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ANALGESICs

An analgesic, or painkiller, is any member of the group of drugs used to achieve analgesia —
relief from pain. The word analgesic derives from Greek "without", and, "pain"

Analgesic drugs act in various ways on the peripheral and central nervous systems. They are
distinct from anesthetics, which reversibly eliminate sensation, and include paracetamol (known
in the US as acetaminophen or simply APAP), the non-steroidal anti-inflammatory
drugs (NSAIDs) such as the salicylates, and opioid drugs such as morphine and oxycodone.

Analgesic choice is also determined by the type of pain: For neuropathic pain, traditional
analgesics are less effective, and there is often benefit from classes of drugs that are not normally
considered analgesics, such as tricyclic antidepressants and anticonvulsants.

The painkillers covered are:

 aspirin
 codeine (in combination products)
 ibuprofen
 paracetamol.

MAJOR CLASSES
1. Paracetamol and NSAIDs
The exact mechanism of action of paracetamol/acetaminophen is uncertain but appears to act
centrally in the brain rather than peripherally in nerve endings. Aspirin and the other non-
steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenases, leading to a decrease
in prostaglandin production. In contrast to paracetamol and the opioids, this reduces not only
pain but inflammation as well.

Paracetamol has few side-effects and is regarded as generally safe, although excess or sustained
use can lead to potentially life-threatening liver damage and occasionally kidney damage.

2. COX-2 inhibitors
These drugs have been derived from NSAIDs. The cyclooxygenase enzyme inhibited by
NSAIDs was discovered to have at least 2 different versions: COX1 and COX2. Research
suggested most of the adverse effects of NSAIDs to be mediated by blocking the COX1
(constitutive) enzyme, with the analgesic effects being mediated by the COX2 (inducible)
enzyme. Thus, the COX2 inhibitors were developed to inhibit only the COX2 enzyme
(traditional NSAIDs block both versions in general). These drugs (such as rofecoxib, celecoxib,
and etoricoxib) are equally effective analgesics when compared with NSAIDs, but cause less
gastrointestinal hemorrhage in particular.

3. Opioids
Morphine, the archetypal opioid, and various other substances
(e.g., codeine, oxycodone, hydrocodone, dihydromorphine, pethidine) all exert a similar
influence on the cerebral opioid receptor system.

Buprenorphine is thought to be a partial agonist of the opioid receptor, and tramadol is an opiate
agonist with SNRI properties.[ Tramadol is structurally closer to venlafaxine than to codeine and
delivers analgesia by not only delivering "opiate-like" effects (through mild agonism of the mu
receptor) but also by acting as a weak but fast-acting serotonin releasing
agent and norepinephrine reuptake inhibitor. Opioids, while very effective analgesics, may have
some unpleasant side-effects.

4. Flupirtine
Flupirtine is a centrally acting K+ channel opener with weak NMDA antagonist properties. It is
used in Europe for moderate to strong pain and migraine and its muscle-relaxant properties. It
has no anticholinergic properties and is believed to be devoid of any activity on dopamine,
serotonin, or histamine receptors.

5. Specific agents
In patients with chronic or neuropathic pain, various other substances may have analgesic
properties. Tricyclic antidepressants, especially amitriptyline, have been shown to improve pain
in what appears to be a central manner. Nefopam is used in Europe for pain relief with
concurrent opioids. The exact mechanism of carbamazepine, gabapentin, and pregabalin is
similarly unclear, but these anticonvulsants are used to treat neuropathic pain with differing
degrees of success. Anticonvulsants are most commonly used for neuropathic pain as their
mechanism of action tends to inhibit pain sensation
Other names
Analgesics are known by their chemical (generic) names and their brand or trade names.

Generic name Brand names


Aspirin Aspro Clear®, Disprin®
Aspirin and codeine Aspalgin®, Codral Cold & Flu Original®
Ibuprofen Brufen®, Nurofen®
Ibuprofen and codeine Nurofen Plus®
Paracetamol Dymadon®, Lemsip®, Panadol®, Panamax®, Tylenol®
Paracetamol and codeine Panadeine Forte®, Panamax Co®
Paracetamol, codeine and doxylamine Mersyndol® and Mersyndol Forte®, Panalgesic®

Effects of analgesics
Long-term effects

Long-term use of analgesics can lead to a psychological dependence. People who are dependent
on analgesics find that using the drug becomes far more important than other activities in their
life. They crave the drug and find it very difficult to stop using it.

