VARIOUS ANALGESICS AND THEIR MECHANISM OF ACTION

Analgesics are common pain relievers.

Many analgesics also have antipyretic properties as well. They can be used to reduce
fever
Some analgesics are also anti-inflammatory drugs as well.
Treatment of pain to the individual animal should be based on:
1.

Species

2.

Breed

3. Age
4. Procedure performed
5. Degree of tissue trauma
6.

Individual behavioral characteristics

7. Degree of pain
8.

Health status

9. Availability of drugs and techniques.

Clinical Use of Analgesic Drugs:
The choice and route of administration of analgesic drug depends on the nature and
duration of the pain.
A progressive approach is often used, starting with nonsteroidal anti-inflammatory drugs,
supplemented first by weak opioid analgesics, and then by strong opioids.
Various analgesics:
1. Opioids
2. Non-steroidal anti-inflammatory drugs (NSAIDs)
3. Alpha-2 adrenergic agonists
4. Local anesthetics
5. NMDA antagonists 6. Corticosteroids
7. Other- Gabapentin, Capsaicin, Amantadine
In general, severe acute pain (e.g. trauma, burns, post-operative pain) is treated with
strong opioid drugs (e.g. morphine, fentanyl) given by injection.

 Mild inflammatory pain (e.g. arthritis) is treated with non-steroidal anti-inflammatory

drugs (e.g. aspirin) supplemented by weak opioid drugs (codeine, pentazocine) given
orally if required.
Chronic neuropathic pain is often unresponsive to opioids, and treated with tricyclic
antidepressants (e.g. Amitriptyline), or other drugs, such as carbamazepine.
Narcotic Analgesics:
Used for acute pain management in small animals.
Relieve moderate to severe pain by inhibiting release of substance P in central and
peripheral nerves.
Reducing the perception of pain sensation in brain, producing sedation and decreasing
emotional upsets associated with pain
Indications:
Before and during surgery
Before and during invasive diagnostic procedures
During labor and delivery
Treating Acute pulmonary edema
Treating severe, nonproductive cough
Contraindications to Use:
Respiratory depression
Chronic lung disease
Chronic liver or kidney disease
Increased intracranial pressure
Hypersensitivity reactions
Mechanism of opiods:
The body contains natural opiates in the brain called endorphins
These are produced in the body during extreme conditions such as running high and
extreme injuries.
When these are absorbed by receptors in the brain the body feels analgesia and the pain is
reduced.

 Opiates derived from the poppy act in the same way as endorphins but are not natural to
the body.
The high is produced because of the absorption of opiates is quicker than endorphins
Endorphins are not used as analgesics because they cannot be stored and are unstable.
Ligands (Drugs/endorphins)

Opioids receptor (/kappa/delta/sigma)

GI

Inhibiting adenylate cyclase

Increasing potassium ion efflux or reducing calcium ion influx

Impeding neuronal firing and transmitter release

Opioid Analgesics:
Opioid drugs include:
1. Phenanthrene derivatives, structurally related to morphine.
2. Synthetic compounds with dissimilar structures but similar pharmacological
effects.
Classification of drug:
1. Origin
A. Natural :
Eg: morphine, heroin, codeine, thebaine, paraverine
B. Synthetic :
Eg: Meperidine, methadone, fentanyl, anadol, etorphine, pentazocine.
2. Potency
A. Strong agonist
Eg: Morphine,heroin,meperidine,methadone,fentanyl

B. Moderate agonist
Eg: Codeine, propoxyphene.
C. Mixed agonist-antagonist
Eg: Buprenorphine, pentazocine
D. Antagonist:
Eg: Naloxone, naltrexone
Morphine (Pure agonist):
Naturally occurring in the poppy.
Very strong pain reliever but also very addictive.
Dose: Dog: 0.30.6 mg/kg IM (or slow IV)
Cat: 0.10.3 mg/kg IM
Morphine can be used as an analgesic to relieve:
Pain in myocardial infarction.
Pain associated with surgical conditions, pre- and postoperatively.
Pain associated with trauma, burns
Severe chronic pain, e.g., cancer
Pain from kidney stones.
Trauma of thorax accompanied by cough (morphine depresses central links of
coughing reflexes).
Contraindications and cautions:
Use in patients with head injures
Use during pregnancy
Use in patients with impaired pulmonary function
Use in patients with impaired hepatic or renal function
Side effects of morphine:

Respiratory depression

Vomiting

Bradycardia

Spasm of sphincters of gastro-intestinal tract accompanied by constipations

Increasing of tone of smooth musculature of urinary and bile-excreting tracts (retentions

of urination, bile stasis)

Decreasing blood pressure.

