Understanding pain pathways and pharmacologic targets (Proceedings)

The COX pathway

Most commonly used veterinary pain drug

o    COX-1 Not really used in veterinary Medicine

o    COX-2 Rimadyl, Metacam, Previcox and Deramaxx

·         Works by stopping production of prostanoids fromprostaglandins by inhibition of the cyclooxygenase pathway.

·         Prostanoids cause pain and inflammation through stimulation of PGE receptors at both the nociceptor and dorsal horn of the spinal cord

·         COX Contraindications

o             Moderate to severe renal disease

o             End stage liver disease

o             Concurrent use of aspirin or corticosteroid

o             Chronic use in cats??

o             In face of gastro-intestinal signs

·         COX Doses - Follow manufacturer's instructions, but try to find lowest effective dose.

Acetaminophen

·         Belongs in a class of its own

·         There have been many attempts to classify it.  It probably works by binding to cannabinoid receptors but other possible pathways include COX, seratonin, opioid, norepinephrine and nitric oxide

·         It only seems to work in some dogs, never use in cats.  It is a good adjunct medicine to try out, but I would never use it by itself...not dependable enough. 

·         Dog Dose is 10 mg/kg q8-12h

Biphosphonates

·         Good analgesic effect for patients with osteosaroma, especially those with metastatic diesease.  Biphosphonates inhibit osteoclastic activitiy, thereby reducing bone resorption and they promote repair through stimulation of osteoblast differentiation and bone formation. They have poor oral absorption so are given by the IV route.

·         Pamidronate is the one most commonly used, but some of the newer ones hold promise.

Opioids

Used in veterinary medicine mostly for acute pain. Oral opioids have poor absorption in animals so there is a tendency not to use them in chronic conditions.  All opioids have peripheral and central effects.  

There are several opioid receptors, but I am only going to talk about two of them.  In general Mu receptors have a stronger somatic effect and Kappa receptors have a stronger visceral effect, but there is some crossover.

Side effects

o    Nausea and Constipation

o    Dysphoria

o    Respiratory Depression

o    Sedation and depression

o    Excitement and seizures

o    Bradycardia

o    Hypertension

Codeine

o    A weak opioid

o    Mu Agonist

o    orally absorbed in dogs

o    Cytochrome P450 transforms it to morphine, so not all dogs benefit

o    Duration 6-12 hours

o             Dose Canine only 0.5-2 mg/kg

Tramadol

o    A weak opioid and an agonist

o    Mu effects but really considered by many not to be a true opioid but is called opioid-like

o    Also a mild seratonin reuptake inhibitor:  Do not use with other SRI's, MOA inhibitors and amitraz

o    Duration is unknown, clinical impression is about 6 hours

o    Dose 5 mg/kg qid

Morphine

o    Strong opioid and Mu agonist

o    Is sage easy and cheap.  Has some limited oral bioavailability

o    Dose for injection:  Dogs, 0.5-2 mg/kg, Cats 0.2-0.5 mg/kg

o    Dose for oral use in Dogs only:  Sustainded release tablets 2-5 mg/kg q12h

Fentanyl

o    A strong Mu agonist, very short acting, less than 30 minutes

o    Available for transdermal use:  Clip hair and wash with water only, warm the patch and apply pressure for at least two minutes. It takes 6-24 hours for the patch to start working

o    Duration of transdermal action is 72-104 hours

o    Dose at 2-4 mcg/kg

Hydromorphone

o    Strong Mu agonist

o    Duration of action 2-6 hors

o    Dose:  Dogs 0.05-0.02 mg/kg.  Cats 0/05-0.01 mg/kg

Buprenorphine

o    Strong Mu partial agonist...has a ceiling effect

o    Great oral bioavailability in cats

o    Has a slightly slower onset of action than some opioids.  It is best given by the IM not SQ route when injecting

o    Duration of Action is 6-12 h

o    Dose:  Oral/IM in cats 0.01-0.02 mg/kg  Dog IM dose is 0.005-0.02 mg/kg

Butorphanol

o    A strong Kappa partial agonist

o    Can be used to displace agonistsin case of adverse reactions while not eliminating analgesia altogether

o    Has a ceiling effect

o    Duration 1-4 hours...one study shows longer duration when given at dose of 0.5 mg/kg

o    Dose 0.1-0.4 mg/kg

Naloxone

o    Full antagonist.