Other effects of analgesic use

Taking analgesics with other drugs

The effects of mixing analgesics with other drugs, including alcohol, prescription medications
and other over-the-counter medicines, are often unpredictable. Some examples of these are:

 Drinking alcohol while taking aspirin and ibuprofen can increase the risk of stomach irritation
and discomfort.
 Aspirin and ibuprofen can alter the effects of some blood pressure medicines and may increase
the risk of bleeding if taken with medicines such as warfarin.
 Taking codeine with other drugs such as benzodiazepines,, certain antidepressants and certain
antihistamines, can increase the depressive effects and reduce the breathing rate.
 Naltrexone blocks the effects of codeine and other opioids.

Pregnancy and breastfeeding

There is generally no increased risk of birth defects if taking over-the-counter analgesics while
pregnant. However, there are some risks including:
 premature closing of the heart duct through which blood bypasses the lungs of the baby in the
womb, if aspirin and ibuprofen are taken late in the pregnancy.
 prolonged labour and bleeding difficulties if aspirin and ibuprofen are taken close to the birth.
 withdrawal symptoms after the birth if the mother has taken large doses of codeine late in the
pregnancy.
HOT PLATE METHOD
The hot plate test is a test of the pain response in animals,
similar to the tail flick test. It is used in basic pain research and
in testing the effectiveness of analgesics by observing the
reaction to pain caused by heat.

It was proposed by Eddy and Leimbach in 1953. They used a


behavioral model of nociception where behaviors such as
jumping and hind paw-licking are elicited following a noxious
thermal stimulus. Licking is a rapid response to painful thermal stimuli that is a direct indicator
of nociceptive threshold. Jumping represents a more elaborated response, with a latency, and
encompasses an emotional component of escaping.

Procedure
 A transparent glass cylinder is used to keep the animal on the heated surface of the plate.
 The temperature of the hot plate is set using a thermoregulated water-circulated pump.
 The time of latency is defined as the time period between the zero point, when the animal is
placed on the hot plate surface, and the time when the animal licks its paw or jumps off to
avoid thermal pain.
HOT PLATE SUMMARY
The Hot Plate test is a common sensorimotor task that measures thermal nociception in
rodent models of CNS disorders. This test measures the nociceptive responses of mice
when they are placed on a warmed metal plate either at a standard, constant temperature
or at slowly increasing temperature, starting from non-noxious levels to a standard,
constant temperature. Subjects are tested for their baseline latency; then in test
conditions, subjects are treated with an analgesic agent and tested for their sensitivity to
pain. The latency to a nociceptive response is recorded, defined as the time elapsed until
the subject licks or flicks its hind paw. This test is commonly used for pain sensitivity
assessment in transgenic strains of mice as well as evaluation of analgesic drugs.

TIL FLICK TEST


The tail flick test is a test of the pain
response in animals, similar to the hot plate
test. It is used in basic pain research and
to measure the effectiveness of analgesics, by observing the reaction to heat.

Procedure
Most commonly, a light beam is focused on the animal's tail and a timer starts. When the animal
flicks its tail, the timer stops and the recorded time (latency) is a measure of the pain
threshold. Alternate methods can be used to apply heat, such as immersion in hot water.

Instruments
Instruments have been designed to implement this testing method, including the
conduction dolorimeter, which has a resistance wire with a constant heat flow. For the tail flick
test, the wire is attached to the tail of the organism, and the wire applies heat to the tail. The
researcher then records the latency to tail flick.

Applications
Researchers testing the effectiveness of drugs on the pain threshold often use the tail flick test to
measure the extent to which the drug being tested has reduced the amount of pain felt by the
model organism. Both laboratory mice and rats are a common model organism for these tests.
These rodents are usually given analgesics, which are responsible for weakening the response to
pain. Under these weakened responses to pain, with effectiveness often peaking about 30
minutes after ingestion, researchers test the effectiveness of the drugs by exposing the tail to
constant heat and measuring how long it takes to flick, signaling its response to the
pain. Naloxone and naltrexone, two opioid antagonists, have been used to study pain sensitivity
in relation to exercise in mice. Experimental tests of the tail flick testing method showed that the
temperature of the skin of the tail plays a major role in the critical temperature, i.e., the
temperature at which the tail flicks in response to pain. Researchers found that if the tail has been
exposed to a cooler temperatures before the test, then the critical temperature decreases.