Codeine:
Most commonly used strong analgesic
Similar to Morphine except for the replacement of a (OH-) group for (OCH3) group
Dose Dog: 0.5-2mg/kg
Pharmacologic effects are similar to morphine, but its analgesic potency is 1/12 of
morphine, cough depressant potency is 1/4 of morphine.
Analgesic effect is stronger than aspirin. 30mg of codeine is equivalent to 600mg of
aspirin.
USE:

Mild to moderate pains and severe cough by oral administration.

Less sedation, respiratory depression and fewer gastrointestinal effects.

Synthetic opioids- Demerol (Meperidine):
They activate opioid receptors, particularly receptors.
Used for moderate to severe pain and to stop muscle spasms.
Usually injected or taken orally.
Dose: Dogs- 1-5 mg/kg.
Less potency and shorter duration in analgesia.
Methadone:
Compared to most strong analgesics it is weaker.
Not having euphoric properties and mild withdrawal effects but is still addictive.
Dose :
Dog: 0.10.5 mg/kg IM (or slow IV)
Cat: 0.10.3 mg/kg IM (or slow IV)
Pethidine:
Like morphine, pethidine exerts its analgesic effects by acting as an agonist at the opioid receptor.

Uses: Analgesic, sedation (decrease the dosage of anesthetic)

Adverse effect: Respiratory depression, possesses addiction liability, although withdrawal
effects are less severe than with morphine.
Dose:
Dog: 35 mg/kg IM only, as IV use is associated with histamine release and severe
hypotension.
Cat: 510 mg/kg IM only
Fentanyl
Its analgesic effect is 80-100 times as effective as morphine with short duration (15 to 30
min) and rapid onset.
DOSE:

Dog: 0.0010.005 mg/kg IV

Cat: 0.0010.002 mg/kg IV during anesthesia

Alfentanil

Alfentanil has a more rapid onset of action and shorter duration of narcotic effect than
fentanyl.

Oxymorphone(Pure agonist):
It elicits its effects by binding to and activating the mu opioid receptor (MOR) and to a
lesser extent, the delta opioid receptor (DOR).
It is about 6-8 times more potent than morphine.
DOSE:
Dog: 0.050.3 mg/kg IM (or slow IV)
Cat: 0.050.1 mg/kg IM
Opioid receptor mixed agonists/antagonists:
Other drugs, such as nalorphine and pentazocine, produce a mixture of agonist and
antagonist effects.
Pentazocin:

Indicated in case of pain of medium intensity in such conditions like other opioid
analgesics.

It can increase blood pressure and tachycardia thats why its not advised to use in case of

acute myocardium infarction.

Dose:
Dog: 1.5-3mg/kg IM
0.25-0.5mg/kg IV
Cat: 0.1-0.25mg/kg IV
Buprenorphine:
Partly agonist of mu-opioid receptors
Acts longer than morphine
Analgesic activity is higher than of morphine
Indicated for pain decreasing in the same situations as other narcotic analgesics.
Dose:
Dog: 0.010.02 mg/kg IM (or slow IV)
Cat: 0.020.03 mg/kg IM
TRAMADOL:

Analgesic activity is similar to the activity of morphine

Less respiratory depression
In case of intravenous administration effect develops after 5-10 min, if administered

orally after 30-40 min, action lasts for 3-5 hours.