o    Duration does not last as long as hydromorphone and morphine...repeat doses may be needed.  IV Duration 20-4- minutes.  IM Duration 40-7- minutes

o    Dose:  IV 0.01 mg/kg  IM 0.04 mg/kg

Sodium channels

·         Local anesthetics.  Nerves signals result from the rapid inward passage of Na+ ions.  Locals stop this action by blocking repolarization

·         Mixing local anesthetics is controversial.  Mixing a short acting with a longer acting may shorten the action of the longer acting local.  Clinically it is often done especially in cases where the safe dose of one local is not sufficient for the nerve blocks.  Toxicity of different local anesthetics are not cumulative

·         Diluting local anesthetics

·         As with mixing anesthetics, it may be done to increase total volume of anesthetic needed to block an area.

·         A rough tule of thumb:  diluting a local 1:1 with saline decreases it's duration of action by half.  1:2 dilution quarters the druation of action, and so on.

·         Diluting does not decrease effectivness, just duration.

Toxicity

o    Cardiovascular effects will be covered under the bupivacaine discussion

o    Neural toxicity at the local level is rare, but irreversible conduction blockades have been reported

o    Skeletal muscle toxicity, especially with longer acting anesthetics after local injection

Lidocaine

o    Amazingly versatile

o    can be locally administered, used transdermally, as a cream, intravenously

o    Duration of 1-2 hours with rapid onset

o    Dose  Dogs:  1-5 mg/kg, Cats 1-2.5 mg/kg

Bupivacaine

o    About 4 times more potent than lidocaine

o    Commonly used for regional, epidural and infiltration catheters

o    CNS and Cardiac toxicity results from lower doses than from lidocaine, never give intravenously!

o    Toxic to skeletal muscle

o    Duration of action 3-10 hours, usually 3-6

o    Dose for dogs and cats is 1-2 mg/kg

Calcium channels

Sometimes called a calcium channel blocker, they are not.  They reduce transmitter release and inhibit N-type calcium currents in the dorsal root ganglion, which reduces neuropathic pain.

Gabapentin

o    Indicated in humans for neuropathic pain.

o    Veterinary studies show a decrease in incisional pain and arthritis

o    May decrease allodynia

o    Works best when used with other pain meds

o    Gabapentin side-effects

o    Somnolence for the first week or two.  You can start patients on night-time dosing only for the first week

o    Cleared (not metabolized) by the kidneys, so decrease the dose in CRF patients

o    Dose:  Dogs 5-50 mg/kg bid-tid.  Start low and titrate up.  Cats 50 mg bid

NMDA agonists

·         The NMDA receptors are located on afferent neurons within the spinal cord.

·         Evokes afferent stimulation and release of Substance P

·         Ketamine and amantadine are the two drugs commonly used

o    Ketamine given as a CRI or intrathecally

·         Amantadine

o    Antiviral and Parkinson's drug in humans

o    Duration 24 hours

o    Dose 1-4 mg/kg.  Use at least three weeks to see if it works

Serotonin

·         Serotonin receptors are widely distributed in the CNS and periphery

·         Serotonin modulates nociceptive activity

·         Tricyclic antidepressant drugs helps stop the reuptake of serotonin in animals which further         modulates the pain. 

·         Amitriptylline is the most common drug used.  Inexpensive.

·         Duration of Action 12 hours

·         Dose is much lower than antidepressant doses.  Dose 0.25-0.5 mg/kg