades may negate this size consideration. When a structural lesion is not apparent or considered potentially incidental CSF evaluation is essential in ruling out inflammatory, infectious causes as well as lymphoma. Electromyography (EMG) is a helpful screening test for neuromuscular diseases. EMG evaluation also may distinguish neurological causes of lameness from orthopedic causes. Animals with purely orthopedic causes have a normal EMG evaluation, while animals with a C6-T2 myeloradiculoneuropathy, neuropathy or myopathy may have an abnormal EMG evaluation. EMG evaluation can be very helpful in dogs with lumbosacral disc disease. The presence of EMG changes with a sciatic distribution is highly suggestive that a lumbosacral disc herniation is a clinical problem. Joint fluid evaluation is clearly indicated in animals with joint pain or joint effusion. It should also be considered when other diagnostic tests are unremarkable and the cause of pain is still in question and when fever of unknown origin is present.

When identified the underlying cause of pain should be treated. Compressive spinal cord lesions may require surgical decompression. Non compressive causes include infectious diseases as well as non infectious inflammatory diseases such as steroid responsive meningitis arteritis. Staphylococcus is a common cause of discospondylitis. Spinal epidural empyema (i.e. abcess) is most often associated with E. Coli, Bacteriodes spp and S. Intermedius.1 Thus, antibiotic choice should be targeted at these organisms when a bacterial infection is suspected. Cephalosporins and amoxicillin/clavulanic acid are both good choices. A fluoroquinolone may be used if a therapeutic response is not initially seen with the previous antibiotic choices. Fungal discospondylitis can be difficult to diagnosis as a bacterial cause is typically suspected. Aspergillus tereus, Cladophialophora and paecilomycosis may also cause discospondylitis. Coccidiomycosis can cause vertebral osteomyelitis. Fungal serology and often biopsy and culture may be required to diagnose fungal infections of the spine. Itraconazole or voriconazole should be considered for fungal discospondylitis and osteomyelitis. While fluconazole is often used for CNS fungal infections because of its penetration in to CSF it has little activity against Aspergillus.2 Corticosteroids should be used with caution when an infectious process is present. However, initially anti-inflammatory dosages may be helpful in alleviating CNS inflammation and edema. An initial dose of dexamethasone SP 0.1 mg/kg may be helpful. Prednisone at 0.5 mg/kg PO BID and tapering off over a 1 to 2 week period may also be of benefit in improving or maintaining neurological function as well as controlling pain. Steroid responsive meningitis typically responds to immunosuppressive courses of prednisone.

Neuropathic pain is caused by abnormal somatosensory processing in the PNS or CNS. There are three key phenomena in the development of neuropathic pain: 1. Central sensitization or "wind up" occurs as high- frequency action potentials in the primary afferent neuron facilitate second-order neurons to act more vigorously to future stimulation. Synaptic neurotransmitter levels (glutamate) and the number of receptors (NMDA) are altered. 2. Central disinhibition is an imbalance between excitatory and inhibitory aspects of the nervous system. Norepinephrine and serotonin (less so) are major factors in the descending inhibitory system. 3. Mechanoreceptors A β-fibers (light touching) undergo a phenotypic change to produce substance P. Input from the mechanorecptors is then perceived as pain.3

NSAIDs produce analgesia primarily by inhibiting prostaglandin production in the arachadonic acid (AA) pathway. NSAIDs block cyclooxygenase (COX), the rate limiting step in the AA pathway.4 NSAIDs also have a direct spinal action by blocking hyperalgesia induced by the activation of glutamate and substance P receptors.3 COX-1 is present under basal conditions and is associated with homeostatic functions such as gastric protection, platelet aggregation, and renal electrolyte balance. COX-2 is present in low concentrations in basal conditions. COX-2 accelerates gastric ulcer healing by promoting angiogenesis at the ulcer edge and is important in maintaining renal perfusion.4 COX-2 is present in the brain and is thought to increase after CNS injury. COX-2 inhibition has been shown to improve recovery after CNS injury in laboratory animals.3 Coxibs are more lipophilic and less acidic than many non selective NSAIDs and readily cross the blood brain barrier.4 Firicoxib, deracoxib, meloxicam and carprofen are all Cox-2 selective NSAIDs. Etodalac, ketoprofen, aspirin and tepoxalin are non selective COX inhibitors. The degree of COX-2 selectivity varies from study to study, likely due to testing methods. Whole blood assays are considered the gold standard for determining COX-1/COX-2 specificity.