It possesses agonist actions at the -opioid receptor

Administration:
For all kinds of acute and chronic pain of moderate and considerable intensity, including
neuralgias, postoperative, traumatic pain diagnostic and therapeutic interventions
oncologic pathology.
Dose:
Dog: 2-5mg/kg BID orally
2mg/kg IV
Cat: 2-4mg/kg BID orally
1-2mg/kg SC
Butorphanol (Partial agonist):

 It exhibits partial agonist and antagonist activity at the opioid receptor, as well as
competitive antagonist activity and partial agonist activity at the opioid receptor.
Stimulation of these receptors on central nervous system neurons causes an intracellular
inhibition of adenylate cyclase, closing of influx membrane Ca channels, and opening of
membrane K channels.
This leads to hyperpolarization of the cell membrane potential and suppression of action
potential transmission of ascending pain pathways.
Dose: Dog & Cat : 0.30.6 mg/kg IM (or slow IV)
Side Effects of Strong Analgesics:
Short term:
Reducing Pain
Euphoria
Slow Nervous system
Slowed heart rate
Loss of cough reflex
Nausea
Overdoses can lead to death
Possibility of stroke
Overall slowdown of biological systems
Long Term:
Constipation
Cross-tolerance
Loss of appetite
NON-OPIOID ANALGESICS:
Possess properties like:
Analgesic
Antipyretic
Anti-inflammatory (except Paracetamol)
NSAIDs:
Mechanism of action: Inactivate cyclo-oxygenases, enzymes required for the production of

prostaglandins
Traditional NSAIDs inhibit both COX 1 and COX 2
COX 1 is present in all tissues esp. GI, kidneys, endothelial cells and in platelets

COX 2 found in brain, bone, kidneys, GI tract, and the female reproductive system.
Overall, prostaglandins produced by COX 2 are associated with pain and
inflammation.

NSAIDs are Propionic acid derivatives such as ibuprofen, ketoprofen, naproxen and
fenoprofen.
Oxicam drugs include Mobic (meloxacam) and Feldene (piroxicam) Celebrex (celecoxib)
NSAIDs commonly used in veterinary medicine are:
Carprofen,
Flunixin meglumine,
Ketoprofen,
Meloxicam,
Phenylbutazone,
Etodolac,
Deracoxib,
Firocoxib
Indications for Use:
Treat mild to moderate pain or inflammation
Musculoskeletal disorders, minor trauma and surgery.
Contraindications to Use:
Gastrointestinal or bleeding disorders
Hypersensitivity reactions
Impaired renal function.
Mechanism of action of non-opioid analgesics:
Depression of cyclooxygenases activity.
Decreasing of prostaglandins synthesis in peripheral tissues and in central nervous system

 Decreasing the sensitivity of nervous endings and depression of transmission of

nociceptive impulses on the level of CNS structures.
Pain-relieving action of non-opioid analgesics is partly connected with their antiinflammatory activity.
Cyclooxygenase:
This exists in 2 forms- COX-1 and COX-2.
COX-1 exists to maintain gastrointestinal integrity, platelet aggregation, and renal blood
flow.
COX-2 is induced to become active in response to tissue damage.
The goal of NSAID therapy is to utilize inhibition of COX-2 without significantly
affecting activity of COX-1.

Effects of COX inhibition by most NSAIDS:

A number of drugs possess some degree of COX-2 selectivity, and are effective analgesic
agents in many species.
Additionally, individual animals differ in their responses to NSAIDs
Selective Cox-2 Inhibitors:
Greater affinity for cyclooxygenase-2
Decreased incidence of negative effects associated with non-selective COX-inhibitors

Name
Deracoxi
b

Dose in dogs
Postoperative
pain relief:
3 to 4 mg/kg/day

Firocoxi
b

Osteroarthitis pain relief:

1 to 2 mg/kg/day

5mg/kg oral

Additional effects of NSAIDs:

Gastrointestinal irritation can cause serious illness including vomiting, bloody diarrhea,
life-threatening ulceration.
Renal damage can also occur if these drugs are administered to animals with pre-existing
renal damage and/or in the face of hypovolemia or significant hypotension.
Paracetamol (Acetaminophen):
Analgesic and antipyretic drug.
Maximal effect if the drug is introduced orally after 2 hrs, lasts approximately for 4 hrs
In case of durable administration of big doses damaging of liver and kidneys,
production of met-hemoglobin
Dose: Dogs- 10-20mg/kg bwt.
Aspirin:
Aspirin is believed to inhibit the enzyme, prostaglandin synthase which is formed at the
site of an injury.
This inhibits the production of prostaglandins which produce fever and swelling as well
as transmitting pain signals to the brain.
It is able to reduce pain and fever.
It enlarges blood vessels which help to prevent blood clots.
This vasodilation of the surface blood vessels also allows an increase of heat released
which lowers the temperature.
Side Effects of Aspirin:
Aspirin can irritate the stomach lining which may lead to ulcers.