A washout period of 1-7 days has been advised when switching from one NSAID to another. However, evidence of the need for a washout period when switching between NSAIDS other than aspirin is lacking.5 In addition, many animals in pain or with paresis may do poorly if medication is withheld during a washout period. While evidence is lacking, it is reasonable to monitor for GI adverse effects closely when switching NSAIDS.

Use of NSAIDs in cats has been limited due to the significant potential for toxicity. The T ½ of carprofen is about 20 hours in cats, doubling the T ½ in dogs, and can vary from 9 to 49 hours. Carprofen is approved for a single dose of 4 mg/kg injectably in the United Kingdom. Meloxicam is palatable to cats. Meloxicam was evaluated and effective in cats at a dose of 0.3 mg/kg PO on day 1 and then 0.1 mg/kg for 4 additional days. Meloxicam may be used with caution longer term in cats at lower dosages of 0.025 mg/kg PO 3 to 4 times weekly.6

Glucocorticoid's main effect is through the inhibition of phospholipase A2. Thus both prostaglandins and leukotrienes are inhibited. Recent data has indicated that dogs treated with glucocorticoids for presumptive disc herniation had lower quality of life scores and decreased odds of a successful outcome compared to NSAID therapy. Glucocorticoids may cause excitoxic neuronal cell death, worsen oxidative injury and cause lactate accumulation within spinal cord parenchyma.7

Opiods act both peripherally and centrally. Peripherally they prevent neurotransmitter release and nociceptor sensitization. Centrally they modulate input into the dorsal horn, where C fibers terminate and in cortical areas that blunt pain perception.3 The use of fentanyl, a pure µ–agonist, has many advantages. Fentanyl is potent and short acting making it ideal for post operative use as a constant rate infusion (CRI) at 2-5 µg/kg/hr. It can easily be titrated to effect with clinical results identified quickly. Its short half life also allows for more accuracy in neurologic evaluation, as it can easily be stopped if its effects are thought to be influencing neurologic deficits. With longer acting opiods such as hydromorphone, morphine and oxymorphone a longer time must be waited before accurate reassessment may take place. Signs of opiod overdosage, "narcotization", can often be confused with signs of pain. Thus, the ability to rapidly titrate the fentanyl CRI allows for optimal pain control, while minimizing adverse effects. The transdermal formulation of fentanyl also gives the advantage of at home use with a longer duration of action. In cats the fentanyl patch has quicker time of onset, 6 -12 hours compared to 18-24 hours in dogs. The duration of action is also longer in cats compared to dogs (72-104 hours). Fentanyl's effect may persist up to 20 hours post patch removal in cats.6

Buprenorphine, a partial µ-agonist, is an effective analgesic in cats. Buprenorphine produced better analgesia than morphine and oxymorphone in cats. Buprenorphine rarely causes vomting, dysphoria or hyperthermia. The buccal route (0.02 mg/kg) is as effective as IV with analgesia lasting greater than 6 hours in cats. The alkaline environment (pH 8-9) of the cats mouth is thought to be the reasons for its almost 100 % bioavailability after buccal administration.6

Tramadol, a synthetic codeine analogue, is a weak µ-receptor agonist. It inhibits neuronal re-uptake of serotonin and norepinephrine, and may also facilitate their release. Tramadol is recommended for both acute and chronic pain in people. Dosages of 5 mg/kg q 6 hours in dogs resulted in plasma concentration that were consistent with analgesic levels in people. Recommended dosages are from 1-5 mg/kg q 6 to 8 hours. Lower dosages are recommended in cats as it may cause sedation and dysphoria, particularly in this species.3