 If aspirin is used over long periods of time, it may lead to problems with blood clotting
Ibuprofen:
It is a more powerful pain reliever than aspirin in high doses, but is inferior for antiinflammation
Side effects include GI bleeding and irritation, Can aggravate kidney problems
Dose- Dog: 5-8mg/kg
Cats are twice as sensitive as dogs, it is generally not recommended
Ketoprophen (ketonal):
Strong analgesic, anti-inflammatory & antipyretic agent
Administered in case of arthroses and arthritis, ancilizing spondilitis.
Administered orally, I/M, in forms of suppositories and ointments
Dose- 0.5-1mg/kg IV, SC
Carprofen:
Carprofen reduces inflammation by inhibition of COX-2 and other sources of
inflammatory prostaglandins. This is targeted protection, in that it does not interfere with
COX-1 activity.
Dose- 2.2-4.4mg/kg SID-BID IV, SC
It is capable of causing GI, liver and kidney problems in some patients.
DRUG

DOGS
(mg/kg)

Cats (mg/kg)

Meloxicam (cox-2 inhibitor)

0.2

0.3

Flunixin (cox-2 inhibitor)

1.1

1.1

Phenylbutazone

22

a2-agonists:
Important analgesic agents for acute pain management in large animal, especially horses;
can be used as adjunctive analgesics in small animal.
The a2-agonists are hypnotic analgesics with significant pain relief.
Mechanism of action:

 Bind to either presynaptic or postsynaptic receptors in the CNS or periphery to mediate

actions such as sedation, analgesia, bradycardia, muscle relaxation, alterations in blood
pressure, insulin inhibition, and changes in thermoregulation.
Depending on the location of the receptor, the actions can either be excitatory or
inhibitory
Dose:
1. Medetomidine and Dexmedetomidine:
Premedication (mini dose): 3-10/kg dogs and 5-15/kg cats IM
Postmedication (micro dose): 1-3/kg both cats and dogs IV or IM
2. Xylazine :
Premedication: 0.2-0.3mg/kg IM
Administration:
IV, IM, SC, oral (buccal), epidural
Desirable effects of alpha-2 adrenergic agonists:
Analgesia,
Sedation,
Relaxation.
They are not irritant when injected via intramuscular or intraperitoneal routes.
Disadvantages:
Cardiovascular depression (decreased heart rate, decreased cardiac output, and
hypotension), which is controlled by pretreatment with atropine.
a2-agonists cause a transient hyperglycemia
Xylazine often causes transient nausea and vomiting, especially in cats.
Local anesthetic/analgesic drugs:
Important drugs in veterinary medicine for selective pain management.
Local anesthetic/analgesic drugs (lidocaine and bupivacaine) may be useful both during
surgery, and post-operatively.
Mechanism of action:
Inhibition of nerve impulse transmission by blocking sodium conduction through nerve
membrane ion channels

Local anesthetics commonly used are:

Lidocaine,
Mepivacaine,
Bupivacaine
Procaine.
1. Lidocaine has a fast onset of action, and provides a couple of hrs of analgesia.
2. Bupivacaine has a slower onset of action (up to 30 minutes) but provides up to 12 hours of
residual analgesia.
Both are infiltrated subcutaneously at the surgical site, or (especially in larger animals) may
be used regionally (epidural, intrathecal, intercostal).
Local Anesthetics Cocaine:
Cocaine used in 1885 as a local anesthetic.
Extracted from the plant Erythoxylum coco
Derivatives of Cocaine:
Cocaine is too addictive and in appropriate for medicinal use
Two derivatives of cocaine are widely used as local anesthetics

Procaine or Novacaine

Lidocaine

Procaine (Novacaine):
Principal use in dentistry for temporary numbing of mouth area
First synthesized in 1905 and was the first injectable man-made local anesthetic
Restricts blood vessels, reducing bleeding
Lidocaine:
First modern local anesthetic agent
Sodium channel blocker
Administered parentrally for ventricular arrhythmias, S/C for minor surgical procedures
and topically to mucosal surfaces prior to invasive procedures
Dose - 2mg/kg
Lidocaine cream:

 Lidocaine cream (EMLA or ELAMax) is used topically on shaved, intact skin prior to
venipuncture, though it requires 30-60 minutes or more of contact with skin to reach full
effect.
This cream can be used on radiation burns and terminal soft tissue pain
Lidocaine patches:
Lidocaine patches (Lidoderm) have been shown to work transdermally, but do not
completely desensitize the area it covers.
The patches appear to be effective for musculoskeletal, inflammatory and neurologic
pain. Patches can be cut.
Advantages:
Intra-operative use can augment the pain relief of general anesthetics, and reduce the
need for frequent redosing.
At appropriate doses, they have minimal cardiovascular effect.
Disadvantages:
Intramuscular and intravenous injection should both be avoided.
Systemic toxicity (including seizures and death) can result from over-dosage (more likely
to occur with smaller subjects) and with accidental intravenous injection.
Bupivacaine:
Bupivacaine binds to the intracellular portion of voltage-gated sodium channels and
blocks sodium influx into nerve cells, which prevents depolarization. Without
depolarization, no initiation or conduction of a pain signal can occur.
Bupivacaine is contraindicated in patients with known hypersensitivity reactions.
Dose - 0.3-0.5mg/kg
NMDA antagonists:
Dextromethorphan,
Amantadine and
Ketamine: This is the currently drug used in veterinary medicine
Ketamine:
Ketamine is a dissociative anesthetic agent that is capable of producing analgesia at
subanesthetic dosages.

 In veterinary practice, ketamine is used in addition to other analgesic agents to produce

adjunctive analgesia.
Dose Dog: 5-10mg/kg
Cat: 11-33mg/kg
Mechanism of action:
Ketamine is a non-competitive antagonist of calcium ion pores at NMDA receptors.
N-methyi-D-aspartate (NMDA) is a member of the glutamate family of excitatory amino
acids mediating pain transmission and increasing the likelihood of central sensitization in
the CNS.
Drugs antagonizing NMDA are capable of providing analgesia and preventing central
sensitization.
Additional effects of ketamine:
When used alone and in high doses, ketamine has sympathomimetic effects- increases in
heart rate, contractility, blood pressure, and intracranial pressure can occur.
Other effects include mydriasis, salivation, increased muscle tone.
At the subanesthetic dosages used for analgesia.
Administration:
ketamine has a rapid onset and short duration of action.
When used as an analgesic agent, it is usually administered as an initial IV followed by a
constant rate IV infusion in order to maintain adequate plasma concentrations to provide
continuous analgesia
Corticosteroids:
Used to decrease inflammation and to treat immune-mediated responses.
Corticosteroids are primarily used to manage chronic pain.
Mechanism of action:
Enter the nucleus of cells, bind to chromatin, and alter RNA synthesis.
End results include (but are not limited to) suppression of inflammatory responses;
blockade of phospholipase A - leading to inhibition of prostaglandin cascade.
Additional effects:

 Many adverse effects of corticosteroids can be serious, and often limit their usefulness in
pain management.
Effects include inhibition of wound healing, iatrogenic hyperadrenocorticism, muscle
wasting, polyuria, polydypsia, increased appetite, alopecia, gastric ulceration,
immunosuppression.
Others:
With increased knowledge of the complexity of pain, a number of drugs and therapeutic
methods are becoming available to treat specific pain states and pathways
Some of them are:
1. Gabapentin
2. Capsaicin
3. Medical MarijuanaGabapentin:
An anti-seizure drug found to be useful in managing neuropathic pain.
It was designed as a structural analog of GABA, an inhibitory NT, however the analgesic
effects appears to be mediated via voltage-dependent calcium ion channels (VDCC).
It has been successfully used in both dogs & cats.
Cats prefer gabapentin to tramadol (taste wise).
Dose: Dogs & Cats- for pain: 3mg/kg
Capsaicin:
An extract of chili peppers; causes release of substance P, leading to its depletion and
subsequent analgesia.
Topical application causes initial burning sensation followed by analgesia.
It is used as an analgesic in topical ointments, nasal sprays (Sinol-M), and dermal patches
to relieve pain, typically in concentrations between 0.025% and 0.25%.