Ketamine provides analgesia and prevents wind-up by binding at both the NMDA and σ-opiod receptors. A loading dose of 0.5 mg/kg IV prior to surgery followed by a CRI at 10 µg/kg/min during surgery and 2 µg/kg/min for 18 hours post surgery was shown to improve postoperative pain scores in patients undergoing amputation. The possibility of increased intracranial pressure (ICP) has been a concern with ketamine administration. However, when pCO2 was held constant or when combined with a benzodiazepine, ketamine has been shown not to raise ICP.3

Amantadine is an oral NMDA receptor antagonist. A starting dose of 3 mg/kg is recommended. A blinded, placebo controlled study for the treatment of osteoarthritis showed increased activity in dogs after 42 days of amantadine and meloxicam therapy compared to meloxicam and placebo.3,8

Lidocaine, a class 1B antiarrythmic and sodium channel blocker, also acts at the NMDA receptor within the dorsal horn. Its analgesic effect occurs at lower doses than needed for anesthesia or to slow cardiac conduction. An initial 1.0 mg/kg bolus followed by 0.025 mg/kg/min CRI may be of benefit. Lidocaine should not be used in cats as it has not been shown to be beneficial and may cause adverse effects in cats.3

Medetomidate and dexmedetomidine belong to the class α2 agonists. They exert their effect in the dorsal horn of the spinal cord and the locus ceruleus in the brainstem. Perioperative CRI's of α2 agonists have gathered recent attention for adjunctive pain control and sedation. Dexmedetomidine CRI was shown to reduce MAC with minimal hemodynamic effects at 0.5 µg/kg/hr. Medetomidine 1.5 µg/kg/hr in combination with fentanyl boluses caused significant hemodynamic adverse effects, such as bradycadia.9 The potential for adverse hemodynamic effects in neurologic patients is of significant concern. Thus they should be used with caution.

Gabapentin binds to and blocks voltage-dependent calcium channels at the spinal and supraspinal levels, thus blocking maintenance of spinal cord central sensitization. Gabapentin may also induce spinal norepinephrine release resulting in analgesia through spinal α2- adrenoceptor stimulation. Gabapentin is excreted by the kidneys, thus animals with renal insufficiency may need less frequent dosing.3 Gabapentin may cause sedation, however is more likely to occur at dosages used to treat seizures than dosages frequently used for analgesia. The dose range is quite wide, ranging from 3 to 10 mg/kg PO SID to TID.

Acupuncture may be effective in providing analgesia. Needle placement can induce the release of several neurotransmitters, affecting the processing of sensory input, including C fiber blockade and amplification of the inhibitory system. Electro acupuncture causes release of endorphins, serotonin and norepinephrine. Long term analgesic effects of acupuncture are likely from activation of a serotonergic and metencephalinergic neurologic circuit in the mid diencephalon.3

References

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Lavely JA, Lipsitz D. Fungal infections of the central nervous system in the dog and cat. Clin Tech Small Anim Pract 2005;20:212-219.

Mathews KA. Neuropathic pain in dogs and cats: if only they could tell us if they hurt. Vet Clin NA Small Anim Pract 2008; 38:1365-1414

Bergh MS, Budsberg SC. The coxib NSAIDs: Potential clinical and pharmacologic importance in veterinary medicine. J Vet Intern Med 2005; 19:633-643.

Papich MG. An update on nonsteroidal anti-inflammatory drugs (NSAIDS) in small animals. Vet Clin NA Small Anim Pract 2008; 38:1243-1266.

Robertson SA. Managing pain in feline patients. Vet Clin NA Small Anim Pract 2005; 35:129-146.

Levine JM, Levine GJ, Johnson SI, et al. Evaluation of the success of medical management for presumptive thoracolumbar intervertebral disc herniation in dogs. Vet Surg 2007; 36:482-491.

Lascelles BDX, Gaynor JS, Smith ES, et al. Amantadine in a multimodal analgesic regimen for alleviation of refractory osteoarthritis pain in dogs. J Vet Intern Med 2008; 22:53-59.

Lamont LA. Adjunctive analgesic therapy in veterinary medicine. Vet Clin NA Small Anim Pract 2008; 38:1187-1203.